CN106102727B - 改善吞咽的包含肉桂醛和锌的组合物 - Google Patents
改善吞咽的包含肉桂醛和锌的组合物 Download PDFInfo
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- CN106102727B CN106102727B CN201580014664.6A CN201580014664A CN106102727B CN 106102727 B CN106102727 B CN 106102727B CN 201580014664 A CN201580014664 A CN 201580014664A CN 106102727 B CN106102727 B CN 106102727B
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- zinc
- cinnamaldehyde
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Abstract
本发明提供了一种组合物,所述组合物包含的肉桂醛的量是口服可耐受的,从而避免出现令人不愉悦的口感,并且在胃肠道中也是可耐受的。肉桂醛的量由锌补充,并且所述组合有效地促进吞咽反射。包含肉桂醛和锌的组合的所述组合物可以被用于治疗咽下困难和/或防止咽下困难带来的吸入性肺炎的方法中。在一个实施方案中,将含肉桂醛的所述组合物施用给人类。含肉桂醛的所述组合物可以是药物、食物产品或食物产品的补充剂。
Description
背景技术
本公开整体涉及用于改善吞咽反射的方法和组合物。更具体地,本公开涉及通过施用提供最小风味影响量的肉桂醛和锌来改善吞咽反射。
咽下困难是一种特征在于吞咽能力降低的病症。正常吞咽包括三个相互依存并且协调良好的不同阶段,即口腔阶段、咽部阶段和食道阶段。在随意控制下的口腔阶段,经过咀嚼并与唾液混合的食物形成食团,通过随意的舌头运动递送至口腔后部,进入咽部。咽部阶段是不随意的并且由穿过咽腭弓进入咽部的食团触发。咽部的三块咽缩肌收缩将食团推向食管上括约肌。同时,软腭关闭鼻咽。喉头向上运动以防止食物或液体进入气道,这通过会厌向后倾斜和声襞关闭来辅助。食道阶段也是不随意的并且以食管上括约肌松弛开始,随后蠕动,将食团下推到胃中。
食管性咽下困难影响着所有年龄层的很多个体,但通常可以采用药物治疗,其被认为是咽下困难的一种不太严重的形式。另一方面,口咽性咽下困难是非常严重的病症并且通常不能采用药物来治疗。口咽性咽下困难也影响着所有年龄层的个体,但在老年个体中更为普遍。在世界范围内,口咽性咽下困难影响着约2200万年龄超过50岁的人。
未经治疗或管理不善的口咽性咽下困难的后果可能很严重,包括脱水、营养不良、固体食物的气道阻塞(窒息)以及液体和半固体食物的气道吸入,从而促进吸入性肺炎和/或局限性肺炎。严重的口咽性咽下困难可能需要管饲来补充营养。轻度至中度口咽性咽下困难需要改良食物的质构以将窒息或吸入的可能性降至最低。
口咽部咽下困难往往是急性事件如中风、脑损伤或者口腔癌或喉癌手术的结果。另外,放射疗法和化学疗法可使肌肉变弱并使与吞咽反射的生理和神经支配相关的神经退化。患有进行性神经肌肉疾病如帕金森病的个体也经常在吞咽起始方面遭遇不断增加的困难。
个体的吞咽能力和效率的改善通过降低肺吸入的风险而提高个体的安全性。有效的吞咽可使得对喂食辅助的依赖更低和/或减少进食过程中喂食辅助所花费的时长。有效的吞咽还降低安全性所要求的液体粘性(例如,布丁、蜂蜜和花蜜粘稠产品),并且还可限制质构改良食物的使用。所有这些前述因素的目的均在于改善个体的生活质量。
对刺激性感觉的潜在分子机理的研究揭示了存在两种阳离子通道,即TRPV1(瞬时受体电位V1)和TRPA1(瞬时受体电位A1),它们在对口腔施加神经支配的体觉纤维中表达。TRPV1是针对热和灼热感的受体,例如辣椒素(红辣椒中的辛辣化合物)。TRPA1则响应于冷的和刺激性的化合物;在适中的浓度下,TRPA1激动剂呈现出令人愉悦的麻刺感。
已证实口服施用TRPV1激动剂辣椒素可促进吞咽反射,但辣椒素是一种特别辛辣且有毒的化合物。与口服施用辣椒素相关联的生理效应包括自舌头中部到喉部的灼热感、呼吸短促、眩晕、恶心和自发性呕吐。因此,只可施用少量的辣椒素,以免引起个体的不适。由于包含辣椒素的食物产品提供了令人感到非常不愉悦的口感,因此这类产品通常不被消费者所接受。具体而言,具有灼热效应的食物产品被认为是很难吃的,从而影响该食物产品的食用。
肉桂衍生化合物肉桂醛是活化TRPA1但不活化TRPV1或TRPM8的α,β-不饱和醛,其EC50为大约10μM。肉桂醛与TRPA1以共价方式相互作用。肉桂醛的风味没辣椒素那么强烈。然而,肉桂醛在相对高浓度时有刺激性,并且具有强烈的肉桂风味。
发明内容
本发明人惊奇并出乎意料地观察到肉桂醛和锌在TRPA1药理活性方面的协同作用。利用这种协同作用,可以通过用少量的锌补充肉桂醛来减少肉桂醛的有效量。肉桂醛的减少量可以减少芳族的影响,同时保持TRPA1活性的良好功效。此外,该协同作用只需要低浓度的锌(体外<1μM),由于咽下困难的患者可能已经通过他们的饮食获取了锌,因此这一点是有利的,尤其是服用了补充剂的情况下。
本发明人确定了肉桂醛和锌对细胞模型中表达的TRPA1药理活性的协同作用。据本发明人所知,这种组合的协同作用是第一次被证实。
因此,在一个常规实施方案中,本公开提供了一种用于促进吞咽反射的方法,包括向有此需要的患者施用包含肉桂醛和锌的组合物。′
在一个实施方案中,肉桂醛以吸收可耐受的量与锌共同存在于组合物中,有效地促进患者的吞咽反射。
在一个实施方案中,吞咽反射的促进包括选自以下的效果:引起吞咽反射、提高患者的吞咽能力、提高吞咽反射的效力、缩短吞咽的延迟以及它们的组合。
在一个实施方案中,组合物包含至少提供一部分肉桂醛的肉桂精油提取物。
在一个实施方案中,至少一部分肉桂醛选自分离的肉桂醛和合成的肉桂醛。
在一个实施方案中,至少一部分锌选自:氯化锌、硫酸锌、乳酸锌、柠檬酸锌以及它们组合。
在另一个实施方案中,本发明提供了一种用于治疗咽下困难的方法。该方法包括向患有咽下困难的患者施用包含肉桂醛和锌的组合物。
在一个实施方案中,咽下困难是与一种病症有关的口咽性咽下困难,所述病症选自:癌症、癌症化疗、癌症放疗、口腔癌手术、咽喉癌手术、中风、脑损伤、进行性神经肌肉疾病、神经退行性疾病、患者的老龄以及它们的组合。
在另一个实施方案中,本公开提供了一种用于预防咽下困难带来的吸入性肺炎的方法,包括向有此风险的患者施用包含肉桂醛和锌的组合物。
在一个实施方案中,肉桂醛以吸收可耐受的量与锌共同存在于组合物中,有效地促进患者的吞咽反射。
在另一个实施方案中,本公开提供了一种包含肉桂醛和锌的组合物。
在一个实施方案中,肉桂醛以口服可耐受的量与锌共同存在于组合物中,有效地促进吞咽反射。
在一个实施方案中,肉桂醛存在的浓度为约100ppm或更少。
在一个实施方案中,肉桂醛∶锌的比例为1∶0.5至1∶0.005,优选为1∶0.03(以摩尔浓度计)。
在一个实施方案中,该组合物所述组分选自蛋白质、碳水化合物、脂肪以及它们的组合。
本公开的一个优点是促进吞咽反射。
本公开的另一个优点是治疗咽下困难。
本公开的又一个优点是预防咽下困难带来的吸入性肺炎。
本公开的又一个优点是用可在食物产品中容易并安全使用的成分来促进吞咽反射。
本公开的一个附加优点是用可见于香料中的天然存在的化合物来促进吞咽反射。
本公开的另一个优点是以副作用可耐受或无副作用的方式促进吞咽反射。
本公开的又一个优点是用相对于辣椒素而言在胃肠道中的可接受性提高、刺激性降低并且耐受性改善的化合物来促进吞咽反射。
本公开的一个优点是治疗患有吞咽功能受损的患者。
本公开的另一个优点是用锌补充肉桂醛从而需要更少的肉桂醛来促进吞咽反射。
本文描述了额外的特征和优点,并且根据以下具体实施方式和附图,这些特征和优点将显而易见。
附图说明
图1示出肉桂醛的化学结构。
图2示出,通过用荧光染料测量细胞内钙离子浓度的方式,对CHO细胞中表达的TRP通道的活性进行体外测定的曲线图。
具体实施方式
本文中表示的所有百分数均以占组合物总重量的重量计,除非另有表示。提及pH时,其值对应于使用标准设备在25℃下测量的pH。如在本发明和所附权利要求中所用,单数形式“一个”、“一种”和“该”包括复数指代物,除非上下文另外明确规定。如本文所用,“约”应理解为是指数值范围内的数字,例如,引用数字的-10%至+10%的范围。此外,本文中的所有数值范围都应理解为包含该范围内的所有整数或分数。本文所公开的组合物可不含本文未明确公开的任何要素。因此,使用术语“包括/包含”的实施方案的公开内容包括“基本上由所确定的组分组成”和“由所确定的组分组成”的实施方案的公开内容。
“预防”包括降低病症或疾病的风险和/或严重程度。术语“治疗”和“缓解”既包括预防性或防止性治疗(预防和/或延缓目标病理学病症或疾病的发展),也包括治愈性、治疗性或疾病改善性治疗,包括治愈、延缓、减轻确诊的病理学病症或疾病的症状并/或中断其进展的治疗性措施;和治疗存在染病风险或怀疑已染病的患者,以及治疗患病或已经诊断为罹患疾病或医学病症的患者。该术语不一定表示个体被治疗直至完全恢复。术语“治疗”也指在未患疾病但可能易于发展不健康状况的个体中进行的健康保持和/或促进。术语“治疗”和“缓解”还旨在包括强化或以其他方式增强一种或多种主要的预防性或治疗性措施。术语“治疗”和“缓解”还旨在包括疾病或病症的膳食管理或用于预防或防止疾病或病症的膳食管理。治疗可与患者或医生相关。
如本文所用,“有效量”是预防个体缺陷、治疗其疾病或医学病症的量,或更一般地说,是减轻个体症状、管理其疾病进展或向其提供营养、生理或医疗益处的量。
“动物”包括但不限于哺乳动物,所述哺乳动物包括但不限于啮齿动物,水栖哺乳动物,诸如狗和猫之类的家畜,诸如羊、猪、牛和马之类的农畜和人类。在使用“动物”、“哺乳动物”或其复数形式时,这些术语还适用于能够具有通过段落上下文表现出的或意欲表现出的作用的任何动物。如本文所用,术语“患者”应被理解为包括接受或意欲接受本文所定义的治疗的动物,尤其是哺乳动物,并且更尤其是人。虽然本文中常用术语“个体”和“患者”来指人,但本发明并非限制于此。因此,术语“个体”和“患者”是指可受益于治疗的任何动物、哺乳动物或人。
如果动物的年龄超过其出生地平均预期寿命的三分之二,优选地超过其出生地平均预期寿命的四分之三,更最优选地超过其出生地平均预期寿命的五分之四,那么就认为该动物为“老年”。“老年人”是指实际年龄为65岁或更大的人。
如上文所述,本发明人惊奇并出乎意料地观察到肉桂醛和锌在TRPA1药理活性方面的协同作用。利用这种协同作用,可以通过用少量的锌补充肉桂醛来减少肉桂醛的有效量。因此,与不含锌的肉桂醛不同,肉桂醛和锌的组合可促进吞咽反射,且在食物中的浓度既在风味/味道上可耐受又在胃肠道内可耐受。此外,该协同作用只需要低浓度的锌(体外<1μM)。吞咽反射的促进可以包括,例如,引起吞咽反射、提高个体的吞咽能力、提高吞咽的效力、缩短吞咽的延迟以及它们的组合。
因此,本公开提供的组合物包含口服可耐受量的肉桂醛,例如不会引起不愉悦的口感,并且与锌共同提供,有效地促进吞咽反射。
肉桂醛可商购。组合物中的肉桂醛可以在肉桂精油提取物(例如,肉桂皮的油的蒸汽蒸馏提取物)中提供;可以是分离的肉桂醛,例如从肉桂精油中分离;或者可以是合成的肉桂醛,例如,乙醛和苯甲醛的醛醇缩合的产物。组合物中肉桂醛的浓度优选为从31.87ppm(调味品、佐料)至6191ppm(口香糖)的调味浓度(Fenaroli’s Handbook;Burdock,2010(《Fenaroli手册》;Burdock,2010年))。在一个实施方案中,肉桂醛在组合物中存在的量为100.0ppm或更少;100ppm等于约756μM,即《Fenaroli手册》(Burdock,2010年)中明胶的调味范围。
作为非限制性的实施例,肉桂醛可以存在于如下组合物中:
酒精饮料:高达498.8ppm,例如约435.6ppm
烘烤产品:高达367.4ppm,例如约273.8ppm
口香糖:高达6191.0ppm,例如约1533.0ppm
调味品或佐料:高达31.87ppm,例如约17.48ppm
冷冻乳制品:高达77.96ppm,例如约72.98ppm
水果冰:高达900.0ppm,例如900.0ppm
明胶或布丁:高达109.4ppm,例如约100.3ppm
肉汁:高达800.0ppm,例如约640.0ppm
硬糖:高达1003.0ppm,例如约792.2ppm
肉类产品:高达39.09ppm,例如约6.97ppm
非酒精饮料:高达67.82ppm,例如约52.71ppm
软糖:高达370.0ppm,例如370.0ppm
锌的优选形式包括氯化锌、硫酸锌、乳酸锌和柠檬酸锌。肉桂醛∶锌的比率优选为1∶0.5至1∶0.005,更优选为1∶0.03(以摩尔浓度计)。
在一个实施方案中,本公开提供了一种方法,包括向动物施用包含一定量的肉桂醛和锌的组合物,该组合物促进吞咽反射并且是口服可耐受的。在动物口咽性咽下困难的治疗中优选采用这样的方法。口咽性咽下困难可能是癌症、癌症化疗、癌症放疗、口腔癌手术、咽喉癌手术、中风、脑损伤、神经退行性疾病、患者的老龄或进行性神经肌肉疾病(例如帕金森氏病)中至少一种的结果。
在一个实施方案中,该方法预防或治疗咽下困难带来的吸入性肺炎。误吸是指食物或饮料进入气管和肺,可发生在吞咽过程中和/或吞咽后(吞咽后误吸)。吞咽后误吸通常是由于吞咽后留在咽部的咽部残留物所导致的。
在一个优选的实施方案中,将肉桂醛和锌施用于营养补充剂(例如营养丰富的饮料)中。在另一个优选的实施方案中,将肉桂醛和锌施用于含水补充剂中,优选含有多于83%的自由水,更优选地多于90%的自由水。此类补充剂可呈增稠液体的形式。在又一个优选的实施方案中,将肉桂醛和锌施用于质地改良食物中。
包含肉桂醛和锌的组合物可以是药物、医疗食品、口服营养补充剂、营养组合物、内服化妆品或食物产品的补充剂,并且优选地通过口服施用。医疗食物产品是专门配制的并用于疾病或医学病症的饮食管理(例如,预防或治疗疾病或不希望的医学病症)。医疗食物产品可提供临床营养,例如,满足存在医学病症的患者或具有特定营养需求的其他人士的特殊营养需求。医疗食物产品的形式可以是完全膳食、部分膳食、作为食品添加剂或者待溶解的粉末。
医疗食品或营养组合物包含任何数目的任选附加成分,包括常规食品添加剂,例如一种或多种蛋白质、碳水化合物、脂肪、酸化剂、增稠剂、缓冲剂或用于pH调节的物质、螯合剂、着色剂、乳化剂、赋形剂、调味剂、矿物质、渗透剂、药学上可接受的载体、防腐剂、稳定剂、糖、甜味剂、质构剂和/或维生素。可以按任何合适的量添加所述任选成分。
医疗食品或营养组合物可以是任何口服营养形式,例如作为保健饮料,作为即食饮料,任选地作为软饮料,包括酒吧里的果汁、牛奶奶昔、酸奶饮料、冰沙或大豆基饮料,或者分散于任何类型的食品中,例如烘烤产品、谷物棒、奶棒、快餐食品、汤、早餐谷物、麦片、糖果、片(tabs)、曲奇(cookies)、饼干、薄脆饼干(如米饼)和乳制品。
补充剂可以是例如片剂、胶囊、锭剂或液体形式。补充剂还可包含保护性亲水胶体(例如胶类、蛋白质类、改性淀粉类)、粘合剂、成膜剂、包囊剂/材料、壁/壳材料、基质化合物、涂层、乳化剂、表面活性剂、增溶剂(油类、脂肪类、蜡类、卵磷脂类等)、吸附剂、载体、填充剂、共化合物、分散剂、润湿剂、加工助剂(溶剂)、流动剂、掩味剂、增重剂、胶凝剂以及凝胶形成剂。补充剂还可包含常规的药物添加剂和佐剂、赋形剂和稀释剂,包括但不限于水、任何来源的明胶、植物胶、木素磺酸盐、滑石、糖类、淀粉、阿拉伯树胶、植物油、聚亚烷基二醇、风味剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、润湿剂、填充剂等。
可将补充剂作为可摄入的载体或承载物添加到为消费者所接受的产品中。此类载体或承载物的非限制性示例为药物、食品组合物和宠物食品组合物。食品和宠物食品组合物的非限制性示例为牛奶、酸奶、凝乳、奶酪、发酵乳、乳基发酵产品、基于发酵谷物的产品、乳基粉、人乳、早产儿配方食品、婴儿配方食品、口服补充剂和管饲物。
实施例
下列非限制性实施例表明,体外科学数据得出并支持如下观点:施用肉桂醛和锌的组合协同地活化TRPA1以促进吞咽反射,且没有无法忍受的味道或胃肠影响。
实施例1
分别测量10μM的肉桂醛、0.3μM的锌以及两者的组合对CHO细胞中表达的hTRPA1的体外活性的影响。结果示于图2,且当肉桂醛和锌组合(肉桂醛+锌)时显示出协同作用。C+表示该测试实验的阳性对照,并且根据剂量-反应曲线,肉桂醛为50mM,给出了最大功效。
应当理解,对本文所述的目前优选的实施方案作出的各种变化和修改对于本领域的技术人员将是显而易见的。可在不脱离本发明主题的实质和范围、且不削弱其预期优点的前提下作出此类变化和修改。因此,这些变化和修改旨在由所附权利要求书涵盖。
Claims (13)
1.包含肉桂醛和锌的组合物用于制备在患者中促进吞咽反射的药物的用途,其中所述肉桂醛∶锌的比例为1∶0.5至1∶0.03。
2.根据权利要求1所述的用途,其中所述肉桂醛以吸收可耐受的量与所述锌共同存在于所述组合物中,有效地促进所述患者的吞咽反射。
3.根据权利要求2所述的用途,其中所述吞咽反射的促进包括选自以下的效果:引起所述吞咽反射、提高所述患者的吞咽能力、提高所述吞咽反射的效力、缩短吞咽的延迟以及它们的组合。
4.根据权利要求1所述的用途,其中所述组合物包含提供至少一部分所述肉桂醛的肉桂精油提取物。
5.根据权利要求1所述的用途,其中至少一部分所述肉桂醛选自分离的肉桂醛和合成的肉桂醛。
6.根据权利要求1所述的用途,其中至少一部分所述锌选自:氯化锌、硫酸锌、乳酸锌、柠檬酸锌以及它们的组合。
7.包含肉桂醛和锌的组合物用于制备治疗咽下困难的药物的用途,其中所述肉桂醛∶锌的比例为1∶0.5至1∶0.03。
8.根据权利要求7所述的用途,其中,所述咽下困难是与选自下列的病症有关的口咽性咽下困难:癌症、癌症化疗、癌症放疗、口腔癌手术、咽喉癌手术、中风、脑损伤、进行性神经肌肉疾病、神经退行性疾病、患者的老龄以及它们的组合。
9.包含肉桂醛和锌的组合物用于制备在患者中预防咽下困难带来的吸入性肺炎的药物的用途,其中所述肉桂醛∶锌的比例为1∶0.5至1∶0.03。
10.根据权利要求9所述的用途,其中所述肉桂醛以吸收可耐受的量与所述锌共同存在于所述组合物中,有效地促进所述患者的吞咽反射。
11.一种由肉桂醛和锌组成的组合物,其中至少一部分所述锌选自:氯化锌、硫酸锌、乳酸锌、柠檬酸锌以及它们的组合,其中所述肉桂醛∶锌的比例为1∶0.5至1∶0.03。
12.根据权利要求11所述的组合物,其中所述肉桂醛以口服可耐受的量与所述锌共同存在于所述组合物中,有效地促进吞咽反射。
13.根据权利要求11所述的组合物,其中所述肉桂醛存在的浓度为90ppm至110ppm。
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