CN108040468B - 用于治疗口腔、咽喉和呼吸道疾病的制剂 - Google Patents
用于治疗口腔、咽喉和呼吸道疾病的制剂 Download PDFInfo
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- CN108040468B CN108040468B CN201680032969.4A CN201680032969A CN108040468B CN 108040468 B CN108040468 B CN 108040468B CN 201680032969 A CN201680032969 A CN 201680032969A CN 108040468 B CN108040468 B CN 108040468B
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- A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
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Abstract
本发明涉及含有姜黄、石榴和姜提取物组合的制剂，其协同作用于治疗和预防口腔、咽喉和呼吸道疾病；该制剂尤其作用于细菌来源的疾病，例如受普通感冒和流感以及它们的并发症影响的患者中发生的那些疾病。目前的制剂特别适用于减少咽喉痛及其感染的发病率，以及消除抗生素使用，尤其是在婴幼儿和老年人中。
Description
背景技术
伴有斑块形成的咽喉炎症和细菌感染是伴随普通流感、寒冷和冬季疾病的症状。普通感冒一般被认为是最常见的人类疾病，影响到所有国家和社会背景的人们。成年人每年可能感冒2至5次，特别是在拥挤的社区和冬季；与其它儿童接触的儿童每年可能有六至十次感冒发作，对于幼儿园或学童甚至每年有高达十二次感冒。(1-10)然而，有些发作可能是最低限度的症状。
普通感冒和流感是局限于上呼吸道的病毒性疾病；感染的原因一般是40％的鼻病毒，10％的冠状病毒和少量的腺病毒，副流感病毒，然后是细菌感染。(1-6)感冒发作可能与诸如鼻咽炎(nasopharyngitis)，咽鼻炎(rhinopharyngitis)，体温升高，耳，咽喉并发症和呼吸问的等症状有关。常见的症状可能包括咳嗽(通常在发病几天后)，咽喉痛，流鼻涕和发烧。症状在五到十天内消失。在某些情况下，尤其是年龄较大、风险较高的受试者，残留症状可能持续长达三周。普通感冒发作的频率在老年受试者和处于风险中的患者中趋于增加，这主要是由于免疫系统的恶化。由于频繁的严重和身体虚弱的并发症，流感在老年人中是特别危险的，可能导致死亡的严重风险。
在工业化国家，特别是在拥挤的社区，每个冬季可能有30％的人口受到影响。由于失去工作时间，药物，并发症和改变的社会交往造成的成本是显著的。有效的疫苗不可用，因为涉及许多不同的病毒(其也随时间而改变)。手部清洁和清洗可能会减少病毒的交换。阿司匹林，补充剂，特别是维生素C和锌，可能有效降低感冒的发生率和每次发作的时间长短。(4-8)镇痛药和退热药可以缓解特定症状。(9-16)解充血剂(即伪麻黄碱，异丙托铵和其它鼻喷雾剂)可以减轻流鼻涕的症状。与流鼻涕相关的症状可能由抗组织胺药控制，但是这些产品可能引起显著的不良反应，例如嗜睡，注意力和驾驶能力受损。由于细菌感染的发病引起发烧和疼痛，感冒疾病有时会涉及并发症。在这些情况下，除了对症治疗之外，抗生素或抑菌治疗是必要的。抗生素正在降低身体的防御能力，特别引起在儿童中频繁复发。一般不建议儿童(<6岁)的咳嗽和感冒药，因为它们可能引起明显的副作用和并发症，并未提供经证实的益处。约30％的老年患者可能出现并发症(上呼吸道感染，支气管炎，肺炎)。在高危受试者(严重危险状况，重度吸烟者，糖尿病人，残疾受试者，先前患有慢性心血管疾病或肺部疾病的患者)中，并发症可能会是严重的并导致住院，而增加社会/人力成本。
目前没有针对感冒的具体治疗或预防。具有良好耐受性的也用于预防的新产品在今天是需要的。
已经提出了用于治疗感冒相关疾病的各种植物疗法；这些天然产物可能具有比合成药物较低的毒性，但它们通常表现出较低/较不一致的活性。通常也提出植物提取物及其混合物；有时，药用植物的组合物也是“保守地”提出的，即涉及将大量活性剂与多种不相关疾病结合起来，以提供最广泛的广谱活性；但混合物中存在的针对特定(群)疾病的特定活性剂的活性仍然是未知的：例如，专利公开JP2013001666描述了用于治疗多种病症的营养组合物，所述疾病包括动脉粥样硬化，癌症，细胞损伤，糖尿病，帕金森氏病，消化道粘膜疾病，肺/支气管疾病，炎症，绝经期疾病，风湿病，特应性疾病，特别是含有姜黄提取物(用比本发明更低的比例)，水飞蓟种子，余甘草提取物，小麦麸皮，日本茶叶提取物，芝麻提取物，石榴籽提取物，姜提取物，大豆异黄酮，睡茄根，假马齿苋叶等等。其它出版物公开了用于较窄医学适应症的组合物，但是不能个体化本发明所基于的试剂的组合物。例如，实用新型DE20 2009 002 126描述了用于在化疗/放疗法下治疗受试者的营养组合物：所述组合物含有多种维生素，矿物质，类胡萝卜素，ω3-脂肪酸，石榴提取物和选自西兰花，姜和姜黄中的至少一种提取物；在例举的组合物中，本发明的活性成分代表了存在的全部活性成分的少数部分。专利申请WO-A1-2011/068812描述了用于治疗口腔的组合物，所述组合物含有石榴(Punica granatum)，肉豆蔻，姜和洋枣(Zizyphus joazeiro)中的至少三种，以及选自另外38种植物的额外提取物；没有具体公开本发明所基于的组合物。
出版物Drugs of the Future，2008,33(4)，第329-346页分别描述了石榴，姜黄或姜的活性：该文献描述了这些植物及其活性成分(抗氧化剂，抗炎剂，抗菌剂，抗癌剂，抗诱变剂等)的一般生物化学效应，对于如何优化其活性没有任何建议或教导；该文献并没有提出这些试剂的任何具体组合，也没有提出它们可能的协同作用。
迄今为止，在确定两种以上提取物的特定组合方面进行的研究很少，特别是没有给出任何指导来确定特定的组合，这些组合可能不仅仅能够提供口腔、咽喉和呼吸道病理上的叠加效应。
发明内容
现已发现，姜黄、石榴和姜提取物组合对口腔、咽喉和呼吸道疾病表现出较强的协同活性，这种涉及强抗菌作用的活性对于普通感冒和流感期间发生的感染特别有用。本发明的目的是上述提取物的组合，相关的药物组合物，制备方法，以及它们在口腔、咽喉和呼吸道疾病的治疗/预防中的用途。特别地，本发明包括用于治疗/预防所述疾病的上述提取物的组合以及相应的治疗方法。
具体实施方式
姜黄(Curcuma longa)是姜黄(turmeric)的植物学名。石榴(Punica granatum)是石榴(pomegranate)的植物学名。姜(Zingiber officinale)是姜(ginger)的植物学名。对于这些植物中的每一个，植物学和通用名称在此均无差别地使用。
在整个说明书和权利要求中，无论何时公开提取物的重量(或重量百分比)量，它们总是指“干燥”提取物，即仅考虑提取物的非液体成分的重量；同样地，无论何时公开提取物中的特定成分的重量(或重量百分比)量，它们总是通过参考“干燥”形式的提取物来计算。
尽管如此，本发明的组合/制剂/药物组合物/应用目的不限于使用干燥的提取物，而是也延伸到使用液体和流体提取物。任何类型的提取物都可以在本文使用，从它们的具体提取方法和它们的自然状况来看是无差别的。
姜黄提取物通常从植物的根和根茎中获得。它们含有与作为天然载体起作用的其它植物组分相关的姜黄素。优选使用总醇提取物；根据药物(姜黄提取物)的阿育吠陀系统的方式，它们可以用乙醇由姜黄根茎提取而制备；它们通常含有20-30重量％姜黄素，优选25重量％(指干燥提取物)。
石榴提取物通常从整个果实中获得。它们的多酚含量通常为60-95重量％，优选75重量％。鞣花酸及其聚合物(punicalgines)是提取物的主要活性成分：它们通常以30重量％的最小量，优选大于40重量％存在于提取物(指干燥提取物)中。在一种优选实施方式中，提取物可以通过用乙醇/水或丙酮的混合物提取整个果实，将提取物浓缩到水中，并且在消除不溶物质之后通过吸收聚苯乙烯树脂上的多酚来纯化水溶液；通过用乙醇洗脱从树脂中回收多酚，然后浓缩至干燥而制备。
姜提取物通常从根茎中获得。它优选是亲脂性提取物；它含有20-50％的姜辣素(gingerol)+姜烯酮(shoagol)的混合物(指干燥提取物)。在一种优选实施方式中，它通过用正己烷或用超临界条件下的CO2在45℃的温度和220巴的压力下萃取干燥的根茎而获得。
在本发明的一种实施方式中，三种上述提取物是使用的唯一活性剂(这不排除联合使用非活性剂即载体和制剂赋形剂，包括可能具有药物作用的那些赋形剂作为副活性：后者仍然可以以符合其作为载体/赋形剂的作用方式/量使用)。
或者，可以使用额外的活性剂，但是在本发明提取物的组合仍然普遍存在的条件下，即：
-所述姜黄，石榴和姜的组合占所存在的总活性剂的重量超过50％(或优选超过75％，85％，90％，95％或99％)和/或
-除所述姜黄，石榴和姜之外的任何可能活性剂存在的量低于所述姜黄，石榴和姜中最低量的至少50重量％：因此，例如60mg姜黄提取物，20mg石榴提取物和10mg姜提取物将允许存在额外的活性剂，每种活性剂的存在量为5mg或更低。
在进一步的本发明中，与其它两种成分(即姜和石榴)相比，姜黄通常以更高的浓度存在，即这三种活性剂(基于其干燥提取物)的重量比为：6(±2)：2(±1)：1(±0.5)，其中，括号中的数据表示每个组分可能的±重量比变化。
根据另一种优选实施方式，所述制剂含有以下重量间隔/每种剂量单位的三种提取物(指干燥提取物)：
姜黄提取物：..............................................20至100mg，
石榴提取物(约40％鞣花酸衍生物)...........................10至60mg
姜提取物(约35％姜辣素)：..................................2至20mg
根据更优选的实施方式，每个剂量单位的含量是(指干燥提取物)：
姜黄提取物：..............................................50mg，
石榴提取物(约40％鞣花酸衍生物)...........................20mg
姜提取物(约35％姜辣素)：..................................10mg，
这些含量中的每一个在±15％的范围内可变。
进一步优选的实施方式涉及本申请实施例1中描述的缓释制剂片剂或本申请实施例2中描述的口腔分散粘膜粘附片剂，其中，每种制剂成分的重量可以在±15％的范围内变化。
最优选地，将本发明的组合配制成口腔组合物，即局部施用于口腔中，能够在施用后的较长时间期间内释放活性成分，典型地配制成口腔分散片或膜(优选粘膜粘附剂)；或者将该组合配制成吸入组合物，例如，作为气雾剂，喷雾剂等。具体而言，本发明人意外地发现，当在口腔中持续适当时间后，本发明的提取物组合确保增加唾液溶菌酶的量，所述唾液溶菌酶参与捕获/灭活进入口腔的可能环境污染物(如细菌和病毒)。更令人惊讶的是，所发现的增加与增强的唾液分泌无关，即它含有在增加的溶菌酶的唾液浓度中，因此与分泌的唾液量无关。因此，当配制成口腔持续释放组合物时，本发明组合出乎意料地有效，对诸如普通流感的病毒感染的细菌产生非常有效的预防作用。考虑到它们广泛传播，其社会影响和一旦感染发生后的治疗疗法的时间长短，通常涉及抗生素药物的不良使用，对这些疾病进行有效预防性治疗的关键重要性立即显而易见。
施用本发明组合的每日剂量可以根据患者病症，施用途径以及待治疗疾病的类型和严重程度而在很大程度上变化。所述每日剂量可以通过单次施用来摄取，或者优选细分为全天重复施用，例如，每天3次。治疗几乎立即有效：然而，建议治疗延长至少2-3天(优选1或2周)以获得显著和连续的症状抑制。
本发明提取物的组合虽然本身是有效的，但优选以适合于口腔(口腔或面颊途径)施用或通过呼吸道的常规递送形式配制并提供给患者。优选的口服施用形式是片剂，胶囊剂，颗粒剂，丸剂，胶质糖锭剂，口香糖等；更优选配制用于缓慢/受控释放的那些施用形式；还优选的是一旦与水接触就能够形成凝胶的片剂，以便于难以吞咽固体的患者的施用，例如婴儿和老人。气雾剂，喷雾剂等也可用于将制剂直接递送至呼吸道。所有上述递送形式可按照制药技术标准书籍中所报道的常规方法制备。
本发明的组合和制剂证明对口腔、咽喉和呼吸道疾病，尤其是细菌起源的疾病具有较高活性；特别是它们成功地预防了细菌斑块，发烧和伴随感冒和流感的其它症状的形成。通过本发明的组合和制剂可治疗的额外疾病是鼻咽炎，咽鼻炎，咽喉痛，咳嗽，流鼻涕，体温升高，耳和/或咽喉并发症，呼吸问题，支气管炎，肺炎，打喷嚏，鼻液溢，鼻塞，不安，头痛和相关的病症。
通过本发明的组合获得的主要治疗效果是：抗菌活性，通过抗炎、抗氧化和抗病毒活性以及唾液中溶菌酶含量的增加有效补充。不受理论束缚，认为石榴的多酚部分可能与NFkB抑制有关，对炎症和对感染的免疫应答有效；存在于提取物中的punicalgines可能负责至少部分负责抗病毒作用；姜可能由于其对NFkB和脂氧合酶的抑制作用而负责抗菌，抗病毒和抗炎活性；也相信的是由于其与香草素受体TRPV1的相互作用而产生镇痛作用。
所有上述活性在本发明的组合中有利地和出乎意料地协同作用，为患者提供对上述疾病的出人意料的高水平的保护。实际上，协同作用的存在不仅在体外被检测到，而且在临床试验中也被检测到，因此在实际需要的临床实践中肯定会发生。该组合还实现了唾液中溶菌酶水平的强烈增强，高达健康受试者水平的5倍：由于溶菌酶参与了细菌和其它异生物的裂解，这种互补作用进一步增强了唾液的免疫保护性能，加强口腔和邻近区域的粘膜抵抗感染的抗性。还发现该制剂在接触的粘膜上建立临时保护层，从而进一步增强其对大气中存在的病原体的抗性。
实施例
实施例1 缓释制剂片剂
姜黄醇提取物(姜黄)或其它种类..................................50mg，
石榴提取物40％鞣花酸衍生物：...................................20mg
姜亲脂性提取物35％姜辣素：.....................................8mg
木糖醇：.......................................................430mg
透明质酸：.....................................................200mg
甘草酸铵......................................................10mg
甜蜜素........................................................40mg
聚山梨醇酯80..................................................5mg
实施例2 口腔分散粘膜粘附片剂
姜黄醇提取物(姜黄)或其它种类...................................50mg，
石榴提取物40％鞣花酸衍生物.....................................20mg
姜亲脂性提取物.................................................10mg
海藻酸钠盐.....................................................200mg
木糖醇.........................................................600mg
甘草酸铵.......................................................10mg
甜蜜素.........................................................40mg
聚山梨醇酯80...................................................5mg
实施例3 临床试验
在本研究中，涉及大量患者(每组超过60名)；受试者被告知任何补充剂或治疗并知道补充剂是什么；仔细解释和考虑了可能的安慰剂效应；在观察期后进行分析数据，理想情况是在收集到足够的证据时；查看各组间差异所需的时间也被视为评估目标。
根据选择患者的标准，使用以下7个感冒“核心”(默克手册2011)：
1.“磨擦”的咽喉痛。
2.打喷嚏。
3.鼻液溢
4.鼻塞。
5.不安。
6.咳嗽。
7.温度。
第1至5体征/症状几乎总是存在，而第6和7体征/症状可能存在于约15-20％的患者中；在一个10厘米的水平模拟刻度线(Cyril Maxwell，临床研究.Cambridge medicalpublications，Cambridge，1973)上对患者的体征/症状进行评分；7个“感冒核心体征”中具有至少有6个的患者被诊断为患有感冒。
临床试验的主要目标是：
a-发作发生的评估
b-减轻体征/症状
c-减少疾病天数，减少其它对症治疗的使用
d-控制与感冒有关的潜在并发症。
e-测定唾液和溶菌酶含量
实施例1中描述的制剂每天施用3次，使其缓慢溶解于口腔中；施用期的持续时间为两周，另加一周观察。该研究是一项试点注册研究，结果和数据由与患者不接触的外部评估小组进行评估。在整个疗程和观察期间每天在日记中监测数据，耐受性和可能的不良反应。结果总结在表1中。
表1：3周后(治疗2周+观察1周)的主要临床结果
对随机选择的患者，在第一次施用之前(对照)和治疗1周后(3片/天)评估唾液中溶菌酶的浓度。结果见表2。
表2已离心的唾液中溶菌酶浓度(微克/毫升，比浊测定)的平均值。患者人数：10名男性受试者/年龄范围35-55岁，平均42.32；3.4岁
| 患者编号 | 施用前的溶菌酶 | 施用后1周 |
| 01 | 2.3 | 2.9 |
| 02 | 2.3 | 7.5 |
| 03 | 2.4 | 12.3 |
| 04 | 2.1 | 11.2 |
| 05 | 2.0 | 12.1 |
| 06 | 2.3 | 11.4 |
| 07 | 2.4 | 12.0 |
| 08 | 2.2 | 11.8 |
| 09 | 2.4 | 13.0 |
| 10 | 2.2 | 11.4 |
为了证明组合与单一成分的协同作用，对口腔细菌感染的5组12个患者进行了试点临床试验；第一组用根据本发明的提取物的组合(样品D)治疗，每天3次共3天。其余组患者在相同的施用方案下施用：安慰剂制剂(样品E)，单独的姜黄提取物(样品A)，单独的石榴提取物(样品B)或单独的姜(样品C)；每种单一提取物以在样品D中存在相同量而施用。最后一次治疗之前一小时和一小时后，患者用生理溶液漱口30秒，并且根据实验室标准条件将0.5ml接种在琼脂上培养36h后进行细菌计数。
结果见于下表3中：
表3
可以注意到，用根据本发明的样品D治疗后的效果出乎意料地高于单独使用样品A，样品B，样品C三种中的每一种。与由样品A+B+C获得的累积效果相比，样品D的效果也更高。
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Claims (8)
1.一种由姜黄、石榴和姜的提取物组成的活性剂的组合物在制备用于预防和/或治疗口腔、咽喉和呼吸道疾病的药物中的用途，其中所述疾病与细菌活性相关和/或所述疾病是普通感冒或流感的结果，
其中，
-所述姜黄的提取物含有20-30重量％的姜黄素；
-所述石榴的提取物含有60-95重量％的多酚；
-所述姜的提取物含有总量为20-50重量％的姜辣素和姜烯酮，
所述姜黄、石榴和姜的提取物以各自重量比6(±2)：2(±1)：1(±0.5)存在。
2.一种用于预防和/或治疗口腔、咽喉和呼吸道疾病的包含姜黄、石榴和姜的提取物的活性剂的组合物，其中所述疾病与细菌活性相关和/或所述疾病是普通感冒或流感的结果，
其中，
-所述姜黄的提取物含有20-30重量％的姜黄素；
-所述石榴的提取物含有60-95重量％的多酚；
-所述姜的提取物含有总量为20-50重量％的姜辣素和姜烯酮，
所述姜黄、石榴和姜的提取物以各自重量比6(±2)：2(±1)：1(±0.5)存在，
并且，其中：
-所述提取物总体上占总施用活性剂的50重量％以上，
-和/或除所述提取物之外的每种可能活性剂存在的量低于所述姜黄、石榴和姜的提取物中最低量的至少50重量％。
3.根据权利要求2所述的组合物，其中，所述姜黄、石榴和姜的提取物总体上占总施用活性剂重量的90％以上。
4.根据权利要求1所述的用途，所述组合物配制成施用的单位剂量，其包含：20-100mg姜黄提取物、10-50mg石榴提取物和2-20mg姜提取物。
5.根据权利要求1所述的用途，所述组合物与药物赋形剂一起配制。
6.根据权利要求1所述的用途，所述组合物为适合于面颊，口腔或吸入施用的形式。
7.根据权利要求1所述的用途，其中，所述疾病是以下中的一种或多种：喉咙痛，咳嗽，流鼻涕，体温升高，打喷嚏，鼻液溢，鼻塞，不安。
8.根据权利要求1所述的用途，进一步通过使所述组合物与唾液的接触用于增强异生物的裂解。
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| US20180169175A1 (en) | 2018-06-21 |
| US10758587B2 (en) | 2020-09-01 |
| TR201908938T4 (tr) | 2019-07-22 |
| EP3307293A1 (en) | 2018-04-18 |
| AU2016276145A1 (en) | 2017-12-21 |
| ES2730088T3 (es) | 2019-11-08 |
| PT3307293T (pt) | 2019-06-12 |
| JP6966998B2 (ja) | 2021-11-17 |
| KR20180030970A (ko) | 2018-03-27 |
| JP2018519361A (ja) | 2018-07-19 |
| MX2017016028A (es) | 2018-04-13 |
| PL3307293T3 (pl) | 2019-11-29 |
| EP3307293B1 (en) | 2019-03-20 |
| BR112017026417B1 (pt) | 2021-04-27 |
| HUE044731T2 (hu) | 2019-11-28 |
| WO2016198943A1 (en) | 2016-12-15 |
| AU2016276145B2 (en) | 2022-05-26 |
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