CN106659215A - 甜味受体拮抗剂组合物 - Google Patents
甜味受体拮抗剂组合物 Download PDFInfo
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- CN106659215A CN106659215A CN201580031394.XA CN201580031394A CN106659215A CN 106659215 A CN106659215 A CN 106659215A CN 201580031394 A CN201580031394 A CN 201580031394A CN 106659215 A CN106659215 A CN 106659215A
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- Prior art keywords
- zinc
- gymnemic acid
- composition
- acid
- gymnemic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002464 receptor antagonist Substances 0.000 title description 2
- 229940044551 receptor antagonist Drugs 0.000 title description 2
- 229930183009 gymnemic acid Natural products 0.000 claims abstract description 205
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 54
- 239000011701 zinc Substances 0.000 claims abstract description 54
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 52
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- 238000000034 method Methods 0.000 claims abstract description 30
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- 239000003795 chemical substances by application Substances 0.000 claims description 18
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- -1 zinc halide Chemical class 0.000 claims description 16
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 16
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- 235000001050 hortel pimenta Nutrition 0.000 claims description 12
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- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 10
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- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
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- ZULTYUIALNTCSA-UHFFFAOYSA-N zinc hydride Chemical compound [ZnH2] ZULTYUIALNTCSA-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明涉及包含匙羹藤酸以及一种形式的锌的组合物,所述组合物阻断匙羹藤酸令人不快的苦味以及延长匙羹藤酸的甜味阻断性质,生成用于递送至口腔以阻断位于其中的甜味受体的可口的组合物。本发明还涉及经由将这样的组合物施用至受试者减少糖摄取和减少卡路里摄入的方法。
Description
优先权数据
根据35U.S.C.§119(e),本发明要求保护2014年6月12日提交的美国临时专利申请系列号62/011,096和2014年7月17日提交的美国临时专利申请系列号62/025,725的优先权,两者都通过引用以其整体并入本文。
发明领域
本发明涉及包含匙羹藤酸(gymnemic acid)以及一种形式的锌的组合物,阻断了匙羹藤酸令人不快的苦味以及延长匙羹藤酸的甜味阻断性质,得到了用于递送至口腔以阻断位于其中的甜味受体的可口的组合物。本发明还涉及经由将这样的组合物施用至受试者减少糖摄取和减少卡路里摄入的方法。
发明背景
匙羹藤酸提取自匙羹藤(Gymnema sylvestre),一种原产于印度、非洲和中国的木质藤本植物。匙羹藤酸是在全球销售的膳食补充剂,主要为封装形式(参见Ogawa et al.,J.Food Hygienic Soc Japan(2004)45:8-18)。当直接应用至口腔时,已知匙羹藤酸临时阻断对甜味的感觉(参见,Kurihara,1969and Sanematsu,J.Biol.Chem.(2014)289:25711-25720)。研究已显示给予匙羹藤酸的受试者比给予安慰剂的受试者摄取更少的卡路里(参见,Brala et al.,Physiol.Behay.(1983)30:1-9)。然而,已知匙羹藤酸具有对人来说不可口的强烈苦味(参见,例如美国公开号2004/007180)。
传统上,在调味科学领域,技术人员会将甜味剂如蔗糖添加至组合物以掩盖必需成分的苦味。强烈的苦味成分会需要较大量的蔗糖或者可能更强的人造甜味剂如三氯蔗糖以掩盖苦味。然而,作为匙羹藤酸的甜味阻断性质的结果,这些传统的苦味阻断方法对减少匙羹藤酸的苦味不起作用。此外,由于甜味剂和匙羹藤酸可相互作用并都与甜味受体结合,因此强烈的天然或人造甜味剂的使用可干扰匙羹藤酸预期的甜味阻断活性(Sanematsu,J.Biol.Chem.(2014)289:2571-25720)。
在调味科学领域公知的是,当与包含苦味成分的组合物共同作用时,可制备意在立即吞咽的封装剂型或片剂剂型。该方式由于苦味成分从不直接接触口腔而避免了任何苦味问题。然而,这种剂型对于意在直接接触口腔和舌头并随后吞咽的含有匙羹藤酸的组合物并不可行。
十多年来,已尝试开发将匙羹藤直接递送入口腔的饮食产品。然而,由于已知调味科学不能够有效消除匙羹藤的强烈苦味,这些尝试都以失败告终。一项这样的尝试讨论于美国公开号2004/007180,其描述了将匙羹藤叶提取物与去苦味剂组合的锭剂,公开了为"Comax Flavors#2588E17379"的苦味掩盖剂。由Genotec Nutritionals,Inc.公司制造的SugarestTM口嚼物(gum)投入了市场以暂时阻断甜味受体20-30分钟(新闻稿,MM2G公司的MM2集团在菲律宾电视新闻上的SugarestTM节目(2007年4月12日),可在http://www.pmewswirc.corninews-releases/mm2-groups-sugaresttm-featured-on-t v-news-in-phitadelphia-58283722.html获得)。该产品失败了,并且多年都未使用。
Supresalin是包含匙羹藤酸的组合物,据称其可将对糖的渴望减少大约30分钟。(http://supresalin.com/faqs/)。Sugar Suppress 60是另一种包含匙羹藤酸的产品,据称其减少卡路里摄取并促进减重。然而,该产品具有强烈苦味且并不可口。多次尝试失败后,对于在舌递送形式中以延长的时间段完全阻断甜味的匙羹藤酸的可口、非苦味组合物仍存在需求。
发明概述
本文描述的是包含匙羹藤酸的组合物,其中还含有一种形式的锌以阻断匙羹藤酸令人不快的苦味以及延长匙羹藤酸的甜味阻断性质,得到了意在直接接触口腔以阻断位于其中的甜味受体的可口的组合物。由于匙羹藤酸的甜味阻断效应需要该药剂保持在口腔内,需要一种有效手段来减少匙羹藤酸在其递送至口腔期间的苦的不可口的味道。该需要通过本公开的舌递送形式(lingual delivery form)、组合物和方法学得以满足,其优选允许匙羹藤酸与一种形式的锌共同递送至口腔,阻断匙羹藤酸的苦味。
一般而言且根据一些实施方案,本公开的舌递送形式和组合物递送匙羹藤酸以及一种形式的锌至舌头的甜味受体,产生持续时间尤其长的甜味封锁并在应用过程中同时减少或消除其苦味。
本发明可涉及包含匙羹藤酸和至少一种形式的锌的舌递送形式。舌递送可包括但不限于锭剂(lozenge)、口腔崩解片、口腔分散片、含片(troche)、硬糖、软糖、胶冻剂(jelly)、口嚼物、食用膜、口腔可溶解膜、薄片状物(wafer)、滴剂、口腔喷雾剂、液体剂、粉剂及其组合。口腔崩解片的崩解时间可在约30秒至约5分钟的范围。
锌的形式可包括但不限于乙酸锌、碳酸锌、氯化锌、柠檬酸锌、葡萄糖酸锌、硫酸锌、连二亚硫酸锌(zinc hydrosulfite)、亚硫酸氢锌(zinc bisulfite)、氧化锌、卤化锌、氢化锌、碳化锌及其组合。优选地,锌的形式是GRAS(Generally Recognized as Safe,fda.gov/Food/IngredientsPackagingLabeling/GRAS/)批准的锌盐,最优选是葡萄糖酸锌。
匙羹藤酸可作为匙羹藤酸的无机盐、匙羹藤酸的有机盐、匙羹藤酸的环糊精复合物、匙羹藤酸的穴状配体复合物、匙羹藤酸的水合物、匙羹藤酸的溶剂合物及其组合存在。匙羹藤酸的溶剂合物可包括匙羹藤酸的多种乙醇溶剂合物。
舌递送形式可进一步包含薄荷。
舌递送形式可进一步包含苦味抑制剂。所述苦味抑制剂可包括但不限于钠盐、脂蛋白及其组合。
舌递送形式可进一步包含至少一种酸味抑制剂。所述酸味抑制剂可以是奇果甜素(miraculin)。
本发明的发明人提供使用本发明的舌递送形式和组合物的方法。本发明提供减少糖摄取的方法,包括将本发明的组合物和舌递送形式施用至受试者。此外,本发明提供减少卡路里摄入的方法以及减少龋齿的方法,所述减少卡路里摄入的方法包括将组合物和舌递送形式施用至受试者,所述减少龋齿的方法包括将组合物和舌递送形式施用至受试者。
发明详述
下文是对本发明的详细说明,提供其以协助本领域的技术人员实践本发明。本领域的技术人员可在本文所述的实施方案中生成修饰和变化而不脱离本发明的精髓和范围。除非另外限定,本文使用的全部技术和科学术语具有与本发明所述领域的技术人员通常所理解的相同的含义。本发明的说明书中使用的术语仅用于描述特定的实施方案且目的并非在于限制本发明。全部的出版物、专利申请、专利、附图和其他本文提及的参考文献通过引用以其整体表述性地并入。
必须注意的是,如在说明书和附加的权利要求中所使用,单数形式"一个"、"一种"和"所述"也包括复数形式,除非上下文清楚表明并非如此。因此,例如,提及“一种化合物”包括复数的化合物。在本说明书和随后的权利要求中,除非相反的目的是显而易见的,否则将参考定义为具有以下含义的多个术语。
必须注意的是,比率、浓度、量和其他数值数据在本文可表述为范围的形式。应该理解的是出于方便和简洁的目的,该范围形式因此应以灵活的方式解读以不仅包括如范围限制所明确记载的数值,还包括全部涵盖在该范围内的单独的数值或子范围,如每个数值和子范围都明确记载般。出于说明目的,“约0.1%至约5%”的浓度范围应解读为不仅包括明确记载的约0.1wt%至约5wt%的浓度,还包括在所示范围内的单独的浓度(例如1%、2%、3%和4%)和子范围(例如0.5%、1.1%、2.2%、3.3%和4.4%)。在一个实施方案中,术语“约”可根据数值的有效数字包括常规的四舍五入。此外,短语“约‘x’至‘y’”包括“约‘x’至约‘y’”。
如本文使用的短语“甜度阻断”定义为引进口腔的食物或饮品或其他物质的可感知甜度的弱化。甜度阻断和甜味封闭是同义词。
如本文使用的短语"减少的苦味"定义为与化合物(例如匙羹藤酸)相关的苦味的减少。在一些实施方案中,减少的苦味为约50%或更多、约75%或更多、约85%或更多、约90%或更多、约95%或更多、或约99%或更多的减少。如本文使用,短语"消除苦味"定义为与化合物(例如匙羹藤酸)相关的苦味减少约100%。
匙羹藤酸在其甜度阻断中并非是选择性的。因此,在将匙羹藤酸递送至口腔后的阶段中摄入或引入口腔的任何包含甜味剂的食物或饮料或其他物质尝起来并不甜或其甜味显著减少。此外,由于苦味和酸味不再由甜味掩盖,对这种食物或饮料中任何苦味或酸味的存在的感知都有所扩大。通过递送至口腔包括舌头来使用匙羹藤酸阻止了对食物或饮料中甜味剂的渴望,导致对这种高卡路里食物摄取的减少。甜度感知与对摄取的甜味食物的选择间的联系是已知的(参见Brala et al.,Physiol.Behay.(1983)30:1-9)。
以该种方式使用匙羹藤酸的缺陷是匙羹藤酸已知具有令人不快的和强烈的苦味,该苦味对于人来说是不可口的。其他缺陷是当匙羹藤酸阻断甜味的感觉时,该效应是暂时的且仅持续短时间段。因此,对于可以更长时间段阻断甜味感觉同时减少或消除匙羹藤酸的苦味的基于匙羹藤酸的改进的组合物存在持续需要。此外,对于在匙羹藤酸递送至口腔的过程中显著减少或消除其强烈苦味和令人不快的味道的有效方式存在需要。
关于甜味受体已知很多。甜度是由人感觉的五类主要味道之一。启动该感觉的受体位于已知为I型、II型和III型的三种味蕾细胞之一中,所述味蕾细胞位于主要位于舌头上的味蕾中,但也在口腔的软腭和其他区域有所发现。甜味受体位于II型味蕾细胞的不同子集中。感觉甜度的味蕾细胞表达经标识为T1R2/T1R3的单独的异二聚体受体。
相反,苦味转导机制是复杂的且尚未完全理解。已知人的苦味由26T2R受体的激活而启动,一般接受的是其作为同二聚化和异二聚化种类的混合物在苦敏感味蕾细胞中存在,因此提供共346个可能的功能性受体,其中认为这些二聚种类的相对数目因人而异(参见C.Kuhn et al.,Chem.Senses 2010,35:395-406)。人之间的这种多样性证明了苦味相对其他味道如甜和酸的复杂性。此外,鉴于匙羹藤酸是超过20种不同三萜系化合物(它们全部可能具有不同的苦味属性)的复杂混合物(参见Imoto et al.,J Chromatography(1991)557:383-389),阻断匙羹藤酸的苦味给出了巨大的挑战。
鉴于存在26种负责感觉苦味刺激的T2R苦味受体,当多重受体被激活时,阻断相关的苦味是非常困难的。由包含在草本提取物中的分子的复杂混合物如包含匙羹藤酸的组合物生成的苦味响应预期会触发大量单独的苦味受体。因此预期具有苦味阻断性质的单一试剂不会完全消除匙羹藤酸的苦味。
已知锌具有阻断甜味和苦味二者的一些能力。利用锌盐作为味道调节剂已在之前多个出版物中进行了描述(Keast,JFS(2003)68:1871-1877)。尽管匙羹藤酸抑制全部天然和人工甜味剂的甜度,锌盐在其抑制作用中是选择性的且并非为通用的抑制剂。例如,Keast和Breslin已证明了硫酸锌是针对奎宁、苯甲酸地那铵和四氢萘酮(tetralone)的有效苦味抑制剂,但对于蔗糖八乙酸酯、伪麻黄碱和右美沙芬不具有显著的苦味抑制活性(Keast,JFS(2003)68:1871-1877)。又例如,已观察到ZnSO4抑制奎宁盐酸盐(QHC1)至多70%的苦味(Keast,JFS(2003)68:1871-1877),然而,必须注意的是,锌仅可干扰负责苦味化合物子集(存在数千种但非全部的苦味化合物)的苦味转导负责的机制(Keast,JFS(2003)68:1871-1877)。
不预期单独的锌作为味觉改良剂将完全有效,且其不足以提供可口的组合物。为完全有效,锌常规伴随其他风味掩盖剂如蔗糖、果糖、山梨糖醇、木糖醇、人造甜味剂和/或调味组合物(即水果或柑橘风味)。此外,锌本身已知具有金属离子共同的令人反感的金属的、似白垩的、涩的回味,且还需要其他风味掩盖剂以掩盖锌令人不愉快的味道。因此,不认为锌是可用于完全阻断苦味成分的单一试剂。
尽管如此,惊讶地发现了将某种形式的锌添加至匙羹藤酸提取物不仅生成无需任何其他味道掩蔽剂以使味道可口并阻断甜味的组合物,而且甜度阻断的持续时间延长至至少60-80分钟,大于单独使用匙羹藤酸获得的甜度阻断持续时间。
通过本发明的组合物,意外地发现了当将匙羹藤酸与锌组合时,匙羹藤酸的苦味减少且几乎完全消除,同时匙羹藤酸的甜味阻断性质仍有效。此外,意外地发现匙羹藤酸和某种形式的锌一起的组合物以比单独施用匙羹藤酸或单独施用锌以更长的时间段阻断人受试者中的甜味。意外地发现,当将包含匙羹藤酸和某种形式的锌的组合的组合物递送至口腔时,甜味封锁的长度可延长至至少60-80分钟或更长的持续时间,大于使用单独的匙羹藤酸获得的甜味封锁持续时间。
本发明提供匙羹藤酸至口腔的递送,进而阻断对甜味剂的感觉。因此,在摄入任何甜味食物或饮料期间,甜味剂不导致甜味的感知。使用本发明组合物的人或受试者将不再能够经历其食用或饮用或引入口腔的物质的甜味,这使得大多食物、饮料和其他物质不再可口。因此,本发明提供允许使用者解决其对于甜食即刻渴望的问题的组合物。此外,通过更多的延长使用,由于使用者不再将愉悦的感觉与之前尝起来甜的食物关联,组合物的使用者可对其行为进行调节。因此,经由对受试者施用本文所述的包含匙羹藤酸的组合物,本发明还提供减少受试者糖摄取和减少受试者卡路里摄入的方法。
一般而言且根据一些实施方案,本发明的舌递送形式和组合物将匙羹藤酸递送至舌头的甜味受体,在应用的过程中导致额外的甜味封锁持续时间并同时减少或消除匙羹藤酸的苦味。
包含匙羹藤酸和某种形式的锌的组合物的独特和令人惊讶的表现提供超过现有技术匙羹藤酸制剂的优势,提供更长时间的甜味阻断并允许受试者在口腔中以较长的持续时间保持包含匙羹藤酸的组合物而不经历匙羹藤酸令人不快的苦味。
申请人意外发现,包含匙羹藤酸以及一种形式的锌的组合物作为额外的甜度抑制剂的应用提供的总甜味封锁大于单独使用锌和单独使用匙羹藤酸的甜味阻断效应的总和。协同效应定义为离散试剂的合作作用,进而总效应大于独立采用的两种或更多种的效应。
鉴于具有多达346种功能性受体的人苦味受体系统的复杂性,其中常常发现特定苦味剂活化多种苦味受体且其中尚不知晓由匙羹藤酸活化的特定苦味受体,对匙羹藤酸特定苦味抑制剂鉴别进行预测是不可能的。此外,各种形式的锌在其苦味抑制活性上是特异性的且未广泛应用。因此,可以预期的是锌的形式和匙羹藤酸的组合将提供完全的甜味阻断而无任何苦味,使其本身提供增加甜味封锁持续时间的协同效应。此外,与T1R2/T1R3结合的匙羹藤酸和锌的位点未知。对其不知晓的话,将不能预测协同效应。
“锌的形式((一种)形式的锌)”可以是任何形式,如锌盐。例如,锌的形式可包括但不限于由U.S.FDA("GRAS")一般认可为安全的锌的形式,如乙酸锌、碳酸锌、氯化锌、葡萄糖酸锌、连二亚硫酸锌、氧化锌和硫酸锌、以及卤化锌、氢化锌、碳化锌、柠檬酸锌和亚硫酸氢锌,及其任何组合。
本发明的舌递送形式和组合物提供额外的甜味封锁持续时间(例如约30分钟或更久、约60分钟或更久、约80分钟或更久、约90分钟或更久或约120分钟或更久),并同时减少或消除与匙羹藤酸相关的苦味。意外发现的是,当将包括匙羹藤酸和一种形式的锌的组合的组合物递送至口腔时,甜度阻断的长度可延长至比单独的匙羹藤酸或锌更长,例如大于80分钟。因此,本发明的舌递送形式和组合物具有协助人们控制其对具有高卡路里的甜的食物和饮品摄取的能力。
本发明的一方面是包含匙羹藤酸和一种形式的锌的舌递送形式。如本文使用,术语“舌”指包含味觉受体的口腔的任何区域,包括舌头和位于其中的任何其他区域。口腔可包括舌、口内、口腔、舌下等。如本文使用,术语"舌递送形式"指任何固态或液态形式,或可用于将匙羹藤酸、至少一种额外的甜味抑制剂和任何其他组分如苦味抑制剂或酸味抑制剂递送至舌头上的味觉受体以及受试者口腔中的其他味觉受体的媒介。
该舌递送形式的实例包括但不限于锭剂、片剂、口腔崩解片、口腔分散片、含片、硬糖、软糖、胶冻剂、口嚼物、食用膜、口腔可溶解膜、薄片状物、滴剂、口腔喷雾剂、液体剂和粉剂。在一些实施方案中,受试者将包含匙羹藤酸和一种形式的锌的固体舌递送形式保持在口腔中约3至5分钟。在其他实施方案中,受试者将包含匙羹藤酸和一种形式的锌的液体舌递送形式保持在口腔中约3至5分钟。在一些其他的实施方案中,舌递送形式是崩解时间为约30秒至约5分钟的口腔崩解片。崩解时间可使用用于崩解和溶出膳食补充剂的USP<2040>方法确定。用于该方法的参数包括去离子水、35°-37°摄氏度的温度和大于6个的样品数目。
本发明的另一方面是包含匙羹藤酸和一种形式的锌的组合物,其可进一步包含至少一种额外的甜味抑制剂,其中前提是所述至少一种额外的甜味抑制剂不是lactisole、3-(4-甲氧基苯氧基)丙酸钠、hodulcine或ziziphin。
本发明的另一方面是包含匙羹藤酸和一种形式的锌和至少一种酸味抑制剂的组合物。
本发明的舌递送形式和组合物包含匙羹藤酸。如本文使用,匙羹藤酸指植物匙羹藤的提取物,其包含能够在人中抑制甜味感觉的一种或多种三萜系化合物。还考虑的是包含匙羹藤酸的组合物,其包括这些提取的三萜系化合物的合成对应物。这种化合物的实例包括但不限于式(I)的化合物:
其中
(参见Di Fabio et al.,Molecules(2014)19:10956-10981)。
在一些实施方案中,本发明的舌递送形式和组合物中使用的匙羹藤酸包含一种或多种上述式(I)的化合物。在其他实施方案中,匙羹藤酸包含匙羹藤酸同系物的任一种或任何组合,包括但不限于GA 1(匙羹藤酸I)、GA 2(匙羹藤酸II)、GA 3(匙羹藤酸III)、GA 4(匙羹藤酸IV)和GA 34(Gymnemoside C)。
在本发明的舌递送形式和组合物中使用的匙羹藤酸可以是各萜类皂苷物质的任何组合的任何纯度、即含量,其中纯度定义为匙羹藤酸比匙羹藤酸和其他来自匙羹藤植物的物质的总和的比例。例如,使用的匙羹藤酸可具有下述纯度:至少20%,和至少30%、至少40%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少90%或至少99%。在一些实施方案中,纯度可以术语重量%或区域%表示(AUC)。匙羹藤酸的纯度可以通过HPLC确定。在一些实施方案中,纯度可使用USP<621>HPLC方法学确定。优选地,HPLC使用Waters XSelect CSH C18管柱、130A,5μm,4.6mm X 250mm实施。
本发明的舌递送形式和组合物中使用的匙羹藤酸可以是匙羹藤酸的无机盐、铵盐、氨基盐包括多氨基盐、有机盐、环糊精复合物、穴状配体复合物、水合物或溶剂合物,或其任何组合。匙羹藤酸的无机盐的实例包括但不限于碱金属盐如钠和钾盐、碱土金属盐如镁和钙盐、过渡金属盐如锰、铁和锌盐,和稀土金属盐如镧,铕和铽盐。匙羹藤酸的铵盐的实例包括但不限于铵盐、单烷基取代的铵盐如甲基铵盐、二烷基取代的铵盐如二甲基铵盐、三烷基取代的铵盐如三甲基铵盐或四烷基取代的铵盐如四甲基铵盐。匙羹藤酸的多氨基盐的实例包括但不限于二氨基盐,如乙二胺盐、三氨基盐如三亚乙基四胺盐和其他多氨基盐,如α-聚鸟氨酸盐、α-聚赖氨酸盐、γ-聚鸟氨酸盐、ε-聚赖氨酸盐或壳聚糖盐。匙羹藤酸的环糊精复合物实例包括但不限于匙羹藤酸的α-环糊精、β-环糊精和γ-环糊精复合物。匙羹藤酸的溶剂合物的实例包括匙羹藤酸的各种乙醇溶剂合物和匙羹藤酸的各种乙酸乙酯溶剂合物。在一些实施方案中,匙羹藤酸可以是具有pI为约7或更大蛋白质的蛋白盐形式。
在本发明的一些实施方案中,匙羹藤酸的氨基盐形式可以是匙羹藤酸的氨基盐形式的单烷基取代的衍生物、匙羹藤酸的氨基盐形式的二烷基取代的衍生物、或匙羹藤酸的氨基盐形式的三烷基取代的衍生物。在本发明的其他实施方案中,匙羹藤酸的二氨基盐形式可以是匙羹藤酸的二氨基盐形式的单烷基取代的衍生物、匙羹藤酸的二氨基盐形式的二烷基取代的衍生物或匙羹藤酸的二氨基盐形式的三烷基取代的衍生物。在本发明的其他的实施方案中,匙羹藤酸的三氨基盐形式可以是匙羹藤酸的三氨基盐形式的单烷基取代的衍生物、匙羹藤酸的三氨基盐形式的二烷基取代的衍生物或匙羹藤酸的三氨基盐形式的三烷基取代的衍生物。在本发明其他的实施方案中,匙羹藤酸的四氨基盐形式可以是匙羹藤酸的四氨基盐形式的单烷基取代的衍生物、匙羹藤酸的四氨基盐形式的二烷基取代的衍生物或匙羹藤酸的四氨基盐形式的三烷基取代的衍生物。在本发明其他的实施方案中,匙羹藤酸的多氨基盐形式可以是匙羹藤酸的多氨基盐形式的单烷基取代的衍生物、匙羹藤酸的多氨基盐形式的二烷基取代的衍生物或匙羹藤酸的多氨基盐形式的三烷基取代的衍生物。
匙羹藤酸以部分或完全阻断受试者中甜味感觉一段时间的任何有效量存在。该量的实例包括但不限于,以舌递送形式或组合物总重量计,约0.01%重量至约25重量%、约0.01重量%至约10重量%、约0.01重量%至约4重量%、约0.05%至约2重量%、约0.01重量%至约1重量%、约0.01重量%至约0.5重量%、约0.01重量%至约0.2重量%的范围中的那些。在一些实施方案中,匙羹藤酸可以舌递送形式的约0.1重量%-5重量%、0.01-1重量%、约0.01重量%-0.5重量%或约0.01重量%-0.2重量%存在。就绝对量而言,本发明的舌递送形式和组合物可包含约0.1mg至200mg的匙羹藤酸,包括但不限于1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150或200mg的匙羹藤酸。本发明的舌递送形式和组合物中的匙羹藤酸的量可取决于组合物和组合物的形式(例如非液体或液体)发生变化。在这方面,匙羹藤酸的量可取决于用途和预期的结果发生变化。舌递送形式的剩余部分可包括其他赋形剂,所述赋形剂包括但不限于蔗糖、葡萄糖、乳糖、玉米糖浆固体、麦芽糖糊精、山梨糖醇、木糖醇、赤藓糖醇和其它糖和多元醇。此外,舌递送形式可包括风味剂如胡椒薄荷、留兰香和薄荷醇。
多种风味如香草和巧克力也需要作为载剂的甜味的存在,即除非甜味也存在,否则所述风味剂不能被品尝到。然而,薄荷不需要甜味作为载剂,且因此可被品尝到且无需甜味存在下即可享受。因此,舌递送形式可进一步包含薄荷。例如,薄荷可以是胡椒薄荷、留兰香和薄荷醇。此外,尽管将薄荷添加至匙羹藤酸不能阻断苦味,至施用包含匙羹藤酸和锌的形式的舌递送形式时无任何残留的苦味的程度,薄荷将掩盖或阻断苦味。
在一些实施方案中,本发明的组合物包含匙羹藤酸、锌的形式和至少一种酸味抑制剂。可使用任何本领域已知的酸味抑制剂。这种酸味抑制剂的实例包括但不限于奇果甜素。
本发明包含匙羹藤酸和一种形式的锌的舌递送形式和组合物还可进一步包含至少一种苦味抑制剂。可使用本领域已知的任何苦味抑制剂。这种苦味抑制剂的实例包括但不限于钠盐。
当包括时,所述至少一种苦味抑制剂以有效减少或消除匙羹藤酸苦味的任何量存在。在一些实施方案中,苦味抑制剂以约1至约200mg的量存在。这样的量的特定实例包括但不限于约1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150或200mg的苦味抑制剂。例如锌的形式如锌盐可作为苦味抑制剂以例如0.2重量%、1重量%、2重量%或5重量%的量存在。在一些其他实施方案中,当苦味抑制剂是锌盐时,锌离子按重量的百分比为0.01%-100%,或1.0%-75%,或1.5%-70%,或2%-65%,或2.5%-50%。锌离子的百分比重量定义为锌离子比锌离子加匙羹藤酸的总和的比例。匙羹藤酸含量根据上文所述的方法确定且锌离子根据作为锌形式的百分比的锌离子确定。例如,Zn2+是硫酸锌(ZnSO4)分子重量的40%,因此10mg的硫酸锌等同于4mg Zn2+。
在一些实施方案中,匙羹藤酸和锌的形式的组合就获得的甜度阻断长度而言起到协同作用。在一些实施方案中,这种协同组合将导致受试者中甜味感觉的部分或完全抑制约30分钟或更久、约60分钟或更久、约90分钟或更久,或约120分钟或更久。在一些实施方案中,匙羹藤酸和锌的形式的组合令人意外地起到协同作用,以比施用至口腔的匙羹藤酸(不存在至少一种其他甜味抑制剂和/或至少一种酸味抑制剂和/或至少一种苦味抑制剂)更长的时间来延长受试者中对甜度的部分或完全的封锁。令人意外地是,申请人发现了匙羹藤酸(15mg)和ZnSO4·7H2O(107mg)的组合导致在施用后60分钟时甜味的完全封锁,而发现仅施用匙羹藤酸时在60分钟甜味感觉部分恢复。
在一些在其他实施方案中,当至少一种其他甜味抑制剂是锌盐时,锌离子重量百分比为0.01%-100%,或1.0%-75%,或1.5%-70%,或2%-65%,或2.5%-50%。锌离子的重量百分比定义为锌离子比锌离子加匙羹藤酸总和的比例,且其中锌离子和匙羹藤酸的含量根据上文所述的方法确定。
本发明的方法包括将舌递送形式和组合物施用至受试者。在一个实施方案中,将上述舌递送形式和组合物施用至受试者的方法导致受试者对于甜味食物和饮料减少的食欲。在另一个实施方案中,将上述舌递送形式和组合物施用至受试者的方法导致受试者中减少的卡路里摄入,这是由于受试者不再对甜味食物渴望。在另一个实施方案中,将上述舌递送形式和组合物施用至受试者的方法导致受试者中减少的龋齿,这是由于受试者摄取(consume)更少的甜味食物和饮料。在一些实施方案中,本发明的方法包括以一定量的舌递送形式或组合物接触(例如处置、咀嚼、吸吮、舔舐等)受试者的口腔。口腔可包括舌、口内(inside of the mouth)、口腔、舌下等。在其他实施方案中,组合物与口腔接触约1-10分钟的时间段。在其他实施方案中,组合物可与口腔接触多次,如通过在一段时间(例如多小时、天等)的不同的时间框咀嚼口嚼物的不同部分。
在一些实施方案中,当将所述组合物与受试者的口腔接触时,本发明的方法在受试者中提供甜味封锁约30-120分钟或约60分钟-120分钟的时间段。在一个实施方案中,该时间框可始于组合物不再于口腔中的时间,例如当移除口嚼物或当锭剂经历完全溶解时。
本发明进一步通过下述实施例说明,其不应理解为是限制性的。对实施例进行阐述进而为本领域的技术人员提供如何实施方法和使用本文公开和要求保护的化合物的说明性公开和描述。本领域的技术人员将认可本发明可以基于公开的结构、材料、化合物和方法的变化进行实践,且这种变化认作在本发明的范围内。除非另外表明,部分是按重量的部分,温度是℃,且压力是处于或接近大气压。标准温度和压力定义为20℃和1个大气压。
实施例
制剂实施例
制剂FLLC-F27c 4mg(延长释放的制剂)
赋形剂名称 | %比率 | 重量(克) | 40X克 | 100X克 | 240X克 |
活性的(四-ccl-15B)[匙羹藤酸] | 0.800 | 0.0040 | 0.160 | 0.400 | 0.960 |
山梨糖醇(Parateck S1 150) | 62.100 | 0.3105 | 12.420 | 31.050 | 74.520 |
赤藓糖醇 | 30.000 | 0.1500 | 6.000 | 15.000 | 36.000 |
葡萄糖酸锌 | 1.300 | 0.0065 | 0.260 | 0.650 | 1.560 |
Firmenich胡椒薄荷 | 2.400 | 0.0120 | 0.480 | 1.200 | 2.880 |
Firmenich薄荷 | 2.400 | 0.0120 | 0.480 | 1.200 | 2.880 |
硬脂酸镁 | 1.000 | 0.0050 | 0.200 | 0.500 | 1.200 |
总计 | 100.000 | 0.5000 | 20.000 | 50.000 | 120.000 |
评论
使用了10mm凹模以制备500mg片剂。
使用的配制过程:
将活性成分与1克赤藓糖醇和葡萄糖酸锌共研磨至精细的均匀粉末
通过30网筛过筛剩余的赋形剂。随后混合除硬脂酸镁的全部赋形剂。
共混30分钟。
添加硬脂酸镁
共混1分钟
将制剂压成片剂
味道阻断实施例
建立了标准的方法以量化本发明的匙羹藤酸组合物封锁甜味的持续时间。下述实施例中使用的匙羹藤酸部分从匙羹藤叶的粗提物纯化且确定为匙羹藤酸的混合物(81%纯度),其主要为GA 1和GA 2,具有较少量的GA3和GA 4,且还包括GA乙酸酯/苯甲酸二酯(即GA34-Gymnemoside C)。在全部的情况中,将蔗糖用作甜味封锁量化中的甜味剂。因此,新鲜制备在反渗透(RO)纯化的水中的10%、8%、6%、4%和2%(w/v)蔗糖溶液且在每次实验的开始,将每种蔗糖溶液的15mL样品用于校准感觉小组成员的甜度强度。感觉小组成员描述为具有感觉评估训练经验至少1年在gustatation区域中作为感觉小组成员的人,且优选具有描述性分析训练。将标准的尺度方法用于量化下述尺度上的甜度强度(SI):
10%蔗糖=10,
8%蔗糖=8,
6%蔗糖=6,
4%蔗糖=4,
2%蔗糖=2,且
0%蔗糖=0。
小组成员以蔗糖参照标准校准后,小组成员以15mL RO水润洗其嘴且随后将在15mL RO水中的甜度抑制剂样品立即放入嘴中并轻轻搅动5分钟。随后咳出甜味抑制剂样品并立即再次品尝15mL的10%蔗糖参照溶液样品,将在15秒内感知的SI在0-10尺度上评级,咳出样品,且以15mL RO水剧烈冲洗嘴。随后每15分钟再次品尝10%蔗糖样品并SI评级。问询小组成员以在每次蔗糖参照测试时间间隔时对非甜味属性的观察做出评论。通过该标准方案的实验中的SI结果是SI评级的简单方式。
匙羹藤酸呈现显著的苦异味。采用尺度方法学以量化单独的匙羹藤酸及与多种物质的组合的苦味以致力于鉴别具有减少或消除的苦味的匙羹藤酸组合物。在该方法学中,将蔗糖用作尺度参照。因此,如上,10、8、6、4、2和0的苦味评级对苦味的感知是指示性的,其分别与对10、8、6、4、2和0%蔗糖的甜味感知强度等同。
比较例1-匙羹藤酸的甜度抑制(15mg剂量)
评估匙羹藤酸以量化其甜味抑制的持续时间进而确定基线值,针对所述基线值比较下述发明实施例。获得的结果总结于表1中。
表1:
比较例2-Lactisole的甜度抑制(3mg剂量)
评估lactisole以量化其甜味抑制的持续时间进而确定其与匙羹藤酸组合的潜在价值。lactisole作为甜度阻断剂与匙羹藤酸不同,例如,由lactisole提供的甜度阻断在暴露至舌部后不萦绕(linger)。然而,意外的是,观察到口腔暴露至lactisole后,未观察到甜味抑制,即使在当lactisole咳出后立即品尝10%蔗糖参照时。
获得的结果总结于表2中。
表2
实施例1-匙羹藤酸(15mg)和Lactisole(3mg)共混物的甜度抑制
评估匙羹藤酸/lactisole共混物以量化其甜味抑制的持续时间。获得的结果总结于表3。
表3:
意外的是,当以匙羹藤酸/lactisole共混物处理口腔后立即品尝10%蔗糖参照样品时,观察到具有弱至中等强度的甜味且并非是无味的,正如以单独的匙羹藤酸实施预处理时一般。该初始甜度对于改善甜味抑制组合物的整体感知经历的显著有益的,并且使用匙羹藤酸或其他匙羹藤酸制剂是不可能的。此外,意外的是,观察到尽管lactisole本身在咳出后未引起甜度抑制,但是匙羹藤酸/lactisole共混物相对于使用单独的匙羹藤酸的甜味抑制的持续时间,引起的延长的甜味抑制持续时间。因此,尽管生化机制并不清楚,显而易见的是lactisole组合匙羹藤酸导致协同的甜味抑制效应,其中弱甜味在匙羹藤酸/lactisole预处理后最初的30分钟观察到。该效应对改善经配制以提供延长甜味封锁的甜味抑制产品的整体感官经历可以是有价值的。
比较例3-硫酸锌七水合物的甜味抑制(ZnSO
4
7H
2
O,107mg剂量)
评估ZnSO4.7H2O以量化其甜味抑制的持续时间进而确定其与匙羹藤酸组合的潜在价值。意外的是,观察到ZnSO47H2O,如匙羹藤酸般,的确引起了延长的甜味抑制期,尽管未接近使用匙羹藤酸的情况中的延长,这是由于60分钟后甜度敏感性100%恢复。获得的结果总结于表4。
表4
实施例2-匙羹藤酸(15mg)和ZnSO
4
7H
2
O(107mg)共混物的甜度抑制
随后评估了匙羹藤酸/ZnSO4.7H2O的共混物的甜味封锁持续时间。结果总结于表5。
表5:
意外的是,当单独使用匙羹藤酸时,在60分钟仍观察到甜味的完全封锁,尽管在该时间发生部分恢复。因此,尽管机制过程并不清楚,ZnSO47H2O与匙羹藤酸的组合清楚地具有协同甜味抑制效应。
比较例4-奇果甜素的甜度抑制(80mg剂量)
评估奇果甜素以量化其甜味抑制的持续时间进而确定其与匙羹藤酸组合的潜在价值。奇果甜素预处理口腔后,未观察到甜味抑制效应。获得的结果总结于表6.
表6:
实施例3-匙羹藤酸(15mg)和奇果甜素(80mg)共混物的甜度抑制
即使未观察到甜味抑制效应,仍评估了奇果甜素与匙羹藤酸的组合以确定是否观察到任何匙羹藤酸甜味抑制持续时间的延长。观察到奇果甜素的确延长了匙羹藤酸甜味封锁的持续时间。由此,奇果甜素与匙羹藤酸的组合导致对甜味的协同抑制效应。结果总结于表7。
表7:
实施例4-匙羹藤酸(15mg)、Lactisole(3mg)和ZnSO4.7H
2
O(107mg)共混物的甜度
抑制
如上文证明,lactisole和ZnSO47H2O,当与匙羹藤酸独立组合时,呈现甜度抑制的协同效应。评估包含这些甜味抑制剂与匙羹藤酸的组合的三元共混组合物以确定是否存在增加的协同效应。结果总结于表8中。
表8:
当将该三元共混物的甜味抑制结果与实施例1和2的结果进行比较时,显示未观察到增加的协同效应。然而,该三元共混物制剂明显的优势在于匙羹藤酸与lactisole和ZnSO47H2O的二元共混物中存在的协同效应保留,同时实现了对匙羹藤酸的苦异味的完全抑制。
当在液体组合物或锭剂或片剂的制剂中使用时,匙羹藤酸呈现弱至中度或甚至强烈的苦异味,这限制了其在经设计以帮助消费者控制其热量甜产品摄入的制剂中的有效使用。
比较例5-匙羹藤酸的苦味(15mg剂量)
评估了15mL RO水中15mg匙羹藤酸的溶液,并发现具有在苦味15分制上为10的苦味评分。
实施例5-匙羹藤酸(15mg)和ZnSO
4
7H
2
O(107mg)共混物的苦味
10mL RO水中15mg匙羹藤酸的溶液与5mL RO水中107mg ZnSO47H2O的溶液进行了组合和评估。发现了具有为0的苦味评分。在5mL RO水中分别包含60、34、19、10.7、6和3.4mg的ZnSO4 7H2O的水性溶液与在10mL RO水样品中的15mg匙羹藤酸进行了组合。获得的混合物分别呈现0、0、0、1、4和7的苦味强度。因此,当ZnSO4 7H2O浓度等于或大于约0.6mg/mL(2mM)时,这些匙羹藤酸/ZnSO4 7H2O组合物表现出不存在苦味。
应该强调的是本发明的上述实施方案仅为可能的实施实例,且仅为了清除理解本公开的原理而阐述。可对本公开上述的实施方案作出多种变化和修饰而基本上不脱离本公开的精髓和原理。本文全部的这些修饰和变化意在包括于本公开的范围内。
Claims (25)
1.一种组合物,其包含匙羹藤酸和至少一种形式的锌。
2.权利要求1的组合物,其中递送形式选自下组:锭剂、口腔崩解片、口腔分散片、含片、硬糖、软糖、胶冻剂、口嚼物、食用膜、口腔可溶解膜、薄片状物、滴剂、口腔喷雾剂、液体剂、粉剂,及其组合。
3.权利要求2的组合物,其中所述递送形式是崩解时间为约30秒至约5分钟的口腔崩解片。
4.权利要求1的组合物,其中所述形式的锌选自下组:乙酸锌、碳酸锌、氯化锌、柠檬酸锌、葡萄糖酸锌、硫酸锌、连二亚硫酸锌、亚硫酸氢锌、氧化锌、卤化锌、氢化锌、碳化锌,及其组合。
5.权利要求1的组合物,其中所述形式的锌是葡萄糖酸锌。
6.权利要求1的组合物,其中所述匙羹藤酸选自下组:匙羹藤酸的无机盐、匙羹藤酸的有机盐、匙羹藤酸的环糊精复合物、匙羹藤酸的穴状配体复合物、匙羹藤酸的水合物、匙羹藤酸的溶剂合物,及其组合。
7.权利要求5的组合物,其中所述匙羹藤酸的溶剂合物选自匙羹藤酸的多种乙醇溶剂合物,及其组合。
8.权利要求1的组合物,其中递送形式可进一步包含薄荷。
9.权利要求1的组合物,其中递送形式可进一步包含苦味抑制剂,所述苦味抑制剂选自下组:钠盐、脂蛋白及其组合。
10.权利要求1的组合物,其进一步包含至少一种酸味抑制剂。
11.权利要求8的组合物,其中所述至少一种酸味抑制剂为奇果甜素。
12.包含权利要求1的组合物的舌递送形式。
13.权利要求12的舌递送形式,其中所述递送形式选自下组:锭剂、口腔崩解片、口腔分散片、含片、硬糖、软糖、胶冻剂、口嚼物、食用膜、口腔可溶解膜、薄片状物、滴剂、口腔喷雾剂、液体剂、粉剂,及其组合。
14.权利要求13的舌递送形式,其中所述递送形式是崩解时间为约30秒至约5分钟的口腔崩解片。
15.权利要求12的舌递送形式,其中所述形式的锌选自下组:乙酸锌、碳酸锌、氯化锌、柠檬酸锌、葡萄糖酸锌、硫酸锌、连二亚硫酸锌、亚硫酸氢锌、氧化锌、卤化锌、氢化锌、碳化锌,及其组合。
16.权利要求12的组合物,其中所述形式的锌是葡萄糖酸锌。
17.权利要求12的组合物,其中所述匙羹藤酸选自下组:匙羹藤酸的无机盐、匙羹藤酸的有机盐、匙羹藤酸的环糊精复合物、匙羹藤酸的穴状配体复合物、匙羹藤酸的水合物、匙羹藤酸的溶剂合物,及其组合。
18.权利要求17的组合物,其中所述匙羹藤酸的溶剂合物选自匙羹藤酸的多种乙醇溶剂合物,及其组合。
19.权利要求12的组合物,其中所述递送形式可进一步包含薄荷。
20.权利要求12的组合物,其中所述递送形式可进一步包含苦味抑制剂,所述苦味抑制剂选自下组:钠盐、脂蛋白及其组合。
21.权利要求12的组合物,其进一步包含至少一种酸味抑制剂。
22.权利要求21的组合物,其中所述至少一种酸味抑制剂是奇果甜素。
23.减少糖摄取的方法,其包括将权利要求1的组合物施用至受试者。
24.减少卡路里摄入的方法,其包括将权利要求1的组合物施用至受试者。
25.减少龋齿的方法,其包括将权利要求1的组合物施用至受试者。
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US201462011096P | 2014-06-12 | 2014-06-12 | |
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US62/025,725 | 2014-07-17 | ||
PCT/US2015/035578 WO2015192015A2 (en) | 2014-06-12 | 2015-06-12 | Sweet taste receptor antagonist compositions |
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EP (1) | EP3154518A2 (zh) |
JP (1) | JP2017519046A (zh) |
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CN (1) | CN106659215A (zh) |
AU (1) | AU2015274362A1 (zh) |
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EP3644745A4 (en) | 2017-06-27 | 2021-04-21 | The Coca-Cola Company | ORAL SWEETENER COMPOSITIONS AND RELATED METHODS |
US11484542B2 (en) | 2018-05-30 | 2022-11-01 | Adam Slank | Specialized tongue spray containing gymnemic acid and exogenous ketones |
WO2020208630A1 (en) * | 2019-04-09 | 2020-10-15 | Gyni S.G Ltd | Sweetness blocker composition |
WO2023195718A1 (ko) * | 2022-04-04 | 2023-10-12 | 서울대학교산학협력단 | 감미 억제용 조성물 및 식품의 감미 억제 방법 |
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SG11201609600UA (en) | 2016-12-29 |
WO2015192015A3 (en) | 2016-02-04 |
IL249466A0 (en) | 2017-02-28 |
BR112016028973A2 (pt) | 2017-08-22 |
AU2015274362A1 (en) | 2016-12-08 |
US9421217B2 (en) | 2016-08-23 |
WO2015192015A2 (en) | 2015-12-17 |
CA2953243A1 (en) | 2015-12-17 |
US20170143793A1 (en) | 2017-05-25 |
US20150359809A1 (en) | 2015-12-17 |
US20190070254A1 (en) | 2019-03-07 |
US9585905B2 (en) | 2017-03-07 |
KR20170020859A (ko) | 2017-02-24 |
JP2017519046A (ja) | 2017-07-13 |
EP3154518A2 (en) | 2017-04-19 |
MA40227A (fr) | 2017-04-19 |
US20160303149A1 (en) | 2016-10-20 |
US20210030839A1 (en) | 2021-02-04 |
MX2016016214A (es) | 2017-08-02 |
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