CN100387255C - 啤酒花酸作为抗微生物剂的改良应用 - Google Patents

啤酒花酸作为抗微生物剂的改良应用 Download PDF

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CN100387255C
CN100387255C CNB038112086A CN03811208A CN100387255C CN 100387255 C CN100387255 C CN 100387255C CN B038112086 A CNB038112086 A CN B038112086A CN 03811208 A CN03811208 A CN 03811208A CN 100387255 C CN100387255 C CN 100387255C
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R·J·H·威尔森
R·J·史密斯
G·哈斯
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Abstract

使用溶解于丙二醇中的碱金属盐形式的β-酸来控制食物制品、工艺物料流和包括化妆品制剂的其它应用中的微生物生长。

Description

啤酒花酸作为抗微生物剂的改良应用
本申请要求US临时申请60/381,659(2002年5月17日提交)的优先权。
本发明涉及存在于丙二醇中的得自于啤酒花的β-酸萃取物用于控制细菌生长的用途。本发明在原料食品加工工业中具有控制细菌的特别的实用性，如糖加工和禽类加工工业中，并且在化妆品和药物中也具有应用性，当然也包括其它方面的用途。
啤酒花主要用于啤酒酿造中。已知得自于雌性啤酒花植物(Humuluslupulus L.)花的化合物可以赋予啤酒合意的苦味。这种苦味来源于所谓的α-酸，一种同系系列有机酸，其在啤酒用麦芽汁的煮沸过程中能够转化成非常苦的、异构化α-酸(异-α-酸)。啤酒花还含有类似系列的β-酸。这些物质具有非常低的水溶性，在酿造中具有很少的价值，并且通过以煮沸过程中形成的似蛋白质的“冷却残渣(trub)”形式沉淀而差不多完全从麦芽汁中除去。很多酿造者现在使用啤酒花的萃取物，它们比传统的干燥啤酒花方便并且更稳定。这种产品是通过将啤酒花用有机溶剂(差不多都只使用乙醇)萃取，或者更常用的是用液态或超临界态的二氧化碳萃取来制得的。这些萃取物中含有高含量的α-酸和β-酸，其余大部分由啤酒花油、蜡和未表征的树脂组成。一般来说，啤酒花萃取物的α-酸含量在35-65wt％范围内，β-酸含量在15-40％范围内。啤酒花加工公司很多年来也提供给酿造者更精制产品的选择，这些更精制的产品是从啤酒花萃取物中借助分级和化学转化来制备的，其中的很多可以在麦芽汁的发酵之后添加至酿造过程中的。这些产品包括纯化异-α-酸的水性制品及其化学还原衍生物，特别是四氢异-α-酸。在这些产品的制备过程中，啤酒花的加工者一般都会获得副产物级分，其主要含有β-酸和啤酒花油的混合物，加上一些次要组分，这些次要组分包括蜡和少量异-α-酸。这种级分，通常已知为“β-级分”“β芳香萃取物(Beta AromaExtract)”或“基础萃取物(Base Extract)”，经常出售给酿造者，用于添加至麦芽汁锅中，在其中啤酒花油组分赋予芳香风味。然而，还经常将油从β-酸中分离出来，使得能够将更有效的“芳香萃取物”提供给其它使用者并且释放β-酸。
除用于给啤酒赋予苦味和芳香风味外，啤酒花已知还在酿造过程中对控制细菌生长是有用的。据证明，啤酒花树脂酸(α-酸、β-酸、异-α-酸和化学还原的异-α-酸，如四氢异-α-酸)具有抗微生物活性并且特别对格兰氏阳性细菌具有活性。所以，有很多啤酒花树脂酸在食品加工、化妆品和药物应用中的使用的描述。β-酸通常被认为是特别有效的天然活性剂。在WO 00/52212中，提到“某些啤酒花酸在含糖的水性介质中显出抗细菌效果。例如，欧洲专利申请681029 A2公开了一种在蔗糖含水介质中抑制嗜热性微生物的方法，其中在50-80℃之间，将啤酒花基物质添加至蔗糖含水介质中。而且，US专利5,286,506公开了一种给固体食物制品涂敷含有β-酸的溶液以防止李斯忒氏菌属(Listeria)的方法。根据Arch.Mikrobiol.94(1973)，p.159-171，相比α-酸和异-α-酸，β-酸显出最高的抑菌效果；然而，由于其溶解性差，β-酸不能超过某些浓度”。啤酒花树脂酸，特别是β-酸，在US临时专利申请2002/0197366、US专利6,251,461和US专利6,475,537中被要求作为食品加工中的有效抗菌剂，并且近来显示其对水体系中的藻类生长(US专利6,379,720和PCT申请WO 02/078450)、原始动物(US专利6,352,726和US专利6,423,317)也具有有用的活性，并且被提出可作为抗母牛乳腺炎的活性剂，其中可以将啤酒花化合物施用给母牛的乳房和乳头(US专利申请2003/0013773)。US专利5,370,863中描述了可以在漱口水或牙膏中使用啤酒花酸，来抑制变异链球菌(Streptococcus mutans)的活性并且由此帮助防止龋齿。Simpson和Smith讨论了啤酒花酸起抗易感(格兰氏+ve)细菌作用的普遍性机理(Simpson，W.J.，和Smith，A.R.W.，1992，″Factors affecting antimicrobial activity of hopcompounds and their derivatives″.The Journal of AppliedBacteriology 72(4)：327-334)。
由于大部分农产品来自于农田，因而细菌污染在所难免。同样，新鲜肉的细菌污染也是难以避免的。
近来，甜菜糖工业开始使用几ppm量级的β-酸作为甜菜糖加工中细菌生长的控制剂。更具体说，糖工业使用β-酸的碱性水溶液作为糖用甜菜加工过程中的添加剂。然而，由于β-酸制品通常多少有些苦味(大部分情况可能是由于沾染了少量的高苦味的异-α-酸)，它们是以非常少的量使用的。WO 00/52212教导了可以制备约10wt％浓度的β-酸碱性水溶液，并且此形式的抗菌活性好于以乳液形式或溶解于有机溶剂中涂敷使用的同样量的β-酸。然而这种溶液的一个大的实际缺陷是它们在储藏期间趋于沉淀出蜡状或树脂状物质，这些物质可能淤塞管道和计量泵。溶液还必须保持不结冻，所以在寒冷季节中运输和储藏时还需要加热。然而，这种溶液是相对不稳定的。相反，我们发现，当β-酸以其碱金属盐的形式溶解于丙二醇中时，具有在宽温度范围内的化学和物理稳定性并且可以显著且有效的较高浓度制备。使用丙二醇作为很多有机物质的溶剂是公知的，并且它还可用作增溶异构化和化学还原的异构化α-酸的助剂。例如，Paul Todd，Jr.于US专利3,486,906中描述了制备以其游离酸形式溶解的异-α-酸。
本发明公开，某些啤酒花萃取物，即碱金属盐形式的β-酸，当溶解于丙二醇(1，1-丙二醇)时，是可溶性的和稳定的，并且因此作为用于处理各种各样食物制品的抗菌剂、作为水处理和在合适的药物和化妆品应用中的抗菌剂是特别有用的，包括添加至富含糖的液体加工物料流中，如在糖加工和蒸馏工业中存在的物料流。碱金属盐，其优选包括钠或钾盐，最方便地通过将β-酸与丙二醇共混，并且同时或随后添加浓缩的碱金属氢氧化物水溶液来制备，其中所说的β-酸是以其水不溶性的游离酸的形式制备的并且通过加热至大于约40℃、优选大约60℃液化。按此方式，可获得稳定的均相溶液，其仅含有少量的水(一般是约5％)。或者，制备这种溶液的方法(虽然有些不太令人满意)包括，将β-酸的碱金属盐(例如，通过US专利5,624,701的方法制备)直接溶解或将固体碱金属氢氧化物添加至β-酸和丙二醇的混合物中。
本发明的其它特点和优点将从以下结合附图1的详细描述中而看出，其中附图1显示了可在本发明中使用的存在于丙二醇中的β-酸的碱金属盐的生产过程。本发明使用了存在于丙二醇中的β-酸的碱金属盐。丙二醇具有甜味，可潜在性地协助遮蔽β-酸制品中的任何残余的苦味，而所说的残余的苦味是由于存在少量非常苦的异-α-酸而造成的。意想不到地，我们发现，β-酸的碱金属盐比游离酸本身更易溶于丙二醇中，并且也比它们在水中更易溶。它们还明显地稳定并且不产生任何沉淀，即使是在远低于0℃的储藏温度下。这些特点使得更浓、更稳定和更有效的溶液能够被制备、运输、储藏和使用，而这些是迄今未实现的。方便地，它们还与水是可溶混的，有助于在低浓度下容易投配。因此，丙二醇在其作为本发明β-酸的溶剂或载体的用途中是特别具有价值的。
本发明中使用的β-酸可以从有机溶剂萃取的啤酒花、液体CO2萃取的啤酒花或超临界CO2萃取的啤酒花中制备。优选的是通过液体CO2萃取啤酒花所获得的β-酸级分。啤酒花的β-酸萃取物中含有三种主要的同系物：合蛇麻酮、蛇麻酮和加蛇麻酮。据信所有这三种同系物作为抗菌剂是活性的。可以将存在于丙二醇中的β-酸喷洒在食料上，或者将食料浸入含有β-酸的溶液中，作为抗菌剂投配至加工物料流中或者作为成分添加至化妆品或药物制品的配方中。
一般来说，将β-酸以其碱金属盐的形式溶解于丙二醇中，以便提供含1-30％β-酸、优选约5-25％、最优选约20wt％β-酸的溶液。也可以制备某些其它啤酒花树脂酸的碱金属盐的有用的稳定溶液。丙二醇被认为是安全的，被广泛用作食物配料载体的GRAS(公认为安全的)物料，通常允许以不超过良好制作实践的量在食物中使用。在美国FDA条例下，它的具体允许量是在冷冻乳制品中最多2.5％，在含醇饮料中5％，在糖食中24％并且在调味品中97％。
本发明的一个特别的特点和优点在于丙二醇具有甜味，从而当在食品加工应用中使用时，可以预期其可部分地遮蔽β-酸制品的正常的轻微苦味。
以下实施例旨在举例说明，但不限制本发明的范围。
实施例1(生产存在于丙二醇中的钾盐形式的β-酸的过程)
本实施例举例说明存在于丙二醇中的β-酸的生产过程。
参看图1，将1.00kg作为异-α-酸制备副产物而获得的“β芳香萃取物”添加至3.365kg软化水中，搅拌并且加热至60℃。将浓的氢氧化钾(45wt％含水溶液)添加至搅拌的溶液中，直至pH达到约10.6，使得大多数β-酸溶解。在搅拌数分钟后，允许含油(有机)层和含水层分离。收集含有大部分β-酸的含水层并且添加50％(重量计)硫酸水溶液，直至pH达到约6.5，β-酸由此大部分从溶液中沉淀出来。搅拌几分钟之后，允许有机层和含水层分离。然后将含水层除去。最后，将热的、富含β-酸的流动有机相添加至计算量的丙二醇中，搅拌加入足够使β-酸转化成其钾盐形式的氢氧化钾水溶液(45％w/w)，同时将此混合物冷却至40℃，获得β-酸(20％w/w)在丙二醇中的溶液。本领域技术人员能够领会，通过改变初始的纯化阶段的条件或者通过在最后的配制阶段之前在工艺过程中增加进一步的水萃取和分离阶段，可以制作β-酸在丙二醇中更纯的制剂。这种额外的纯化在下一个实施例中应用于用作原料的β-酸树脂的生产中。
实施例2(生产存在于丙二醇中的钾盐形式的β-酸)
将46.35g β-酸(游离酸树脂形式制剂，含有71.7wt％β-酸，通过HPLC(使用ICE-2标准))和100.0g丙二醇(USP级)的混合物加温至60℃并且在玻璃烧杯中使用6cm直径叶轮以500rpm共混在一起。然后，添加8.5ml 45％(w/w)氢氧化钾溶液。所得的产物是含有19.9wt％β-酸(HPLC，ICE-2标准)的褐色、澄清、微粘的流体。将此样品的5g等分试样用10ml水稀释并且具有的pH为10.7。此样品当冷却至常温时保持半透明并且保持基本上均相流体，但相当粘，即使当在冷冻机中冷冻至约-15℃。
实施例3(制备存在于丙二醇中的15％β-酸(钠盐)的过程)
将33.2g游离酸形式的β-酸制剂(67.6％β-酸，通过HPLC，使用ICE-2标准)和71.9g丙二醇(USP级)加温至60℃并且搅拌，然后添加3.6ml 50％(w/w)氢氧化钠水溶液。在4g等分试样中加8g水具有的pH为11.1。此样品的等分试样当冷却至常温时胶凝化(gellified)。总共需要添加另外的33g丙二醇来防止冷却至常温时的凝胶形成。此样品由14.8％β-酸(HPLC，ICE-2标准)组成。将5g等分试样用10ml水稀释，具有的pH为10.8。
实施例4(比较存在于水中的10％β-酸与存在于丙二醇中的20％β- 酸的稳定性)
向193.6g“β芳香萃取物”(47.1％β-酸，通过HPLC，使用ICE-2标准)添加550ml去离子水。搅拌的同时，在60℃下，加入18.2ml 45％KOH，以便使pH达10.3。在放置在60℃烘箱中的分离用漏斗中使相分离1.5小时之后，除去下部的混浊含水相。在冷却至常温之后，将此含水相通过Whatman 1号纸过滤；滤液是半透明的并且由10.7％β-酸(w/w，通过HPLC)组成。允许此滤液在约3℃的冷藏器中放置过夜，并且通过用Whatman 1号纸第二次过滤，除去更多的沉淀。最后，将滤液用水稀释至10.1％ β-酸(HPLC，ICE-2标准)并且用少量45％KOH使pH达到11.1。将此溶液的等分试样常温下存放于PETG瓶中6个月。溶液中β-酸的浓度降低至9.0％并且在瓶子的底部有一层树脂。相比而言，常温下在PETG瓶中储藏一年后，实施例2的存在于丙二醇中的20％β-酸没有可看得见的树脂沉降出来并且β-酸浓度为20.2％(HPLC，ICE-2标准)，这说明β-酸的浓度没有明显的变化。本实施例表明，存在于丙二醇中的β-酸的20％溶液具有优异的稳定性，由此完全消除了10％β-酸水溶液中随时间出现的β-酸和其它蜡质物质的不期望的沉淀。
实施例5(存在于丙二醇中的β-酸的热稳定性)
将来自实施例2的20％β-酸(钾盐)溶液产品的样品放入玻璃小瓶中并且在60℃下储藏4周，然后通过HPLC检验和重新分析。发现，该溶液中没有出现沉淀并且β-酸含量保持在19.9％未变化，说明钾盐形式的β-酸溶液在试验期间是稳定的。
实施例6(存在于丙二醇中的钾盐形式的β-酸的抗细菌活性)
将实施例2的20％β-酸产品溶液的等分试样稀释至水中，达到当添加至接种胰酶解酪蛋白豆汁培养液时测定细菌生长最小抑制量所必需的浓度。分两个独立的实验对以下Gm阳性细菌测试表1和2中所示浓度的样品：枯草芽孢杆菌(Bacillus subtilis)，巨大芽孢杆菌(Bacillus megaterium)，腐生葡萄球菌(Staphylococcussaprophyticus)和唾液葡萄球菌(Streptococcus salivarius)。可以看出，在10-100μg/mL下达到了完全抑制，取决于特定的微生物。
表1存在于丙二醇中的钾盐形式β-酸的抗细菌潜力的实验测试
Figure C0381120800091
++++＝无抑制
表2存在于丙二醇中的钾盐形式β-酸的抗细菌潜力的第二次实验测试
Figure C0381120800092
++++＝无抑制
实施例7
将实施例2的20％β-酸产品溶液的等分试样添加至软膏中，其加入量为2mg/g软膏，表示添加400ppm β-酸。在研钵中将成分完全共混之后，在扩散试验中如下测定对枯草芽孢杆菌(Bacillus subtilis)的抑制活性。
将接种密度为大约1×108CFU/m l(菌落形成单位/mL)的细菌悬浮液于46℃下添加至10mL熔融胰酶解酪蛋白豆汁琼脂中。在接种测试用微生物后，将琼脂完全混合，然后倾入塑料培养皿中。待琼脂硬化后，使用木塞钻孔器(7mm直径)做孔。然而给每个孔填充基料软膏(对照)或含有添加的β-酸的软膏。
制备一式两份的平板，并且将两个平皿在37℃下保温培养24小时，在这段时间内细菌在琼脂的表面长出均匀的菌苔，只是在含有测试软膏的孔周围可看到透明区域。测定抑制区的半径，精确至0.1cm，并且每次抑制区经测定为0.2cm，这表明少量β-酸以其存在于丙二醇中的钾盐溶液形式添加至测试软膏中所产生的效力。
虽然本发明通过实施例的方式和针对优选的实施方案进行了描述，但应当理解的是本发明不限于所公开的实施方案。相反，本发明意图覆盖对本领域技术人员而言显而易见的各种改进和类似方案。因此，所附的权利要求书的范围应当按最宽的含义去解释，以便包括所有的改进和类似方案。

Claims (13)

1.一种得自于啤酒花的β-酸的溶液的制备方法，其中所说的β-酸的溶液适宜用于防止或抑制细菌的生长，所说的方法包括以下步骤：
(a)将β-酸和丙二醇的混合物加热；
(b)同时或随后向加热的混合物中添加碱金属氢氧化物的浓缩水溶液，以便足以获得用水3x稀释后pH为至少约9.0的均相溶液，和
(c)将所得的混合物冷却。
2.权利要求1的方法，其中碱金属是钾或钠。
3.一种抑制细菌或其它微生物生长的方法，包括将含有在丙二醇中的β-酸的碱金属盐的溶液施用于固体或液体介质中或工艺物流中。
4.权利要求3的方法，其中β-酸的溶液是以纯形式或以含水稀释液的形式施用。
5.权利要求4的方法，其中β-酸的溶液是通过将固体食物制品浸入含在丙二醇中的β-酸的碱金属盐的溶液中来施用的。
6.权利要求4的方法，其中β-酸的溶液是通过用含在丙二醇中的β-酸的碱金属盐的溶液喷洒固体食物制品来施用的。
7.化妆品或药物霜膏或软膏，其含有足以防止或延缓细菌生长量的在丙二醇中的β-酸的碱金属盐的溶液。
8.药物制剂，其含有足以防止或延缓细菌生长量的在丙二醇中的β-酸的碱金属盐的溶液。
9.权利要求1的方法，其中β-酸的溶液中含有约1-30wt％的β-酸。
10.权利要求1的方法，其中β-酸的溶液中含有约5-25wt％的β-酸。
11.权利要求1的方法，其中β-酸的溶液中含有约20wt％的β-酸。
12.一种按权利要求1的方法制备的在丙二醇中的得自于啤酒花的β-酸的碱金属盐的溶液，其中β-酸的浓度超过10wt％。
13.权利要求12的溶液，其中水含量低于约7％。
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EP1505998B1 (en) 2014-07-09
CN1652809A (zh) 2005-08-10
US7910140B2 (en) 2011-03-22
BR0309918A (pt) 2005-02-09
WO2003097079A1 (en) 2003-11-27
BRPI0309918B1 (pt) 2015-07-28
DK1505998T3 (da) 2014-10-06
AU2003270103A1 (en) 2003-12-02
US20080113048A1 (en) 2008-05-15
EP1505998A4 (en) 2009-06-10
AU2003270103B2 (en) 2007-01-25
EP1505998A1 (en) 2005-02-16
NZ536090A (en) 2007-06-29
BRPI0309918B8 (pt) 2022-11-22

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