CN1860236A - 1,4-二羟基-2-萘甲酸的制造方法 - Google Patents
1,4-二羟基-2-萘甲酸的制造方法 Download PDFInfo
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- CN1860236A CN1860236A CNA2004800284544A CN200480028454A CN1860236A CN 1860236 A CN1860236 A CN 1860236A CN A2004800284544 A CNA2004800284544 A CN A2004800284544A CN 200480028454 A CN200480028454 A CN 200480028454A CN 1860236 A CN1860236 A CN 1860236A
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- naphthoic acid
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Abstract
1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧条件下开始培养,在培养基中的碳源浓度达到3.5质量%以下时,向培养基中进行空气通气来培养。
Description
技术领域
本发明涉及使用丙酸菌发酵的1,4-二羟基-2-萘甲酸(以下也称DHNA)的高浓度制造方法及其培养物的味道改善技术。
背景技术
已知DHNA以往作为染料、颜料和感光材料用作工业材料,至今通过有机化学合成法开发了各种合成法。本发明者对与它们不同的DHNA的制造方法进行研究后,发现丙酸菌在菌体内外大量产生DHNA,同时发现从该培养物采集的含DHNA的组合物、或者1,4-二羟基-2-萘甲酸或其盐具有改善乳糖不耐症患者摄入牛奶时的腹部不适症状的作用,可以用于代谢性骨疾病的预防治疗(专利文献1)。采用该方法,可以将DHNA用于饮食品和医药品,但是含DHNA的组合物从味道的角度看未必令人满意,难以用于众多商品。
专利文献1:国际公开第WO 03/016544号小册子
发明的揭示
发明要解决的课题
本发明的目的在于提供基于丙酸菌发酵的、味道得到改善的含DHNA的组合物的高效的制造方法。
解决课题的方法
本发明者为了得到抑制了苦味的含DHNA的组合物从各方面进行了认真研究后,完全意外地获得了有用的新发现,即通过在丙酸菌发酵的一定的时期进行培养基的空气通气,培养物中的DHNA浓度升高。此外,通过在培养后的培养物中添加丙酸菌的碳源,在弱碱性条件下进行低温保存,虽然培养结束了,但DHNA浓度升高。另外,还发现由此得到的含DHNA的组合物的苦味受到抑制,味道良好,可以用于饮食品和医药品。
即,本发明提供1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧的条件下开始培养,培养基中的碳源浓度达到3.5质量%以下时,向培养基内进行空气通气来培养。
此外,本发明提供1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧的条件下进行培养,向得到的培养物中添加碳源,在弱碱性下于3~20℃进行保存。
本发明提供1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧的条件下开始培养,培养基中的碳源浓度达到3.5质量%以下时,向培养基内进行空气通气来培养,再向得到的培养物中添加碳源,在弱碱性下于3~20℃进行保存。
此外,本发明提供含有通过上述制造方法得到的1,4-二羟基-2-萘甲酸的组合物。
此外,本发明提供作为有效成分含有通过上述制造方法得到的1,4-二羟基-2-萘甲酸的组合物的腹部不适症状改善用饮食品、腹部不适症状改善剂、代谢性骨疾病预防治疗用饮食品或代谢性骨疾病预防治疗剂。
此外,本发明提供含有通过上述制造方法得到的1,4-二羟基-2-萘甲酸的组合物在腹部不适症状改善用饮食品、腹部不适症状改善剂、代谢性骨疾病预防治疗用饮食品或代谢性骨疾病预防治疗剂的制造中的应用。
另外,本发明提供腹部不适症状的处置方法或代谢性骨疾病的处置方法,其特征在于,给予有效量的含有通过上述制造方法得到的1,4-二羟基-2-萘甲酸的组合物。
发明的效果
若采用本发明,则可以高效地生产DHNA,而且得到的含DHNA的组合物的味道良好,可以用于饮食品、医药品。
附图的简单说明
[图1]表示改变切换到空气通气的时间的情况下的DHNA浓度的变化。
[图2]表示改变切换到空气通气的时间的情况下的乳糖浓度的变化。
[图3]表示切换到空气通气的时间和丙酸菌数量的变化。
[图4]表示改变切换到空气通气的时间的情况下的丙酸浓度的变化。
[图5]表示改变切换到空气通气的时间的情况下的醋酸浓度的变化。
[图6]表示改变空气通气的流量的情况下的DHNA浓度。
实施发明的最佳方式
本发明的制造方法中所使用的丙酸菌只要是DHNA产生菌,没有特别限定,较好是属于丙酸杆菌属的菌,可以例举例如费氏丙酸杆菌(Propionibacteriumfreudenreichii)、特氏丙酸杆菌(P.thoenii)、产丙酸丙酸杆菌(P.acidipropionici)、詹氏丙酸杆菌(P.jensenii)等干酪用菌,贪婪丙酸杆菌(P.avidum)、疮疱丙酸杆菌(P.acnes)、嗜淋巴丙酸杆菌(P.lymphophilum)、颗粒丙酸杆菌(P.granulosam)等。其中,较好是费氏丙酸杆菌,更好是P.freudenreichii IFO 12424和P.freudenreichii ATCC 6207、P.freudenreichii ET-3(FERM P-18454)。
本发明所使用的培养基较好是含有碳源的培养基,本发明中的碳源是指丙酸菌可利用的碳源。可以例举例如乳糖、葡萄糖、乳酸、甘油、麸质、纤维素等,特别好是乳糖。培养开始前的培养基中的碳源含量较好是4~8质量%,更好是4~7质量%,特别好是4~6.7质量%。其中,作为碳源含有乳糖的培养基可以例举乳清粉、酪蛋白、脱脂奶粉、或者将乳清进行透析处理而使乳糖含量减少的乳清蛋白浓缩物、或者更高纯度地分离乳糖的乳清蛋白分离物。它们可以直接使用,或者进行蛋白酶处理后使用,可以通过添加以下成分来制备培养基:酵母提取物、胰蛋白胨等蛋白胨,葡萄糖、乳糖、乳糖的乳糖酶处理物等可以作为丙酸菌利用的碳源的单糖类和/或双糖类等适量的糖类,乳酸、甘油、麸质、纤维素、乳清矿物等矿物成分,以及根据需要添加的牡蛎、生姜等含有大量矿物成分的动植物性食品或其提取物。以下,例举培养基原料中以脱脂奶粉的蛋白酶处理物为主要成分的培养基制备方法的一个例子。
将脱脂奶粉用水溶解,使其浓度达到10~20质量%,将温度调整至47℃。向其中以脱脂奶粉量的2.5质量%添加蛋白酶,分解脱脂奶粉溶液中的蛋白质。蛋白酶可以例举动植物来源或细菌来源的蛋白质分解酶,酸性、中性、碱性都可以使用。分解进行6小时,分解中的温度调整至47℃,pH调整至6.8。pH的调整可以使用碳酸钾水溶液。利用蛋白酶的分解结束后,通过将脱脂奶粉溶液加温至80℃,保持10分钟,使蛋白酶失活。失活后,用水使脱脂奶粉的质量浓度达到10%并混匀,添加脱脂奶粉的1~10质量%、较好是3~7质量%的啤酒酵母提取物后,进行灭菌。灭菌条件在使用高压灭菌锅的情况下设为121℃下、7分钟以上,使用灭菌加热板的情况下设为140℃以上、4秒以上。这样得到的培养基中通常含有4~5质量%的乳糖。
培养在厌氧条件下进行。厌氧条件可以是例如氮气、氦气、氩气、氢气等惰性气体中的一种或两种以上的组合,其中较好是氮气或二氧化碳气氛下的条件。更具体来说,在发酵罐中使氮气、二氧化碳等在上方通气,进行搅拌,将培养基温度调整为33℃。培养基温度稳定在33℃后,接种丙酸菌起子,在厌氧条件下开始培养。起子可以使用丙酸菌的活化培养液或培养液的菌体浓缩物等。向培养基的添加量的标准在前者的情况下为相对于培养基0.05%、在后者的情况下为0.3%左右,这些量可以根据需要适当地改变。
在培养温度为20~40℃、培养基的pH为中性~微酸性(较好是pH5.5~7.5)的条件下进行培养。为了抑制培养中的酸度上升,可以使用碳酸钾水溶液、碳酸钠水溶液等已知作为中和剂的公知的试剂。
接着,对向培养基空气通气的方法进行说明。通过该方法DHNA生产量的增大是令人吃惊的。对于通过连续地进行空气通气使DHNA的生产量增大的原因并不清楚,但由于该空气通气,丙酸菌开始消耗丙酸。
开始空气通气的时间为培养基中的碳源浓度达到3.5质量%以下时,标准之一是丙酸菌的碳源枯竭的24小时前。空气通气开始的时间更好是碳源浓度达到1.0~3.5质量%时,特别好是达到1.5~3.0质量%时。通过在碳源浓度达到3.5质量%以下时进行空气通气,丙酸菌除了碳源之外开始消耗丙酸,最终碳源基本枯竭。空气通气开始时的培养基中的丙酸菌数量较好是在1.0×1010cfu/mL(10.0log cfu/mL)以上,更好是1.4×1010cfu/mL(10.1log cfu/mL)以上。由此,可以使培养基中的碳源基本枯竭。在前述的含乳糖的培养基和培养条件下,培养开始后约48小时后,乳糖浓度达到3.5质量%以下,成为空气通气开始的时间。已知在中途添加乳糖、葡萄糖之类成为丙酸菌的碳源的糖类的培养方法(例如专利文献1,日本专利特开平10-304871号公报),但本发明中最好是不在中途添加这些糖类而使碳源枯竭。
通过空气通气的空气的供给量较好是对于丙酸菌产生刺激的程度的量。若作为与该条件相当的一个例子例举实验室规模(1.5L容量)下的具体例子,则在使用分布器以搅拌机叶轮150rpm的条件下进行培养的情况下,空气的供给量为2L以上/分,更好是2L/分~4L/分,可以根据容量、搅拌速度、装置等进行适当调整。液中的溶解氧量超过所需时,丙酸菌的繁殖停止,DHNA的产生也停止。在前述的培养基和培养条件的情况下,通常在自培养开始约168小时终止培养。
空气通气的方法可以例举在培养基中插入多孔性的通气管由整个管输送空气的方法,和用分布器输送气泡的方法。
由此,积聚在培养基和菌体中的DHNA在停止培养后马上可以由该培养物供于DHNA的采集。此外,培养的终点的标准为菌数达到稳定期,自培养基中的碳源枯竭后3~5天。
接着,对在培养结束后的培养物中添加丙酸菌的碳源、在弱碱性下于3~20℃保存来制造DHNA的方法进行说明。在这里,培养物可以是前述的空气通气后的培养物,也可以是没有经过空气通气的厌氧或微好氧条件下的培养结束后的培养物。
设定向培养物添加的碳源量,使培养物中的碳源浓度较好是达到0.2~3.0质量%、更好是0.4~2.5质量%、特别好是0.8~2.2质量%。此外,为了使其达到弱碱性,较好是添加碳酸钾、碳酸钠、磷酸钠等碱,使培养物的pH达到7~9,特别好是7.5~8.5。此外,保存温度较好是3~20℃,特别好是3~15℃,更好是5~15℃。保存时间较好是1~3周,特别好是1~2周。
通过这样的弱碱性下的低温保存,培养物中的DHNA含量上升。因此,不需要新的设备、节省空间、而且保存中可以增大DHNA量的本方法可以说是非常有用且高效的制造方法。
接着,对DHNA的采集方法进行说明。较好是对得到的培养物使用吸附色谱法。吸附剂可以在较广的范围内使用活性炭或合成吸附剂(例如ダイアイオンHP-20,三菱化学株式会社制)等反相类的吸附剂。首先,将吸附剂填充到柱中,用0.5%(w/v)抗坏血酸钠水溶液洗涤。接着,将得到的培养物添加到柱中(弃取通过液),再用0.5%(w/v)抗坏血酸钠水溶液除去水溶性部分。然后,用添加了0.5%(w/v)抗坏血酸钠的乙醇洗脱,通过浓缩该乙醇洗脱部分,可以得到含有高浓度DHNA的组合物。再进行纯化,可以得到纯净的DHNA或它的盐。从柱中出来的DHNA的洗脱液可以使用甲醇等其它醇代替乙醇。此外,作为替代它的方法,也可以从离心分离培养物回收的上清液,使用液相色谱法分离DHNA。使用异抗坏血酸钠代替抗坏血酸钠也是可以的,它们被用作DHNA的稳定剂,本发明中,除了抗坏血酸、异抗坏血酸这些游离的酸之外,还可以同样地使用脂肪酸酯及其它各种酯类、碱金属盐、其它盐类。
DHNA的盐可以例举药学上或食品学上允许的盐,代表性的盐可以例举钠、钾、锂等的一价金属盐,镁、钙、锌等的多价金属盐,氨、乙醇胺等的无机或有机胺盐等。此外,也可以通过使用本身公知的反应进行盐置换。该盐可以使用与无机酸(例如盐酸、磷酸、氢溴酸、硫酸)的盐、或与有机酸(例如甲酸、丙酸、富马酸、马来酸、琥珀酸、酒石酸、柠檬酸、苹果酸、草酸、安息香酸、甲磺酸、苯磺酸)的盐等,但这些是示例,本发明并不局限于这些盐。
由于DHNA包含在DHNA产生菌的培养物中(菌体内和/或外),所以可以不使用吸附色谱法,而对培养物本身通过使用旋转式汽化机等进行浓缩,从而得到含有高浓度DHNA的组合物。此外,可以浓缩通过通常的离心分离法从培养物分离菌体而得到上清。这样得到的组合物根据使用的方式可以直接使用,也可以加工成粉末状。
这样得到的含DHNA的组合物的DHNA浓度高,苦味受到抑制,味道良好。因此,本发明的含DHNA的组合物或者DHNA或其盐以饮食用或医药品的方式都可以使用,例如通过作为医药品直接给药,或者通过作为特定保健用食品等特别用途食品、营养功能食品直接摄入,再或者通过预先添加在各种食品(牛奶、清凉饮料、发酵乳、酸奶、干酪、面包、饼干、脆点心、匹萨饼等)中并摄入,可以改善肠道菌群,缓解摄入牛奶时出现的腹部不适症状,预防治疗代谢性骨疾病。
为了制造前述食品,作为主要成分可以组合水和蛋白质、糖类、脂质、维生素及矿物质类、有机酸、果汁、调味品类等。可以例举全脂奶粉、脱脂奶粉、部分脱脂奶粉、酪蛋白、乳清粉、乳清蛋白、乳清蛋白浓缩物、乳清蛋白分离物、α-酪蛋白、β-酪蛋白、β-乳球蛋白、α-乳白蛋白、乳吩咛、大豆蛋白、鸡蛋蛋白、肉蛋白等动植物性蛋白质,它们的水解产物,黄油,乳清矿物,奶油,乳清,非蛋白质状态的氮,唾液酸,磷脂、乳糖等各种乳来源成分;蔗糖、葡萄糖、果糖、糖醇类、麦芽糖、寡糖类、化工淀粉(除糊精之外,可溶性淀粉、英国淀粉、氧化淀粉、淀粉酯、淀粉醚等)、食物纤维等碳水化合物;猪油、鱼油等动物性油脂;棕榈油、红花油、玉米油、菜油、椰子油等植物性油脂,它们的分选油、加水油、酯交换油等植物性油脂;维生素A、维生素B族、维生素C、异抗坏血酸、维生素D族、维生素E、维生素K族、维生素P、维生素Q、维生素PP、烟酸、泛酸、生物素、肌醇、胆碱、叶酸等各种维生素;钙、钾、镁、钠、氯、铜、铁、锰、锌、硒、氟、硅、碘等矿物质;苹果酸、柠檬酸、乳酸、酒石酸等有机酸或有机酸盐等。可以从它们中适当选择一种或两种以上进行添加。上述各种成分除了合成品,根据需要添加大量含有它们的食品也是理想的。此外,其形态并不局限于前述食品,只要到最终制品都维持活性,没有特别限定,可以是液状、固体状(包括颗粒、粉末、片状、凝胶状)、半固体状(包括冻胶状)、糊状、乳化状等任意形态。
将本发明所述组合物、或者DHNA或其盐作为医药品使用的情况下,可以以各种形态给药。其形态可以是通过例如片剂、胶囊剂、颗粒剂、散剂、糖浆剂等口服给药。上述各种制剂可以按照常规方法在主剂中使用赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、除臭剂、溶解助剂、悬浊剂、包覆剂等医药制剂技术领域中通常可使用的已知的助剂来进行制剂化。
实施例
以下,例举试验例、实施例,对本发明进行说明,但本发明并不局限于这些实施例。以下的试验例和实施例中,DHNA的定量按照WO 03/016544第9页所记载的方法进行。乳糖浓度的测定通过使用乳糖电极的流式注射(flowinjection)分析法(使用王子计测机器株式会社制,流式注射分析装置,BioFlow Analyzer(商品名))进行。丙酸菌数量的测定用BL琼脂培养基进行。丙酸、醋酸浓度用HPLC法(柱:RS pak KC-811+前柱KC-G,检测:445nm)进行测定。
[试验例1]空气通气切换时间的讨论
(1)培养基的制备
将150g脱脂奶粉(明治乳业株式会社制)溶解于1000g水中,将温度调整至47℃。向其中添加3.75g蛋白酶,在47℃下进行6小时蛋白质的分解。蛋白质分解中的pH用碳酸钾溶液调整至6.6~6.8。蛋白质分解后,通过加温至80℃,保持10分钟,使蛋白酶失活,添加7.5g啤酒酵母提取物,用碳酸钾溶液将pH调整至6.95。用水将溶液的容量调整至1500mL,放入2L容量的发酵罐中,进行培养基灭菌。灭菌条件为121℃、7分钟。
(2)培养条件
在发酵罐中用氮气通气,使培养基温度稳定在33℃,添加0.75mL冻结浓缩起子(P.freudenreichii ET-3),开始培养。发酵中的温度调整至33℃,pH调整至6.5,用氮气通气。pH的调整使用40%(wt/wt)的碳酸钾水溶液。培养方法实施以下的5种。
1)自培养开始到结束持续氮气通气;
2)除了自培养开始72小时后、96小时后添加培养液的2%重量的乳糖之外,与1)同样;
3)自培养开始24小时后,从氮气通气切换到空气通气(2L/分);
4)自培养开始48小时后,切换到空气通气(2L/分);
5)自培养开始72小时后,切换到空气通气(2L/分);
它们全都在培养开始168小时后结束培养。
(3)结果
DHNA浓度、乳糖浓度、丙酸菌数量、丙酸浓度、醋酸浓度的经时变化分别如图1、图2、图3、图4、图5所示。由该结果可知,通过4)、5)得到的培养物中,DHNA的浓度达到约45μg/mL(图1)。此外,还发现4)、5)中,96小时后乳糖基本枯竭(图2),自培养开始持续增加的丙酸浓度缓慢减少(图4)。丙酸菌数量,除了3),培养结束时都超过了1.0×1010cfu/mL(10.0log cuf/mL),4)、5)达到了约1.0×1011cfu/mL(11.0 log cuf/mL)(图3)。
由上可知,通过自培养开始至少48小时后从氮气通气切换到空气通气,可以得到含有高浓度DHNA的培养物(图6)。此外,切换时的乳糖浓度,4)为3.3质量%,5)为2.9质量%(图2)。
[试验例2]空气通气量的讨论
除了改变空气通气量之外,以与试验例1的5)同样的条件进行培养。自发酵开始72小时后,将空气通气的流量改变为0.5L/分、1.0L/分、2.0L/分、4.0L/分,进行培养。其结果,通过将流量定为2.0L/分以上,自培养开始144小时后,DHNA浓度达到约40μg/mL。
[实施例1]
将180g脱脂奶粉(明治乳业株式会社制)溶解于1000g水中,将温度调整至47℃。向其中添加3.75g蛋白酶,在47℃下进行3小时蛋白质的分解。蛋白质分解中的pH用碳酸钾溶液调整至6.6~6.8。蛋白质分解后,通过加温至80℃,保持10分钟,使蛋白酶失活,添加7.5g啤酒酵母提取物、15g乳糖,用碳酸钾溶液将pH调整至6.95。用水将溶液的容量调整至1500mL,放入2L容量的发酵罐中,进行培养基灭菌(乳糖浓度约6.1质量%)。灭菌条件设为121℃、7分钟。灭菌后,在发酵罐中用氮气通气,使培养基温度稳定在33℃,添加0.75mL冻结浓缩起子(P.freudenreichii ET-3),开始培养。发酵中的温度调整至33℃,pH调整至6.5,用氮气通气。pH的调整使用40%(wt/wt)的碳酸钾水溶液。自培养开始72小时后,从氮气的通气切换到空气通气,自培养开始168小时后结束培养。空气通气时的空气流量设为2L/分,搅拌速度设为150rpm。其结果,得到了DHNA的浓度达到52μg/mL的培养物。72小时后的乳糖浓度为约1.9质量%,丙酸菌数量为3.5×1010cfu/mL。
[实施例2]
将120kg脱脂奶粉(明治乳业株式会社制)溶解于750kg水中,将温度调整至47℃。向其中添加2.5kg蛋白酶,将pH调整至7.6,在47℃下进行3小时蛋白质的分解。分解结束后,通过加温至80℃,保持10分钟,使蛋白酶失活,添加5kg啤酒酵母提取物、10kg乳糖,以140℃、4秒进行培养基灭菌。灭菌开始前的培养基pH为6.9。灭菌后,用水将培养基量调整至1000L(乳糖浓度约6.1质量%),在发酵罐中用氮气以20L/分通气,使培养基温度稳定在33℃,添加3.0L起子(P.freudenreichii ET-3)。发酵中的温度调整至33℃,pH调整至6.5,用氮气通气。pH的调整使用23%(wt/wt)的碳酸钾水溶液。自培养开始72小时后,从氮气的通气切换到空气通气,自培养开始168小时后结束培养。空气通气时的空气流量设为200L/分,搅拌速度设为52rpm。其结果,得到了DHNA的浓度达到42μg/mL的培养物。培养开始72小时后的乳糖浓度为约1.5质量%,丙酸菌数量为3.0×1010cfu/mL。
[实施例3]
向前述实施例2得到的含DHNA的培养物中添加1.0%抗坏血酸钠、2.0%乳糖,将pH调整至8.0后,在10℃下保存2周,结果DHNA浓度达到了55μg/mL。
此外,将乳糖换成葡萄糖,同样地进行保存后,DHNA浓度比培养结束时有所增加。
[比较例]
除了培养中,不切换到空气通气,持续氮气通气之外,以与实施例1全部相同的条件进行操作。其结果,得到了DHNA的浓度为32μg/mL的培养物。
[实施例4]
将前述实施例1得到的含DHNA的培养物加入到120g的纯酸乳酪(明治乳业株式会社制)中,制备的酸奶的感官评价如表1和表2所示。加入了通过本发明方法得到的含DHNA的培养物的酸奶的DHNA浓度高,与以往的方法(纯酸乳酪中加入比较例得到的含DHNA的培养物的酸奶),没有酸味,苦味也感觉不到。
[表1]
项目 | 味道 | 酸味 | 苦味 | 综合评价 |
实施例1中制备的培养物 | ○ | ○ | - | ◎ |
比较例中制备的培养物 | ○ | ○ | × | △ |
×:不好 △:稍差 ○:普通 ◎:优良 -:没感觉
在纯酸乳酪中添加1g
纯酸乳酪:120g
[表2]
项目 | 味道 | 酸味 | 苦味 | 综合评价 |
实施例1中制备的培养物 | △ | ○ | - | ○ |
比较例中制备的培养物 | △ | △ | × | × |
×:不好 △:稍差 ○:普通 ◎:优良 -:没感觉
在纯酸乳酪中添加2g
纯酸乳酪:120g
[实施例5]
将120kg脱脂奶粉(明治乳业株式会社制)溶解于750kg水中,将温度调整至47℃。向其中添加2.5kg蛋白酶,将pH调整至7.6,在47℃下进行6小时蛋白质的分解。分解结束后,通过加温至80℃,保持10分钟,使蛋白酶失活,添加5kg啤酒酵母提取物、10kg乳糖,以140℃、4秒进行培养基灭菌。灭菌开始前的培养基pH为6.9。灭菌后,用水将培养基量调整至1000L(乳糖浓度约6.1质量%),在发酵罐中用氮气以20L/分通气,使培养基温度稳定在33℃,添加3.0L起子(P.freudenreichii ET-3)。培养中的温度调整至33℃,pH调整至6.5,用氮气通气。pH的调整使用23%(wt/wt)的碳酸钾水溶液。自培养开始72小时后,从氮气的通气切换到空气通气,自培养开始168小时后结束培养。空气通气时的空气流量设为200L/分,搅拌速度设为52rpm。其结果,得到了DHNA的浓度达到48μg/mL的培养物。培养开始72小时后的乳糖浓度为约3.0质量%,丙酸菌数量为2.9×1010cfu/mL。
[实施例6]
向前述实施例5得到的含DHNA的培养物中添加1.0%抗坏血酸钠、1.0%乳糖,将pH调整至8.0后,在10℃下保存2周,结果DHNA浓度达到了60μg/mL。
Claims (22)
1.1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧的条件下开始培养,在培养基中的碳源浓度达到3.5质量%以下时,向培养基内进行空气通气来培养。
2.如权利要求1所述的制造方法,其特征还在于,培养基是含有4~8质量%碳源的培养基。
3.如权利要求1或2所述的制造方法,其特征还在于,厌氧条件为氮气或二氧化碳气氛下的条件。
4.1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧的条件下进行培养,向得到的培养物中添加碳源,在弱碱性下于3~20℃进行保存。
5.如权利要求4所述的制造方法,其特征还在于,培养物中的碳源添加量为使培养物中的碳源浓度达到0.2~3质量%的量。
6.如权利要求4或5所述的制造方法,其特征还在于,保存为将培养物的pH设为7~9,在3~20℃下保存1周~3周。
7.1,4-二羟基-2-萘甲酸的制造方法,其特征在于,对属于丙酸菌的1,4-二羟基-2-萘甲酸生产菌在厌氧的条件下开始培养,在培养基中的碳源浓度达到3.5质量%以下时,向培养基内进行空气通气来培养,再向得到的培养物中添加碳源,在弱碱性下于3~20℃进行保存。
8.如权利要求7所述的制造方法,其特征还在于,培养基是含有4~8质量%碳源的培养基。
9.如权利要求7或8所述的制造方法,其特征还在于,厌氧条件为氮气或二氧化碳气氛下的条件。
10.如权利要求7~9中的任一项所述的制造方法,其特征还在于,培养物中的碳源添加量为使培养物中的碳源浓度达到0.2~3质量%的量。
11.如权利要求7~9中的任一项所述的制造方法,其特征还在于,保存为将培养物的pH设为7~9,在3~20℃下保存1周~3周。
12.含1,4-二羟基-2-萘甲酸的组合物,其特征在于,所述1,4-二羟基-2-萘甲酸通过权利要求1~11中的任一项所述的制造方法得到。
13.腹部不适症状改善用饮食品,其特征在于,作为有效成分含有权利要求12所述的组合物。
14.腹部不适症状改善剂,其特征在于,作为有效成分含有权利要求12所述的组合物。
15.代谢性骨疾病的预防治疗用饮食品,其特征在于,作为有效成分含有权利要求12所述的组合物。
16.代谢性骨疾病预防治疗剂,其特征在于,作为有效成分含有权利要求12所述的组合物。
17.权利要求12所述的组合物在腹部不适症状改善用饮食品的制造中的应用。
18.权利要求12所述的组合物在腹部不适症状改善剂的制造中的应用。
19.权利要求12所述的组合物在代谢性骨疾病的预防治疗用饮食品的制造中的应用。
20.权利要求12所述的组合物在代谢性骨疾病预防治疗剂的制造中的应用。
21.腹部不适症状的处置方法,其特征在于,给予有效量的权利要求12所述的组合物。
22.代谢性骨疾病的处置方法,其特征在于,给予有效量的权利要求12所述的组合物。
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