CN104812768A - 晶体3-o-岩藻糖基乳糖 - Google Patents
晶体3-o-岩藻糖基乳糖 Download PDFInfo
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- CN104812768A CN104812768A CN201380059014.4A CN201380059014A CN104812768A CN 104812768 A CN104812768 A CN 104812768A CN 201380059014 A CN201380059014 A CN 201380059014A CN 104812768 A CN104812768 A CN 104812768A
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- fucosyllactose
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
公开了可用于药物组合物和营养制剂中的晶体3-O-岩藻糖基乳糖。
Description
发明领域
本发明提供处于晶体形式的三糖3-O-岩藻糖基乳糖(3-FL)、制备它的方法和含有它的制剂。
发明背景
近年来,已经日益进行了努力,以在工业上制备复杂的碳水化合物,如分泌型低聚糖。这是由于这些化合物在活体中的许多生物过程中的功能。分泌型低聚糖,如人乳低聚糖(“HMOs”),对于营养和治疗应用而言已经成为特别重要的商业目标。然而,这些低聚糖的合成和纯化留有挑战性的任务。最简单的重要人乳低聚糖之一是3-O-岩藻糖基乳糖β-D-吡喃半乳糖基-(1→4)-(α-L-吡喃岩藻糖基-(1→3))-D-葡萄糖(“3-FL”):
已经报道了3-FL的若干生物活性,包括它的益生元的(prebiotic)、抗菌的、抗病毒的、免疫系统增强的和脑发育增强的活性。3-FL的这些活性已经使得它成为用于营养和治疗产品的潜在有吸引力的添加剂。然而,难以获得纯净形式的3-FL,除非花费非常高的成本。
已经通过非常昂贵和复杂的色谱程序从人乳分离了3-FL。通过酶的、生物技术的和化学的方法合成的3-FL(Dumon等,Biotechnol.Prog.20,412[2004],Fernandez-Mayoralas等,Carbohydrate Res.154,93[1986],和Pereira等,Heterocycles 84,637[2012])已被分离为非晶态物质,并且因此它纯化起来是非常昂贵的。这已使得之前的制备3-FL的方法对于商业化而言过于昂贵。
结晶或再结晶是将化学产品与污染物分离并获得处于纯净形式的化学品的最简单和最便宜的方法之一。此外,固体化合物的晶体变形(多晶形物)是其产品开发中的重要因素,原因在于不同的晶体形式多样地影响化合物的性质-例如它的热力学稳定性、溶解性、密度、吸湿性、电学性质(如介电常数、电导率)、力学性质(如脆性、硬度、断裂强度、弹性)、光学性质(如颜色、透明性、折射)等等。
出于该原因,已经寻求用于获得晶体3-FL的方法。
发明概述
本发明提供了一种晶体3-FL和据信适合用于它的大规模纯化的用于制备它的方法。因此,本发明的晶体产物是适合用于营养和药物产品的高纯度3-FL。
相应地,当处于糖浆状的形式的3-FL在高真空下延长的时间干燥时,可以获得晶体3-FL。此外,当非晶态/沉淀的3-FL在一种或多种差溶剂(badsolvent)中悬浮并搅拌一段时间时,它们可以转变为晶体物质。而且,在已获得晶体样品的情况下,它可以用作种晶,用于经典的从溶剂体系的结晶,优选包含醇溶剂、更优选包含醇溶剂和水的那些溶剂体系。
附图简述
在下文中将参照附图更详细地描述本发明,在附图中:
图1显示了根据实施例6-9(1:实施例6;2:实施例9;3:实施例7;4:实施例6)获得的晶体3-O-岩藻糖基乳糖样品的X射线粉末衍射图案的比较。
图2显示了晶体3-O-岩藻糖基乳糖的DSC热分析图。
发明详述
本发明提供了一种晶体3-FL,其可以作为多晶物质获得。基于使用CuKa辐射的测量,该晶体3-FL包含在18.36±0.20 2Θ处,更优选在18.36±0.20 2Θ和14.26±0.20 2Θ处,甚至更优选在18.36±0.20 2Θ、14.26±0.20 2Θ和23.75±0.20 2Θ处,且最优选在18.36±0.20 2Θ、14.26±0.202Θ、23.75±0.20 2Θ和9.99±0.20 2Θ处的X射线粉末衍射反射。XRPD图案示于图1中,并且晶体3-FL的XRPD图案的峰的列表记载在下表1中。
表1.
3-FL的该新颖晶体可以认为是α-和β-端基异构体的端基异构混合物或者甚至是端基异构体之一的纯净形式。
在DSC研究中,晶体3-O-岩藻糖基乳糖显示吸热反应,所述吸热反应具有在243±5℃处,更优选在243±4℃处,甚至更优选在243±3℃处,最优选在243±2℃处,尤其在243±1℃处的峰最大值(见图2)。
优选地,晶体3-FL基本上不含有有机溶剂和/或水。术语“基本上不含有有机溶剂和/或水”在本文中优选表示任何一种或多种有机溶剂和/或水的含量为最多1000ppm,优选最多800ppm,更优选最多600ppm,最优选最多400ppm且尤其最多200ppm。
还优选地,晶体3-FL基本上是纯的。术语“基本上是纯的”在本文中优选表示晶体3-FL含有少于10w/w%的杂质,优选少于5w/w%的杂质,更优选少于1w/w%的杂质,最优选少于0.5w/w%的杂质,尤其少于0.1w/w%的杂质。术语“杂质”在本文中优选表示任何与晶体3-FL不同的物理实体,如非晶态3-FL,由3-FL的合成遗留的未反应的一种或多种中间体,一种或多种副产物,一种或多种降解产物,一种或多种无机盐,和/或不同于一种或多种有机溶剂和/或水的其他污染物。
当将悬浮在抗溶剂(其中3-FL实际上不可溶或具有有限溶解度的溶剂)中的固体3-FL,优选非晶态的或仅仅部分结晶的3-FL搅拌时,可以获得晶体3-FL。抗溶剂优选为C1-C6醇,更优选甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇或叔丁醇,特别优选甲醇或异丙醇。为了将非晶态物质转变成晶体,需要长时间的、并且优选激烈的搅拌,在室温下至少4-6、优选10-12、更优选18-20小时。可以将抗溶剂加热至50-60℃,这将结晶时间减少至约1-3小时。
此外,可以通过以下方式将糖浆状的或油状的3-O-岩藻糖基乳糖固化并结晶:例如用油泵,将它在高真空下,优选约30毫巴以下,更优选约15毫巴以下,尤其约5毫巴以下,保持延长的时间,优选至少4-6、更优选10-12,特别是16-18小时。
本发明也提供了一种通过在种晶的存在下从溶剂体系结晶来制备晶体3-FL的方法。溶剂体系优选包含优选与水混合的一种以上C1-C6醇。术语“C1-C6醇”优选表示具有1至6个碳原子的羟基-或二羟基-烷烃,如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、叔丁醇、戊醇、正己醇、乙二醇或丙二醇。优选的C1-C6醇选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇和叔丁醇的组。优选的溶剂体系包含甲醇、乙醇、正丙醇、异丙醇或它们的混合物,尤其是甲醇或异丙醇,以及水。
待结晶的非晶态或糖浆状的3-FL可以通过已知方法制得,但是优选经由在以下方案1中描述的程序。在这点上,可以将苯硫基岩藻糖基给体(WO 2011/115934)和乳糖衍生物受体(WO 93/10796)偶联成完全受保护的3-FL衍生物,其依序由Zemplén脱酰基化、酸处理和催化氢解脱保护的,以制备3-FL。
方案1.
本发明的晶体3-FL适合用作药剂。用于这种用途的药物组合物可以含有作为活性成分的晶体3-FL和如在标准参考文本雷明顿制药科学(Remington′s Pharmaceutical Sciences)中描述的一种以上常规药用载体、以及添加剂、辅剂、赋形剂和稀释剂(水、明胶、滑石、糖、淀粉、阿拉伯树胶、植物胶、植物油、聚亚烷基二醇、增香剂、防腐剂、稳定剂、乳化剂、润滑剂、着色剂、填充剂、润湿剂等)。这些成分的量可以取决于药物组合物是否意在用于婴儿、儿童或成人或具有特殊需要的患者而变化。
本发明的晶体3-FL也适合用于营养用途。用于这种用途的营养制剂,如食物、饮料或饲料,可以含有和其他可食用的微量营养物、维生素和矿物质一起的晶体3-FL,其作为活性成分。这些成分的量可以取决于该营养制剂是否意在用于正常的、健康的婴儿、儿童、成人或具有特殊需要的患者(例如,遭受新陈代谢失调的患者)而变化。微量营养物包括,例如,食用油、脂肪或脂肪酸(如椰子油、大豆油、单甘油酯、二甘油酯、棕榈油精、葵花油、鱼油、亚油酸、亚麻酸等)、碳水化合物(如葡萄糖、果糖、蔗糖、麦芽糖糊精、淀粉、水解玉米淀粉等)、以及来自酪蛋白、大豆、乳清或撇乳的蛋白质、或者这些蛋白质的水解产物,但是也可以使用来自其他源的蛋白质(原样的或水解的)。也可以使用维生素A、B1、B2、B5、B6、B12、C、D、E、H、K、叶酸、肌醇和烟酸,以及矿物质和微量元素,如Ca、P、K、Na、CI、Mg、Mn、Fe、Cu、Zn、Se、Cr和I。
优选的含有本发明的晶体3-FL的营养制剂是婴儿乳粉(infant formula),即,一种意在由婴儿在他们生命的最初4-6个月使用并且它自己满足婴儿们的营养需要的食物。婴儿乳粉可以含有日常饮食中必要的一种以上益生元的(probiotic)双歧杆菌属(Bifidobacterium)物种,益生元如低聚果糖和半乳低聚糖,来自酪蛋白、大豆、乳清或撇乳的蛋白质,碳水化合物如乳糖、蔗糖、麦芽糖糊精、淀粉或它们的混合物,类脂(例如棕榈油精、葵花油、红花油),以及维生素和矿物质。婴儿乳粉优选含有0.1-3.0g的晶体3-FL/100g的罂儿乳粉。
本发明的晶体3-FL也可以用作食物增补剂(food supplement)。食物增补剂也可以含有其他活性成分,如一种以上益生元、维生素、矿物质、微量元素和其他微量营养物。食物增补剂可以为例如片剂、胶囊、锭剂或液体的形式,并且含有常规添加剂如粘合剂、包衣、乳化剂、增溶剂、包封剂、成膜剂、吸附剂、载体、填充剂、分散剂、润湿剂、成胶状剂(jellifyingagent)和凝胶形成剂。3-FL的每日剂量可以在0.1至3.0g之间。
本发明的晶体3-FL还适合在营养制剂的制备中用作活性成分,所述营养制剂包括食物、饮料和饲料,优选婴儿乳粉和食物增补剂。可以以常规方式,例如通过将微量营养物组分以合适的比例混合,随后添加维生素和矿物质,来准备营养制剂。为了避免热降解或分解,可以在均匀化之后,加入热敏性的维生素。亲脂性的维生素可以在混合前溶解在脂肪源中。可以用水制备液体混合物,水的温度优选为约50-80℃,以帮助成分的溶解或分散。随后,可以加入晶体3-FL多晶形物。随后,可以利用蒸汽注入、热交换器或高压釜,通过急骤加热至约80-150℃,将所得的混合物均匀化。此热处理也明显降低了细菌负荷。随后,可以将热的混合物迅速冷却至约60-80℃。如果需要,可以在此温度下,在约2-30MPa的高压下进行进一步的均匀化。在冷却之后,可以随后加入热敏性的成分,并且可以便利地调节pH和固体含量。随后,通过例如常规的喷雾干燥或冷冻干燥方法,将所得的混合物干燥成为粉末。随后可以通过干燥混合加入益生元。
由以下实施例,本发明的其他特征将变得明显,所述实施例举例说明本发明但不限制本发明。
实施例
实施例1.苄基3’,4’-O-亚异丙基-2,6,2’,6’-四-O-苯甲酰基-β-乳糖苷
将苄基3’,4’-O-亚异丙基-β-乳糖苷(20g)溶解在吡啶(30ml)中。将溶液冷却至0℃,并且通过滴液漏斗在6h内滴加苯甲酰氯(21ml)和DCM(40ml)的混合物。将反应混合物在0℃搅拌另外2h,并且在5℃搅拌24小时。随后,加入甲醇(10ml),并在真空中移除溶剂。将剩余的残余物再溶解在EtOAc(200ml)中,并且用水(100ml)、饱和NaHCO3(100ml)、2 x 1M HCl(100ml)、水(100ml)和盐水(100ml)洗涤。于真空中移除溶剂之后,将残余物从MeOH再结晶(28g,72%)。
实施例2.苄基3-O-(2,3,4-三-O-苄基-α-L-吡喃岩藻糖基)-3’,4’-O-亚异丙基-2,6,2′,6′-四-O-苯甲酰基-β-乳糖苷
在0℃,向苯基2,3,4-三-O-苄基-1-硫代-β-L-吡喃岩藻糖苷(133g)在DCM(439ml)的溶液中,在60分钟的时间段内滴加在DCM(50ml)中的溴(16ml)。在加入溴溶液后,将反应混合物搅拌额外的15至20分钟。随后滴加环己烯(35ml),之后加入实施例1(120g)的产物和在DCM(330ml)和DMF(330ml)中的TBAB(8g)。搅拌反应混合物,直至TLC(甲苯/丙酮12∶1)显示完成,随后用1.7l的EtOAc将它稀释。用饱和Na2S2O3/饱和NaHCO3(1∶1)、饱和NaHCO3/盐水(4∶1)、水/盐水、水/盐水/1N HCl(1∶1∶1)、饱和NaHCO3/盐水(2∶1)、以及盐水,洗涤有机层。将有机相经过MgSO4干燥,并且在真空中移除溶剂,以获得橙色油状物,将其从EtOAc/己烷(1∶3)再结晶,以获得148g的晶体(84%)。
实施例3.苄基3-O-(2,3,4-三-O-苄基-α-L-吡喃岩藻糖基)-3’,4’-O-亚异丙基-β-乳糖苷
将实施例2的产物(148g)加入至NaOMe在甲醇中的0.1M溶液(1.51)中。将悬浮液升温至40℃。通过TLC(甲苯/丙酮1∶1),证实完全脱苯甲酰化。加入H+-IR120Amberlite树脂,以将溶液中和,并且在真空中移除甲醇。将残余物再溶解在EtOAc(1350ml)中,并且用水(900ml)0.5N HCl(900ml)、饱和NaHCO3(900ml)以及盐水(450ml)萃取。在真空中移除溶剂,并且将产物从EtOAc/己烷(1∶2)结晶,以获得79g的产物(79%)。M.p.:101-103℃
实施例4.苄基3-O-(2,3,4-三-O-苄基-α-L-吡喃岩藻糖基)-β-乳糖苷
将实施例3的产物(79g)溶解在DCM(400ml)、MeOH(280ml)和水(40ml)中。随后在室温缓慢加入TFA(80ml)。在加入完成后,将温度升至40℃。通过TLC(甲苯/丙酮1∶2)追踪反应的进程。当不能检测到起始物质时,将反应物在冰浴中冷却至0℃。缓慢地且分份地加入500ml的饱和NaHCO3溶液,随后将EtOAc(1.21)与额外的250ml的饱和NaHCO3溶液以及250ml的盐水一起加入。用500ml的饱和NaHCO3溶液和500ml的盐水将有机层再萃取两次。在真空中移除溶剂,并且将残余物从EtOAc/Et2O(2∶3)再结晶,以得到60g的产物(80%)。1H-NMR(CD3OD)δ(ppm):1.18(d,J=6.1Hz,3H);3.34-3.56(m,4H);3.57-3.69(m,2H);3.78(m,2H);3.95(m,7H);4.1(dd,J=2.9Hz,J=10.1Hz,1H);4.4(d,J=7.6Hz,1H);4.44(d,J=7Hz,1H);4.57(d,J=11.0Hz,1H);4.65(d,H=11.7Hz,1H);4.69(d,11.7Hz,1H);4.81(m,1H);4.93(m,3H);5.7(d,J=3.96Hz,1H);7.15-7.57(m,20H)。13C-NMR(CD3OD)δ(ppm):15.75,60.17,60.18,62.34,66.43,69.00,70.77,71.78,71.93,72.82,73.65,75.25,75.55,75.93,76.14,76.28,77.57,78.90,78.94,78.97,97.09,102.38,102.58,127.22,127.28,127.32,127.37,127.51,127.62,127.98,128.07,128.11,128.12,128.16,128.45,137.78,138.50,139.11,139.42。M.p.:123-125℃
实施例5.3-O-岩藻糖基乳糖
将实施例4的产物(3.8g)溶解在异丙醇-甲醇的混合物(1∶2,60ml)中。加入在木炭上的10%Pd(0.23g),并且在40℃将混合物在H2气氛(在高压釜中20巴)下搅拌24小时。通过加入少量水和几滴乙酸将沉淀的产物溶解,并且继续氢解8小时。将催化剂滤除,并移除溶剂。将产物在真空中干燥,并通过加入丙醇沉淀(实际上定量的收率),以得到非晶态的粉末。1H-NMR(D2O)δ(ppm):1.0(d,J=7Hz,3H);3.23-3.34(m,2H);3.35-3.51(m,3H);3.52-3.74(m,9H);3.74-3.83(m,2H);4.24(d,J=7.9Hz,1H);4.46(d,J=7.9Hz,0.52H);5.00(d,J=3.7Hz,0.43H);5.19(d,J=4Hz,0.43H);5.25(d,J=4.1Hz,0.57H)。13C-NMR(D2O)δ(ppm):15.34,59.78,59.87,61.62,61.66,66.57,66.61,68.13,68.16,68.43,69.32,69.38,71.01,71.24,72.06,72.50,72.69,72.75,72.78,74.80,75.06,75.47,75.63,77.09,92.19,95.92,98.48,98.61,101.90。HPLC纯度:95-98%。
实施例6.结晶
重复根据实施例5的程序-不同之处在于:在移除溶剂之后,将所得的糖浆状的或油状的产物在室温保持在高真空(5毫巴)下18小时,并且获得作为晶体物质的3-O-岩藻糖基乳糖产物。
实施例7.结晶
将根据实施例5的非晶态3-FL(1.0g)悬浮在甲醇(10ml)中,并在室温搅拌过夜。随后滤出固体,用冷甲醇洗涤并干燥,以得到晶体3-FL(614mg)。
实施例8.结晶
将根据实施例5的非晶态3-FL(1.5g)悬浮在甲醇(6ml)中,并在60℃加热3小时。在冷却后,滤出固体,用冷甲醇洗涤并干燥,以得到晶体3-FL(778mg)。
实施例9.结晶
将根据实施例5的非晶态3-FL(2.76g)悬浮在甲醇(4ml)中,并加热至50-60℃。随后加入水,直至在相同的温度获得澄清的溶液。使该溶液开始冷却,加入种晶(根据实施例6至8中任一个所获得的),并且在将加晶种的溶液冷却的同时,连续加入6份甲醇(每份2ml)。随后将形成的固体滤出,用冷甲醇洗涤并干燥,以得到晶体3-FL(1.31g)。
实施例10.X射线粉末衍射
在透射几何中,用Philips PW 1830/PW1050仪器,使用利用石墨单色器制成单色的CuKα辐射,进行XRPD研究。基于的波长,从2Θ值计算D间距。作为一般规律,2Θ值有的误差率。图1清楚地显示了在实施例6-9中获得的晶体3-FL样品的X射线粉末衍射图案是相同的。
实施例11.DSC分析
在SETARAM Labsys Evo TG-DSC热分析仪上,在流动高纯度(6.0)氦气氛中(流量30ml/分钟),在30-300℃的温度范围内,以恒定的10K/分钟的加热速率,使用标准的100μl铂坩埚,进行测量。样品量为4.65mg。
Claims (15)
1.晶体3-O-岩藻糖基乳糖。
2.根据权利要求1所述的晶体3-O-岩藻糖基乳糖,其特征在于,基于使用CuKa辐射的测量,它显示在18.36±0.20 2Θ处的,更优选在18.36±0.20 2Θ和14.26±0.20 2Θ处的,甚至更优选在18.36±0.20 2Θ、14.26±0.20 2Θ和23.75±0.20 2Θ处的,并且最优选在18.36±0.20 2Θ、14.26±0.20 2Θ、23.75±0.20 2Θ和9.99±0.20 2Θ处的X射线粉末衍射反射。
3.根据权利要求1至2中任一项所述的晶体3-O-岩藻糖基乳糖,其特征在于,在DSC研究中,它显示吸热反应,所述吸热反应的峰温度在243±5℃处,更优选在243±4℃处,甚至更优选在243±3℃处,最优选在243±2℃处,尤其在243±1℃处。
4.根据权利要求1至3中任一项所述的晶体3-O-岩藻糖基乳糖,其基本上是纯的。
5.根据权利要求1至4中任一项所述的晶体3-O-岩藻糖基乳糖,其基本上不含有有机溶剂和/或水。
6.一种用于制备根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖的方法,其特征在于,将糖浆状的3-O-岩藻糖基乳糖保持在30毫巴以下、优选约15毫巴以下、更优选约5毫巴以下的真空下。
7.一种用于制备根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖的方法,其特征在于,将非晶态3-O-岩藻糖基乳糖悬浮在抗溶剂中并搅拌。
8.一种用于制备根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖的方法,其特征在于,在种晶的存在下从溶剂或溶剂体系进行结晶,所述种晶优选通过根据权利要求6或7所述的方法中的任一种获得。
9.用作药剂的根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖。
10.根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖作为在药物组合物中的药物活性成分的用途。
11.一种药物组合物,所述药物组合物包含根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖和药用载体。
12.一种营养制剂,所述营养制剂包含根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖。
13.根据权利要求12所述的营养制剂,所述营养制剂是婴儿乳粉。
14.根据权利要求12所述的营养制剂,所述营养制剂是食物增补剂。
15.根据权利要求1至5中任一项所述的晶体3-O-岩藻糖基乳糖多晶形物作为用于制备营养制剂的营养活性成分的用途。
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