CN101574327B - 密封的微胶囊凝聚体及其制备方法 - Google Patents

密封的微胶囊凝聚体及其制备方法 Download PDF

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CN101574327B
CN101574327B CN2009101457969A CN200910145796A CN101574327B CN 101574327 B CN101574327 B CN 101574327B CN 2009101457969 A CN2009101457969 A CN 2009101457969A CN 200910145796 A CN200910145796 A CN 200910145796A CN 101574327 B CN101574327 B CN 101574327B
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严年喜
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Abstract

包含初级微胶囊凝聚体的微胶囊，每个单独的初级微胶囊具有初级壳，且此凝聚体被外壳所密封，此微胶囊的制备方法可以是：提供装载物和壳体材料的水性混合物；调整pH、温度、浓度和/或混合速度，在装载物周围形成壳体材料的初级壳；以及将水性混合物冷却到初级壳凝聚及在凝聚体周围形成壳体材料的外壳。这种微胶囊用于储存物质和向需要的环境释放物质。

Description

密封的微胶囊凝聚体及其制备方法
发明领域
本发明涉及微胶囊、制备微胶囊方法及它们的用途。
发明背景
微胶囊的定义是在壳体材料薄涂层内的固体小颗粒或小液滴，壳体材料如蜂蜡、淀粉、明胶或聚丙烯酸。它们的用途是例如将液体制备成流动性良好的粉末或被压缩的固体；隔离反应性物质；降低毒性；防止氧化和/或控制物质如酶、调味剂、营养物、药物等的释放速率。
在过去五十年，现有技术集中在所谓的“单-核”微胶囊。然而，单-核微胶囊的问题之一是它们容易破裂。为了提高微胶囊的强度，本领域已知增加微胶囊的壁厚。然而这导致微胶囊装载容量的降低。另一个途径是制造所谓“多重-核”微胶囊。例如美国专利5,780,056公开了一种明胶作壳体材料的“多重-核”微胶囊。这些微胶囊是通过喷雾冷却油或类胡萝卜素颗粒的水性乳液，使得明胶在油或类胡萝卜素颗粒“核”周围硬化来形成的。Yoshida等(化学文摘1990：140735或1989年6月9日发表的日本专利出版物JP 01-148338)公开了一种制造微胶囊的复合凝聚法，该方法中将明胶和石蜡的乳液加到阿拉伯胶溶液中，然后与表面活性剂混合形成“多重-核”微胶囊。Ijichi等(J.Chem.Eng.Jpn.(1997)30(5)：793-798)使用复合凝聚法将大滴联苯包入微胶囊形成多层微胶囊。美国专利4,219,439和4,222,891中公开了用于压敏复印纸和热敏记录纸的“多重-核”含油微胶囊，微胶囊的平均直径为3～20μm，所带油滴的大小为1～10μm。虽然使用这些方法可实现微胶囊强度方面的某些改进，但仍需要对被包入胶囊的物质有良好抗裂强度及良好阻挡氧化特性并优选具有高装载量的微胶囊。说明有这种需要的例证是目前还没有可商购的“多核”微胶囊。
发明概述
这里提供了一种包含初级微胶囊凝聚体的微胶囊，每个单独的初级微胶囊具有初级壳(primary shell)，且此凝聚体被外壳密封。
这里还进一步提供了一种制备微胶囊的方法，此方法包含：
(a)提供装载物、壳体材料的第一聚合物组分和壳体材料的第二聚合物组分的水性混合物；
(b)调整pH、温度、浓度、混合速度或其组合，来形成包含第一和第二聚合物组分的壳体材料，此壳体材料在装载物周围形成初级壳；
(c)将水性混合物冷却到高于壳体材料的胶凝点的温度，直到初级壳形成凝聚体；及
(d)进一步冷却水性混合物，壳体材料在凝聚体周围形成外壳。
此外，这里还提供一种制备微胶囊的方法，此方法包含：
(a)提供壳体材料第一聚合物组分的水性混合物；
(b)将装载物分散到水性混合物中；
(c)然后在水性混合物中加入壳体材料的第二聚合物组分；
(d)调整pH、温度、浓度、混合速度或其组合来形成含有第一和第二聚合物组分的壳体材料，此壳体材料在装载物周围形成初级壳；
(e)将水性混合物冷却到高于壳体材料胶凝点的温度，直到初级壳形成凝聚体；及
(f)进一步冷却水性混合物，壳体材料在凝聚体周围形成外壳。
本发明的微胶囊可用于包含各种用途的装载物。
附图简述
图1是根据本发明密封的微胶囊凝聚体的光学显微照片(400X)。
图2是根据本发明密封的微胶囊凝聚体的第二张光学显微照片(400X)。
详细描述
组成：
装载物实际上可以是完全不溶于水性混合物的任何物质。优选此装载物是固体、疏水性液体、或固体和疏水性液体的混合物。更优选装载物是疏水性液体，如脂膏、油或它们的混合物。典型的油可以是鱼油、植物油、矿物油、它们的衍生物或它们的混合物。优选的装载物可包括纯化的或部分纯化的油状物如脂肪酸、甘油三酯或它们的混合物；ω-3脂肪酸如α-亚麻酸(18:3n3)、十八碳四烯酸(18:4n3)、二十碳五烯酸(20:5n3)(EPA)和二十二碳六烯酸(22:6n3)(DHA)及它们的衍生物和它们的混合物。本领域的技术人员都非常了解很多类型的衍生物。衍生物适宜的实例有酯类如植物甾醇酯、带支链的或不带支链的C1～C30烷基酯、带支链的或不带支链的C2～C30链烯基酯、或带支链的或不带支链的C3～C30环烷基酯，特别是植物甾醇酯和C1～C6烷基酯。优选油的来源是源自水生生物(例如凤尾鱼、鳞鱼、大西洋鳕鱼、大西洋鲱鱼，大西洋鲭鱼、大西洋油鲱鱼、鲑鱼、沙丁鱼、鲨鱼、金枪鱼等)和植物(如亚麻、蔬菜、海藻等)的油。虽然装载物可以是或可以不是生物活性物质，但本发明微胶囊特别适合生物活性物质，例如药物、营养补剂、调味剂或它们的混合物。特别优选的装载物包括抗氧化剂如CoQ10和维生素E。
壳体材料可以是能在有关装载物周围形成微胶囊的任何材料。壳体材料典型地至少含有一个聚合物组分。聚合物组分的实例包括但不限于明胶、多磷酸盐、多糖及它们的混合物。优选的聚合物组分是明胶A、明胶B、多磷酸盐、阿拉伯树胶、藻酸盐、聚氨基葡糖、角叉菜聚糖、果胶、羧甲基纤维素(CMC)、或它们的混合物。一种特别优选形式的A型明胶具有的布卢姆强度为50～350，更优选具有布卢姆强度为275。
优选壳体材料是由不同类型聚合物组分的混合物制备的二组分体系。更优选壳体材料是两个或多于两个聚合物组分之间的复合凝聚层。组分A优选A型明胶，尽管其它聚合物也可考虑作为组分A。组分B优选B型明胶、多磷酸盐、阿拉伯树胶、藻酸盐、聚氨基葡糖、角叉菜聚糖、果胶、羧甲基纤维素或它们的混合物。所使用的组分A∶组分B的摩尔比依赖于组分的类型，但典型地为1∶5～15∶1。例如，当分别使用A型明胶和多磷酸盐作组分A和组分B时，组分A∶组分B的摩尔比优选8∶1～12∶1；当分别使用A型明胶和B型明胶作组分A和组分B时，组分A∶组分B的摩尔比优选2∶1～1∶2；当分别使用A型明胶和藻酸盐作组分A和组分B时，组分A∶组分B的摩尔比优选3∶1～8∶1。
壳体材料中可包含加工助剂。可因为各种理由使用加工助剂。例如，它们可用于促进初级微胶囊的凝聚、控制微胶囊的大小和/或起抗氧化剂的作用。抗氧化剂的性能在加工过程(如在凝聚和/或喷雾干燥过程中)及在微胶囊形成后的微胶囊二者中都是有用的(即延长保存期限等)。优选使用少量助剂就能起大量作用的加工助剂。例如，抗坏血酸或其盐可用于促进初级微胶囊的凝聚、控制微胶囊大小和起抗氧化剂的作用。抗坏血酸或其盐的用量优选大约100ppm～大约12,000ppm，更优选大约1000ppm～大约5000ppm。特别优选该限度内的抗坏血酸的盐，如抗坏血酸钠盐或抗坏血酸钾盐。
图1和图2中可看到根据本发明密封的微胶囊凝聚体的结构，它们显示了较小的(初级)微胶囊已经凝聚在一起，及凝聚体被壳体材料包围形成更大的微胶囊。每个单独的初级微胶囊有其自己独立的壳体，被称作初级壳。此外，较小微胶囊之间存在的任何空间被更多的壳体材料填充以容纳及包围较小的微胶囊，由此除了在较大微胶囊中形成较小微胶囊的初级壳外，还提供了非常坚固的较大微胶囊的外壳。就某种意义来说，被密封的微胶囊凝聚体可被看成为悬浮在壳体材料基体中的被壁围起来的泡状凝聚体，即“类似泡沫”的结构。与过去本领域已知的结构比较，这种密封的微胶囊凝聚体提供了更坚固的、更抗裂的结构，并同时实现了装载物的高装载量。
初级微胶囊(初级壳)典型地具有的平均直径为大约40nm～大约10μm，更特别地为大约0.1μm～大约5μm，甚至还更特别地为大约1μm。密封的凝聚体(外壳)可具有的平均直径为大约1μm～大约2000μm，更典型地为大约20μm～大约1000μm，更特别地为大约20μm～大约100μm，甚至还更特别地为大约50μm～大约100μm。
通过本发明方法制备的被密封的微胶囊凝聚体典型地具有有效载荷和结构强度的结合，其有效载荷和结构强度都优于先前技术的多重-核微胶囊。例如，本发明外壳平均尺寸为大约50μm及初级壳平均尺寸为大约1μm的微胶囊中，装载物的有效载荷可高达大约70重量％。
方法：
在制备微胶囊的方法中，形成装载物、壳体材料的第一聚合物组分和壳体材料的第二聚合物组分的水性混合物。水性混合物可以是机械混合物、悬浮液或乳液。当使用液体装载材料特别是疏水性液体时，优选水性混合物是装载材料和聚合物组分的乳液。
在更优选的方案中，优选第一聚合物组分与加工助剂如抗氧化剂一起供入水溶液中。装载物可然后例如使用均化器分散到水性混合物中。如果装载物是疏水液体，就会形成乳液，乳液中第一聚合物组分部分开始沉积在装载物单个液滴的周围，并开始形成初级壳。如果装载物是固体颗粒，就会形成悬浮液，悬浮液中第一聚合物组分部分开始沉积在单独颗粒周围，并开始形成初级壳。这时可将另一个第二聚合物组分的水溶液加到水性混合物中。
优选水性混合物中装载物的液滴或颗粒具有的平均直径为小于100μm，更优选小于50μm，还更优选小于25μm。平均直径小于10μm、或小于5μm、或小于3μm、或小于1μm的装载物液滴或颗粒都是可以使用的。颗粒大小可使用任何本领域已知的典型仪器例如美国佛罗里达州迈阿密生产的CoulterTM LS230颗粒尺寸分析仪来测定。
水性混合物中提供的壳体材料聚合物组分的数量典型地是能足以形成初级壳和密封微胶囊凝聚体的外壳二者的量。水性混合物中提供的装载物的数量优选大约1重量％～大约15重量％，更优选大约3重量％～大约8重量％，及甚至更优选大约6重量％。
然后调整pH、温度、浓度、混合速度或其组合，以加速在装载物的液滴或颗粒周围形成初级壳。如果有多于一种类型的聚合物组分，在组分间将发生复合凝聚来形成凝聚层，它进一步在装载物周围沉积形成壳体材料的初级壳。pH的调节依赖于形成壳体材料的类型。例如，如果一种聚合物组分是A型明胶，此pH值可被调整到3.5～5.0，优选4.0～5.0。如果混合物的初始pH在所要求的范围内，那么很少需要或不需要调节pH。水性混合物的初始温度优选地设定为大约40℃～大约60℃，更优选大约50℃。优选调节混合方式，以便具有良好的混合，而又不会使微胶囊在其形成时破裂。详细的混合参数依赖于所使用设备的类型。可使用本领域已知的任何品种类型的混合设备。特别有用的是轴流式叶轮如LightninTM A310或A510。
然后水性混合物在控制冷却速度和混合参数下冷却，以便允许初级壳的凝聚体形成密封的初级壳凝聚体。被密封的凝聚体本身是离散颗粒。在高于壳体材料胶凝点的温度来控制密封凝聚体的形成，并让多余的壳体材料形成较厚的外壳是有利的。还可在这一阶段加入更多的无论是相同种类或不同种类的聚合物组分，以便使外壳变厚和/或生产具有不同组成的初级和外壳的微胶囊。优选温度降低的速度为1℃/10分钟，直到温度达到大约5℃～大约10℃，优选大约5℃。外壳将初级壳的凝聚体包入胶囊密封，形成刚性的密封微胶囊凝聚体。
可在此阶段加入交联剂，通过外壳和初级壳二者壳体材料的交联，使壳体既不溶于水又不溶于油状介质中，进一步增加微胶囊的刚性。可使用任何适宜的交联剂，交联剂的选择有些依赖于壳体材料的选择。优选的交联剂是酶促交联剂(例如转谷氨酰胺酶)、醛(例如甲醛或戊二醛)、鞣酸、明矾或它们的混合物。如果将微胶囊用于向有机体递送生物活性物质，优选交联剂是无毒的或充分低毒的。交联剂的用量依赖于壳体材料的类型，并可调节用量，以便根据需要提供程度不同的结构刚性。例如，在壳体材料中使用A型明胶时，交联剂适宜的用量为A型明胶的重量的大约1.0％～大约5.0％，优选大约2.5％。通常，本领域的技术人员可在任何给定的条件下按常规通过简单的试验确定需要的数量。
最后，微胶囊可用水洗涤和/或干燥来提供流动性良好的粉末。干燥可通过许多本领域已知的方法来完成，如冷冻干燥、用乙醇干燥或喷雾干燥。干燥微胶囊特别优选的方法是喷雾干燥。K.Masters的“喷雾干燥手册”第5版中公开了喷雾干燥技术，该书在1991年由英国Longman ScientificTechnical(朗曼科技)出版，其公开内容作为参考并入本文。
用途：
本发明方法生产的微胶囊可用于：将液体制备成流动性良好的粉末或被压缩的固体、储存物质、隔离反应性物质、降低物质的毒性、防止物质氧化、向指定的环境释放物质和/或控制物质的释放速度。特别是，此微胶囊可用于营养或医药目的向有机体释放生物活性物质。生物活性物质可以是例如营养补剂、调味剂、药物和/或酶。有机体优选哺乳动物，更优选人类。例如食品或饮料或药物传递系统中可包括含有生物活性物质的微胶囊。使用本发明微胶囊在人类食品中配制营养增剂是特别优选的。
本发明微胶囊具有良好的抗裂强度，在与食品或其他配方制剂结合的过程中它帮助减少或防止微胶囊的破裂。此外微胶囊的壳体既不溶于水性又不溶于油性介质，在微胶囊制备过程中；在长时间储存过程中；和/或在微胶囊与制剂载体如食品、饮料、营养物(nutraceutical)制剂或药物制剂结合过程中，帮助减少或防止装载物的氧化和/或变质。
实施例
实施例1：
54.5克布卢姆(Bloom)A型明胶275(等电点大约为9)和600克含有0.5％抗坏血酸钠的去离子水，在50℃搅拌混合直到完全溶解。5.45克多磷酸钠溶解在104克含有0.5％抗坏血酸钠的去离子水中。90克含有30％二十碳五烯酸乙酯(EPA)和20％二十二碳六烯酸乙酯(DHA)的鱼油浓缩物(获自Ocean Nutrition Canada有限公司)和1.0％抗氧化剂(天然调味剂、维生素E和柠檬酸的混合物，可利用KalsecTM的商品DuraloxTM)，使用高速PolytronTM均化器分散到明胶溶液中。形成一种水包油型乳液。由CoulterTMLS230型颗粒尺寸分析仪测定，此油滴大小具有狭窄的分布，平均大小为大约1μm。此乳液在50℃用700克含有0.5％抗坏血酸钠的去离子水稀释。然后乳液中加入多磷酸钠溶液，并由LightninTM搅拌机在600rpm下混合。然后用10％的乙酸水溶液将pH调到4.5。在pH调节过程中及pH调节后的冷却步骤过程中，由明胶和多磷酸盐形成的凝聚层包到油滴表面形成初级微胶囊。进行冷却到高于明胶和多磷酸盐的胶凝点时，初级微胶囊在搅拌下开始凝聚形成团块。紧接着进一步冷却混合物，水相中剩余的聚合物进一步包到初级微胶囊小块的表面，形成被密封的微胶囊凝聚体，它们具有外壳，平均尺寸为50μm。一旦温度被冷却到5℃，在混合物中加入2.7克50％的戊二醛，使壳体进一步加固。然后混合物升到室温并保持搅拌12小时。最后，微胶囊悬浮液用水洗涤。然后洗过的悬浮液喷雾干燥，得到流动性良好的粉末。得到的有效载荷为60％。
实施例2：
除了使用0.25％的抗坏血酸钠以外，根据实施例1的方法形成被密封的微胶囊凝聚体。得到有效载荷为60％。
实施例3：
除了不使用抗坏血酸盐以外，根据实施例1的方法形成被密封的微胶囊凝聚体。得到有效载荷为60％。
实施例4：
除了使用105克鱼油浓缩物以外，根据实施例l的方法形成被密封的微胶囊凝聚体。得到有效载荷为70％。
实施例5：
根据实施例1的方法形成被密封的微胶囊凝聚体，除了将它们应用于鱼油甘油三酯(TG)(获自Ocean Nutrition Canada有限公司)而不是鱼油乙酯以外。
实施例6：
除了使用明胶(A型)和阿拉伯树胶作为壳体材料的聚合物组分以外，根据实施例1的方法形成被密封的微胶囊凝聚体。
实施例7：
除了使用150布卢姆明胶(A型)和多磷酸盐作为壳体材料的聚合物组分及使用105克鱼油浓缩物以外，根据实施例1的方法形成被密封的微胶囊凝聚体，得到有效载荷为70％。
实施例8：
除了使用转谷氨酰胺酶交联壳体材料以外，根据实施例1的方法形成被密封的微胶囊凝聚体。
实施例9：微胶囊的评价
评价实施例1～8中微胶囊的机械强度、被密封的油的质量和氧化稳定性。
通过在25℃将给定量的实施例1～8中制备的各微胶囊粉末在SorvallTMSuper T-21型离心机中34,541g下离心30分钟，来评价微胶囊壳体强度。用己烷洗涤原始粉末和离心过的粉末，萃取由于壳体在离心力作用下破损而从微胶囊中释放的油。离心过的粉末对原始粉末的游离油百分比被用作壳体强度的指标。百分比越低，微胶囊的壳体越坚固。
微胶囊中油的质量是使用研磨机将实施例1～8制备的各微胶囊粉末的壳体碾碎来评价的。然后被包入胶囊的油用己烷萃取。过氧化值(PV)用美国油脂化学家协会的方法(AOCS官方方法Cd 8-53：过氧化值)分析。高PV表示在包入胶囊的油中有较高浓度的初级氧化产物。
将实施例1～8制备的各微胶囊粉末放入氧弹(OxipresTM，丹麦MIKROLAB AARHUS A/S公司)中来评价它们增加的氧化稳定性，氧弹中初始氧气压力为5巴、温度为恒温65℃。当被包入胶囊的鱼油开始氧化时，氧气压力下降。氧气压力开始下降的时间被称作诱导期。诱导期比较长表示微胶囊的内含物受到比较好的保护，不容易被氧化。
结果列于表1。此结果表明根据本发明制备的凝聚的微胶囊具有出色的强度和密封的装载物的抗氧化性。
表1
 实施例#   载荷(％)   抗坏血酸盐(％)   诱导期(小时)   PV值   游离油比例   注释
 1   60   0.50   38   3.0   2.0
 2   60   0.25   34   4.1   1.5
 3   60   0.0   26   7.8   1.5
 4   70   0.50   38   3.2   1.7
 5   60   0.50   37   0.28   3.0   TG油
 6   60   0.50   30   3.4   1.5   阿拉伯树胶
 7   70   0.50   38   4.4   2.2   150布卢姆明胶
 8   60   0.50   33   3.2   1.1   酶促交联
本发明显而易见的和固有的其它优点，对于本领域的技术人员来说是明显的。应当理解某些特征及变形(sub-combination)是有效的，其可应用性与其它特征及变形无关。这是权利要求的范围所考虑的并在此范围内。因为在不违背本发明范围的情况下可以由其构成很多可能的实施方案，应当理解这里阐明的和附图中所示的全部内容都是举例说明性的，而没有限制的含义。

Claims (13)

1.微胶囊在制备用于将装载物传递至受试者的药物中的应用，其中所述微胶囊包含初级微胶囊凝聚体，每个单独的初级微胶囊具有初级壳，并且所述凝聚体被外壳密封，其中所述装载物被密封在初级微胶囊中，
其中所述装载物包含ω-3脂肪酸、其衍生物或它们的混合物；
其中所述初级壳和所述外壳各自由二组分体系的复合凝聚层形成；和
其中所述微胶囊的壳体材料在酶促交联剂作用下交联。
2.根据权利要求1的应用，其中所述酶促交联剂是转谷氨酰胺酶。
3.根据权利要求1的应用，其中所述外壳具有的平均直径为50μm～100μm。
4.根据权利要求1的应用，其中所述外壳具有的平均直径为20μm～100μm。
5.根据权利要求1的应用，其中所述初级壳具有的平均直径为40nm～10μm。
6.根据权利要求1的应用，其中所述初级壳具有的平均直径为0.1μm～5μm。
7.根据权利要求1的应用，其中所述初级壳具有的平均直径为1μm～5μm。
8.根据权利要求1的应用，其中所述初级壳具有的平均直径为1μm。
9.根据权利要求1的应用，其中所述二组分体系由A型明胶和多磷酸盐制备。
10.根据权利要求1的应用，其中所述微胶囊是喷雾干燥的。
11.根据权利要求1的应用，其中所述受试者是哺乳动物。
12.根据权利要求1的应用，其中所述受试者是人。
13.根据权利要求1的应用，其中所述微胶囊进一步包含抗坏血酸或其盐。
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US20050019416A1 (en) 2005-01-27
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