CN110075308B - 稳定化的全水乳液及其制备和使用方法 - Google Patents
稳定化的全水乳液及其制备和使用方法 Download PDFInfo
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- CN110075308B CN110075308B CN201910232111.8A CN201910232111A CN110075308B CN 110075308 B CN110075308 B CN 110075308B CN 201910232111 A CN201910232111 A CN 201910232111A CN 110075308 B CN110075308 B CN 110075308B
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Abstract
本申请涉及稳定化的全水乳液及其制备和使用方法。本文描述用于制备全水乳液，包括稳定的乳液和/或具有高粘度和/或超低界面张力的乳液的方法。所述方法包括混合、合并或使含有第一种溶质的第一带电相与至少一种含有第二种溶质的第二相接触。这些溶质互不相容。这两相之间的静电力诱导在连续相形成分散相的液滴。所述分散和连续相含有带相反电荷的分子，它们稳定分散相的液滴。
Description
相关申请的交叉参考
本申请是申请号为201480067369.2母案的分案申请。该母案的申请日为2014年12月9日；发明名称为“稳定化的全水乳液及其制备和使用方法”。本申请要求2013年12月9日递交的美国临时申请第61/913653号的权益。2013年12月9日递交的申请第61/913653号通过参考以其全部结合到本文中。
技术领域
本发明属于全水乳液(all-aqueous emulsions)，特别是稳定化的全水乳液领域。
背景技术
通过把两种不相容的溶质高于相分离的临界浓度溶于水中，形成含水双相系统(ATPSs)，或者全水乳液。如果焓的减少足以克服与增加的熵有关的能量消耗，则这些不相容的溶质可在水中重新分配并形成不混溶的水相。这通常需要ATPS的各溶质类物质与其本身比与其它类物质更强烈地相互作用，导致相同类物质的溶质的分离和相分离。然而，这种分离不完全并且每一相通常仍然含有少量的其它类物质分子。
例如，在PEG/葡聚糖/H2O系统的平衡相图，富含葡聚糖的相含有微量的PEG，类似地，富含PEG的相也含有葡聚糖。平衡相的组成随着不相容溶质的分子量、温度及其它盐添加剂而变化。这种不完全的分离导致混合熵低于完全分离，并因此减少相分离的能量消耗。
通过ATPSs相分离形成的不混溶相不含有机溶剂，因此它们在生物医学研究与应用方面为生物相容性的和生态友好的。在生物材料比如蛋白微球和水凝胶珠粒的合成中，通常涉及有机溶剂。在使分散相固化形成固体材料时，必须通过反复洗涤提取有机溶剂。当ATPSs用于形成乳液时，可避免这些繁琐的除去有机相的步骤。此外，当蛋白溶液暴露于油相时，通常在水-油(w/o)界面发生蛋白变性，减少蛋白的生物活性。使用ATPS可避免有机溶剂对蛋白生物活性和细胞活力的有害影响。
用于制备全水乳液的传统方法，比如涡旋混合和均质化，不考虑控制生成的全水乳液的尺寸和/或结构。为了克服这些局限性，研究了用于制备全水乳液的微流体。尽管微流体装置使得能够产生具有高单分散性及对液滴形状和结构的控制的油包水(w/o)或水包油(o/w)型乳液，但是由于这种系统的界面张力低，以典型的微流体通道不容易实现单分散w/w乳液的形成。低界面张力系统的射流分散通常由于大的毛细管和韦伯数而导致多分散液滴。
已经探索了试图克服微流体法的局限性。例如，作为产生全水乳液的手段研究了扰动。为了诱导w/w射流的分散，在系统中引入振动源，以在w/w射流的表面产生最初的波纹。通过在通道壁嵌入压电致动器，或者通过使用挤压连接至进入通道的软管的机械振动器，这些振动可被结合至微流体装置中。振动器对驱动压力施加波动，并调节扰动阶段的瞬时流速，局部改变w/w射流的直径。波纹射流的形状可通过施加适当频率和振幅的扰动进行控制。
然而，扰动方法在具有100 mPa•s或以上动态粘度的全水系统尚未得到证实。粘性w/w射流的有效分散受到瑞利-普拉陶(Rayleigh-Plateau)不稳定性的低增长率限制。此外，采用该法制备的乳液由于分散相的聚结仅可稳定短的时间段。
需要产生具有高单分散性的稳定的全水乳液，特别是具有高粘度(例如≥100mPa•s)和/或超低界面张力的乳液的方法。
因此，本发明的目的是提供产生具有高单分散性的稳定的全水乳液，特别是具有高粘度(例如≥100 mPa•s)和/或超低界面张力的乳液的方法。
发明内容
本文描述用于制备全水乳液，包括稳定的乳液和/或具有高粘度和/或超低界面张力的乳液的方法。所述方法包括混合、合并或使含有第一种溶质的第一带电相(例如分散相)与至少含有第二种溶质的第二相(例如连续相)接触。这些溶质互不相容。两相之间的静电力诱导在连续相形成分散相的液滴。
分散和连续相含有带相反电荷的分子和胶体，比如表面活性剂、大分子、纳米粒子或纳米纤维，它们稳定分散相的液滴。带相反电荷的分子或胶体在两个水相界面的复合凝聚，导致形成防止液滴的聚结或聚集的膜或屏障。这种膜还防止任何包封的物质(例如治疗药物、预防药物和/或诊断用药物)自液滴渗漏。
本文描述的乳液可用于多种应用，比如药物递送(例如小分子、生物分子、细胞等)、材料制备、生物细胞器的建模，包封用于食品和饮料应用的调味料、染料、维生素等；包封用于化妆品的活性物质；包封生长因子、干细胞或用于生物医学应用的其它生物分子；包封用于化学反应的化学反应物，及其组合。
附图说明
图1显示水性液滴的形成。小图(panel) a为以全水电喷射法形成水性液滴的示意图。小图b为通过全水电喷射产生的单分散水性液滴的光学显微镜图像。小图c为具有芯-壳结构的全水乳液的显微镜图像。液滴收集在载玻片上。比例尺(scale bar)为200 μm。
图2为显示作为所施加的DC电压(kV)的函数的PEG-液滴直径(微米)的图。
具体实施方式
I. 定义
“全水乳液”和“含水双相系统(ATPSs)”可互换使用，并且指的是在水性连续相中含有水性分散相的乳液。
本文使用的“超低界面张力”通常意指两个水相之间的界面张力小于2 mN/m。
本文使用的“稳定的”通常意指分散相经延长的时间段保持分开而不融合成连续的液相。
本文使用的“不相容”通常意指两个同类溶质分子之间的结合能低于两个不同类溶质分子之间的结合能。
II. 用于产生全水乳液的静电方法
本文描述用于制备全水乳液，包括稳定的乳液和/或具有高粘度和/或超低界面张力的乳液的方法。所述方法包括混合、合并或使含有第一种溶质的第一带电相(例如第一相)与至少含有第二种溶质的第二相(例如连续相)接触。在一些实施方案中，仅有一种溶液带电，尽管可以是两种溶液带电。这些溶质互不相容。已经发现两种溶液之间的静电力诱导在连续相形成分散相的液滴。
分散和连续相含有带相反电荷的分子和胶体，比如表面活性剂、大分子、纳米粒子或纳米纤维，比如表面活性剂或其它大分子，它们稳定分散相的液滴。带相反电荷的分子或胶体在两个水相界面的复合凝聚导致形成防止液滴的聚结或聚集的膜或屏障。这种膜还防止任何包封的物质(例如治疗药物、预防药物和/或诊断用药物)自液滴渗漏。
A. 不相容的溶质
通过把两种不相容的溶质高于相分离的临界浓度溶于水中，形成含水双相系统(ATPSs)。如果焓的减少足以克服与增加的熵有关的能量消耗，则这些不相容的溶质可在水中重新分配并形成不混溶的水相。这通常需要ATPS的各溶质类物质与其本身比与其它类物质更强烈地相互作用，导致相同类物质的溶质的分离和相分离。
本领域已知的多种溶质可用于形成全水乳液。示例性的溶质包括但不限于聚合物，比如聚乙二醇(PEG)、葡聚糖、甲基纤维素、硫酸葡聚糖钠、聚乙烯醇(PVA)和聚乙烯吡咯烷酮(PVP)、酪蛋白酸盐和藻酸盐；盐类，比如磷酸盐(例如磷酸三钾和磷酸二钠)、枸橼酸盐(例如柠檬酸钠)、硫酸盐(例如硫酸钠)和碳酸盐。在一些实施方案中，一相含有PEG和另一相含有葡聚糖。
溶质的浓度可依溶质的性质而定变化。通常，浓度为约3.5 wt%-水中受限制的溶解度。在其中溶质为PEG和葡聚糖的那些实施方案中，PEG的浓度为约3.5 wt%-约20 wt%和葡聚糖的浓度为约3.5 wt%-葡聚糖的溶解度极限。
PEG的重均分子量为约1000道尔顿-约100000道尔顿，优选地为约2000道尔顿-约20000道尔顿，优选地为约2000道尔顿-约10000道尔顿，更优选地为约5000道尔顿-约10000道尔顿。在一些实施方案中，PEG的分子量为约8000道尔顿。
葡聚糖的重均分子量为约40000道尔顿-约1000000道尔顿，优选地为约70000道尔顿-约500000道尔顿。在一些实施方案中，分子量为约500000道尔顿。
B. 治疗药物、预防药物和诊断用药物
一个或多个相可含有一种或多种治疗药物、预防药物和/或诊断用药物。在一些实施方案中，形成分散相的溶液含有一种或多种在形成乳液时包封在液滴内的治疗药物、预防药物和/或诊断用药物。在本文描述的方法中，溶液可含有带与向其加入的溶液的电荷相反的电荷的表面活性剂。带电的表面活性剂在不相容溶液界面的凝聚，导致形成可防止所包封的物质渗漏的膜。
一种或多种治疗药物、预防药物和/或诊断用药物可为小分子治疗药物(例如具有小于2000 amu、1500 amu、1000 amu、750 amu或500 amu的分子量的治疗药物)和/或生物分子，比如蛋白、核酸(例如DNA、RNA、siRNA等)、酶等；和/或细胞。
在一些实施方案中，所述药物为生物分子，比如蛋白、酶、核酸等。生物分子在有机溶剂存在下可变性。因此，全水乳液提供用于递送这类药物，同时保持所述药物的生物活性的媒介物。
要递送的物质包括治疗、营养、诊断和预防性化合物。蛋白、肽、碳水化合物、多糖、核酸分子和有机分子以及诊断用药物可被递送。要掺杂的优选物质为药物和显像剂。治疗药物包括抗生素、抗病毒药物(尤其是单独或与用于治疗HIV或者乙型或丙型肝炎的核苷联合的蛋白酶抑制剂)、抗寄生虫药(寄生虫、原生动物)、抗癌药(本文称为“化学疗法”，包括细胞毒药物比如多柔比星、环孢霉素、丝裂霉素C、顺铂和卡铂、BCNU、5FU、甲氨蝶呤、阿霉素、喜树碱和紫杉醇)、抗体及其生物活性片段(包括人源化、单链和嵌合抗体)、抗原和疫苗制剂、肽类药物、抗炎药、营养物质比如维生素以及寡核苷酸药物(包括DNA、RNAs、反义的、适配子、核糖酶、核糖核酸酶P的外部引导序列及三链体形成剂)。要递送的特别优选的药物包括抗血管生成剂、抗增殖和化学治疗药物比如雷帕霉素。
示例性的诊断用物质包括顺磁分子、荧光化合物、磁性分子和放射性核素。
基于肽、蛋白和DNA的疫苗可用于对多种疾病或病症诱导免疫力。例如，性传播的疾病和意外怀孕为影响女性健康和福利的世界性问题。在女性生殖道内诱导特异性免疫的有效疫苗可大大降低STDs的风险，而引发抗精子抗体的疫苗起免疫避孕的作用。广泛的研究已经证实，在远端部位-例如经口、鼻或直肠-接种疫苗可在女性生殖道内诱导粘膜免疫。在这些选项中，经口给予由于其潜在的患者依从性、易于给予和适合广泛使用而获得最大兴趣。蛋白口服疫苗接种是可能的，但是通常效率不高或需要很高剂量。DNA口服疫苗接种尽管在较低剂量下可能有效，但是在大多数情况下已经无效，因为‘裸DNA’易受胃肠道中胃的酸度和消化酶两方面影响。
C. 细胞
本文描述的乳液自水性分散相和水性连续相制备，并且因此不含任何有机溶剂。这种乳液对于包封细胞是合乎需要的，细胞的活力可受到有机溶剂的不利影响。可将细胞加入到变为分散相的溶液中和/或变为连续相的溶液中。
示例性的细胞类型包括但不限于角质形成细胞、成纤维细胞、韧带细胞、内皮细胞、肺细胞、上皮细胞、平滑肌细胞、心肌细胞、骨骼肌细胞、胰岛细胞、神经细胞、肝细胞、肾细胞、膀胱细胞、泌尿道上皮细胞、干或祖细胞、神经母细胞瘤、软骨细胞、皮肤细胞和成骨细胞。
D. 乳液稳定化
尽管已经用不同方法产生了具有可控和可调结构的全水乳液，但是所有这些乳液都仅是暂时性的稳定，并且往往随后聚结。因此这些乳液的稳定在科学研究和实际应用两方面是有用的。
1. 全水乳液为模板的材料
通过选择性地使分散相固化，形成水凝胶珠粒或胶囊，可产生稳定化的乳液结构。为了防止液滴聚结，可向乳相加入光致固化单体比如PEGDA或葡聚糖-HEMA，并且快速的光致聚合有助于使乳液在数秒内固化。然而，光致聚合一般产生毒性的自由基，可能危害所包封的种类，尤其是活的种类。为了实现无自由基凝胶化，乳相可通过向乳相中的凝胶前体扩散生物相容性的交联剂来固化。例如，当藻酸钠溶液用作乳相时，乳液可通过引入钙离子而在1分钟内快速固化。所包封种类的渗漏在乳液凝胶化的时间量程内可以忽略。然而，许多生物相容性的凝胶化反应，比如酶诱导的凝胶化，持续数小时至数天，此时所包封种类的渗漏不能忽视。在这种方式中，必须在w/w界面快速形成致密的膜，防止所包封种类的渗漏。
2. 水/水界面为模板的材料
在其它的实施方案中，乳液可通过在分散相液滴的表面形成膜或屏障，以防止聚结而得到稳定。粒子或大分子表面活性剂在w/w界面聚集，是乳液不稳定的主要机制。亚微米尺寸的乳胶微球和蛋白粒子能够不可逆地捕集在w/w界面。该特征表明，吸附能大于热激活所施加的动能。由于足够大浓度的蛋白粒子和高w/w界面张力，蛋白粒子成功地使PEG/葡聚糖乳液稳定几周。然而，在剪切流存在下，这些粒子与w/w界面脱离且不能使乳液稳定。加强蛋白粒子间的结合力，可防止由剪切流引起的与界面脱离。通过加入交联剂，比如戊二醛、聚乙烯亚胺、硫酸葡聚糖钠、多糖等；或者通过热温育引起蛋白粒子凝胶化，可实现结合力的增强。
大分子在w/w界面的自组装，提供稳定全水乳液的另一种可能的解决方案。为了形成稳定的乳液，大分子表面活性剂应在w/w界面聚集，并形成致密的膜。表面活性剂在w/w界面聚集受到其与水相中溶解的溶质相互作用的强烈影响。通过观察包封两种不混溶的水相的脂质体形成，证实这种相互作用的存在。在该实例中，自脂质体提取水后，两个水相选择性地接近不同的脂质区域。膜与不相容溶质间的相互作用还在w/w界面保持膜。该假设通过采用共聚物自w/w乳液模板形成囊泡得到证实。在该研究中，PEG-聚已内酯(PCL)和葡聚糖-PCL共聚物分别被加入到富含PEG和富含葡聚糖的相中。在涡旋混合这两相时，两种共聚物在w/w界面自发聚集。更重要的是，可能是由于疏水性相互作用，PCL部分促进形成致密的膜。
i. 带电表面活性剂/脂质
分散相和连续相可含有一种或多种带相反电荷的表面活性剂和/或脂质。在使两种溶液接触时，带相反电荷的表面活性剂在两个水相的界面经历表面活性剂的复合凝聚，导致形成防止液滴聚结或聚集的膜或屏障。这种膜还防止任何所包封的物质(例如治疗药物、预防药物和/或诊断用药物)自液滴的渗漏。
合适的带电表面活性剂包括阳离子型表面活性剂和阴离子型表面活性剂。阴离子型表面活性剂一般含有一个或多个带负电荷的基团或基团，比如硫酸根、磺酸根、磷酸根和羧酸根。示例性的阴离子型表面活性剂包括但不限于烷基硫酸盐，比如月桂基硫酸铵、月桂基硫酸钠(SDS，十二烷基硫酸钠)及相关的烷基醚硫酸盐月桂醇聚醚硫酸酯钠，也称为月桂基醚硫酸钠(SLES)，和肉豆蔻醇聚醚硫酸钠；多库酯钠，比如磺基琥珀酸二辛酯钠、全氟辛磺酸盐(PFOS)、全氟丁磺酸盐、直链烷基苯磺酸盐(LABs)、烷基-芳基醚磷酸盐和烷基醚磷酸盐，以及羧酸盐，比如烷基羧酸盐(肥皂)，包括硬脂酸钠。其它实例包括月桂酰肌氨酸钠和基于羧酸盐的含氟表面活性剂比如全氟壬酸盐、全氟辛酸盐(PFOA或PFO)。
阳离子型表面活性剂一般含有一个或多个带正电的基团或头基，比如pH依赖性伯、仲或叔胺及永久带电的季铵阳离子。示例性的阳离子型表面活性剂包括但不限于烷基三甲基铵盐，比如十六烷基三甲基溴化铵(CTAB)和十六烷基三甲基氯化铵(CTAC)、氯化十六烷基吡啶 
(CPC)、苯扎氯铵(BAC)、苄索氯铵(BZT)、5-溴-5-硝基-1,3-二
烷、二甲基双十八烷基氯化铵、西曲溴铵和双十八烷基二甲基溴化铵(DODAB)。
其它带电分子包括但不限于脂质(例如磷脂、鞘脂类、皮肤脂质等)、两亲性嵌段共聚物、聚电解质及其组合。
带相反电荷的材料浓度通常接近临界胶束浓度，例如为约0.1 wt%-约1.0 wt%。然而，对于给定的带电分子浓度可以变化。
E. 制造技术
本领域已知的技术可用于制备本文描述的稳定化的乳液。在一些实施方案中，乳液采用电喷射技术制备。
电喷射为通过静电带电产生非常精细的液体气溶胶的方法。在电喷射中，液体通过喷嘴。通过使液体带电到很高电压产生一缕缕液滴。当被迫带有越来越多的电荷，喷嘴中的带电液体变得不稳定。很快液体达到临界点，此时它可能不再带有更多的电荷，且在喷嘴的尖端它被吹开，成为一团微小的、高度带电的液滴。这些微小的液滴一般直径小于10 μm，并且四处飞散寻找电荷与其自身相反的潜在的表面降落。当液滴四处飞散，它们由于溶剂分子自其表面蒸发而快速收缩。因为电荷很难蒸发，液滴中电荷之间的距离显著减小。如果液滴不能发现及时驱散其电荷的表面，电荷达到临界状态，并且液滴再次猛烈地吹开。
在本文描述的方法中，电喷射用于使含有第一种溶质的第一种水溶液与含有第二种溶质的第二种水溶液接触，其中这些溶质是不相容的。其中一种溶液变为乳液中的分散相，而另一种变为连续相。分散和连续的水相由空气的中间相分开，防止高电压诱导的带电溶质混合。在一些实施方案中，分散相(例如含有PEG的溶液)用高DC电压带电，并通过空气喷射到含有第二种溶质(例如葡聚糖)的不混溶的水溶液中。分散相与空气之间大的表面张力有助于使射流快速分散成液滴。在增大所施加的电压时观察到下滴至射流转变。在下滴状态中，带电射流在喷嘴的末端立即分散，产生具有少于5%、4%、3%、2%或1%的多分散性的单分散液滴。在射流态中，在泰勒圆锥(Taylor cone)的末端形成具有一般高于在下滴状态形成的那些的多分散性的液滴。减小喷嘴尺寸减小射流直径，因此促进在电滴态快速形成液滴。
分散液滴的直径可作为所施加电压的函数变化。例如，通过把电场强度从1.0 kV/cm增大至8.0 kV/cm，在葡聚糖连续相中分散的PEG-液滴的直径从约800微米变化至约120微米。在这些电压下，液滴为单分散的。进一步增大所施加的电压，得到多分散液滴。
用全水电喷射方法也可产生芯-壳结构的乳液。可将具有锥形喷嘴的圆形毛细管共轴插入另一个锥形直角的(squared)毛细管，形成同向流动的几何形状。两个不混溶的水相分别注入到内外玻璃毛细管中，形成外相包内相(inner phase-in-outer phase)射流。外相可通过高压电源带电，并迫使复合射流在静电力下通过环形对电极。在射流分散时，芯-壳结构的液滴最后落入连续相。乳液芯和壳的相对大小可通过改变两种流体的流速比易于进行调整。例如，把壳(例如富含PEG的相)与芯(例如富含葡聚糖的相)的流速比从4:1调整至1:1至1:5，导致芯的尺寸增大，如由光学成像显示的那样。
关键优势是，存在两种不混溶的水相意指两相可具有不同浓度的要包封的活性成分。一个水相中活性成分与另一个水相中的浓度比定义为分配系数。只要分配系数不是1，预计在两个水相中的浓度不同。这可用于保持两相之间的浓度梯度，如果两个水相可混溶则这是不可能的，因为两相间的混合更快速。甚至对于可跨界面扩散的种类，界面的存在起阻挡这种扩散的屏障作用，这帮助把渗漏的活性成分更长时间保持在所期望的相内。
本文描述的乳液比现有技术乳液呈现更大的稳定性。例如，乳液至少约14天、21天、30天、45天、60天、75天、90天、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、1年或更长时间显示很少或没有聚集。
III. 应用
许多全水乳液具有超低界面张力和相对大的动态粘度，因此，形成w/w乳液不能依靠如在现有技术中依靠的常规微流体设计中的自发性射流分散。在修改的装置几何学成功产生w/w乳液，限于具有高于0.1 mN/m的界面张力和低于102 mPa•s的动态粘度的ATPSs，比如葡聚糖/PEG系统和PEG/盐系统。在含有富含蛋白的相或其它聚电解质相的ATPS，甚至当采用水动力扰动时，w/w射流的分散通常受到ATPS的超低界面张力和高粘度的限制。
本文描述的全水电喷射法代表该领域一种有前途的方法。所施加的高电压提供给粘性射流强力拉动，并且大的表面张力诱导射流分散，这适合于具有高粘度(>100 mPa•s)和超低界面张力的乳液。然而，具有高于10-4 N/m的界面张力和小于102 mPa•s的动态粘度的ATPS系统尚未研究。在包含无机盐的系统中已经发现这种ATPSs，但是溶液相中的浓盐对于蛋白和细胞通常是太苛刻的环境，部分原因是由于不可避免的高摩尔渗透压浓度。包含生物相容性大分子的ATPS是包封这种材料的有前途的备选方案。不相容性溶质的分子结构可以专门设计，关于分子间力及其在w/w界面的构象有特别考虑，以使系统适合于要包封的材料。
A. 材料制备
尽管多功能材料的制备可由具有复杂结构的乳液为模板，但是这个概念尚不充分适合全水系统。在亚微米尺寸范围，ATPS中大分子和粒子的自组装受到其与周围分子相互作用的影响。这些相互作用可被操控，以控制生物分子在全水多相系统中的构象，并指导共聚物、大分子和胶体组装成期望的聚集体。
在微米或更高的尺寸范围，产生具有柔性结构和尺寸的多重全水乳液提供在设计多功能材料，比如药物递送媒介物、生物传感器、微型反应器和微型容器方面需要的多功能性。乳液和乳液为模板的材料的大规模堆叠将导致高度有组织的层级结构，包括微纤维、膜和多孔支架。这些结构的成功构建是人工材料比如组织样支架和光子材料的功能复制的先决条件。材料的层级组装可通过全水相或其界面引导。在功能仿生装置的组装中，液滴网络可通过3-D打印和腔室中液滴填充构建。同时，已经研究了纳米粒子在两个可混溶的水相界面的层级组装。当这个概念应用于不混溶的水相时，可证实纳米粒子在w/w界面组装而没有延伸到主体水相中。
B. 生物细胞器的建模
含水双相系统创建优良的全水环境，用于模拟细胞中的细胞质环境。在单细胞胚胎分化期间，发现RNA-结合蛋白通过分配使自己定位，因此，水相分离可能在生物组分的结构和组装方面发挥重要作用。生物分子选择性分配至不同的水相，并且这种选择性可在蛋白配体或酶存在下得到增强。生物分子在ATPS的分配增加其局部浓度，因此加速生化反应和分子组装。
生物分子在由水相形成的不同腔室间的转移可通过半渗透膜调节，这提供给细胞代谢一个稳定和动态的微环境。不同的生物分子和生物细胞器在全水乳液为模板的囊泡中的区域化，代表获得细胞模拟腔室的新途径。这提供了研究生物分子和生物细胞器的活性及其协同相互作用的机会。一旦开发了人工细胞模拟腔室，可在生理微环境实施蛋白和DNA的合成，其中这些生物分子的分子结构和生物功能得到最好保存。
C. 药物递送
这里描述的乳液可用于向有需要的患者递送一种或多种治疗药物、预防药物和/或诊断用药物和/或细胞。如以上讨论的那样，其中描述的乳液不含有机溶剂，并因此对于包封可能受到存在有机溶剂的不利影响的生物分子(蛋白、核酸等)和/或细胞是合乎需要的。此外，存在带相反电荷的大分子形成的膜提高乳液的稳定性，使其能够制备并在使用前储存一段时间。
乳液可配制成用于多种给予途径。在一些实施方案中，乳液肠内(例如经口)或经肠胃外给予。
本文使用的“经肠胃外给予”意指通过除了经消化道或非侵入性的局部或区域途径以外的任何方法给予。例如，经肠胃外给予可包括经注射和经输注，静脉内、皮内、动脉内、腹膜内、病灶内、颅内、关节内、前列腺内、胸膜内、气管内、玻璃体内、瘤内、肌内、皮下、结膜下、囊泡内、心包内、脐带内给予患者。
乳液可纯净(neat)给予，即不含另外的载体/赋形剂。或者，乳液可与一种或多种载体和/或赋形剂组合制备药用组合物。
载体可为含有例如水、乙醇、一种或多种多元醇(例如甘油、丙二醇和液体聚乙二醇)、油类比如植物油(例如花生油、玉米油、芝麻油等)及其组合的溶剂或分散介质。例如通过使用包衣比如卵磷脂、通过在分散体的情况下保持所需的粒度和/或通过使用表面活性剂，可保持适当的流动性。在许多情况下，优选地包括等渗剂，例如糖类或氯化钠。
合适的表面活性剂可为阴离子、阳离子、两性离子或非离子型表面活性剂。合适的阴离子型表面活性剂包括但不限于含有羧酸根、磺酸根和硫酸根离子的那些。阴离子型表面活性剂的实例包括长链烷基磺酸和烷基芳基磺酸的钠、钾、铵盐比如十二烷基苯磺酸钠；磺基琥珀酸二烷基酯钠比如十二烷基苯磺酸钠；磺基琥珀酸二烷基酯钠比如双-(2-乙基硫醇基(thioxyl))-磺基琥珀酸酯钠；和烷基硫酸盐比如月桂基硫酸钠。阳离子型表面活性剂包括但不限于季铵化合物比如苯扎氯铵、苄索氯铵、西曲溴铵、硬脂基二甲基苄基氯化铵、聚氧乙烯和椰油胺。非离子型表面活性剂的实例包括乙二醇单硬脂酸酯、丙二醇肉豆蔻酸酯、甘油单硬脂酸酯、甘油硬脂酸酯、聚甘油-4-油酸酯、脱水山梨糖醇丙烯酸酯、丙烯酸蔗糖酯、PEG-150月桂酸酯、PEG-400单月桂酸酯、聚氧乙烯单月桂酸酯、聚山梨醇酯、聚氧乙烯辛基苯基醚、PEG-1000十六烷基醚、聚氧乙烯十三烷基醚、聚丙二醇丁基醚、泊洛沙姆®401、硬脂酰单异丙醇酰胺和聚氧乙烯氢化牛脂酰胺。两性离子表面活性剂的实例包括N-十二烷基-β-丙氨酸钠、N-月桂基-β-亚氨基二丙酸钠、肉豆蔻酰两性基乙酸盐(myristoamphoacetate)、月桂基甜菜碱和月桂基磺基甜菜碱。
制剂可含有防腐剂，以防止微生物的生长。合适的防腐剂包括但不限于对羟基苯甲酸酯类、氯丁醇、苯酚、山梨酸和硫汞撒。制剂还可含有抗氧化剂，以防止活性剂的降解。
对于经肠胃外给予，制剂在重新组成时一般地缓冲至pH 3-8。合适的缓冲剂包括但不限于磷酸盐缓冲剂、醋酸盐缓冲剂和枸橼酸盐缓冲剂。
水溶性聚合物通常用于经肠胃外给予的制剂。合适的水溶性聚合物包括但不限于聚乙烯吡咯烷酮、葡聚糖、羧甲基纤维素和聚乙二醇。
肠内制剂采用药学上可接受的载体制备。本文通常使用的“载体”包括但不限于稀释剂、防腐剂、粘合剂、润滑剂、崩解剂、膨胀剂、填充剂、稳定剂及其组合。用于剂型的聚合物包括疏水性或亲水性聚合物及pH依赖性或非依赖性聚合物。优选的疏水性和亲水性聚合物包括但不限于羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙二醇、乙基纤维素、微晶纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚醋酸乙烯酯和离子交换树脂。
载体还包括包衣组合物的所有组分，其可包括增塑剂、颜料、着色剂、稳定剂和助流剂。
制剂可采用一种或多种药学上可接受的赋形剂制备，包括稀释剂、防腐剂、粘合剂、润滑剂、崩解剂、膨胀剂、填充剂、稳定剂及其组合。
延迟释放剂量制剂可如在标准参考文献中描述的那样制备，比如“药用剂型片剂”，Liberman等编辑(纽约, Marcel Dekker, Inc., 1989)、“雷明顿-药剂学的科学与实践”，第20版，利平科特威廉姆斯&威尔金斯(Lippincott Williams & Wilkins)，巴尔的摩(Baltimore)，MD，2000及“药用剂型和药物递送系统”，第6版，Ansel等(Media, PA: 威廉姆斯和威尔金斯(Williams and Wilkins), 1995)。这些参考文献提供了关于用于制备片剂和胶囊剂及片剂、胶囊剂和颗粒剂的延迟释放剂型的赋形剂、材料、设备和方法的信息。这些参考文献提供了关于用于制备片剂和胶囊剂及片剂、胶囊剂和颗粒剂的延迟释放剂型的载体、材料、设备和方法的信息。
稳定剂用于抑制或延缓药物分解反应，包括例如氧化反应。合适的稳定剂包括但不限于抗氧化剂、丁羟甲苯(BHT)、抗坏血酸、其盐和酯；维生素E、生育酚及其盐；亚硫酸盐比如偏亚硫酸氢钠；半胱氨酸及其衍生物；枸橼酸；没食子酸丙酯和丁基化羟基茴香醚(BHA)。
实施例
实施例1: 采用静电效应制备全水乳液
将通过高DC电压带电的分散相8 wt% PEG (Mw=8000)溶液通过空气喷射到其不混溶的水相15 wt%葡聚糖(Mw=500000)溶液中。分散相与空气之间大的表面张力帮助使射流快速分散成液滴(图1, 小图a)。在增大所施加的电压时观察到下滴至射流转变。在下滴状态中，带电射流在喷嘴的末端立即分散，产生具有少于5%的多分散性的单分散液滴(图1,小图b和c)。例如通过把所施加的电场从2.1 kV/cm增大至2.5 kV/cm，所产生的液滴直径从810 μm显著减小至120 μm (图2)。在这种情况下，带正电的喷嘴与带负电的电极环之间的距离为2 cm，和喷嘴直径为40微米。进一步增大电场强度导致具有更小尺寸的多分散液滴。减小喷嘴尺寸可产生具有更小尺寸的单分散液滴，例如当喷嘴尺寸减小至20 μm时。可产生具有小于50 μm直径的均匀液滴。
实施例2: 采用静电效应制备芯-壳全水乳液
把两个不混溶的水相10%葡聚糖(Mw=500000)和8 wt% PEG (Mw=8000)溶液分别注入到内外玻璃毛细管中，形成PEG包葡聚糖的射流(图1, 小图a)。富含PEG的相通过高压电源带电，并迫使复合射流在静电力下通过环形对电极。在射流分散时，芯-壳结构的液滴落入葡聚糖溶液连续相中或固体基体的表面上(图1, 小图c)。芯的直径通过改变富含PEG(壳)和富含葡聚糖(芯)相的流速比来改变。当流速比从4:1变为1:1至1:5，芯的直径增大。
除非另外定义，本文使用的所有技术和科学术语具有与所公开的发明所属领域技术人员通常理解的相同含义。本文引用的出版物和它们所引用的材料通过参考具体结合。
本领域的技术人员将认识到，或者仅仅采用常规实验就能够确定，本文所描述发明的具体实施方案的许多等同方案。这种等同方案打算由以下权利要求包括在内。
Claims (7)
1.一种乳液，所述乳液通过以下方法制备，所述方法包括使含有第一种溶质和一种或多种带电表面活性剂的带电第一水相与含有第二种溶质和一种或多种带电表面活性剂的第二水相接触，第二水相的表面活性剂带有与第一水相中表面活性剂的电荷相反的电荷，其中所述溶质不相容并且在连续相中诱导形成分散相的液滴，其中所述第一水相和第二水相采用电喷射接触，其中所述液滴包含在液滴表面上的膜，所述膜防止液滴聚结和/或防止液滴的内容物渗漏，其中所述乳液具有>100 mPa•s的动态粘度或小于2 mN/m的界面张力。
2.根据权利要求1所述的乳液，其中所述第一和第二种溶质选自聚乙二醇、葡聚糖、甲基纤维素、硫酸葡聚糖钠、聚乙烯醇、聚乙烯吡咯烷酮、磷酸三钾、柠檬酸钠、硫酸钠和磷酸二钠。
3.根据权利要求2所述的乳液，其中所述第一种溶质为聚乙二醇和所述第二种溶质为葡聚糖。
4.根据权利要求3所述的乳液，其中聚乙二醇的分子量为8000-20000道尔顿，和聚乙二醇的浓度为8wt%，和葡聚糖的分子量为500000道尔顿，和葡聚糖的浓度为5-15wt%。
5.根据权利要求1所述的乳液，其中所述第一水相和/或所述第二水相还含有一种或多种包封在分散相的液滴中的治疗药物、预防药物和/或诊断用药物。
6.根据权利要求1所述的乳液，其中所述第一水相和/或所述第二水相还含有包封在分散相的液滴中的细胞。
7.根据权利要求1所述的乳液，其中所述液滴的直径为100微米-1000微米。
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