CN101951895B - 药物给药用的纳米粒子载体及其制备方法 - Google Patents

药物给药用的纳米粒子载体及其制备方法 Download PDF

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CN101951895B
CN101951895B CN2008801270301A CN200880127030A CN101951895B CN 101951895 B CN101951895 B CN 101951895B CN 2008801270301 A CN2008801270301 A CN 2008801270301A CN 200880127030 A CN200880127030 A CN 200880127030A CN 101951895 B CN101951895 B CN 101951895B
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隆基·卡隆博
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Abstract

本发明提供了一种用于制备药物递送用的纳米粒子载体的方法，所述纳米粒子是通过如下步骤制备的：制备水-油-水的双乳液，所述双乳液包含一种或多种形成所述纳米粒子载体的基材的聚合物；将待递送的所述药物共混到一个乳液相中；将碳水化合物掺入油相或外水相；和将所述乳液进行喷雾干燥以形成100nm至1000nm的窄粒度分布的纳米粒子，所述纳米粒子基本上是球形的。

Description

药物给药用的纳米粒子载体及其制备方法
发明领域
本发明涉及用于药物活性化合物和/或其它化合物的口服给药的纳米粒子载体。 
发明背景 
已知喷雾干燥技术在具有特定特性比如粒度、密度和形状的药物粉末的制备中得到了广泛应用，所述药物粉末主要用于肺部药物递送(drug delivery)。通过将悬浮液或溶液雾化成液滴，之后在流动热空气中进行干燥处理而制备固体粉末是一种早已确立的方法。 
尽管通常被认为是一种脱水方法，但是喷雾干燥也可以被用作将活性物质包埋在聚合物基体或壳中的包封法。据报导，使用干燥助剂，尤其是糖比如乳糖、山梨糖醇和海藻糖，已成功地将若干种胶体体系比如乳液或脂质体在保持它们的结构的情况下喷雾干燥。 
喷雾干燥技术的优点之一在于它是一种可应用于许多药物产品并且导致产生易流动粉末的成本有效且快速干燥的方法，其特征在于非常低的水含量，因而防止了活性成分的降解。这对于开发长时间稳定载体是有意义的，这主要是在这些载体处于为了活性化合物在感兴趣的部位上的递送而特别设计的纳米尺度范围内时。 
最近，已经表明，喷雾干燥技术可以制备负载有活性剂的纳米尺度固体粒子和固体类脂纳米粒子，以将其用作用于肺部气道(pulmonary airways)的递送体系。值得注意的是，在这种技术被应用于制备固体纳米粒子的大多数情况下，它实际上是通过其它技术获得的纳米胶囊的干燥方法。之后，将该纳米粒子的悬浮液进行喷雾干燥。这通常导致具有从纳米至微米尺寸的非常宽尺寸范围的粒子的产生，尽管在制剂中存在作为干燥赋形剂的二糖。 
最近，报导了在药物递送领域中的液体胶体体系的喷雾干燥，其中含 有包封在乳酸-乙醇酸共聚物(PLGA)中的DNA的单乳液(油包水乳液)成功地被喷雾干燥。另一个报导是在乳糖的存在下对双乳液(水包油-油包水(oil-in-water-in-oil)或O/W/O)进行了喷雾干燥，其旨在保持橙色油(orange oil)并且在两种情况下，所产生的粒子均处于微米尺寸范围内。 
已经确定需要具有窄尺寸分布范围，典型地为180至250nm的球形纳米粒子。理想地，这种粒子应当具有基本上平滑的表面并且是易流动的。 
发明概述 
本发明提供了一种用于制备药物递送用的纳米粒子载体的方法，所述纳米粒子是通过如下步骤制备的： 
-制备水-油-水的双乳液，所述双乳液包含一种或多种形成所述纳米粒子载体的基材(basis)的聚合物； 
-将待递送的所述药物共混到一个或多个乳液相中； 
-将碳水化合物掺入油相或外水相；和 
-将所述乳液进行喷雾干燥以形成100nm至1000nm的窄粒度分布的纳米粒子。 
由此制备出的纳米粒子可以是多功能纳米粒子。 
碳水化合物可以是糖类。 
所述糖类可以是二糖。 
二糖可以是乳糖、麦芽糖、异麦芽糖、甘露二糖(mannobiose)、海藻糖、纤维二糖等。 
糖类可以与可阳离子生物降解的粘膜粘附多糖(muco-adhesive polysaccharide)组合。 
多糖可以是壳聚糖或其衍生物。 
可以将表面活性剂掺入乳液的油相。 
可以将表面活性剂掺入乳液的水相。 
表面活性剂可以是非离子型表面活性剂。 
表面活性剂可以基于炔二醇化学物质(acetylenic diol chemistry)。 
表面活性剂可以是聚合物非离子型表面活性剂。 
在水相中的聚合物非离子型表面活性剂可以是部分水解的聚乙烯醇 (PVA)。 
聚合物可以在乳液的油相中。 
在油相中的聚合物可以是PLGA(乳酸-乙醇酸共聚物)。 
油相和水相聚合物可以同时存在。 
可以向油相中添加药物。 
药物可以是添加到内水相中的亲水性药物。 
药物可以是疏水性的，并且可以任选地被添加到油相中。 
药物可以是利福平、异烟肼、乙胺丁醇或吡嗪酰胺(Pyrazynamide)。 
乳液的外水相可以包含聚乙二醇(PEG)。 
油相可以包含硬脂酸。 
由此形成的纳米粒子可以基本上是球形的。 
该纳米粒子的粒度分布可以为直径180nm至250nm。 
下面对实施方案的描述应当宽泛解释，而不应当解释为限制本发明的范围。 
本发明实施方案详述 
1.实验物品 
对于本实验而言，包括异烟肼(INH)、乙胺丁醇(ETH)、吡嗪酰胺(PZA)和利福平的抗结核病抗生素已经被成功负载在DL乳酸-乙醇酸共聚物(PLGA50:50))的聚合物核-壳纳米粒子中，所述DL乳酸-乙醇酸共聚物是一种广泛用作载体的可生物降解的和生物相容性的聚合物。掺混INH(或Eth或PZA或RIF)的PLGA的亚微米固体粒子已经通过将典型油包水-水包油(W/0/W)双乳液直接喷雾干燥而获得。 
在制剂中，壳聚糖，一种可阳离子生物降解的粘膜粘附多糖，被用作吸收促进剂，而采用一水合乳糖用作喷雾干燥助剂。PVA被视为双乳液的主要稳定剂组分，而PEG被掺混以增加载体的生物循环。 
作为助表面活性剂的Surfynol 104PG-50TM在使粒度朝纳米尺寸范围降低，同时使尺寸分布显著变窄方面扮演了重要的角色。 
2.材料和方法 
2.1材料 
第一线(frontline)的抗结核病药物是从Sigma购买的。DL乳酸-乙醇酸共聚物(PLGA)50:50(Mw：45000-75000))和壳聚糖(低Mw，85％脱乙酰)均由Sigma提供。聚乙烯醇(PVA)(Mw：13000-23000，并且部分水解(87-89％))也从Sigma获得。硬脂酸由Merck提供，而Surfynol 104PG-50TM，即一种二聚(Gemini)二醇型表面活性剂由Air Products提供。聚乙二醇(PEG)(Mw 9000)从BASF Chemicals购买。由Merck提供的一水合乳糖被用作赋形剂。 
二氯甲烷、乙酸乙酯和乙腈为分析和HPLC级，也由Merck提供。 
2.2方法 
2.2.1制剂 
纳米粒子的制备通过基于如下过程的方法实现：从双乳液W/O/W中进行界面聚合物沉淀，随后进行有机溶剂的蒸发。在本发明中，溶剂蒸发和干燥的步骤通过应用喷雾干燥技术而被组合在一个步骤中。 
简要地，将50mg的INH溶解在2ml的磷酸盐缓冲溶液(pH7.4)中，其被添加到将100mg的PLGA(50:50)溶解在8ml有机溶剂(DCM或乙酸乙酯)中所得的溶液中。还可以将任选的2ml的0.2％(w/v)硬脂酸溶解在相同的溶剂(DCM或乙酸乙酯)中。将Surfynol 104PG-50TM的液滴有意添加到PLGA油相中或含有PVA的外水相中。 
使用高速均化器(Silverson L4R)将该混合物在5000rpm下进行乳化3分钟，以产生W/O乳液。然后，立即将所得的这种第一乳液以限定体积比倾倒入已知浓度的PVA(1或2％w/v)、PEG 0.5％w/v、壳聚糖和乳糖水溶液的水相容积(volume)内，并且通过高速均化器(Silverson L4R)在8000rpm乳化5min以再次形成双乳液W/O/W。将得到的最终乳液直接进料通过喷雾干燥器，以利用在表1中所规定的条件制备纳米粒子。 
喷雾干燥 
使用具有标准喷嘴(0.7mm直径)的Büchi小型喷雾干燥器型号B-290(Büchi Lab，瑞士)制备各种制剂的干燥粉末。在表1中编辑了所使用的条 件。 
表1B-290Büchi小型喷雾干燥器的喷雾干燥工艺条件 
Figure BPA00001205497900051
喷雾干燥器装备有高性能的旋风分离器，其被设计为在接收容器中得到极好的材料回收，并且降低了产物在干燥室的壁上的粘附。 
2.2.2粒度和粒度分布 
粒度和粒度分布通过使用Malvern Zetasizer Nano ZS(Malvern Instruments Ltd，UK)的动态激光散射或光子相关能谱法(Photon Correlation Spectroscopy)进行测量。对于每一个样品，通过将粒子悬浮在过滤后的水(0.2μm过滤器)中，进行涡流和/或超声波处理2分钟(必要时)，制备出3-5mg的喷雾干燥粉末。每一个样品均测量三次。 
2.2.3ζ电势 
粒子的ζ电势使用Zetasizer Nano ZS(Malvem Instruments Ltd，UK)测量。为此，将3mg的喷雾干燥纳米粒子的样品悬浮在1-2ml的去离子水中， 然后进行涡流或超声波处理，之后进行测量。每一次测量均进行三次。 
2.2.4扫描电子显微镜 
通过扫描电子显微镜(LEO 1525场发射SEM)显现出喷雾干燥纳米粒子的表面形貌。使用双面胶带将少量的纳米粒子粉末安放在黄铜桩(brass stub)上，并且通过溅射真空涂覆薄的金层。 
2.2.5药物掺混 
使用分光光度法(紫外-可见光，Thermo Spectronic Heliosα)，对在纳米包封处理之后被包埋在粒子粉末中的一定量亲水性药物异烟肼进行三次测量。在纳米粒子中的INH的包封效率被确定为包埋的INH与制备时所使用的INH的理论量的质量比。为此，将50mg的沉淀粒子重新悬浮在20ml的去离子水中，离心(10000rpm/10C/5min)以移除未包封的药物，并且将上清液进行紫外-可见光分光光度测量，在λ＝262nm的读数用于INH的评价。INH的包封量通过从总的初始INH量减去在上清液中的INH而确定。 
使用HPLC对INH稳定性评价 
使用装配有Photodiode Array(PDA)检测器的Shimadzu机器，通过反相-高效液相色谱-分析(RP-HPLC)来评价INH喷雾干燥粉末的稳定性。 
使用下面的特性：Column Phenomenex[(C18(5μm)；(250x4.6mmID)]，流动相是5％(v/v)乙腈和95％(v/v)缓冲剂NaH2P04(pH 6.8)，流速为1ml/min，温度为30℃。检测使用PDA在λ＝259nm进行，总的注射体积为20μl。 
3.结果与讨论 
所有的喷雾干燥试验均制备了尺寸在约220至800nm的范围内的纳米粒子。如所示的，在使用PVA浓度从1％改变为2％的样品的情况下，液体进料的浓度没有显示对粒度有任何影响。只有乳糖和Surfynol 104PG-50 TM的添加表现出对纳米粒子的尺寸和形貌有显著影响。有趣的是，仅仅一滴二聚表面活性剂添加到油相中，就剧烈地降低产物的尺寸和粒度，而与 有机溶剂的种类或PVA的浓度无关。 
在除温度之外的所有实验设定的过程中，喷雾干燥器的所有其它参数均保持恒定。质量比PLGA∶INH(2∶1)也未改变。乳糖的添加明显改善了纳米粒子的形状。在使用二氯甲烷作为有机溶剂时，这种效果是显著的。 
对于所有被研究的制剂，粉末的收率均在40-70％的范围内。 
由热分析测定的所选取样品的残留水含量显示为非常低的水分量(～3％)。 
由HPLC获得的结果表明了INH的降解，这可能是归因于与乳糖的相互作用。这种难题通过用壳聚糖将乳糖的官能团在将它们掺混到制剂中之前封端而得到克服。 
INH的包封效率接近60％。 
3.1溶剂对于粒度和形貌的影响 
在双乳液技术中最通常使用的有机溶剂是二氯甲烷(DCM)和乙酸乙酯(EA)。 
因此，本发明人决定通过改变有机溶剂来监测纳米粒子的尺寸和形貌。在所有情形下，当采用乙酸乙酯作为有机溶剂时，所得的第一乳液显示了短暂稳定乳液的一面，这种观察基于以下情况：在与使用DCM获得的乳液相比时，乳液的乳状外观更差。 
相比于使用DCM制备的样品，EA样品产生非常不规则的表面形貌。来自EA的粒子在添加乳糖之前是高度凹陷和皱缩的。还观察到小的环形的粒子。 
3.2添加剂的影响 
3.2.1乳糖对粒度和形貌的影响 
相的组成强烈影响纳米粒子的尺寸和形状以及表面形貌。当乳糖的初始浓度从5％w/v增加至10％w/v时，粒子从高度皱缩转变成接近平滑的球形。如图1C和D的SEM图所示，环形的粒子的分数明显地减小，而与所使用的溶剂的种类无关。然而，在观察的尺度内，在使用DCM的情况下观察到大得多的表面平滑度。 
当本发明人将其与不添加乳糖的制剂相比时，粒度降低，而与所使用的有机溶剂的种类无关。如图2中提供的结果所示，在DCM的情况下，衰减远远是更显著的：当向制剂中添加乳糖时，粒子的z-平均尺寸从多于1200nm降低至450nm。 
ζ电势在正的范围内，原因是在制剂中存在壳聚糖。其初始浓度在0.05、0.1和0.3％(w/v)之间变化，并且制剂的最佳化是使用壳聚糖0.3％进行的，这样产生高的正ζ电势～+45mV。 
3.2.2Surfynol 104PG-50TM对于粒度和收率的影响 
基于炔二醇化学物质的非离子型表面活性剂是一类提供低表面张力和良好脱泡及表面润湿特性的独特表面活性剂。 
与在水/空气界面上垂直取向的大部分表面活性剂相反，炔二醇表面活性剂由于它们的分子结构而水平取向。这种表面活性剂的紧凑分子可以非常快速地迁移到界面区域，从而提供低的动态表面张力(DST)值。据报道，Surfynol 104PG-50TM体相浓度(bulk concentration)为2.10-6mol.cm-3，DST下降约35达因.cm-1。确实，正是这种显著降低表面张力的特殊性质促使本发明人选择它作为在本发明制剂中的助表面活性剂。 
Surfynol 104PG-50TM在将药物水相引入之前被添加到内部油相中。所得的产物的特征在于约230nm的非常小的粒度，并且实验结果是可重复的。 
粒度分布同样地非常窄(多分散指数(PDI)～0.1)，这大概是由于Surfynol 104PG-50TM的防止聚集的能力。 
3.2.3PEG和硬脂酸对于形貌的影响 
早已确立的是，聚乙二醇(PEG)广泛用于药物递送策略中，以产生更不容易被巨噬细胞识别并且因此在血液中表现出长循环时间的实体(entity)。在生物水平上，具有PEG的包覆纳米粒子在空间上阻碍了血液成分与它们的表面的相互作用，并且降低了血浆蛋白质与PEG化的纳米粒子的结合。这样防止了药物载体与调理素的相互作用，并且减缓了网状内皮系统(RES)对它们的捕获。 
PEG以溶解在去离子水中的初始浓度0.5％w/v与PVA一起被引入到外相中。 
当本发明人将外水相中存在的5ml的PEG(0.5％w/v)与添加到聚合物的油相中的2ml硬脂酸(0.2％w/v)结合与Surfynol 104PG-50TM一起作为助表面活性剂时，观察到表面形貌的显著改善，如图3所示。Zetasizer上的读数提供了约270nm的更小粒度以及非常窄的分布(PDI～0.2)。 

Claims (16)

1.一种用于制备药物递送用的纳米粒子载体的方法，所述纳米粒子是通过如下步骤制备的：
-制备水-油-水的双乳液，所述双乳液在油相中包含一种或多种形成所述纳米粒子载体的基材的聚合物；
-将待递送的所述药物共混到一个乳液相中；
-将糖类掺入油相或外水相；
-将非离子型表面活性剂掺入所述油相或水相，其中将具有炔二醇结构的所述非离子型表面活性剂掺入所述油相；和
-将所述乳液进行喷雾干燥以形成100nm至1000nm的窄粒度分布的纳米粒子。
2.如权利要求1所述的方法，其中这样制备的所述纳米粒子是多功能纳米粒子。
3.如权利要求1所述的方法，其中所述糖类是二糖。
4.如权利要求3所述的方法，其中所述二糖选自包括乳糖、麦芽糖、异麦芽糖、甘露二糖、海藻糖和纤维二糖的组。
5.如权利要求1所述的方法，其中将所述糖类与可阳离子生物降解的粘膜粘附多糖组合。
6.如权利要求5所述的方法，其中所述多糖是壳聚糖和/或其衍生物。
7.如权利要求1所述的方法，其中在所述油相中的所述聚合物是PLGA(乳酸-乙醇酸共聚物)。
8.如权利要求1所述的方法，其中聚合物同时存在于所述油相和所述水相中。
9.如权利要求1所述的方法，其中将所述药物添加到所述油相中。
10.如权利要求1所述的方法，其中所述药物是被添加到内水相中的亲水性药物。
11.如权利要求9所述的方法，其中所述药物是疏水性的。
12.如权利要求1所述的方法，其中所述药物选自利福平、异烟肼、乙胺丁醇或吡嗪酰胺。
13.如权利要求1所述的方法，其中所述乳液的所述外水相包含聚乙二醇(PEG)。
14.如权利要求1所述的方法，其中所述油相包含硬脂酸。
15.如权利要求1所述的方法，其中这样形成的所述纳米粒子是球形的。
16.如权利要求15所述的方法，其中所述纳米粒子的粒度分布是直径180nm至250nm。
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