CN1179698A - 纳米级胶态粒子 - Google Patents
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Abstract
本发明涉及纳米级胶态粒子及其生产方法。纳米级胶态粒子是将一种油、一种稳定剂/表面活性剂和一种含水溶液的乙醇引发剂的混合物水合而成的。这些纳米级胶态粒子直径通常小于100纳米。因为尺寸小而易于渗透,它们尤其有利于输送例如雌二醇等材料局部通过表皮。
Description
发明背景
本发明涉及构造平均直径小于1000纳米(1微米)的“纳米级胶态粒子”胶态样粒子的材料和方法。这些纳米级胶态粒子是亚微米级的油基粒子,其中最小的可透过例如标准用于微生物纯化的0.2微米滤器。本发明的纳米级胶态粒子在水溶液和缓冲液中可形成稳定分散体。
由于纳米级胶态粒子的尺寸小,它们具有各种用途。例如脂质体、非磷脂脂膜泡和微胶囊等其它合成粒子,通常为1微米或更大。相比之下,形成直径小于100纳米的本发明纳米级胶态粒子是可能的。与脂膜泡不同,其中的一些可设计成带一种油的,例如见Wallach的美国专利No.4911928,在本发明粒子的制备中需要至少一种油、一种稳定剂/表面活性剂、一种引发剂和水或另一种稀释剂。但是既不用胆甾醇,也不用磷脂。实际上,这些纳米级粒子可由适于人使用的食品级,USP或NF级材料制成。如果这些纳米级胶态粒子用于将一种材料局部转运至血流中,这一点便尤其重要。此类系列的一个特定用途是例如雌二醇等天然或合成激素的输送。这些材料通常有溶解性问题,例如,它们通常只溶解于难以渗入稳定的颗粒系列,例如乙醇这样的材料中。
纳米级胶态粒子的独特之处在于,它们使溶于水、油或引发剂(即乙醇或甲醇)中任一种的物质渗入到平均直径约30~1000纳米的稳定粒子中。大多数制品的粒子直径约30~500纳米,可在水中混合,并且可滤过0.2或0.45微米的滤器,可在-20~25℃下贮存。
利用所述材料和方法,便可生产行使以下功能的纳米级胶态粒子:
1.将可溶于乙醇或甲醇的药物渗入到粒子中。
2.将可溶于乙醇或甲醇的农药渗入到粒子中。
3.将辅剂渗入粒子中。
4.将蛋白质渗入粒子中。
5.将含完整核酸的全病毒渗入粒子中,但必须指出,本发明的这些
较小粒子与许多病毒的大小相同。
6.将乙醇提取的香精渗入粒子中。
7.将挥发油(香精和香料)渗入粒子中。
8.将一种电荷渗入粒子中。
9.产生有色粒子。
局部转运药物的能力尤其重要。多年来已经知道,小粒子,例如那些直径小于1微米的,能比大粒子更容易穿过皮肤界面,但是因小粒子转运的药物的量少通常限制了它们的使用。此外,大多数粒子只能转运有限的材料类别。
因此,本发明的一个目的是为了生产能转运不同材料类别的亚微米粒子。
本发明的另一个目的是为了生产能转运溶于甲醇或乙醇,而在水溶液和油系统中溶解度有限或不溶解的材料的亚微米粒子。
本发明的进一步目的是为了生产能用于药物转运的直径小于100纳米的粒子。
本发明还有的一个目的是为了生产用于局部转运例如雌二醇等激素的粒子。
本发明的这些和其它目的及特点将在说明书和权利要求中可见。发明概述
本发明描述了纳米级胶态粒子和制备它们的方法。这些纳米级胶态粒子作为药物转运载体具有特殊应用,特定应用于溶于甲醇或乙醇的材料的局部转运。但是这些纳米级胶态粒子还可用于转运许多不同类的药物和其它材料。纳米级胶态粒子的小尺寸及其与组织的共容性使其可广泛使用。
本发明的纳米级胶态粒子直径约10-1000纳米,其中大多数粒子直径小于100纳米。这种小粒子尺寸可使其通过0.2微米的滤器。纳米级粒子由包括油、稳定剂(或表面活性剂)的亲油相和例如甲醇或乙醇的引发剂制成。此亲油相经过例如水或缓冲液的水溶液水合。优选的稳定剂是非磷脂表面活性剂,尤其表面活性剂中的吐温类(脱水山梨醇脂肪酸酯的聚氧乙烯衍生物)和壬基酚聚乙烯乙二醇醚。最优选的表面活性剂为吐温60(聚氧乙烯20脱水山梨醇单硬脂酸酯)和吐温80(聚氧乙烯20脱水山梨醇单油酸酯),和Tergitol NP-40(聚(氧-1,2-乙二基),α-(4-壬基酚)-ω-羟基,分支的〔平均分子量1980〕)和Tergitol NP-70(一种混合表面活性剂,AQ=70%)。这些表面活性剂的高分子量在制备方面及所得的纳米级胶态粒子稳定性方面表现出具有优点。
在本发明中优选的引发剂是乙醇或甲醇,但在某些情况下,其它短链醇和/或氨基酸也可使用。尽管纯乙醇或甲醇为优选,但这两者的混合物和含至少50%乙醇的混合或未混合材料均可使用。这类引发剂可包括加味引发剂,例如象薄荷、柠檬、橙子及诸如此类香味的醇提物。
除了引发剂和稳定剂的表面活性剂以外,通过选择合适的油,可调整或定做胶态粒子。尽管大多数油看上去可起作用,但优选的油是从蔬菜油、坚果油、鱼油、猪由、矿物油、角鲨烷、三辛精及它们的混合物中选择出来的。
许多其它物质可以加到纳米级胶态粒子中以改制粒子。除了形成粒子的其它油外,挥发油,例如挥发香味油,可用来替代一些油或者加入其中。也可使用着色剂,例如食品着色剂,优选地将它加至引发剂中。引发剂或油还可运载掺到最终粒子悬浮液中的活性物质。这些活性物质在液体中可溶解或悬浮。一种优选的添加剂是类固醇或激素例如雌二醇,它们溶于乙醇引发剂,并可掺到粒子中。因为雌二醇在水溶液中沉淀,水相的加入会使雌二醇沉淀,然后雌二醇会在局部制剂中释放。出现的一个有趣现象是,用本发明方法形成的结晶类型在形状上与雌二醇的标准水溶液沉淀物的有所不同。
用于水合亲油相的水溶液优选地为一种例如水或缓冲液等生理相容溶液,例如磷酸盐缓冲液盐水。水溶液可以具有溶解于或悬浮于其中以供掺入的活性物质。制备纳米级胶态粒子的基本步骤是将油、稳定剂/表面活性剂和引发剂混合以形成亲油相,并且优选地以约4∶1的比例将过量的亲油相与水稀释溶液混合。用穿过孔径1/18000英寸的产生相对速度约50m/s的设备,来优选完成亲油相与水相的混合或水合。这种剪切使粒子在优选的大小范围,而小的剪切值会产生较大尺寸的粒子,例如用较大外径或较低速度。
此外,这里所述的所有不同材料和过程可调整或选择,以控制所得纳米级胶态粒子的性质。活性物质可载于油中、引发剂中或用于掺入粒子的水相中。虽然粒子是胶态的,它们仍可以是反胶态的形式而不改变本发明的范围。通过以下详述和附图将对本发明进一步阐述。
附图简述
图1a和1b是本发明纳米级胶态粒子在两个不同放大倍数时的电子显微图;图2是用三种不同型的载体,给予1mg雌二醇后,卵巢切除的Rhesus猴的血清雌二醇水平图。
发明详述
本发明涉及纳米级胶态粒子和它们的制备方法。与微胶囊和脂质体系统不同,本发明纳米级胶态粒子具有大量直径100纳米以下的粒子,而仍载大量活性成分。这些纳米级胶态粒子作为局部药物转运载体尤其有用,因为它们颗粒小并具有允许快速皮下渗透的其它特点。纳米级胶态粒子还具有极多功能,用于能够运载包括那些悬浮或溶解于油、水稀释液或优选引发剂的任一种活性材料。这些特性使此系统得以使用难于在其它转运系统中使用的活性物质。
首先将至少一种油,优选选自表1的一种油、一种稳定剂(表面活性剂),优选选自表2的一种表面活性剂,和一种引发剂,优选甲醇或乙醇,混合而制成纳米级胶态粒子。最优选的稳定剂是吐温60、吐温80、Tergitol NP-40和Tergitol NP-70。其余可能的引发剂见于表3(醇和有关化合物)和表4(醇加香的提取物)。如果使用表4中任一小于50%乙醇的醇加香的提取物,则用乙醇和提取物的1∶1混合物以保证至少使用50%乙醇。挥发油也可加至这些化学组分(表5)中,色素可加到油-稳定剂引发剂混合物中。通过将油加至油-稳定剂-引发剂中,可引入负电荷。预先混合这些材料后,将水或例如显示于表7的合适的缓冲液,在高速度下注入此混合物中。油∶稳定剂∶引发剂的优选比例分别为25∶3∶5,以体积比为基准。预先混合的含油相与水的优选比例为4∶1。用往复式注射装置、连续流动装置、或高速混合仪可生产出纳米级粒子。在4∶1比例时所得粒子的直径为30-500纳米。这些水混溶粒子然后既可通过0.2、又可通过0.45微米滤器过滤。生产出较大的胶态粒子的方法是通过简单增加水含量,降低油-稳定剂-引发剂含量或改变形成粒子时的剪切力。我们将平均直径小于1000纳米(1微米)的粒子命名为“纳米级胶态粒子”。表1:用于制备纳米级胶态粒子的油
杏仁油,甜的
杏种子油
琉璃苣油
Canola oil
椰子油
玉米油
棉籽油
鱼油
加州希蒙得木豆油
猪油
亚麻子油,煮沸的
macadamia果仁油
矿物油
橄榄油
花生油
红花油
芝麻油
大豆油
角鲨烷
向日葵籽油
三辛酸甘油酯(1,2,3三辛酰基甘油)
麦胚油表2:用于制备纳米级胶态粒子的稳定剂/表面活性剂
吐温60
吐温80
壬基酚聚乙二醇醚
(烷基酚-羟基聚氧乙烯)
1.聚(氧-1,2-ethanediyl),α-(4-壬基酚)-Ω-羟基
-,分支的(即Tergitol NP-40表面活性剂)
通式:C95H185O40 MW(平均)=1980
2.壬基酚聚乙二醇醚混合物
(即Tergitol NP-70(70%AQ)表面活性剂)
通式及MW:无法得知 (混合物)表3:用于制备纳米级胶态粒子的引发剂
乙醇
甲醇表4:用于制备纳米级胶态粒子的加香味引发剂(加香提取物*)
纯茴香提取物 (73%乙醇)
人造的香蕉提取物 (40%乙醇)
人造的樱桃提取物 (24%乙醇)
巧克力提取物 (23%乙醇)
纯柠檬提取物 (84%乙醇)
纯橙子提取物 (80%乙醇)
纯薄荷提取物 (89%乙醇)
人造菠萝提取物 (42%乙醇)
人造甜油提取物 (35%乙醇)
人造草莓提取物 (30%乙醇)
纯香草提取物 (35%乙醇)
* 所用的提取物为食品级材料(McCormick)其它来源的材
料可以代用。表5:用于制备纳米级胶态粒子的挥发油或香料
滇荆芥油
月桂油
香柠檬油
雪松木油
樱桃油
肉桂油
丁子香油
牛至油
薄荷油表6:用于制备纳米级胶态粒子的食用色素
绿
黄
红
兰
* 所用的食用色素为食品级材料(McCormick)其它来源的
材料可以代用。表7:用于制备纳米级胶态粒子的稀释剂
注射用水
磷酸盐缓冲盐
以下实例将更清楚地阐明本发明及其用途。实例1-不带电荷的纳米级胶态粒子的生产
表8含有用于生产纳米级胶态粒子的材料,其中水作稀释剂。用Coulter L130激光分级仪的分级参数见表9。表8:用水作稀释剂的纳米级胶态粒子的制备
化学组分
量
大豆油(油) 25ml
聚失水山梨酸酯80(吐温80)(稳定剂) 3ml
乙醇(引发剂) 5ml
将以上油-稳定剂-引发剂组合物混合60秒,用往复式注射仪将1ml水注入4ml混合物中。此仪器具有通过一个不锈钢Leurlok连结管与一个1/18000英寸小孔连在一起的两个5ml注射器,溶液通过连结管在注射器之间推注约100秒。生成的粒子在EM栅板上干燥,用乙酸双氧铀着色,并且进行电子显微图研究。图1a显示了在60000×放大倍数下此制备的电子显微图,而图1b显示了在150000×放大倍数下的相同制备。纳米级胶态粒子的生产方法简述于下列各表之后。表9-用水作稀释剂的纳米级胶态粒子的分级
制剂 LS-130 LS-130
平均直径 范围
(纳米) (纳米)
纳米级胶态粒子 312 193-455
(SBO/Tw80/E/WFI)
使用LS-130分级仪的一个问题在于,它不能准确将直径小于200纳米的粒子分级。用图1a和1b,可证实,大多数粒子直径在70-90纳米,只有5%的粒子直径大于90纳米。20-30纳米的粒子在表1b中的较高放大倍数下可见。实例2-将雌二醇掺入纳米级胶态粒子中
表10和12含有用于生产两份将雌二醇以两种不同浓度掺入其中的不带电荷的纳米级胶态粒子材料。每种制剂以水为稀释剂而制成。雌二醇浓度较高的材料用于下面实例3所述的rhesus猴的研究。将50或100mg雌二醇溶于纳米级胶态粒子形成前的制剂的引发剂中(乙醇组分),这一点很重要,因为雌二醇在有水存在时会沉淀。实际上,试剂级乙醇中少量的水足以沉淀雌二醇,因为用这里所述的材料和过程而形成的胶态粒子显示出其中含有雌二醇结晶。但是,这些结晶呈片状而不是标准发现于水中的针状沉淀。表10:含雌二醇的纳米级胶态粒子的制备
化学组分
量
大豆油(油) 25ml
聚失水山梨酸酯80(吐温80)(稳定剂) 3ml
乙醇(引发剂) 5ml
雌二醇 50mg
用与实例1中所述基本相同的过程制得纳米级胶态粒子,除了在引发剂与其它组分混合之前将雌二醇溶解(或悬浮)于乙醇引发剂中。用手混合油-稳定剂-引发剂/雌二醇组合物或用涡流混合器混合60秒。用例如实例1中所述的往复式注射仪将1ml水注入到4ml生成的混合物中。表11:含纳米级胶态粒子(50mg)的雌二醇分级数据
制剂 LS-130 LS-130
平均直径 范围
(纳米) (纳米)
纳米级胶态粒子 289 174-459
(SBO/Tw80/Etoh-雌二醇/WFI)
用Coulter LS 130激光分级仪测定的这些制剂的分级数据分别见表11和13。LS 130分级仪不能准确将直径小于200纳米的粒子分级。这些材料还在EM栅板上干燥,用乙酸双氧铀着色,并且进行电子显微图研究。电子显微图显示出大多数粒子小于200纳米,20-30纳米的粒子可见。在较大的胶态粒子中,易见结晶的雌二醇。在任何范围内无游离药物结晶,表明药物完全掺至胶态粒子中。表12:含雌二醇的纳米级胶态粒子的制备
化学组分
量
大豆油(油) 25ml
聚失水山梨酸酯80(吐温90)(稳定剂) 3ml
乙醇(引发剂) 5ml
雌二醇 100mg表13:含纳米级胶态粒子的雌二醇分级数据
制剂 LS-130 LS-130
平均直径 范围
(纳米) (纳米)
纳米级胶态粒子 217 151-291
(SBO/Tw80/Etoh 雌二醇/WFI)实例3-含雌二醇制剂的Rhesus猴检测
用标准雌二醇的乙醇制剂来检测实例2的100mg雌二醇制剂,以表明其效力。将乙醇(表14)或纳米级胶态粒子(表15)中的1mg雌二醇应用于四只卵巢切除的Rhesus猴的表皮,其后32天记录系列血样,并且确定血清雌二醇水平,血清雌二醇数据图示于图2。没有额外的药物作用于任何动物表皮,其后观察动物60天以确定发生时间、周期和阴道出血的严重程度(表16)。
表14-一次局部给予相当于1mg雌二醇的纳米级胶态
粒子后卵巢切除雌性猴的血清雌二醇水平
样品时间 | 猴数量 | 组平均±血清雌二醇 | |||
血清雌二醇 | |||||
#19567(pg/ml) | #21792(pg/ml) | #22366(pg/ml) | #22405(pg/ml) | ||
0小时 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
0.5小时 | 22.2 | 49.8 | 36.9 | 77.5 | 46.6±11.7 |
1小时 | 37.4 | 60.9 | 65.6 | 108.6 | 68.1±14.8 |
2小时 | 61.5 | 80.5 | 87.3 | 191.3 | 105.2±29.2 |
4小时 | 77.2 | 132.1 | 120.6 | 120.4 | 112.6±12.1 |
6小时 | 89.0 | 166.3 | 119.0 | 158.3 | 133.2±18.0 |
8小时 | 87.5 | 157.3 | 116.1 | 148.1 | 127.3±15.9 |
12小时 | 83.0 | 160.5 | 100.6 | 140.3 | 121.1±17.8 |
第1天 | 90.7 | 178.0 | 105.7 | 132.6 | 126.8±19.2 |
第2天 | 95.5 | 152.8 | 90.6 | 83.5 | 105.6±15.9 |
第3天 | 81.9 | 122.6 | 51.1 | 47.2 | 75.7±17.5 |
第4天 | 91.5 | 83.9 | 58.7 | 50.3 | 71.1±9.9 |
第5天 | 41.6 | 74.7 | 35.1 | 40.0 | 47.9±9.1 |
第6天 | 45.2 | 63.7 | 25.6 | 40.9 | 43.9±7.8 |
第7天 | 18.3 | 25.9 | 21.9 | 27.0 | 23.3±2.0 |
第12天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
第17天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
第22天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
第27天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
第32天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
a CDB 3988=2.4mg雌二醇/每ml Tween/oil给药体积为0.42ml。
b 0=未检出,分析的测定限度(ED90)为13.3±2.4pg/ml(平均±血
清雌二醇,n=4)
表15-一次局部给予含雌二醇a的1mg乙醇
后卵巢切除雌猴的血清雌二醇水平
样品时间 | 猴数量 | 组平均±血清雌二醇 | |||
血清雌二醇 | |||||
#G-558(pg/ml) | #G-603(pg/ml) | #E-920(pg/ml) | #E-924(pg/ml) | ||
0小时 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
0.5小时 | 17.7 | 97.1 | 44.8 | 19.5 | 44.8±18.5 |
1小时 | 53.2 | 44.1 | 88.3 | 99.9 | 71.4±13.5 |
2小时 | 144.3 | 89.4 | 138.5 | 155.1 | 131.8±14.6 |
4小时 | 143.7 | 202.3 | 165.1 | 193.6 | 176.2±13.4 |
6小时 | 155.8 | 257.8 | 173.1 | 203.7 | 197.6±22.4 |
8小时 | 114.2 | 266.1 | 130.7 | 130.0 | 160.3±35.5 |
12小时 | 80.8 | 219.5 | 86.4 | 115.9 | 125.7±32.2 |
第1天 | 92.4 | 145.2 | 56.9 | 109.4 | 101.0±18.4 |
第2天 | 74.1 | 124.2 | 55.3 | 107.2 | 90.2±15.6 |
第3天 | 65.0 | 67.4 | 51.9 | 89.2 | 68.4±7.7 |
第4天 | 70.5 | 79.6 | 57.8 | 90.0 | 74.5±6.8 |
第5天 | 53.6 | 53.2 | 51.6 | 47.3 | 51.4±1.4 |
第6天 | 60.1 | 59.0 | 59.4 | 53.0 | 57.9±1.6 |
第7天 | 48.7 | 40.6 | 50.3 | 36.6 | 44.1±3.3 |
第12天 | 28.5 | 24.2 | 53.3 | 0.0b | 26.4±10.9b |
第17天 | 0.0b | 0.0b | 28.9 | 0.0b | 7.2±7.2b |
第22天 | 0.0b | 0.0b | 13.8 | 0.0b | 3.5±3.5 |
第27天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
第32天 | 0.0b | 0.0b | 0.0b | 0.0b | 0.0±0.0b |
a CDB 100=2.4mg雌二醇每ml无水乙醇给药体积为0.42ml。
b 0=不可测定,分析的测定限度(ED90)为13.3±2.4pg/ml(平均±
血清雌二醇,n=4)
表14和15中的数据及图2表明,雌激素的治疗血清水平存在于一次给药后1小时的两组卵巢切除动物的血流中。用乙醇制剂,平均雌二醇水平大于40pg/ml保持7天,用纳米级粒子制剂保持6天。当雌激素水平低时(见图2,和表16),两组均发生阴道出血。另外尤其有趣的是图2中曲线的形状。乙醇-雌二醇制剂产生一个“尖齿”曲线,显示有高的开始反应和陡然下降,而纳米级胶态粒子制剂以近乎平坦的水平产生许多“平台”效应数小时。这种“平台效应”通常为优选,因为可以将一些与峰相伴的问题减到最少。表16-一次局部给予乙醇或纳米级胶态粒子的雌二
醇后,卵巢切除RHESUS猴的雌激素止血
CDB数目 | 雌二醇酯 | 止 血 | 强度a | |
天 | ||||
起效时间 | 持续时间 | |||
100 | 雌二醇的乙醇溶液 | 19.5±0.3 | 4.3±0.9 | 1.6±0.2 |
3988 | 乙醇制剂b | 16.5±0.5c | 7.3±1.5 | 1.6±0.1 |
a 出血的平均强度除以出血周期(1=极微、2=中等,3=严重)
b Novavax MN悬浮物11294 2
c 用方差单侧分析和学生Neuman-Keuls多重范围检测与乙醇溶液
中的雌二醇相比较,有显著差异(p<0.01)
因此,此实例表明在非人灵长目动物中,本发明的纳米级胶态粒子可应用于将雌二醇转运通过未受损表皮,一次给药后治疗血清雌二醇水平保持6天。此技术在医疗中具有许多治疗应用。
雌二醇制剂在不同温度下也是稳定的。表17显示实例2在-20℃、25℃、65℃时的纳米级胶态粒子制剂的热稳定数据。显而易见,尽管纳米级胶态粒子高温时不稳定,它们在室温和低温时是稳定的。
表17:纳米级胶态粒子的热稳定性
制剂 LS-130 LS-130
平均直径 范围
(纳米) (纳米)
纳米级胶态粒子 361 168-599
(SBO/Tw80/Etoh-雌二醇/WFI)
25℃保存
纳米级胶态粒子 312 179-510
(SBO/Tw80/Etoh-雌二醇/WFI)
-20℃保存
纳米级胶态粒子
(SBO/Tw80/Etoh-雌二醇/WFI) 不稳定
65℃保存
此外,本发明的纳米级胶态粒子可用水溶液稀释而不丧失其稳定性,这使得在必要时采用可稀释的高浓度产物成为可能。
本领域的技术人员用常规实验便可认识或确信,有许多与本发明在此所述的特定实施方案等同的实施方案,这种等同将包含在以下权利要求中。
Claims (26)
1.一种直径约为25~1000nm的纳米级胶态粒子,该纳米级胶态粒子包括含有油、稳定剂和引发剂的、用合适的水基溶液水合的亲油相。
2.权利要求1的纳米级胶态粒子,其中的稳定剂从吐温60、吐温80、壬基酚聚乙二醇醚及其混合物中选择。
3.权利要求1的纳米级胶态粒子,其中的引发剂从含甲醇、乙醇及其混合物的醇类材料中选择。
4.权利要求2的纳米级胶态粒子,其中的引发剂从含50%或更高的甲醇、乙醇及其混合物的醇类基材料中选择。
5.权利要求1的纳米级胶态粒子,其中的油从蔬菜油、坚果油、鱼油、猪油、矿物油、角鲨烷、三辛酸甘油酯及其混合物中选择。
6.权利要求1的纳米级胶态粒子,其中的水溶液包含生理相容性溶液。
7.权利要求9的纳米级胶态粒子,其中的水溶液从水和磷酸盐缓冲溶液中选择。
8.权利要求1的纳米级胶态粒子,其中的水相具有溶解或悬浮其中的活性材料。
9.权利要求1的纳米级胶态粒子,其中的油具有溶解或悬浮其中的活性材料。
10.权利要求1的纳米级胶态粒子,其中的引发剂具有溶解或悬浮其中的活性材料。
11.权利要求10的纳米级胶态粒子,其中的活性材料包含雌二醇。
12.权利要求1的纳米级胶态粒子,其中的纳米级胶态粒子在水溶液中可分散。
13.权利要求1的纳米级胶态粒子,其中的纳米级胶态粒子的直径可通过0.2mm的滤器。
14.一种制备纳米级胶态粒子的方法,包括以下步骤:
将过量的油与稳定剂和引发剂混合而形成亲油相;
制备具有水溶液基的稀释溶液;并且
将过量的该亲油相与该稀释液混合而形成纳米级胶态粒子。
15.权利要求14的方法,其中的稳定剂选自吐温60、吐温80、壬基酚聚乙二醇醚及其混合物。
16.权利要求14的方法,其中的引发剂从含甲醇、乙醇及混合物的醇类基材料中选择。
17.权利要求16的方法,其中的引发剂从含50%或更高的乙醇、甲醇及其混合物的醇类基材料中选择。
18.权利要求14的方法,其中的油从蔬菜油、坚果油、鱼油、猪油、矿物油、角鲨烷、三辛酸甘油酯及其混合物中选择。
19.权利要求18的方法,其中的水溶液包含生理相容性溶液。
20.权利要求19的方法,其中的水溶液从水、磷酸盐缓冲溶液中选择。
21.权利要求14的方法,其中的水相含有溶解或悬浮其中的活性材料。
22.权利要求14的方法,其中的油含有溶解或悬浮其中的活性材料。
23.权利要求14的方法,其中的引发剂含有溶解或悬浮其中的活性材料。
24.权利要求23的方法,其中的活性材料包含雌二醇。
25.权利要求14的方法,其中的亲油相与稀释剂的混合是通过一个1/18,000英寸的孔,用约50m/s的相对速度来完成的。
26.权利要求14的方法,其中的亲油相与水相的比例约为4∶1。
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- 1996-01-29 KR KR1019970705166A patent/KR100482390B1/ko not_active IP Right Cessation
- 1996-01-29 BR BR9606996A patent/BR9606996A/pt not_active Application Discontinuation
- 1996-01-29 EP EP96906271A patent/EP0806894B1/en not_active Expired - Lifetime
- 1996-01-29 DE DE69627309T patent/DE69627309T2/de not_active Expired - Lifetime
- 1996-01-29 DK DK96906271T patent/DK0806894T3/da active
- 1996-01-29 WO PCT/US1996/001410 patent/WO1996023409A1/en not_active Application Discontinuation
- 1996-01-29 JP JP52373596A patent/JP3974170B2/ja not_active Expired - Fee Related
- 1996-01-29 CN CNB96192912XA patent/CN1144583C/zh not_active Expired - Fee Related
- 1996-01-29 ES ES96906271T patent/ES2200055T3/es not_active Expired - Lifetime
- 1996-01-29 CA CA002211262A patent/CA2211262C/en not_active Expired - Fee Related
- 1996-01-29 AU AU49709/96A patent/AU711744B2/en not_active Ceased
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110881462A (zh) * | 2019-11-25 | 2020-03-17 | 南京启佑生物科技有限公司 | 一种基于磷酸盐与金属离子的纳米农药复合制剂及其制备方法 |
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CN1144583C (zh) | 2004-04-07 |
DK0806894T3 (da) | 2003-08-04 |
EP0806894A1 (en) | 1997-11-19 |
KR100482390B1 (ko) | 2005-08-31 |
AU4970996A (en) | 1996-08-21 |
CA2211262C (en) | 2005-08-30 |
DE69627309D1 (de) | 2003-05-15 |
EP0806894B1 (en) | 2003-04-09 |
PT806894E (pt) | 2003-08-29 |
CA2211262A1 (en) | 1996-08-08 |
EP0806894A4 (en) | 1999-12-15 |
DE69627309T2 (de) | 2004-03-04 |
US5629021A (en) | 1997-05-13 |
KR19980701770A (ko) | 1998-06-25 |
JP3974170B2 (ja) | 2007-09-12 |
AU711744B2 (en) | 1999-10-21 |
MX9705663A (es) | 1998-07-31 |
BR9606996A (pt) | 1997-10-28 |
ZA96738B (en) | 1996-09-26 |
ES2200055T3 (es) | 2004-03-01 |
JPH10513185A (ja) | 1998-12-15 |
WO1996023409A1 (en) | 1996-08-08 |
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