CN1993380A - 基于环糊精的纳米海绵的超声辅助合成 - Google Patents
基于环糊精的纳米海绵的超声辅助合成 Download PDFInfo
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Abstract
本发明描述了基本上为球形的纳米海绵,其可通过将环糊精和它们的副产物在没有溶剂的条件下与作为交联剂的有机碳酸酯进行交联并进行超声而获得。
Description
本发明涉及可通过将天然的环糊精(CD)与有机的碳酸酯进行反应而获得的纳米海绵,以及它们用作药物或化妆品活性成分的载体或作为去污剂的用途。
背景技术
首先,根据它们的化学和物理性质和它们的分子结构,所施用的药物活性成分分布于有机体内。在大多数情况下该分布不是最理想的,到达作用点的药物量仅仅是所施用剂量的小部分。由于这个理由,人们已经开发了多种的治疗系统,例如用于携带药物的脂质体、微胶粒、聚合或油脂性的微米和纳米颗粒。这些系统的主要目的是优化活性成分的化学和物理和生物药学性质(例如生物利用度、施用途径和剂量)。
口服施用是进入系统循环的最容易和最方便的途径,但同时还会产生一些与生物利用度有关的缺点,例如通过酶或通过胃肠pH的降解。在口服施用后,通常由于溶出现象,影响药物吸收的过程不但包括它从药物剂型的释放和透过肠屏障的能力,也包括它在胃肠道的稳定性。以活性形式到达系统循环的这部分药物产生药物的生物可用性,即生物利用度。为了能够被吸收并具有治疗作用,活性成分必须以分子水平分散或完全溶解于体液中。因此,需要以比完成治疗作用真正所需的剂量高得多的剂量配制和施用低溶解性的药物。这可导致毒性和患者依从性的问题。
鉴于此,在药学领域所要解决的主要问题之一是增加低溶解性活性成分在水性液体例如生理体液中的溶解性。
尽管某种物质具有令人感兴趣的药效学性质,但是该物质的溶解性可能是限制它在治疗中应用的因素。所以,日益增加的新策略研究在于提高活性成分的溶解性和释放的动力学。
在药学领域,为了改善溶解性,采用了多种多样的制剂方法,例如使用助溶剂、表面活性剂、微粒子系统和复合物。包合配合物-活性成分和环糊精-是最令人感兴趣的方法之一。
环糊精(CD)是非还原性环状低聚糖,通过6-8个葡萄糖分子与1,4-α-糖苷键键合而形成,其具有特征的切去顶端的锥体结构。葡萄糖分子的官能团的排列是这样的:分子的表面是极性的,与此同时内部的腔是亲脂的。
亲脂的腔使得环糊精具有形成包合配合物的能力,该包合配合物在适宜极性和大小的有机分子溶液中也是稳定的。
鉴于这一理由,已经研究了环糊精,环糊精在多个化学领域(药学、分析、催化、化妆品等)中有许多应用,其中利用了包合化合物的性质。
在药学技术中,可采用这些复合物以增加药物溶解的速度、溶解性和稳定性,或用于掩盖令人厌恶的味道,或用于将液体物质转化成固体。
在为了增加包合常数并使得它们不溶于水而进行聚合之后,近来它们的用途已经从有机污染物质(例如POP、PCB)中扩展去除污染。可以使用二异氰酸酯、表氯醇或有机碳酸酯完成聚合。但是,迄今为止它们作为药物和/或活性成分的载体的用途尚未报道。
实际上,使用有机碳酸酯作为交联剂而获得的基于环糊精的纳米海绵的最初用途是成功清除了在水中存在的痕量的氯化芳族化合物,一般也针对清除在土壤和空气中存在的氯化疏水有机分子,这些物质作为污染物的浓度水平在ppb-ppm数量级(WO 03/085002)。
DE 10008508公开了通过将环糊精和有机碳酸酯化合物或其活性衍生物(例如光气)在有机溶剂如吡啶或丁酮中反应而获得的包含环糊精单位的聚碳酸酯。尤其是D1的实施例3提及非天然环糊精(二甲基-β-环糊精)在存在溶剂(丁酮)的条件下与碳酸二苯酯交联生成粉末。尽管D1假定鉴于所用的特殊的环糊精(二甲基衍生物),所获产物的交联度低于通过使用仅仅具有游离OH基而不具有甲基基团的天然环糊精而获得的产物的交联度,但是,D1却没有给出所获粉末的粒度和形状的任何信息。
EP 502194公开了环糊精和聚氨基甲酸酯、聚脲、聚酯、聚碳酸酯、聚酰胺或聚砜的直链共聚物的制备。该聚合物可用作渗透膜,或以粉末或珠状物形式作为色谱的固定相。用于制备直链共聚物的环糊精衍生物只具有两个游离的OH基,另一个被保护(在方案中的基团R)以提供双官能的起始物质。
WO 03/041095公开了将铁酸金属盐、氢氧化物和环糊精的水溶液进行蒸发而获得的以磁性颗粒形式存在的复合材料。
发明内容
现已发现,与在WO 03/085002中公开的现有技术物质相比,通过将天然的环糊精与有机二碳酸酯在不存在溶剂和在声波振荡的条件下进行反应可获得具有更好的性质的纳米海绵。
根据本发明可获得的纳米海绵,在许多特征中即在基本上是球形的粒子形状上以及在粒度的一致性上可区别于先前已知的物质。
鉴于本发明的纳米海绵的结构特性,它们可用于先前没有公开的这类物质的应用,例如作为用于药物活性成分的气雾剂施用的载体。
鉴于它们的特征,本发明的纳米海绵可用于解决活性成分的内在问题,例如差的水溶解性、不稳定性、降解、保护和毒性。
本发明的纳米海绵也可同时携带在环糊精疏水腔中的亲脂分子和在单个环糊精之间的空隙中的亲水分子。
纳米海绵具有胶体的大小并可在水中形成清澈和发乳光的混悬液。
随着用于它们的制备的合成方法的发展,纳米海绵固化成了颗粒,在光学显微镜下观察发现它们的形态是球形的。
合成的纳米海绵的这一特性以及它们的适宜的密度使得它们也有可能作为载体用于除了口服施用外的吸入途径中。
在高温下在溶液中使用有机碳酸酯合成纳米海绵是已知的方法,其涉及使用溶剂如DMF、丁酮、吡啶或DMSO,在这些溶剂中两种试剂均是可溶的。该反应在温度高于130-140℃进行并形成网状物,已经证明网状物在络合众多的有机分子中是有活性的。
作为本发明的目的的产物可以通过天然环糊精(即α、β或γ环糊精,优选β环糊精)和二碳酸酯(优选碳酸二苯酯(DPC))在不存在溶剂的条件下、在环境温度和90℃之间、在声波振荡的条件下进行反应而获得。
在这些条件下可获得的产物在光学显微镜下显示特殊的形态:它由类似球体的颗粒组成,具有规则的小于5微米的大小,例如如图1所示。
个体粒子的球形形状是用于非常先进和非常创新的药学应用的聚合物的基本条件。
根据本发明在超声辅助下制备的纳米海绵可与众多的有机化合物例如PCB、氯化和芳族的有机溶剂、苯二甲酸酯、POP(持久性有机污染物)和PAH(持久性芳族烃)结合,所以可以用作去污剂,与在US 5425881、WO03/085002和DE 10008508中公开的相似,例如可用于处理环境基质例如空气、水、土壤和表面。
本发明的纳米海绵也可用于下列领域和应用:
-在分析化学中用于色谱法作为固定相;
-作为赋形剂用于制备片剂、小丸、大小在0.5mm和20mm之间的颗粒和粉剂,也用于吸入施用;
-植物和/或动物活性成分的提取;
-以磁化的形式存在,用于络合活性成分;
-除去有机和无机的放射活性物质,特别是放射活性元素碘。
-在对抗化学攻击和活性剂的个体保护系统中;
-在液体和/或气体流出物脱臭方法中。
通过简单的热解吸、用溶剂的萃取和/或使用微波和超声,可再生本发明的纳米海绵。
下列实施例更详细地说明本发明。
实施例1
将4.54g(0.001mols)的无水β-CD和0.856g(0.004mols)的碳酸二苯酯在250ml的烧瓶中混合。将该烧瓶放置在充满水的超声浴中并加热至90℃。将该混合物声波振荡5h。
将反应混合物放置至冷,粗略地打碎获得的产物。在烧瓶的光亮表面和颈部可以看到苯酚的数目众多的针形结晶,产生的部分苯酚有助于凝聚产物。
用水洗涤该产物以除去未反应的环糊精,然后在索格利特(Soxhlet)中用乙醇洗涤以除去产生的苯酚和剩余的DPC。
获得的产物是不溶于水的细小白色粉末。在光学显微镜下观察(图1)显示出颗粒的极好的球形形状,它们的平均直径低于5微米,并具有低比例的多分散性。此外,微球形的纳米海绵拥有高的结晶度,这一点可从实施例3样本在低θ值时的X射线分析中看出(图2)。
实施例2
将100ml的DMF、4.54g(0.001mols)的无水β-CD和0.856g(0.004mols)的碳酸二苯酯在250ml的烧瓶中混合。将该烧瓶放置在充满水的超声浴中并加热至90℃。将该混合物声波振荡5h。
冷却反应混合物,并在旋转蒸发器中将其浓缩至小的体积。在结束时加入过量的水,过滤,长时间用水洗涤,并将所获得的产物干燥。
获得的产物是不溶于水的细小白色粉末。
实施例3
将4.54g(0.001mols)的无水β-CD和0.428g(0.002mols)的碳酸二苯酯在250ml的烧瓶中混合。将该烧瓶放置在充满水的超声浴中并加热至90℃。将该混合物声波振荡5h。
将反应混合物放置至冷,粗略地打碎获得的产物。在烧瓶的光亮表面和颈部可以看到苯酚的数目众多的针形结晶,产生的部分苯酚有助于凝聚产物。
用水洗涤该产物以除去未反应的环糊精,然后在130℃在氮气流中通过蒸发清除产生的苯酚。
获得的产物是不溶于水和常见有机溶剂的细小白色粉末。
实施例4
将20g(0.0176mols)的无水β-CD和7.54g(0.0352mols)的碳酸二苯酯在100ml的烧杯中混合。将烧杯放置于油浴水浴器中并加热至90℃。使用在19kHz处可提供最大功率250W的超声探头,在19kHz处将混合物声波振荡4h。
将反应混合物放置至冷,粗略地打碎获得的产物。在烧杯的光亮表面可以看到苯酚的数目众多的针形结晶,产生的部分苯酚有助于凝聚产物。
用水洗涤该产物以除去未反应的环糊精,然后在索格利特中用丙酮洗涤以除去产生的苯酚和剩余的DPC。
获得的产物是不溶于水和常见有机溶剂的细小白色粉末。
实施例5
将20g(0.0176mols)的无水β-CD和11.30g(0.0528mols)的碳酸二苯酯在100ml的烧杯中混合。将烧杯放置于油浴水浴器中并加热至90℃。使用在19kHz处可提供最大功率250W的超声探头,在19kHz处将混合物声波振荡4h。
将反应混合物放置至冷,粗略地打碎获得的产物。在烧杯的光亮表面可以看到苯酚的数目众多的针形结晶,产生的部分苯酚有助于凝聚产物。
用水洗涤该产物以除去未反应的环糊精,然后在索格利特中用丙酮洗涤以除去产生的苯酚和剩余的DPC。
获得的产物是不溶于水和常见有机溶剂的细小白色粉末。
实施例6
将10g(0.0088mols)的无水β-CD和9.416g(0.044mols)的碳酸二苯酯在100ml的烧杯中混合。使用在19kHz处可提供最大功率250W的超声探头,在环境温度在19kHz处将混合物声波振荡5h。
将反应混合物放置至冷,粗略地打碎获得的产物。在烧杯的光亮表面可以看到苯酚的数目众多的针形结晶,产生的部分苯酚有助于凝聚产物。
用水洗涤该产物以除去未反应的环糊精,然后在索格利特中用丙酮洗涤以除去产生的苯酚和剩余的DPC。
获得的产物是不溶于水和常见有机溶剂的细小白色粉末。
实施例7
将实施例1的0.25g聚合物加入到被19ppm的氯苯污染的10ml水中。随时抽取各个样本,通过紫外-可见分光光度法分析每一个样本。发现氯苯的浓度在30分钟后为8.2ppm,在180分钟后为3.1ppm。
在3小时后发现减少了约84%。
实施例8
将实施例3的2g聚合物加入到被氯苯(820ppb)、4-氯甲苯(830ppb)、2,6-二氯甲苯(770ppb)、1,3,5-三氯苯(540ppb)和六氯苯(225ppb)的混合物污染的50ml水中。随时抽取各个样本,每一个样本通过气相色谱法-质谱法进行分析。在50分钟后有机物的总浓度为180ppb,减少了约94%。
就单个组分而言,对于氯化程度高的化合物具有高效性,减少的程度可高于97%。
实施例9
将实施例4的2g聚合物加入到被316ppb的PCB(可购得的混合物Aroclor 1242)污染的50ml水中。
随时抽取各个样本,每一个样本通过气相色谱法-质谱法进行分析。在50分钟后PCB的总浓度为32ppb,减少了约90%。
实施例10
将实施例3的100mg纳米海绵加入到含有20mg的氟比洛芬的3ml水中。在环境温度下磁力搅拌一夜。在结束时过滤并回收和冻干固相。100mg的纳米海绵结合10mg的氟比洛芬。
将冻干物质在3℃并搅拌的pH 7.4缓冲液中进行释放实验。图3给出了获得的结果,可以清楚地看到被结合的活性成分的逐步和恒定的释放。
实施例11
将实施例3的50mg纳米海绵加入到含有3mg的阿霉素的3ml水中。在环境温度下磁力搅拌一夜。在结束时过滤并回收和冻干固相。该冻干物质结合1%重量百分比的阿霉素。将冻干物质在两种不同的水性缓冲液中进行释放实验。图4给出了获得的结果,可以清楚地看到被结合的活性成分的逐步和恒定的释放。应该注意的是,释放主要取决于所用的pH。在酸性pH(胃环境)下释放的动力学是缓慢的。在pH 7.4时释放是相当大的,具有较快的释放动力学。该实验证明纳米海绵可携带活性成分,并且可以无变化地通过人胃的胃环境并在肠中释放活性成分。所以纳米海绵可以作为活性成分的载体。鉴于纳米海绵的低溶血性(这一点在实施例12中详述),所以该可控和延时释放的结果极为重要。
实施例12
为了确定溶血性,将取自供血者的250μl血液加入到NANO-CD的量递增的一系列试管中,然后加入PBS 10mM pH=7.4的无菌缓冲液使之为1ml。所测定的NANO-CD的量为:0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、5.0mg、7.5mg、10.0mg、15.0mg、20.0mg和25.0mg。对于这一系列的试管,一支试管中加入250μl血液和750μl PBS 10mM pH=7.4的无菌缓冲液作为对照管,同时另一支试管含有250μl血液和750μl PBS 10mM pH=7.4的无菌缓冲液并加入过量氯化铵以获得红血球总溶血值。
然后将这些试管在37℃孵育90分钟。在90分钟后以2000rpm离心10分钟;取250μl的上清液,并将其放置在含有2.5ml的10mM pH7.4无菌磷酸盐缓冲液的石英比色皿中。使用血液样本作为参比,通过在其中加入氯化铵获得总溶血值。然后将所有的样本在543nm处在分光光度计(Lambda 2,Perkin Elmer)上进行分析。由于在上清液中存在血红蛋白,从吸光度可以计算出溶血百分数。100%的溶血对应于完全溶血样本(参比)在543nm处的吸光度。
即使在高至6mg/ml的浓度下也没有出现任何溶血性。
Claims (6)
1.基本上为球形的纳米海绵,可通过将天然环糊精在不存在溶剂和在声波振荡的条件下与作为交联剂的有机碳酸酯进行反应而获得。
2.根据权利要求1的类似球体的形状和大小小于5微米的纳米海绵。
3.根据权利要求1或2的纳米海绵,其中的环糊精是β-环糊精,碳酸酯为碳酸二苯酯。
4.权利要求1、2或3的纳米海绵作为药物活性成分、食物、化妆品和土地产出物(植物药)的载体的用途。
5.权利要求1或2的纳米海绵作为多氯联苯(PCB)、氯化和芳族有机溶剂、苯二甲酸酯、持久性有机污染物(POP)、PAH和无机类物质的去污剂的用途。
6.组合物,该组合物包含被包括在权利要求1-3的纳米海绵中的活性成分。
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CN104140544A (zh) * | 2013-05-10 | 2014-11-12 | 国家纳米科学中心 | 一种环糊精多孔纳米囊、其制备方法及其用途 |
CN107709441A (zh) * | 2015-04-20 | 2018-02-16 | 康奈尔大学 | 多孔环糊精聚合材料及其制备和使用方法 |
CN111286051A (zh) * | 2020-02-10 | 2020-06-16 | 山西和佳通生物科技有限公司 | 一种基于β-环糊精的交联聚合物的微波制备方法 |
CN114931553A (zh) * | 2022-06-09 | 2022-08-23 | 山东百晟药业有限公司 | 一种包被恩诺沙星可溶性粉及其制备方法 |
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JP5130454B2 (ja) * | 2006-10-10 | 2013-01-30 | 地方独立行政法人青森県産業技術センター | ヨウ素の吸着および回収方法 |
ITMI20071321A1 (it) * | 2007-07-04 | 2009-01-05 | Sea Marconi Technologies Di Va | Nanospugne a base di ciclodestrine come veicolo per farmaci antitumorali |
ITMI20081056A1 (it) * | 2008-06-10 | 2009-12-11 | Sea Marconi Technologies Sas | Nanospugne a base di ciclodestrine come supporto per catalizzatori biologici e nella veicolazione e rilascio di enzimi, proteine, vaccini ed anticorpi |
JP2010247083A (ja) * | 2009-04-16 | 2010-11-04 | Neos Co Ltd | 媒体に含有されるハロゲン化芳香族化合物の選択固着剤及び選択固着方法 |
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EP4013765B1 (en) | 2019-08-17 | 2024-02-14 | Prefere Resins Holding GmbH | Multifunctional cyclic organic carbonates as curing agents for organic compounds having phenolic hydroxyl groups |
EP3786172A1 (en) | 2019-09-02 | 2021-03-03 | Prefere Resins Holding GmbH | Multifunctional cyclic organic carbonates as curing agents for organic compounds having hydroxyl groups |
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DE10008508A1 (de) * | 2000-02-24 | 2001-08-30 | Bayer Ag | Cyclodextrin-enthaltende Polycarbonate |
BR0105499F1 (pt) * | 2001-11-05 | 2018-01-09 | Univ Minas Gerais | processo de obtenção de nanocompósitos ferrita/ciclodextrina e uso como dispositivos de descontaminação magneticamente dirigível |
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CN1456150A (zh) * | 2003-06-04 | 2003-11-19 | 王景成 | 大蒜素注射剂的制备方法 |
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CN104140544A (zh) * | 2013-05-10 | 2014-11-12 | 国家纳米科学中心 | 一种环糊精多孔纳米囊、其制备方法及其用途 |
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CN111286051A (zh) * | 2020-02-10 | 2020-06-16 | 山西和佳通生物科技有限公司 | 一种基于β-环糊精的交联聚合物的微波制备方法 |
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PT1786841E (pt) | 2010-03-12 |
BRPI0514580A2 (pt) | 2017-05-30 |
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JP2008503624A (ja) | 2008-02-07 |
CN1993380B (zh) | 2010-05-12 |
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EP1786841A1 (en) | 2007-05-23 |
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