CN104610497B - Core-shell structure bioadhesive polymer nanoparticles and its preparation method and application - Google Patents

Core-shell structure bioadhesive polymer nanoparticles and its preparation method and application Download PDF

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CN104610497B
CN104610497B CN201310539766.2A CN201310539766A CN104610497B CN 104610497 B CN104610497 B CN 104610497B CN 201310539766 A CN201310539766 A CN 201310539766A CN 104610497 B CN104610497 B CN 104610497B
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nanoparticles
silver
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shell polymer
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刘瑜
李春燕
许书源
陆伟跃
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复旦大学
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Abstract

本发明属于药物制剂领域,涉及一种用于阴道给药的核壳结构生物粘附性纳米粒子及其制备和应用。 The present invention belongs to the field of pharmaceutical preparations, it relates to a core-shell structure for vaginal administration bioadhesive nanoparticles and its preparation and application. 所述的聚合物纳米粒子以银纳米粒为核,通过丙烯酰胺类交联剂与单烯类苯硼酸功能单体共聚于银纳米粒表面成壳制得。 The polymeric nanoparticles of silver nanoparticles as the core, by acrylamide crosslinking agent monoethylenically phenylboronic acid functional monomer copolymerized in the shell surface of the silver nanoparticles prepared. 本发明的聚合物纳米粒子对粘蛋白具有良好的亲和力,黏膜给药后体内滞留时间长,在阴道给药领域具有较好的实用价值和应用前景。 Polymeric nanoparticles of the present invention have a good affinity for mucin mucosa after in vivo administration long residence time, and has good practical applications in the fields vaginal administration.

Description

一种核壳结构生物粘附性聚合物纳米粒子及其制备方法和应用 Core-shell structure bioadhesive polymer nanoparticles and its preparation method and application

技术领域 FIELD

[0001] 本发明属药物制剂领域,具体涉及一种核壳结构生物粘附性聚合物纳米粒子及其制备方法和在阴道给药中的应用。 Particles and preparation method and application [0001] The present invention belongs to the pharmaceutical field, particularly to a core-shell structure nano bioadhesive polymer in vaginal administration.

背景技术 Background technique

[0002] 现有技术公开了在阴道等部位的黏膜给药时,生物粘附性给药系统能实现制剂与黏膜接触的持续性和紧密性,从给药系统中不断释放的药物或可在局部维持较高浓度,长时间起效,或可持续不断吸收入体循环,发挥全身作用。 [0002] When the prior art discloses a vaginal mucosal site of administration, etc., bioadhesive drug delivery system enables sustained contact with the mucosal formulations and tightness, continuously released from the delivery system may be a pharmaceutical or maintain a high local concentration, time of onset, or sustainable constantly absorbed into the systemic circulation, which exert a systemic effect. 研究显示,对于阴道给药来说,粒径在100~500nm之间的生物粘附性纳米粒子无异物感,易于分布,粘液穿透能力较强,是最为理想的给药形式之一。 Research shows that for vaginal administration, bioadhesive particle diameter of the nanoparticles is between 100 ~ 500nm no foreign body sensation, easy distribution, mucous strong penetrating power, is one of the most desirable form of administration.

[0003] 研究显示,粘蛋白是生物粘附性给药系统的最重要的粘附对象。 [0003] Studies show, mucin adhesion is the most important objects bioadhesive drug delivery system. 粘蛋白是一类广泛存在于人体粘膜表面的糖蛋白,其中分泌型粘蛋白构成了粘液的主要成分,而膜结合型粘蛋白则分布于粘膜上皮细胞表面。 Mucins are a class of widely present on the mucosal surface of the human glycoprotein, wherein the mucin secreted mucus constitute the main component, and the membrane-bound mucins are distributed over the surface of mucosal epithelial cells. 现有技术公开的生物粘附性材料中,卡波普类、壳聚糖类等合成或天然高分子材料依靠自身长链与粘蛋白长链的交缠达到粘附目的,巯基化修饰、凝集素修饰等策略则是依靠巯基与粘蛋白可能的交联或凝集素对粘蛋白的天然亲和力加强给药系统与粘蛋白的相互作用。 Bioadhesive materials disclosed in the prior art, Carbopol type, chitosan and synthetic or natural polymeric material on their own long-chain entangled with mucin adhesion achieve the purpose of long-chain, mercapto group modification, aggregation by modified strategy is to rely on other mercapto mucin possible crosslinking or aggregating pigment strengthen interaction with mucin delivery systems for natural affinity for mucin.

[0004] 现有技术还公开了硼酸能够与1,2_二羟基化合物或1,3_二羟基化合物在水溶液中可逆性地共价结合,形成五元或六元环状酯,因此硼酸基团可以与糖环结构中的顺式邻二羟基发生相互作用。 [0004] The prior art also discloses reversibly boric acid can be covalently bound 1,2_ 1,3_ dihydroxy compound or a dihydroxy compound in an aqueous solution, form a five- or six-membered cyclic ester, a boric acid group and therefore groups may interact with sugar ring structure of cis-ortho-hydroxy. 这构成了硼酸功能化材料在针对糖的智能化材料设计中的独特优势。 This constitutes a unique advantage boric acid functional materials in intelligent design for sugar in the material. 利用单糖(如葡萄糖)和糖链上的邻二羟基和材料表面硼酸基团间的可逆作用可实现对糖蛋白的分析、分离和富集(如JP3252555A、CN103304732、CN100506982、CN102962471)、S 因的包载和递送(如CN101597349)、葡萄糖响应型药物递送(CN102068700、CN102391504、 CN102294212、CN102070756)和针对糖蛋白的分子印迹(CN102516458)等。 Using monosaccharides (such as glucose) and reversible interactions between the ortho-dihydroxy sugar chains and boric acid material surfaces would be analyzed a group of glycoproteins, separation and enrichment (e.g. JP3252555A, CN103304732, CN100506982, CN102962471), S because of entrapment and delivery (e.g., CN101597349), glucose-responsive drug delivery (CN102068700, CN102391504, CN102294212, CN102070756) and molecularly imprinted (CN102516458) for other glycoproteins.

[0005] 迄今为止,针对粘液层及黏膜上的粘蛋白的硼酸基团功能化材料/递药系统的相关报道有,具粘蛋白亲和力的接触镜(CN101312754); -种载环孢素A眼用纳米粒(Shengyan Liu,Lyndon Jones,Frank X Gu,Macromol Biosci.2012 Dec;12 (12):1622_6);但其中所述的硼酸功能化生物粘附性纳米粒子上存在如下:粒径偏小(<50nm),在有效穿透粘液方面存在困难,难以到达黏膜,且制备中涉及硼酸功能化高分子的合成,工艺繁琐等缺陷。 [0005] So far, for the mucus layer and the boronic acid groups of mucin on mucous functional material / delivery system reports have, having affinity for mucin contact lens (CN101312754); - cyclosporine A species contained Eye with nanoparticles (Shengyan Liu, Lyndon Jones, Frank X Gu, Macromol Biosci.2012 Dec; 12 (12): 1622_6); but the presence of the acid functional bioadhesive wherein said nanoparticles are as follows: small diameter (<50nm), difficulty in effectively penetrate mucous aspect, difficult to reach the mucosa, and relates to the preparation of boronic acid functionalized polymer synthesis, defects such as complicated process.

发明内容 SUMMARY

[0006] 本发明的目的是针对现有技术的不足,提供一种制备简便、粒径适合的核壳结构聚合物纳米粒子。 Objective [0006] The present invention is a deficiency of the prior art, to provide a simple preparation, the particle size of suitable core-shell polymer nanoparticles. 尤其是一种核壳结构生物粘附性聚合物纳米粒子及其制备方法和应用。 In particular a bioadhesive polymer core-shell nanoparticles and its preparation method and application.

[0007] 为实现上述目的,本发明采用的技术方案为: [0007] To achieve the above object, the technical solution adopted by the invention is:

[0008] 提供一种以银纳米粒为核,于银核表面包裹聚4-乙烯基苯硼酸,形成带有硼酸功能基团的核壳结构聚合物纳米粒子,其特征在于:粒径在IOOnm左右,粒度的多分散系数不大于ο. 15,所谓"多分散系数"是激光动态散射粒度仪提供的粒子多分散性参数,多分散系数越小,说明粒子粒径分布越均匀。 [0008] to provide a core of silver nanoparticles, silver core surface wrapped poly 4-vinyl phenyl boronic acid, is formed with a core-shell polymer nanoparticles boronic acid functional groups, wherein: the particle size IOOnm so, a particle size polydispersity index of not more than ο. 15, the so-called "polydispersity index" is a parameter of the laser particle polydispersity provide dynamic scattering particle size analyzer, the smaller the polydispersity index, indicating the particle size distribution more uniform.

[0009] 本发明中,先以硼氢化钠还原法制备银纳米粒作为银核,进一步以4-乙烯基苯硼酸为功能单体,以N,N'_亚甲基双丙烯酰胺和/或二甲基丙烯酸乙二醇酯为交联剂,在银核表面聚合成壳,制得一种具有核壳结构的聚合物纳米粒子。 [0009] In the present invention, prior to reduction with sodium borohydride as silver nanoparticles prepared silver core, 4-vinyl phenyl boronic acid is further functional monomer, N, N'_ methylene-bisacrylamide and / or ethylene glycol dimethacrylate as a crosslinking agent, a polymerization silver core to shell surface, to prepare a polymeric nanoparticles having a core-shell structure.

[0010] 本发明提供了制备核壳结构聚合物纳米粒子的方法,其具体步骤如下: [0010] The present invention provides a process for preparing a core-shell polymer nanoparticle structure, the specific steps are as follows:

[0011] 1)形成银核:向硝酸银和柠檬酸钠的混合水溶液中加入硼氢化钠,室温下反应制得银核; [0011] 1) forming a silver core: sodium boron hydride to the mixed aqueous solution of silver nitrate and sodium citrate was added, the reaction at room temperature to obtain the silver core;

[0012] 2)聚合包裹:在所得银核中加入十二烷基硫酸钠作为稳定剂,向银核溶液体系中加入4-乙烯基苯硼酸功能单体及N,N'_亚甲基双丙烯酰胺和/或二甲基丙烯酸乙二醇酯等交联剂,引发剂引发聚合反应,60-80 °C下反应3-8小时; [0012] 2) Polymerization Packages: sodium lauryl sulfate in the resultant silver core as a stabilizer, was added 4-vinyl phenyl boronic acid functional monomer and N silver solution system to nuclear, N'_ methylenebis acrylamide and / or ethylene glycol dimethacrylate ester crosslinking agents, polymerization initiators, reaction 3-8 hours at 60-80 ° C;

[0013] 3)分离纯化:所得到的核壳结构的聚合物纳米粒子用纯水透析72小时以上,离心分离沉淀,真空干燥或冷冻干燥至恒重。 [0013] 3) Purification: The resulting polymer of the core-shell nanoparticles with pure water for more than 72 hours of dialysis, precipitate was isolated by centrifugation, and dried in vacuo or freeze-dried to constant weight.

[00M] 所述步骤1)中,硝酸银浓度为0.01~ImM,梓檬酸钠浓度为0.01~ImM,加入硼氢化钠溶液(5~15mM)的体积为硝酸银-柠檬酸钠混合溶液体积的1/100~1/50; [00M] step 1), the concentration of silver nitrate is 0.01 ~ ImM, Zi sodium citrate at a concentration of 0.01 ~ ImM, volume was added a solution of sodium borohydride (5 ~ 15mM) of silver nitrate - the volume of a mixed solution of sodium citrate 1/100 to 1/50;

[00Ί5] 所述步骤2)中,用于稳定银纳米粒的十二烷基硫酸钠浓度为0.1~1%,4_乙烯基苯硼酸功能单体与交联剂的摩尔比为2.5~10:1,单体和交联剂总摩尔浓度为50~IOOmM,弓丨发剂为:2,2'-偶氮二异丁基脒二盐酸盐,加入量占(功能单体+交联剂)总摩尔数的1~3%。 [00Ί5] step 2), the concentration of sodium dodecyl sulfate for stabilization of silver nanoparticles is 0.1 to 1%, molar ratio of divinylbenzene 4_ acid functional monomer and the crosslinking agent is 2.5 to 10 : 1, the total molar concentration of monomer and crosslinking agent is 50 ~ IOOmM, bow Shu initiators are: 2,2'-azobis isobutyl amidine dihydrochloride was added an amount (+ crosslinking functional monomer 1 to 3% of the total agent) mole.

[0016] 本发明所制得得核壳结构聚合物纳米粒子可通过物理吸附的方法包载蛋白多肽类药物(例如干扰素等),用于阴道给药。 [0016] The method of the present invention is prepared by core-shell polymer nanoparticles obtained by physical adsorption of entrapped proteins and peptides (e.g. interferon), for vaginal administration. 例如包载了干扰素的纳米粒阴道给药可用于阴道病毒感染性疾病的治疗,如尖锐湿疣、宫颈糜烂等。 E.g. interferon entrapped vaginal administration nanoparticles useful in the treatment of vaginal viral infectious diseases, such as genital warts, cervical erosion.

[0017] 本发明具有以下优点: [0017] The present invention has the following advantages:

[0018] 1)本发明核壳结构聚合物纳米粒大小在IOOnm左右,分布较窄,具有良好的亲水性,且原料均为商品化试剂,经济简便。 [0018] 1) core-shell polymer nanoparticles of the present invention is about the size IOOnm, narrow distribution, having good hydrophilicity, and the raw materials are commercially available reagents, economic and simple.

[0019] 2)在银核表面形成的聚4-乙烯基苯硼酸外壳表面具有大量的苯硼酸基团,对粘蛋白具有亲和力,生物粘附性显著,阴道给药后能够长时间滞留在局部,起到长效、缓释的效果,适合阴道给药。 [0019] 2) poly-4-vinyl phenyl boronic acid formed in the surface of the housing surface of the silver core having a large number of phenyl boronic acid group, having affinity for mucin, significant bioadhesive vaginal administration can be prolonged stay in the local , play a long-term, slow release effect, suitable for vaginal administration.

[0020] 3)纳米银本身具有的抗炎、杀菌效果,用作阴道给药纳米粒子的核心,有望与所载药物一起,起到协同抗感染的效果。 [0020] 3) itself has anti-inflammatory nanosilver, the sterilization effect, as a core vaginal administration nanoparticles, together with the drug contained expected, synergistic effect against the infection.

[0021] 4)本发明核壳结构聚合物纳米粒可以物理吸附干扰素等蛋白多肽药物,为蛋白多肽药物黏膜给药提供了一种新的载体形式。 [0021] 4) core-shell polymer nanoparticles of the present invention may be physically adsorbed interferon polypeptide drugs, provides a new form of vector mucosal administration of polypeptide drugs.

附图说明 BRIEF DESCRIPTION

[0022] 图1为核壳结构聚合物纳米粒的形态与粒径分布图,其中, [0022] FIG. 1 is in the form of core-shell polymer particle size distribution of the nanoparticles, wherein

[0023] 左图:TEM照片,右图:DLS粒径图。 [0023] Left: TEM photograph, right panel: DLS particle FIG.

[0024] 图2为核壳结构聚合物纳米粒在不同pH下对粘蛋白的吸附量(n=3,mean土SD)。 [0024] FIG. 2 is a core-shell polymer nanoparticles at different pH on the adsorption of mucin (n = 3, mean soil SD).

[0025]图3为核壳结构聚合物纳米粒在小鼠阴道给药后的局部滞留随时间的变化(n=5, mean ± SD)〇 [0025] FIG. 3 is a core-shell polymer nanoparticles remain in mice after local vaginal administration over time (n = 5, mean ± SD) square

[0026] 图4为核壳结构聚合物纳米粒在不同pH下对IFN的吸附能力(n=3,mean土SD) [0026] FIG. 4 is a core-shell polymer nanoparticles at different pH on the adsorption capacity of IFN (n = 3, mean soil SD)

具体实施方式 Detailed ways

[0027]下面采用具体实施例对本发明的技术方案做进一步说明。 [0027] The following specific examples further use of the described technical solution of the present invention.

[0028] 实施例1 [0028] Example 1

[0029] 1、制备核壳结构聚合物纳米粒子 [0029] 1. Preparation of core-shell polymer nanoparticles

[0030] 1)形成银核:在搅拌条件下向200mL硝酸银(0.1 mM)和柠檬酸钠(0.1 mM)的混合水溶液中逐滴加入硼氢化钠水溶液(IOmM) 2.5mL,室温下反应制得银核; [0030] 1) forming a silver core: by mixing an aqueous solution (0.1 mM) and sodium citrate (0.1 mM) was added dropwise a solution of sodium borohydride (IOmM) 2.5mL, at room temperature to a 200mL reaction of silver nitrate with stirring of silver nuclei;

[0031] 2)聚合包裹:在所得银核中加入十二烷基硫酸钠作为稳定剂,浓度为0.5% (w/w)。 [0031] 2) Polymerization Packages: sodium lauryl sulfate in the resultant silver core as a stabilizer at a concentration of 0.5% (w / w). 向IOOmL银核溶液中加入4-乙烯基苯硼酸(I. 00g)、N,N 亚甲基双丙烯酰胺交联剂(2mg)和二甲基丙烯酸乙二醇酯(40yL),通入N2除去可能溶解在溶液中的O2,加入ImLO . 1M2,2 ' -偶氮二异丁基脒二盐酸盐引发聚合反应,70°C下反应5小时; Was added 4-vinyl phenyl boronic acid (I. 00g) to IOOmL silver core solution, N, N-methylene bisacrylamide crosslinking agent (2mg) and ethylene glycol dimethacrylate (40yL), into N2 removing O2 may dissolve in the solution, was added ImLO 1M2,2 '- azobis isobutyl amidine dihydrochloride initiator under the polymerization reaction, 70 ° C 5 hours;

[0032] 3)分离纯化:2)中所得反应液用纯水透析72小时除去未反应的单体和低聚物, 8000rpm离心10min,分离沉淀,真空干燥至恒重,即得核壳结构聚合物纳米粒子。 [0032] 3) Purification: 2) The reaction solution obtained in the dialysis with pure water monomer and oligomer 72 hours to remove unreacted, centrifuged 8000 rpm for 10min, the precipitate was isolated and dried in vacuo to constant weight, the polymerization to obtain core-shell structure It was nanoparticles.

[0033] 2、表征核壳结构聚合物纳米粒子 [0033] 2, characterized by core-shell polymer nanoparticles

[0034] 1)形态表征 [0034] 1) Morphological Characterization

[0035] 纳米粒子进行透射电镜(JE0L2100F场发射投射电子显微镜)观察,如图1 (以磷钨酸负染后)所示,粒径在IOOnm左右,大小比较均匀。 [0035] The nanoparticles TEM (JE0L2100F field emission transmission electron microscope), as shown in FIG. 1 (in the phosphotungstic acid negative stain), a diameter of about IOOnm, uniform size.

[0036] 2)粘蛋白吸附性能 [0036] 2) Adsorption of mucin

[0037] 将纳米粒子分散液(每ml含IOmg纳米粒,简称NP)或纯水(简称w)与粘蛋白溶液(含有IOmM梓檬酸/柠檬酸钠或Tris-HCl缓冲盐,pH分别为4,5,6或者7,粘蛋白浓度0.5mg/mL) 以体积比1:10混合,室温放置过夜,离心后以BCA试剂盒测定上清液中粘蛋白浓度,按以下公式计筧栽药量。 [0037] The nanoparticle dispersion liquid (IOmg nanoparticles per ml, abbreviated NP) or pure water (hereinafter referred w) and mucin solution (containing IOmM Azusa citric acid / sodium citrate buffered saline or Tris-HCl, pH were 4,5,6 or 7, mucin concentration of 0.5mg / mL) in a 1:10 mixture allowed to stand overnight at room temperature, a volume ratio to BCA kit mucin concentration in the supernatant was determined after centrifugation, the following formula planted drugs majority meter the amount. 其中公式中的C指的都是粘蛋白的浓度。 Wherein in the formula refers to C are adhesive protein concentration.

[0038] [0038]

Figure CN104610497BD00051

[0039] 结果显示,本发明的纳米粒子对粘蛋白具有较强的吸附性(如图2所示),且这种吸附性能对pH表现出了一定的依赖性,较低的pH有利于吸附。 [0039] The results show that nanoparticles of the present invention have a strong adsorption (FIG. 2) of the mucin, and such adsorption performance showed some pH dependence, lower pH is conducive to adsorption .

[0040] 3)在体阴道内滞留 [0040] 3) retained in the body of the vagina

[0041] 在制备的第2步中,向反应体系中加入lmg/mL荧光探针(IR783),得到荧光标记的纳米粒,将荧光标记的纳米粒按照lOmg/mL的浓度分散在生理盐水中,用钝头针管在ICR雌性小鼠上进行阴道给药,每只小鼠给予I OyL纳米粒分散液,同时设溶液对照组,即同样阴道给予10yLIR783生理盐水溶液(浓度10yg/mL,其荧光强度与纳米粒分散液接近),以ISIS在体荧光成像系统检测给药局部(下腹部及会阴)荧光信号的变化,测定给药局部的荧光强度,以每只动物给药后马上成像所得的荧光强度作为100%,对结果进行归一化,作为"局部滞留量%"表示给药1,2,3天后的相对荧光强度;本实施例中纳米粒组和溶液对照组各5只动物,实验结果显示,与溶液对照组相比,纳米粒组的局部滞留显著改善(如图3所示)。 [0041] prepared in step 2 was added lmg / mL fluorescent probe (IR783) to the reaction system, to obtain nanoparticles fluorescently labeled, fluorescently labeled nanoparticles that the concentration lOmg / mL dispersed in physiological saline , blunt scalp tube for vaginal administration in ICR female mice used per mouse administered I OyL nanoparticles dispersion, while the control group was set, i.e. the same vaginal administration 10yLIR783 physiological saline solution (a concentration of 10yg / mL, fluorescence strength and dispersion of nanoparticles close), varying ISIS system detects fluorescence imaging in vivo administered topically (lower abdomen and perineum) fluorescence signal, the fluorescence intensity was measured topical administration, to the resulting image immediately after the administration each animal the fluorescence intensity is 100%, the results are normalized, as "local retention%" represents the relative fluorescence intensity of 1,2,3 days administration; Examples nanoparticle group and control group was 5 animals of the present embodiment, experimental results show that, compared with the control group, a solution, a partial retention nanoparticles was significantly improved (Figure 3).

[0042] 实施例2核壳结构聚合物纳米粒子的载药 [0042] The drug-loaded polymeric nanoparticles of the Example 2 shell structure embodiment

[0043] 本实施例以重组人α-干扰素为模型药物,将其溶解在pH分别是4、5、6的IOmM柠檬酸/柠檬酸钠和pH分别是7、8、9的Tris-HCl缓冲溶液中,使其浓度为0.8mg/mL。 [0043] In this embodiment, the recombinant human interferon α- model drug, which was dissolved in citric acid pH 4, 5 are IOmM / sodium citrate and pH are 7,8,9 Tris-HCl buffer solution to a concentration of 0.8mg / mL. 将上述6种干扰素溶液与纳米粒分散液(每ml含IOmg纳米粒)以体积比1:1混合,室温放置过夜,离心后以BCA试剂盒测定上清液中干扰素浓度,按以下公式计算载药量。 The above six interferon solution with a dispersion of nanoparticles (IOmg nanoparticles per ml) in a volume ratio of 1: 1 mixture allowed to stand overnight at room temperature, the supernatant was determined after centrifugation to a concentration of interferon BCA kit, according to the following formula calculation drug loading.

[0044] [0044]

Figure CN104610497BD00061

[0045] 结果显示,在pH4~9范围内,较低的pH对纳米粒子吸附干扰素有利(如图4所示), 在pH4~6的范围内,纳米粒能够有效地吸附干扰素。 [0045] The results show that, in the range pH4 ~ 9, a lower pH is advantageously interferon adsorbed on the nanoparticles (FIG. 4), in the range pH4 ~ 6, the nanoparticles can be effectively adsorbed interferon.

Claims (5)

1. 一种核壳结构聚合物纳米粒子,其特征在于:以银纳米粒为核,银核表面包裹聚4-乙烯基苯硼酸外壳,形成带有硼酸功能基团的核壳结构聚合物纳米粒子,所述纳米粒子粒径为在IOOnm,粒度的多分散系数不大于0.15;所述的银纳米粒核心为20~30nm,4-乙烯基苯硼酸在聚合物壳中占28~91 %摩尔百分比; 通过下述方法制备:先以硼氢化钠还原法制备银纳米粒作为银核,进一步以4-乙烯基苯硼酸为功能单体,以N,N'_亚甲基双丙烯酰胺和/或二甲基丙烯酸乙二醇酯为交联剂,在银核表面聚合成壳,制得一种具有核壳结构的聚合物纳米粒子,其包括步骤: 1) 形成银核:向硝酸银和柠檬酸钠的混合水溶液中加入硼氢化钠,室温下反应制得银核; 2) 聚合包裹:在所得银核中加入十二烷基硫酸钠作为稳定剂,向银核溶液体系中加入4-乙烯基苯硼酸功能单体及N,N'_亚甲基双 A core-shell polymer nanoparticles, characterized in that: as a core of silver nanoparticles, silver core surface of the wrapping poly 4-vinyl phenyl boronic housing is formed with a core-shell polymer nanoparticles boronic acid functional groups particles, the particle size of the nanoparticles IOOnm, a particle size polydispersity index not greater than 0.15; the core of the silver nanoparticles is 20 ~ 30nm, 4- divinylbenzene acid accounts for 28 to 91 mol% in the polymer shell percentage; prepared by the following method: first with sodium borohydride preparation of Ag nanoparticles as a silver core, to further function as a 4-vinyl phenyl boronic acid monomer, N, N'_ methylene bisacrylamide and / or ethylene glycol dimethacrylate as a crosslinking agent, a polymerization silver core to shell surface, to prepare a polymeric nanoparticles having a core-shell structure, comprising the steps of: 1) forming a silver core: the silver nitrate and sodium borohydride mixed aqueous solution of sodium citrate was added, reacted at room temperature to obtain the silver core; 2) polymerization Packages: sodium lauryl sulfate in the resultant silver core as a stabilizer, was added 4- core system silver acid functional monomer, divinylbenzene and N, N'_ methylenebis 烯酰胺和/或二甲基丙烯酸乙二醇酯等交联剂,引发剂引发聚合反应,60-80 °C下反应3-8小时; 3) 分离纯化:所得到的核壳结构的聚合物纳米粒子用纯水透析72小时以上,离心分离沉淀,真空干燥或冷冻干燥至恒重。 Acrylamide and / or ethylene glycol dimethacrylate ester crosslinking agents, polymerization initiators, reaction 3-8 hours at 60-80 ° C; 3) Purification: core-shell structure of the polymer obtained nanoparticles dialyzed with purified water more than 72 hours, the precipitate was isolated by centrifugation, and dried in vacuo or freeze-dried to constant weight.
2. 按照权利要求1所述核壳结构聚合物纳米粒子,其特征在于:所述的制备方法中,形成银核时期,硝酸银浓度为0.01~ImM,柠檬酸钠浓度为0.01~ImM,加入5~15mM硼氢化钠溶液的体积为硝酸银-柠檬酸钠混合溶液体积的1/100~1/50; 聚合成壳期间,用于稳定银纳米粒的十二烷基硫酸钠浓度为〇. 1~1 %,4_乙烯基苯硼酸功能单体与交联剂的摩尔比为2.5~10:1,单体和交联剂总摩尔浓度为50~IOOmM,引发剂为:2,2'_偶氮二异丁基脒二盐酸盐,加入量占功能单体和交联剂的总摩尔数的1~3%。 2. The according to claim 1 core-shell polymer nanoparticles, characterized in that: in the production method, during the formation of silver nuclei, silver nitrate concentration of 0.01 ~ ImM, sodium citrate at a concentration of 0.01 ~ ImM, was added volume of a solution of sodium borohydride in 5 ~ 15mM silver nitrate - sodium citrate mixture solution volume of 1/100 to 1/50; during the polymerization into the shell, for the concentration of sodium dodecyl stabilized silver nanoparticles is square. 1 to 1%, molar ratio of divinylbenzene 4_ acid functional monomer and the crosslinking agent is 2.5 to 10: 1, the total molar concentration of monomer and crosslinker of 50 ~ IOOmM, the initiator is: 2,2 ' _ azobis isobutyl amidine dihydrochloride, 1 to 3% of the total number of moles of added amount of functional monomer and crosslinker.
3. 按照权利要求1所述的核壳结构聚合物纳米粒子,其特征在于:所述的核壳结构聚合物纳米粒子通过物理吸附的方法包载蛋白多肽类药物。 3. The core-shell polymer as claimed in claim 1 of the nanoparticles, wherein: the core-shell polymer nano particles by physical adsorption method of entrapped proteins and peptides.
4. 按权利要求3所述的核壳结构聚合物纳米粒子,其特征在于:所述的蛋白多肽类药物为干扰素。 4. The core-shell polymer as claimed in claim 3 of the nanoparticles, wherein: the protein is an interferon peptide drugs.
5. 权利要求1所述的核壳结构聚合物纳米粒子在制备用于阴道给药制剂中的用途。 Core-shell polymer nanoparticles according to claim 1 formulations for vaginal administration use for the preparation.
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