CN101628970B - Hyperbranched polymer and preparation method and application thereof - Google Patents

Hyperbranched polymer and preparation method and application thereof Download PDF

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CN101628970B
CN101628970B CN 200810116689 CN200810116689A CN101628970B CN 101628970 B CN101628970 B CN 101628970B CN 200810116689 CN200810116689 CN 200810116689 CN 200810116689 A CN200810116689 A CN 200810116689A CN 101628970 B CN101628970 B CN 101628970B
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polymer
hyperbranched polyurethane
micelle
generation
polyurethane
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CN101628970A (en
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吴雁
蒋明
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国家纳米科学中心
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Abstract

The invention provides a hyperbranched polymer and a preparation method and application thereof. The polymer has a structure shown as the following formula (I), wherein n is a positive integer from 1 to 5; B is aliphatic polyester; and the molecular weight of the polymer is between 4,000 kDa and 7,000 kDa. The invention also provides the method for preparing the polymer and a micelle formed by the polymer and a method for preparing the micelle. The micelle prepared by the polymer can be used for a medicament carrier material and has good biocompatibility; as the critical micelle concentrationCMC is quite low and the formed micelle is stable and has small particle diameter and long circulation, the polymer micelle can be used for coating various hydrophilic and hydrophobic medicaments andis a medicament carrier with development prospect.

Description

Figure CN101628970BD00041

其中m为210-400的正整数;x、y为50-200的正整数;z为140-250的正整数。 Wherein m is a positive integer of 210-400; x, y is a positive integer of 50-200; Z is a positive integer of 140-250.

2.根据权利要求1所述的聚合物,其中所述的超支化聚胺酯的支化度为0. 5-0. 7。 2. The polymer according to claim 1, wherein the degree of branching of the hyperbranched polyurethane is 0. 5-0. 7.

3. 一种制备权利要求1或2所述聚合物的方法,该方法包括以下步骤: The method of claim 1 or 2 for preparing a polymer as claimed in claim 3, the method comprising the steps of:

a.将超支化聚胺酯、脂肪族酯类单体和催化剂进行混合,所述催化剂优选为辛酸亚 a. hyperbranched polyurethanes, aliphatic ester monomer and catalyst are mixed, the catalyst is preferably stannous

锡; tin;

b.在真空无水条件下,将步骤a得到的混合物在100-140°C保持8-14小时,得到超支化聚胺酯-脂肪族聚酯的聚合物。 . B under anhydrous conditions in vacuo, the mixture obtained in step a holder 8-14 hours at 100-140 ° C, to give a hyperbranched polyurethane - aliphatic polyester polymer.

4.根据权利要求3所述的方法,其中步骤a中超支化聚胺酯和脂肪族酯类单体的摩尔比为1 : 3-1 : 10,所述催化剂为超支化聚胺酯和脂肪族酯类单体的重量总和的 4. The method according to claim 3, wherein in step a molar ratio of hyperbranched polyurethane and aliphatic ester monomer is 1: 3-1: 10, the catalyst is a hyperbranched polyurethane and aliphatic mono esters body weight of the sum of the

0. 3% -0. 7%。 0.3% -0. 7%.

5. 一种胶束,该胶束由权利要求1或2所述的聚合物形成。 A micelle, the micelle or a polymer according to claim 1 or 2 is formed.

6.根据权利要求5所述的胶束,其中该胶束的临界胶束浓度为 6. The critical micelle concentration of the micelle according to claim 5, wherein the micelles is

1. 40 X 10_4-8. 40 X 10_4mg/ml。 1. 40 X 10_4-8. 40 X 10_4mg / ml.

7.根据权利要求5或6所述的胶束,其中所述胶束的胶束粒子为球形,直径为110-215nm。 7. The micelle of claim 5 or claim 6, wherein said particles are spherical micelles micelle diameter of 110-215nm.

8. 一种制备权利要求5至7中任一项所述胶束的方法,该方法包括以下步骤: The method according to any one of claims 5-7 micelle 8. A preparation as claimed in claim, the method comprising the steps of:

a.纯化权利要求3得到的超支化聚胺酯-脂肪族聚酯的聚合物; . A 3 hyperbranched polyurethane was purified claim - the aliphatic polyester polymer;

b.纯化后的聚合物在水中形成所述的聚合物胶束。 B. The purified polymer was formed in the polymer micelle in water.

9.根据权利要求8所述的方法,其中步骤a包括以下步骤:首先将超支化聚胺酯-脂肪族聚酯的聚合物溶解在二氯甲烷中,接着向二氯甲烷中加入石油醚,去除不溶物,再蒸发去除溶液中的石油醚。 9. The method according to claim 8, wherein step a comprises the following steps: first a hyperbranched polyurethane - aliphatic polyester polymer was dissolved in methylene chloride, followed by petroleum ether was added to the methylene chloride, insolubles were removed It was then removed by evaporation in petroleum ether solution.

10.根据权利要求8或9所述的方法,其中所述的步骤b包括以下步骤:首先将纯化后的聚合物溶于丙酮中,接着将溶解于丙酮中的聚合物滴加到去离子水中,形成带蓝光乳液, 再去除丙酮,得到所述的聚合物胶束。 10. The method of claim 8 or claim 9, wherein said step b comprises the following steps: First, the purified polymer was dissolved in acetone, followed by the polymer dissolved in acetone was added dropwise to deionized water , polymeric micelles formed with blue latex, and then the acetone is removed to obtain the.

11.权利要求5至7中任一项所述的胶束在作为药物载体中的应用。 11. The use as drug carrier micelles 5-7 in any one of claims. 一种超支化聚合物及其制备方法和应用 One hyperbranched polymer and its preparation method and application

技术领域 FIELD

[0001] 本发明涉及一种超支化聚合物、其制备方法、由该聚合物形成的胶束、胶束的制备方法和应用。 [0001] The present invention relates to a hyperbranched polymers, their preparation, preparation and application of polymeric micelles formed by the micelles. 具体地,本发明涉及能够形成胶束的超支化聚胺酯-脂肪族聚酯,属于纳米材料技术领域。 In particular, the present invention relates to a hyperbranched polyurethane is capable of forming micelles - aliphatic polyesters, belongs to the technical field of nanomaterials.

背景技术 Background technique

[0002] 树枝状大分子是一类高规整度、三维结构的树状大分子,其结构和分子尺寸大小具有良好的可控性,而且通过不平行控制可使树枝状大分子利用不同反应的同时连上药物及靶向基团,通过表面修饰不同的聚合物使其带有不同的功能基团,可使表面具有亲水性, 增加生物相容性。 [0002] The dendrimers are a class of highly structured, three-dimensional structure of the dendrimer, the structure and molecular size having good controllability, and can control by not parallel reactions using different dendrimers connected to both the drugs and targeting group, so that different polymers with different functional groups, the surface has hydrophilicity, increases biocompatibility by surface modification. 通过构建反应可使树枝状大分子的内部形成巨大的疏水空间。 Dendrimers can internal hydrophobic space formed by constructing huge reaction. 由于树枝状大分子表层结构结构亲水性的,内部空腔和结合点可以携带药物,所以这为树枝状大分子作为药物载体提供了得天独厚的条件,它可以实现真正意义上的纳米给药和药物缓释。 Since the dendrimer structure as hydrophilic surface, the interior cavity, and may carry a drug binding site, so this provides dendrimers as a drug carrier a unique condition, the true sense of the nano administration it may be realized and drug delivery. 从而,树枝状大分子作为药物载体引起了越来越多的科学工作者的注意,成为当今研究热点之一。 Thus, dendrimers as drug carriers attracted the attention of a growing number of scientists, it has become one of today's hot topic. 然而,树枝状大分子由于其昂贵的价格和繁琐的合成步骤,很大程度上限制了它的应用范围。 However, dendrimers because of its high price and complicated synthesis steps, largely limits its scope of application.

[0003] 超支化聚合物是一类具有独特结构和性能的高分子。 [0003] Hyperbranched polymers are a unique class of polymer structure and properties. 由于具有传统线性聚合物所没有的低粘度、高流变性、良好的溶解性、大量末端官能团以及低成本快速合成等一系列优良特性,超支化聚合物成为高分子学科以及其它交叉学科的研究热点。 Since the conventional linear polymer having a number of excellent features not low viscosity, high rheology, good solubility, low cost, and a large number of terminal functional groups of fast synthesis, hyperbranched polymers become a hot Polymer Science and other interdisciplinary . 它是一类具有独特结构和性能的高分子,由于超支化聚合物与树状聚合物结构和性能都极为相似,而且其一步法的合成过程方便、快捷、适合大批量生产,因而被认为它是树状大分子聚合物的替代品。 It is a kind of polymer having a unique structure and properties, since hyperbranched polymer structure and properties of dendrimers are very similar, and convenient one-step synthesis which, fast, suitable for mass production, thus it is considered alternate dendrimer polymer.

[0004] 在现有技术中,由于超支化聚合物在其内部和外部含有大量的官能团可以固定目标分子,或超支化特有的核壳结构可以作为主体来包埋客体分子,因此它已经被广泛应用于药物载体和医用材料中。 [0004] In the prior art, since hyperbranched polymer thereof contain large amounts of internal and external fixation target molecule can be a functional group, or hyperbranched specific core-shell structure may be embedded as the main guest molecule, it has been widely pharmaceutical carriers and applied to medical materials.

[0005] 脂肪族聚酯,如聚乳酸(PLA)、聚乙交酯-丙交酯(PLGA)、聚己内酯(PCL)是获美国FDA批准认可能进入人体的可生物降解高分子材料。 [0005] Aliphatic polyesters, such as polylactic acid (PLA), polyglycolide - lactide (PLGA), polycaprolactone (PCL) is approved by the US FDA approved can enter the body of a biodegradable polymer material . 它们是生物相容性好、可以在体内生物降解的聚合物,因此很适宜于用作药物载体材料,在人工皮肤及组织工程、药物的控制释放等方面已被广泛应用。 They are good biocompatibility, may be a biodegradable polymer in vivo, and therefore is suitable as a pharmaceutical carrier material, has been widely used in tissue engineering and artificial skin, controlled release of the drug, and the like. 然而这些脂肪族聚酯的亲水性差并且具有高结晶性,因而降低了它们的降解速率,导致与软器官的相容性降低,克服这些问题的有效方法就是在脂肪族聚酯链段中引入生物相容性和血液相容性亲水性链段,可以使脂肪族聚酯的性能有很大的改善。 However, these hydrophilic aliphatic polyester having a high crystallinity and a difference, thereby reducing the rate of degradation thereof, results in reduced compatibility with soft organs, an effective way to overcome these problems is to introduce in the aliphatic polyester segment biocompatibility and blood compatibility of the hydrophilic segment, an aliphatic polyester can have performance greatly improved. 这种接枝或嵌段聚合物因为具有两亲性,所以作为药物释放、创伤敷料的载体具有更大的优越性。 Such graft or block polymers having amphipathic because, so as drug delivery, wound dressing carrier more advantageous.

[0006] 众所周知,如果聚合物中同时具有亲水和疏水两部分组成,那么这种两亲性聚合物在水溶液中就可以自组装形成聚合物纳米胶束,聚合物纳米胶束作为药物载体发展于20 世纪90年代,是由两亲性聚合物在水溶液中自发形成的一种自组装结构,亲水性片段形成外壳,疏水性片段形成内核,构成独特的核-壳结构。 [0006] It is well known that, if the polymer has both hydrophilic and hydrophobic in two parts, the amphiphilic polymer can be self-assembled to form the polymer micelles in an aqueous solution, a polymer as a drug carrier micelles development in the 1990s, is a self-assembled structure, the hydrophilic segment is formed from a housing amphiphilic polymers in aqueous solution spontaneously formed, the hydrophobic segment form a core, constitute a unique core - shell structure. 具有载药量高、载药范围广、稳定性好、体内滞留时间长、独特的体内分布以及增加药物的稳定性、提高生物利用度和降低毒副作用等特点。 Having a high drug load, a wide range of drug loading, good stability, long in vivo residence time distribution and increase the unique in vivo drug stability, improved bioavailability characteristics and reduced toxicity. 两亲性聚合物胶束因具有核-壳结构、临界胶束浓度低、热稳定性好等特点在药物释放体系等领域具有广泛的应用前景。 Amphiphilic polymer micelles by having a core - shell structure, low critical micelle concentration, thermal stability and good characteristics having wide application prospect in the field of drug delivery systems and the like.

[0007] 近十几年,由两亲型聚合物材料组成的胶束给药体系以其突出的优点以及在肿瘤药物、基因药物、抗传染药物等方面的极大应用前景而受到了国际医药界的广泛关注。 [0007] Over the last decade, micellar delivery system amphiphilic polymer material is its outstanding advantages and great potential applications in oncology, gene drugs, anti-infective drugs and the like by the International Medicine world wide attention. 两亲型聚合物胶束体系是目前研究的最多和最成熟的聚合物胶体给药体系。 Amphiphilic polymer micelle system is currently the largest and most sophisticated polymer colloid drug delivery systems research. 大量研究表明,两亲型聚合物给药系统的载体能够自聚集成为独特核壳结构的胶束,由于聚合物胶束具有的“核-壳”结构类似于生物体中脂蛋白和病毒的结构在某种意义上具有一定的仿生性,而且聚合物胶束的较高稳定性决定了其在浓度极稀时仍能稳定存在,胶束表面的亲水性外壳可降低巨噬细胞对粒子的识别和吞噬能力,延长其在血液中的循环时间,可保护药物免遭生理环境的破坏,在体内缓慢释放;胶束的粒径小,能通过毛细胞血管直接进入器官和细胞内部,被更有效的吸收;胶束给药系统的广泛给药方式是其它任何剂型都无法比拟的,它可通过口服、注射(静脉注射、肌肉注射、皮下注射)、透皮等方式加入人体血液循环系统等显著优点。 Numerous studies show that the amphiphilic polymer carrier delivery system capable of self-aggregation of the micelles become unique core-shell structure, since the polymer micelles having a "core-shell" structure similar organisms and viruses lipoprotein structure in a certain sense bionic, higher stability of the micelles and polymer determines its stability even in the presence of a very dilute concentration, the hydrophilic surface of the micelles of the housing can be reduced to particles macrophages recognition ability and phagocytosis, which extend circulation time in the blood, may protect the drug from the physiological environment of the damage, slow release in vivo; small particle size of micelles, by hair cells directly into organs and blood vessels inside the cell, were more effective absorption; broad micellar delivery systems mode of administration is any other dosage forms can match, it can be administered by oral, injectable, transdermal, etc. added (intravenous intramuscular, subcutaneous,) human blood circulation system, significant advantages.

[0008] 高分子学报2000年第4期发表了《超支化聚胺酯的分子设计及其制备》一文,其中的超支化聚胺酯是以丙烯酸甲酯和二乙醇胺为原料由Michael加成反应制得N,N- 二羟乙基-3-胺基丙酸甲酯单体,再用“准一步法”和“发散法”使之与1,1,1-三羟甲基丙烷反应合成一种新型超支化聚胺酯,通过核磁共振和元素分析方法对N,N- 二羟乙基-3-胺基丙酸甲酯单体的分子结构进行了表征。 [0008] Polymer Journal 2000, No. 4 published "hyperbranched polyurethane Molecular Design and preparation of" a text, which is a hyperbranched polyurethane acrylate and diethanolamine as a raw material obtained by the Michael addition reaction of N, N- methyl dihydroxyethyl -3-Aminomethyl monomer, then "quasi one-step" and the "divergent method" so as 1,1,1-trimethylol propane reacted with a novel synthesis of hyperbranched of polyurethane, of N, N- dihydroxyethyl -3- methyl amine monomer molecular structure was characterized by NMR and elemental analysis. GPC测定表明合成的超支化聚胺酯分子量分布窄,具有单分散性;粘度小于同分子量的线形分子;耐热性能较好,失重温度高于200°C,所形成的超支化聚胺酯不能形成胶束,无法作为药物载体使用。 GPC measurement showed that the synthesis of the hyperbranched polyurethane narrow molecular weight distribution, monodisperse; viscosity of less than the linear molecules with molecular weight; good heat resistance, mass loss temperature above 200 ° C, the hyperbranched polyurethane can not form micelles formed, It can not be used as a drug carrier.

发明内容 SUMMARY

[0009] 本发明的一目的提供了一种超支化聚胺酯-脂肪族聚酯的聚合物,该聚合物能够形成两亲性胶束,该聚合物制备过程重复性好,在药物载体上具有广泛的应用性。 [0009] The object of the present invention provides a hyperbranched polyurethane - aliphatic polyester polymer which is capable of forming an amphiphilic micelle, reproducible preparation of the polymer, in the drug carrier having a wide applicability.

[0010] 本发明的另一目的提供了该聚合物的制备方法。 [0010] Another object of the present invention provides a method of preparing the polymer.

[0011] 本发明的再一目的提供了一种由该聚合物形成的胶束。 [0011] A further object of the present invention to provide micelles formed from the polymer.

[0012] 本发明的再一目的提供了该胶束的制备方法。 [0012] A further object of the present invention provides a preparation method of micelles.

[0013] 本发明的再一目的提供了所述的胶束在作为药物载体中的应用。 [0013] A further object of the present invention provides the use of a micelle in a pharmaceutical carrier.

[0014] 本发明一方面提供了一种超支化聚合物,该聚合物具有如下式(I)所示结构: [0014] In one aspect the present invention provides a hyperbranched polymer having a structure shown by the following formula (I):

[0015] [0015]

Figure CN101628970BD00071

[0016] (I), [0016] (I),

[0017] 式中D为 [0017] where D is the

[0018] [0018]

Figure CN101628970BD00072

1-5的正整数,B为脂肪族聚酯,并且该聚合物的分子量为4000kDa-7000kDa。 N is an integer of 1-5, B is an aliphatic polyester, and the molecular weight of the polymer is 4000kDa-7000kDa.

[0019] 优选地,所述的脂肪族聚酯为具有如下分子式的脂肪族聚酯 [0019] Preferably, the aliphatic polyester is an aliphatic polyester of the formula

Figure CN101628970BD00073

其中m为210-400的正整数,X、y为50-200的正 Wherein m is a positive integer of 210-400, X, y is a positive 50-200

整数; Integer;

Figure CN101628970BD00074

为140-250的正整数 140-250 is a positive integer

Figure CN101628970BD00075

为聚乳酸, Polylactic acid,

Figure CN101628970BD00076

为聚乙交酯-丙交酯 As polyglycolide - lactide

Figure CN101628970BD00077

为聚己内酯。 Polycaprolactone.

[0020] 优选地,其中所述的超支化聚胺酯的支化度为0. 5-0. 7。 [0020] Preferably, wherein the degree of branching of the hyperbranched polyurethane is 0. 5-0. 7.

[0021] 本发明另一方面提供了制备聚合物的方法,该方法包括以下步骤: [0021] In another aspect the present invention provides a process for preparing a polymer, the method comprising the steps of:

[0022] a.将超支化聚胺酯、脂肪族酯类单体和催化剂进行混合,所述的催化剂优选为辛酸亚锡; . [0022] a hyperbranched polyurethane, aliphatic ester-based monomer and a catalyst are mixed, the catalyst is preferably stannous octoate;

[0023] b.在真空无水条件下,将步骤a得到的混合物在100-140°C保持8_14小时,得到超支化聚胺酯-脂肪族聚酯的聚合物。 . [0023] b under anhydrous conditions in vacuo, the mixture obtained in step a held 8_14 hours at 100-140 ° C, to give a hyperbranched polyurethane - aliphatic polyester polymer. 以丙交酯为例,超支化聚胺酯和丙交酯的反应生成聚合物的过程如下: Lactide, for example, the process of generating a hyperbranched polyurethane polymers and lactide reaction as follows:

[0024] [0024]

Figure CN101628970BD00081

上式中与氧相连的黑色粗线表示重复单元,从上面给出的式(I)的结构可以推断 Repeating units represented by the above formula with a thick black line connected to an oxygen, the formula (I) given above may be inferred from

[0025] [0025]

其结构。 Its structure.

[0026] 优选地,其中步骤a中超支化聚胺酯和脂肪族酯类单体的摩尔比为1 : 3-1 : 10, 所述催化剂为超支化聚胺酯和脂肪族酯类单体的重量总和的0. 3% -0. Ί%。 By weight of the sum of 10, the catalyst is a hyperbranched polyurethane and aliphatic ester monomers: [0026] Preferably, a step wherein the molar ratio of the hyperbranched polyurethane and aliphatic ester monomer is 1: 3-1 0. 3% -0. Ί%.

[0027] 本发明的再一方面还提供了一种胶束,该胶束由所述的超支化聚胺酯-脂肪族聚酯聚合物形成。 Another aspect [0027] The present invention further provides a micelle, the micelle by the hyperbranched polyurethane - forming an aliphatic polyester polymer.

[0028] [0028]

[0029] [0029]

[0030] [0030]

[0031] [0031]

[0032] [0032]

[0033] 溶解在醚。 [0033] was dissolved in ether.

[0034] 优选地,其中步骤b包括以下步骤:首先将纯化后的聚合物溶于丙酮中,接着将溶解于丙酮中的聚合物滴加到去离子水中,形成带蓝光乳液,再去除丙酮,得到所述的聚合物胶束。 [0034] Preferably, wherein step b comprises the following steps: First, the purified polymer was dissolved in acetone, followed by the polymer dissolved in acetone was added dropwise to deionized water to form an emulsion with blue light, then the acetone is removed, the polymer micelle obtained.

[0035] 本发明再一方面还提供了所述的胶束在作为药物载体中的应用。 [0035] In another aspect of the present invention also provides the use as a drug in the micelle carrier.

[0036] 由于本发明制备的超支化聚胺酯-脂肪族聚酯聚合物中,其中超支化聚胺酯端具有亲水性,脂肪族聚酯端具有疏水性,所以用超支化聚胺酯和脂肪族酯类单体作为基本材料制备的两亲性聚合物可组装形成纳米胶束作为药物载体,可以避免被网状内皮细胞捕获,有效地延长了药效,提高了生物利用度和生物活性。 [0036] Since the preparation of the hyperbranched polyurethanes of the present invention - the aliphatic polyester polymer, wherein the hyperbranched polyurethane having terminal hydrophilic, aliphatic polyester having a hydrophobic end, the hyperbranched polyurethane and aliphatic mono esters amphiphilic polymer precursor can be prepared as a base material assembled to form micelles as drug carriers, can avoid being captured by the reticuloendothelial cells, effectively extending the efficacy, improved bioavailability and biological activity.

[0037] 本发明的有益效果是:(1)本发明的聚合物其中超支化结构的超支化聚胺酯端和脂肪族聚酯端具有良好的生物相容性;(¾该聚合物胶束保留了超支化聚胺酯的形式和结构,超支化聚胺酯的亲水性和超支化的特殊结构可以有效地避免被网状内皮细胞捕获,有 [0037] Advantageous effects of the present invention are: (1) hyperbranched polyurethane polymer wherein the aliphatic polyester side end and hyperbranched structure of the present invention have good biocompatibility; (¾ polymer micelle retains the form and structure of the hyperbranched polyurethane, hyperbranched polyurethane and a hydrophilic hyperbranched specific structure can effectively avoid capture by the reticuloendothelial cells,

优选地,所述的聚合物胶束的临界胶束浓度为1. 40X 10_4-8. 40X 10-4mg/mL· 更优选地,所述的聚合物胶束的胶束粒子为球形,直径为110-215nm。 Preferably, the polymer micelle critical micelle concentration of 1. 40X 10_4-8. 40X 10-4mg / mL · More preferably, the polymer micelle particles are spherical micelles, diameter 110-215nm. 本发明的再一方面还提供了一种制备胶束的方法,该方法包括以下步骤: Another aspect of the present invention further provides a method of preparing the micelle, the method comprising the steps of:

a.纯化得到的超支化聚胺酯-脂肪族聚酯的聚合物; . A to give a hyperbranched polyurethane - aliphatic polyester polymer;

b.纯化后的聚合物在水中形成所述的聚合物胶束。 B. The purified polymer was formed in the polymer micelle in water.

优选地,其中步骤a包括以下步骤:首先将超支化聚胺酯-脂肪族聚酯的聚合物:氯甲烷中,接着向二氯甲烷中加入石油醚,去除不溶物,再蒸发去除溶液中的石油效地延长了药效,可以提高药物包载及提高了生物利用度和生物活性;C3)本发明的聚合物胶束由于临界胶束浓度CMC很低,形成的胶束稳定,粒径小,具有长循环性,可用于包载各种亲、疏水药物,是具有发展前途的药物载体;(4)本发明的聚合物胶束制备方法简单, 重复性好,在药物载体上具有广泛的应用性。 Preferably, wherein step a comprises the following steps: first a hyperbranched polyurethane - aliphatic polyester polymer: methyl chloride, followed by addition of petroleum ether in dichloromethane, the insoluble material was removed, and then the solution was removed by evaporation efficiency oil extend the efficacy can be enhanced drug entrapping and improved bioavailability and biological activity; a C3) polymer micelle according to the present invention, since a low critical micelle concentration CMC, micelle formation of a stable, small particle size, having long-circulating properties can be used for a variety of pro-entrapment, hydrophobic drug, a drug carrier having a promising; polymer micelle preparation method (4) of the present invention is simple, reproducible, of wide application in the pharmaceutical carrier .

附图说明 BRIEF DESCRIPTION

[0038] 图1表示第四代超支化聚胺酯-聚乳酸聚合物胶束的照片。 [0038] FIG. 1 shows a fourth-generation hyperbranched polyurethane - polylactic acid polymer micelle picture.

[0039] 图2表示载有牛血清白蛋白(BSA)的第四代超支化聚胺酯-聚乳酸聚合物胶束的照片。 [0039] FIG. 2 shows contain bovine serum albumin (BSA) in the fourth generation hyperbranched polyurethane - polylactic acid polymer micelle picture.

[0040] 图3表示实施例7中的第四代超支化聚胺酯的红外谱图。 [0040] FIG. 3 represents the fourth-generation hyperbranched polyurethane of Example 7 IR spectrum FIG.

[0041] 图4表示实施例7中的第四代超支化聚胺酯-聚乳酸聚合物的红外谱图。 [0041] FIG. 4 shows a fourth generation hyperbranched polyurethane according to embodiment 7 - IR spectrum of polylactic acid polymer.

[0042] 图5表示实施例7中的第四代超支化聚胺酯的核磁共振谱图。 [0042] FIG. 5 shows a fourth generation in Example 7 NMR spectrum of a hyperbranched polyurethane embodiment.

[0043] 图6表示实施例7中的第四代超支化聚胺酯-聚乳酸聚合物的核磁共振谱图。 [0043] FIG. 6 shows a fourth generation hyperbranched polyurethane according to embodiment 7 - NMR spectrum of polylactic acid polymer.

具体实施方式 Detailed ways

[0044] 实施例1 [0044] Example 1

[0045] 1.超支化聚胺酯的制备 [0045] 1. Preparation of hyperbranched polyurethane of the

[0046] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0046] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0047] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇混合物,在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇,得到一种无色透明的油状液体即,N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0047] In the three-neck flask were added 8.609g of methyl acrylate, 10. 514g diethanolamine and IOml methanol mixture, stirred at room temperature for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess methyl acrylate and methanol, to give a colorless transparent oily liquid i.e., N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0048] B.第二代超支化聚胺酯聚合物的制备 [0048] B. Second Generation hyperbranched polyurethane polymers prepared

[0049] 在三口瓶中加入l.;342g 1,1,1-三羟甲基丙烷、5.93g N,N-二羟乙基-3-胺基丙烯酸甲酯单体和0. 017g四异丁氧基钛为催化剂,反应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0049] In the three-neck flask was added l;. 342g 1,1,1- trimethylolpropane, 5.93g N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer and 0. 017g tetraisopropyl titanium butoxide catalyst, the reaction system under protection of N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、 减压蒸馏除去乙醇,然后产物真空干燥,得到第二代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give the second-generation hyperbranched polyurethane. 其分子式如下: Its molecular formula is as follows:

[0050] [0050]

Figure CN101628970BD00101

[0051] 在上面的结构式中的黑色粗线部分表示重复的结构单元,与氮原子相连的另一个轻乙基的氧原子上所连接的化学结构与和该羟乙基对称的氧原子上连接的化学结构是相同的,在上面的结构式中用黑色粗线表示这一部分。 [0051] In the above portion of the heavy black line represents the structural formula of the repeating structural units, the chemical structure of the light on the other nitrogen atom with an oxygen atom of the ethyl group connected to symmetrical and the oxygen atom-hydroxyethyl the chemical structure is the same, in the above structural formula represented by the heavy black line portion.

[0052] 与1,1,1_三羟甲基丙烷的另外两个羟甲基上的氧原子相连的结构和上图中表示的另外一个羟甲基上的氧原子相连的结构是相同的,在上面的结构式中也用黑色的粗线进行了表示。 [0052] The structure and two additional oxygen atoms hydroxymethyl 1,1,1_ trimethylolpropane and further connected to the structure of the oxygen atom attached to a hydroxymethyl group is the same as the above figure represent in the above formulas also represent the black bold line.

[0053] 2.第二代超支化聚胺酯-聚乳酸聚合物的合成 [0053] 2. Second-generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0054] 将得到的第二代超支化聚胺酯产物放在真空干燥箱中干燥,将1. 512g第二代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 020g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0054] The resulting second generation hyperbranched polyurethane product was dried in a vacuum oven, the second generation hyperbranched 1. 512g polyurethane product with 5g lactide on single-neck flask, then added 0. 020g octanoic acid stannous stopper with a single port and then stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的产物第二代超支化聚胺酯-聚乳酸的聚合物在真空干燥箱中25°C下干燥2天。 After filtration of the resulting second generation hyperbranched polyurethane product - the polylactic acid polymer was dried at 25 ° C in a vacuum oven for 2 days. 通过红外和核磁表征证实第二代超支化聚胺酯-聚乳酸的聚合物已经生成;分子量为4000kDa。 The second generation hyperbranched polyurethane confirmed by IR and NMR characterization - polylactic acid polymers has been generated; molecular weight 4000kDa.

[0055] 3.制备第二代超支化聚胺酯-聚乳酸聚合物胶束 [0055] 3. Preparation of second generation hyperbranched polyurethane - polylactic acid polymer micelle

[0056] 将0. 2g纯化后的第二代超支化聚胺酯-聚乳酸的聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第二代超支化胺酯-聚乳酸聚合物胶束。 [0056] After the second generation hyperbranched polyurethane purified 0. 2g - the polylactic acid polymer was dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally with blue latex form, by reducing acetone pressure evaporated, obtaining a second-generation hyperbranched amine ester - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察。 Then micelle dynamic light scattering, electron microscopy and fluorescence spectroscopy observation. 结果表明:动态光散色射测定其粒径为llOnm,分散指数为0. 05 ;透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为1.42X10_4mg/ml。 The results show: the dynamic light scattering particle diameter measured emission color llOnm, the dispersion index was 0.05; TEM observation regular spherical particles; Fluorescence Spectrometry critical micelle concentration 1.42X10_4mg / ml.

[0057] 实施例2[0058] 1.超支化聚胺酯的制备 [0057] Example 2 [0058] 1. Preparation of hyperbranched polyurethane

[0059] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0059] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0060] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇,混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后得到一种无色透明的油状液体N,N- 二羟乙基-3-胺基丙烯酸甲酯单体。 [0060] methyl acrylate was added 8.609g three-neck flask, 10. 514g IOml diethanolamine and methanol, and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0061] B.第二代超支化聚胺酯的制备 [0061] B. Preparation of second generation hyperbranched polyurethane of the

[0062] 在三口瓶中加入l.;342g 1,1,1-三羟甲基丙烷、15.93g N,N-二羟乙基-3-胺基丙烯酸甲酯单体和0. 017g四异丁氧基钛为催化剂,反应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0062] In the three-neck flask was added l;. 342g 1,1,1- trimethylolpropane, 15.93g N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer and 0. 017g tetraisopropyl titanium butoxide catalyst, the reaction system under protection of N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、 减压蒸馏除去乙醇,然后产物真空干燥,得到第二代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give the second-generation hyperbranched polyurethane.

[0063] 2.第二代超支化聚胺酯-聚乳酸聚合物的合成 [0063] 2. Second-generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0064] 将得到的第二代超支化聚胺酯产物放在真空干燥箱中干燥,将0. 648g第二代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 020g的辛酸亚锡,用胶塞将单口瓶塞紧并密封。 [0064] The resulting second generation hyperbranched polyurethane product was dried in a vacuum oven, the second generation hyperbranched 0. 648g polyurethane product with 5g lactide on single-neck flask, then added 0. 020g octanoic acid stannous, a single port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到100°C保持8小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 100 ° C for 8 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的产物第二代超支化聚胺酯-聚乳酸的聚合物在真空干燥箱中25°C下干燥2 天。 After filtration of the resulting second generation hyperbranched polyurethane product - the polylactic acid polymer was dried at 25 ° C in a vacuum oven for 2 days. 通过红外和核磁表征证实第二代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为4700kDa。 The second generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 4700kDa.

[0065] 3.制备第二代超支化聚胺酯-聚乳酸聚合物胶束 [0065] 3. Preparation of second generation hyperbranched polyurethane - polylactic acid polymer micelle

[0066] 将0. 2g纯化后的第二代超支化聚胺酯-聚乳酸溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第二代超支化聚胺酯-聚乳酸聚合物胶束。 [0066] After the second generation hyperbranched polyurethane purified 0. 2g - the polylactic acid dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water with blue latex formed last, the acetone was removed by evaporation under reduced pressure to give the second-generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察, 结果表明动态光散色射测定其粒径为lMnm,分散指数为0. 07 ;透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为2. 31 X 10-4mg/ml ο Then micelle dynamic light scattering, electron microscopy and fluorescence spectra were observed, the results indicate that the dynamic light scattering particle diameter measured emission color lMnm, the dispersion index was 0.07; TEM observation regular spherical particles; fluorescence spectra Determination of critical micelle concentration of 2. 31 X 10-4mg / ml ο

[0067] 实施例3 [0067] Example 3

[0068] 1.超支化聚胺酯的制备 [0068] 1. Preparation of hyperbranched polyurethane of the

[0069] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0069] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0070] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇混合物,在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0070] In the three-neck flask were added 8.609g of methyl acrylate, 10. 514g diethanolamine and IOml methanol mixture, stirred at room temperature for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0071] B.第二代超支化聚胺酯聚合物的制备 [0071] B. Second Generation hyperbranched polyurethane polymers prepared

[0072] 在三口瓶中加入l.;342g 1,1,1-三羟甲基丙烷、15.93g N,N_二羟乙基-3-胺基丙烯酸甲酯单体和0. 017g四异丁氧基钛为催化剂,应体系在N2保护下,120°C恒温反应12h, 得到一种黄色粘稠液体。 [0072] In the three-neck flask was added l;. 342g 1,1,1- trimethylolpropane, 15.93g N, N_ -3-Aminomethyl-dihydroxyethyl methacrylate monomer and 0. 017g tetraisopropyl butoxy titanium catalyst system to be protected under N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第二代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give the second-generation hyperbranched polyurethane.

[0073] 2.第二代超支化聚胺酯-聚乳酸聚合物的合成 [0073] 2. Second-generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0074] 将得到的第二代超支化聚胺酯产物放在真空干燥箱中干燥,将0. 454g第二代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 020g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0074] The resulting second generation hyperbranched polyurethane product was dried in a vacuum oven, the second generation hyperbranched 0. 454g polyurethane product with 5g lactide on single-neck flask, then added 0. 020g octanoic acid stannous stopper with a single port and then stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持14小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C for 14 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的第二代超支化聚胺酯-聚乳酸的聚合物产物在真空干燥箱中25°C下干燥2天。 After filtration of the resulting second generation hyperbranched polyurethane - polylactic acid polymer product was dried in a vacuum oven at 25 ° C for 2 days. 通过红外和核磁表征证实第二代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为5100kDa。 The second generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 5100kDa.

[0075] 3.制备第二代超支化聚胺酯-聚乳酸聚合物胶束 [0075] 3. Preparation of second generation hyperbranched polyurethane - polylactic acid polymer micelle

[0076] 将0. 2g纯化后的第二代超支化聚胺酯-聚乳酸聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第二代超支化聚胺酯-聚乳酸聚合物胶束。 [0076] After the second generation hyperbranched polyurethane purified 0. 2g - polylactic acid polymer is dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally formed with blue latex, acetone under reduced pressure evaporated, to give the second-generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明:动态光散色射测定其粒径为144·,分散指数为0. 08,透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为3. 02X 10-4mg/mlο Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results showed that: a dynamic light scattering particle size was measured color emitting 144. dispersion was 0.08, TEM observation of regular spherical particles; fluorescence spectrometry critical micelle concentration of 3. 02X 10-4mg / mlο

[0077] 实施例4 [0077] Example 4

[0078] 1.超支化聚胺酯的制备 [0078] 1. Preparation of hyperbranched polyurethane of the

[0079] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0079] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0080] 在三口瓶中加入8. 609g丙烯酸甲酯、10. 514g二乙醇胺和IOml甲醇混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0080] 8. 609g methyl acrylate was added three-neck flask, 10. 514g IOml diethanolamine and methanol and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0081] B.第三代超支化聚胺酯聚合物的制备 [0081] B. The third-generation hyperbranched polyurethane polymers prepared

[0082] 在三口瓶中加入5g第二代超支化聚胺酯7. 32g、N,N-二羟乙基-3-胺基丙烯酸甲酯单体和0. 017g四异丁氧基钛为催化剂,应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0082] 5g of the second generation hyperbranched polyurethane 7. 32g in three-neck flask, N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer and 0. 017g tetraisobutoxy titanium catalyst, under the protection system should N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第三代超支化聚胺酯; The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give third generation hyperbranched polyurethane;

[0083] 2.第三代超支化聚胺酯-聚乳酸聚合物的合成 [0083] 2. The third generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0084] 将得到的第三代超支化聚胺酯产物放在真空干燥箱中干燥,将1.677g第三代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 030g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0084] The resulting third generation hyperbranched polyurethane product was dried in a vacuum oven, the third generation hyperbranched polyurethane 1.677g product with 5g lactide on single-neck flask, then added 0. 030g of stannous tin, then the one-port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的产物第三代超支化聚胺酯-聚乳酸的聚合物在真空干燥箱中25°C下干燥2天。 After filtration to give the product of the third-generation hyperbranched polyurethane - the polylactic acid polymer was dried at 25 ° C in a vacuum oven for 2 days. 通过红外和核磁表征证实第三代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为4850kDa。 Third generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 4850kDa.

[0085] 3.制备第三代超支化聚胺酯-聚乳酸聚合物胶束 [0085] 3. Preparation of third generation hyperbranched polyurethane - polylactic acid polymer micelle

[0086] 将0. 2g纯化后的第三代超支化聚胺酯-聚乳酸的聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第三代超支化聚胺酯-聚乳酸的聚合物胶束。 [0086] After the third generation hyperbranched polyurethane purified 0. 2g - the polylactic acid polymer was dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally with blue latex form, by reducing acetone pressure evaporated, to give third generation hyperbranched polyurethane - polylactic acid polymeric micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明,动态光散色射测定其粒径为153·,分散指数为0. 06,透射电镜观测粒子为规整的圆球形,荧光光谱测定其临界胶束浓度为4. 15X 10-4mg/mL· Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results indicate that the dynamic light scattering particle size was measured color emission-153, a polydispersity index of 0.06, TEM observation of regular spherical particles, fluorescence spectrometry critical micelle concentration 4. 15X 10-4mg / mL ·

[0087] 实施例5[0088] 1.超支化聚胺酯的制备 [0087] Example 5 [0088] 1. Preparation of hyperbranched polyurethane

[0089] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0089] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0090] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇混合物,在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0090] In the three-neck flask were added 8.609g of methyl acrylate, 10. 514g diethanolamine and IOml methanol mixture, stirred at room temperature for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0091] B.第三代超支化聚胺酯聚合物的制备 [0091] B. The third-generation hyperbranched polyurethane polymers prepared

[0092] 在三口瓶中加入5g第二代超支化聚胺酯、7. 32g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 03g四异丁氧基钛为催化剂,应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0092] In the three-neck flask was added 5g second generation hyperbranched polyurethane, 7. 32g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 03g tetraisobutoxy titanium catalyst, under the protection system should N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第三代超支化聚胺酯; The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give third generation hyperbranched polyurethane;

[0093] 2.第三代超支化聚胺酯-聚乳酸聚合物的合成 [0093] 2. The third generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0094] 将得到的第三代超支化聚胺酯产物放在真空干燥箱中干燥,将0.719g第三代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 030g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0094] The resulting third generation hyperbranched polyurethane product was dried in a vacuum oven, the third generation hyperbranched polyurethane 0.719g product with 5g lactide on single-neck flask, then added 0. 030g of stannous tin, then the one-port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的产物第三代超支化聚胺酯-聚乳酸聚合物在真空干燥箱中25°C下干燥2 天。 After filtration to give the product of the third-generation hyperbranched polyurethane - polylactic acid polymer was dried at 25 ° C in a vacuum oven for 2 days. 通过红外和核磁表征证实第三代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为5310kDa。 Third generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 5310kDa.

[0095] 3.制备第三代超支化聚胺酯-聚乳酸聚合物胶束 [0095] 3. Preparation of third generation hyperbranched polyurethane - polylactic acid polymer micelle

[0096] 将0. 2g纯化后的第三代超支化聚胺酯-聚乳酸聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第三代超支化聚胺酯-聚乳酸聚合物胶束。 [0096] After the third generation hyperbranched polyurethane purified 0. 2g - polylactic acid polymer is dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water with blue latex formed last, the acetone under reduced pressure removed by evaporation to give third generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明,动态光散色射测定其粒径为168·,分散指数为0. 09,透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为5. 36X 10-4mg/mlο Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results indicate that the dynamic light scattering particle size was measured emission color 168 · dispersion was 0.09, TEM observation of regular spherical particles; fluorescence spectrometry critical micelle concentration 5. 36X 10-4mg / mlο

[0097] 实施例6 [0097] Example 6

[0098] 1.超支化聚胺酯的制备 [0098] 1. Preparation of hyperbranched polyurethane of the

[0099] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0099] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0100] 在三口瓶中加入8. 609g丙烯酸甲酯、10. 514g二乙醇胺和IOml甲醇混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0100] 8. 609g methyl acrylate was added in the three-neck flask, 10. 514g IOml diethanolamine and methanol and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0101] B.第三代超支化聚胺酯聚合物的制备 [0101] B. The third-generation hyperbranched polyurethane polymers prepared

[0102] 在三口瓶中加入5g第二代超支化聚胺酯、7. 32g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 030g四异丁氧基钛为催化剂,应体系在队保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0102] In the three-neck flask was added 5g second generation hyperbranched polyurethane, 7. 32g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 030g tetraisobutoxy titanium catalyst, under the protection system should the team, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第三代超支化聚胺酯; The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give third generation hyperbranched polyurethane;

[0103] 2.第三代超支化聚胺酯-聚乳酸聚合物的合成 [0103] 2. The third generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0104] 将得到的第三代超支化聚胺酯产物放在真空干燥箱中干燥,将0.503g第三代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 030g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0104] The resulting third generation hyperbranched polyurethane product was dried in a vacuum oven, the third generation hyperbranched polyurethane 0.503g product with 5g lactide on single-neck flask, then added 0. 030g of stannous tin, then the one-port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的第三代超支化聚胺酯和聚乳酸聚合物产物在真空干燥箱25°C下干燥2 天。 After filtration to obtain the third generation hyperbranched polyurethanes and polylactic acid polymer product was dried in a vacuum oven at 25 ° C 2 days. 通过红外和核磁表征证实第三代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为5800kDao Third generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 5800kDao

[0105] 3.制备第三代超支化聚胺酯-聚乳酸聚合物胶束 [0105] 3. Preparation of third generation hyperbranched polyurethane - polylactic acid polymer micelle

[0106] 将0. 2g纯化后的第三代超支化聚胺酯-聚乳酸聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第三代超支化聚胺酯-聚乳酸聚合物胶束。 [0106] After the third generation hyperbranched polyurethane purified 0. 2g - polylactic acid polymer is dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water with blue latex formed last, the acetone under reduced pressure removed by evaporation to give third generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明:动态光散色射测定其粒径为172·,分散指数为0. 05,透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为6. 14X 10-4mg/mL· Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results showed that: a dynamic light scattering particle size was measured emission color 1721, a polydispersity index of 0.05, TEM observation of regular spherical particles; fluorescence spectrometry critical micelle concentration 6. 14X 10-4mg / mL ·

[0107] 实施例7 [0107] Example 7

[0108] 1.超支化聚胺酯的制备 [0108] 1. Preparation of hyperbranched polyurethane of the

[0109] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0109] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0110] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇,混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0110] methyl acrylate was added 8.609g three-neck flask, 10. 514g IOml diethanolamine and methanol, and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0111] B.第四代超支化聚胺酯聚合物的制备 [0111] B. The fourth-generation hyperbranched polyurethane polymers prepared

[0112] 在三口瓶中加入5g第三代超支化聚胺酯、6. 60g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 050g四异丁氧基钛为催化剂,反应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0112] In the three-neck flask was added 5g third generation hyperbranched polyurethane, 6. 60g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 050g tetraisobutoxy titanium catalyst, the reaction system under N2 protection, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第四代超支化聚胺酯聚合物。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give a fourth-generation hyperbranched polyurethane polymer.

[0113] 2.第四代超支化聚胺酯-聚乳酸聚合物的合成 [0113] 2. The Fourth Generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0114] 将得到的第四代超支化聚胺酯产物放在真空干燥箱中干燥,将1. 760g第四代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 040g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0114] The resulting fourth-generation hyperbranched polyurethane product was dried in a vacuum oven, the fourth-generation hyperbranched 1. 760g polyurethane product with 5g lactide on single-neck flask, then added 0. 040g octanoic acid stannous stopper with a single port and then stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的第四代超支化聚胺酯-聚乳酸聚合物产物在真空干燥箱中25°C下干燥2 天。 After filtration to give the fourth-generation hyperbranched polyurethane - polylactic acid polymer product was dried in a vacuum oven at 25 ° C for 2 days. 通过红外和核磁表征证实第四代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为5250kDao The fourth-generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 5250kDao

[0115] 第四代超支化聚胺酯的红外谱图可参见附图3,在该附图中,3369. OSkm1表示聚胺酯上的OH峰、1727. 933cm-1表示该聚胺酯上的C = 0峰,1614. 152^1表示该聚胺酯上的CN峰,1457. 944cm"1表示该聚胺酯上的CH2峰。 [0115] The fourth-generation hyperbranched polyurethanes can be found in the IR spectrum of Figure 3, in this figure, 3369. OSkm1 represents OH peak on polyurethane, 1727. 933cm-1 expressed on the C = 0 peak polyurethane, 1614.152 ^ 1 denotes CN peak on the polyurethane, 1457. 944cm "1 represents the CH2 peaks polyurethane.

[0116] 第四代的超支化聚胺酯-聚乳酸聚合物的红外谱图见图4,在该附图中,3450CHT1 表示该聚合物上的OH峰、1753cm—1表示该聚合物上聚胺酯上的C = O峰和聚乳酸上的C = 0峰、1648CHT1表示该聚合物上的CN峰、145km 1表示该聚合物上的CH2峰,1383cm"1表示该聚合物上的CH2峰,由于第四代超支化聚胺酯和聚乳酸发生了共聚,所以在该聚合物上的[0119] 第四代超支化聚胺酯一聚乳酸聚合物的核磁共振谱图见图6,在该谱图中的j峰、 k峰分别与下式中的超支化聚胺酯-聚乳酸聚合物中标号为j和K的H相对应。由此可见, 超支化聚胺酯-聚乳酸聚合物己经形成。 [0116] The fourth-generation hyperbranched polyurethane - the polylactic acid polymer IR spectrum shown in Figure 4, in this figure, 3450CHT1 represents OH peak present on the polymer, 1753cm-1 expressed on the polyurethane polymer C = C = 0 O peak and peak on polylactic acid, 1648CHT1 represents CN peak on the polymer, 145km 1 represents CH2 peak on the polymer, 1383cm "1 represents CH2 peak on the polymer, since the fourth Generation hyperbranched polyurethane copolymer and the polylactic acid occurs, so in the polymer [0119] the fourth-generation hyperbranched a polylactic acid polymer, polyurethane NMR spectrum shown in Figure 6, j is a peak in the spectrum, k peaks of the formula hyperbranched polyurethane - the polylactic acid polymer is designated K and H j corresponding Thus, the hyperbranched polyurethane - polylactic acid polymer has been formed.

[0120] [0120]

CN峰、CH2峰发生了位移。 CN peak, CH2 peak displacement occurred.

[0117] 第四代超支化聚胺酯的核磁共振谱图见图5,在该谱图中的3、13、(3、(1、6、厂8、11、士峰均与下式中的超支化聚胺酯中标号为a、b、c、d、e、f、g、h、i的H相对应。 [0117] The fourth-generation hyperbranched polyurethane NMR spectrum shown in Figure 5, the spectra of 3, 13, (3, (1,6, 8,11 plant, Shi peaks were overrun with the formula in reference to polyurethane of H a, b, c, d, e, f, g, h, i corresponds.

[0118] [01]

Figure CN101628970BD00161

[0121] 3.制备第四代超支化聚胺酯-聚乳酸聚合物胶束 [0121] 3. Preparation of fourth generation hyperbranched polyurethane - polylactic acid polymer micelle

[0122] 将0. 2g纯化后的第四代超支化聚胺酯-聚乳酸聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成带蓝光的乳液,丙酮通过减压蒸发除去,得到第四代超支化聚胺酯-聚乳酸聚合物胶束。 [0122] The fourth generation of the Purification of hyperbranched polyurethanes 0. 2g - polylactic acid polymer is dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally form an emulsion with blue light, the acetone under reduced pressure removed by evaporation to give a fourth-generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明:动态光散色射测定其粒径为175nm,分散指数为0. 07透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为6. 48X 10-4mg/mlο Then micelle dynamic light scattering, electron microscopy and fluorescence spectra were observed, the results showed that: a dynamic light scattering particle diameter measured color emission 175nm, a dispersion index of 0.07 for the TEM observation regular spherical particles; fluorescence spectra Determination of critical micelle concentration of 6. 48X 10-4mg / mlο

[0123] 实施例8 [0123] Example 8

[0124] 1.超支化聚胺酯的制备 [0124] 1. Preparation of hyperbranched polyurethane of the

[0125] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0125] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0126] 在三口瓶中加入8.609g丙烯酸甲酯,10. 514g 二乙醇胺和IOml甲醇,混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0126] methyl acrylate was added 8.609g three-neck flask, 10. 514g IOml diethanolamine and methanol, and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0127] B.第四代超支化聚胺酯聚合物的制备 [0127] B. The fourth-generation hyperbranched polyurethane polymers prepared

[0128] 在三口瓶中加入5g第三代超支化聚胺酯,6. 60g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 050g四异丁氧基钛为催化剂,应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0128] In the three-neck flask was added 5g third generation hyperbranched polyurethane, 6. 60g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 050g tetraisobutoxy titanium catalyst, under the protection system should N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第四代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give a fourth-generation hyperbranched polyurethane.

[0129] 2.第四代超支化聚胺酯-聚乳酸聚合物的合成 [0129] 2. The Fourth Generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0130] 将得到的第四代超支化聚胺酯产物放在真空干燥箱中干燥,将0.754g第四代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 040g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0130] The resulting fourth-generation hyperbranched polyurethane product was dried in a vacuum oven, the fourth-generation hyperbranched polyurethane 0.754g product with 5g lactide on single-neck flask, then added 0. 040g of stannous tin, then the one-port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的第四代超支化聚胺酯-聚乳酸聚合物产物在真空干燥箱中25°C下干燥2天。 After filtration to give the fourth-generation hyperbranched polyurethane - polylactic acid polymer product was dried in a vacuum oven at 25 ° C for 2 days. 通过红外和核磁表征证实第四代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为6142kDa。 The fourth-generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 6142kDa.

[0131] 3.制备第四代超支化聚胺酯-聚乳酸聚合物胶束 [0131] 3. Preparation of fourth generation hyperbranched polyurethane - polylactic acid polymer micelle

[0132] 将0. 2g纯化后的第四代超支化聚胺酯-聚乳酸聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第四代超支化聚胺酯-聚乳酸聚合物胶束。 [0132] The fourth generation of the Purification of hyperbranched polyurethanes 0. 2g - polylactic acid polymer is dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally formed with blue latex, acetone under reduced pressure removed by evaporation to give a fourth-generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明:动态光散色射测定其粒径为183·,分散指数为0. 06;透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为7. 21 X 10-4mg/mlο Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results showed that: a dynamic light scattering particle size was measured color emitting 183. dispersion was 0.06; TEM observation regular spherical particles; fluorescence spectrometry critical micelle concentration of 7. 21 X 10-4mg / mlο

[0133] 实施例9 [0133] Example 9

[0134] 1.超支化聚胺酯的制备 [0134] 1. Preparation of hyperbranched polyurethane of the

[0135] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0135] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0136] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇,混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后,得到一种无色透明的油状液体N,N-二羟乙基-3-胺基丙烯酸甲酯单体。 [0136] methyl acrylate was added 8.609g three-neck flask, 10. 514g IOml diethanolamine and methanol, and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0137] B.第四代超支化聚胺酯聚合物的制备 [0137] B. The fourth-generation hyperbranched polyurethane polymers prepared

[0138] 在三口瓶中加入5g第三代超支化聚胺酯、6. 60g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 050g四异丁氧基钛为催化剂,应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0138] In the three-neck flask was added 5g third generation hyperbranched polyurethane, 6. 60g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 050g tetraisobutoxy titanium catalyst, under the protection system should N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第四代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give a fourth-generation hyperbranched polyurethane.

[0139] 2.第四代超支化聚胺酯-聚乳酸聚合物的合成 [0139] 2. The Fourth Generation hyperbranched polyurethane - Synthesis of polylactic acid polymer

[0140] 将得到的第四代超支化聚胺酯产物放在真空干燥箱中干燥,将0.528g第四代超支化聚胺酯产物与5g丙交酯放在单口瓶中,再加入0. 040g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0140] The resulting fourth-generation hyperbranched polyurethane product was dried in a vacuum oven, the fourth-generation hyperbranched polyurethane 0.528g product with 5g lactide on single-neck flask, then added 0. 040g of stannous tin, then the one-port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的第四代超支化聚胺酯和聚乳酸聚合物产物,在真空干燥箱中25°C下干燥2天。 After filtration to give the fourth-generation hyperbranched polyurethanes and polylactic acid polymer product was dried in a vacuum oven at 25 ° C for 2 days. 通过红外和核磁表征证实第四代超支化聚胺酯-聚乳酸的聚合物已经生成,分子量为7000kDao The fourth-generation hyperbranched polyurethane confirmed by IR and NMR characterization of - generating a polylactic acid polymer has a molecular weight of 7000kDao

[0141] 3.制备第四代超支化聚胺酯-聚乳酸聚合物胶束 [0141] 3. Preparation of fourth generation hyperbranched polyurethane - polylactic acid polymer micelle

[0142] 将0. 2g纯化后的第四代超支化聚胺酯-聚乳酸聚合物溶于6ml的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第四代超支化聚胺酯-聚乳酸聚合物胶束。 [0142] The fourth generation of the Purification of hyperbranched polyurethanes 0. 2g - polylactic acid polymer is dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally formed with blue latex, acetone under reduced pressure removed by evaporation to give a fourth-generation hyperbranched polyurethane - polylactic acid polymer micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明:动态光散色射测定其粒径为186·,分散指数为0. 07;透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为7. 53X 10-4mg/mlο Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results showed that: a dynamic light scattering particle size was measured color emitting 186. dispersion was 0.07; TEM observation regular spherical particles; fluorescence spectrometry critical micelle concentration of 7. 53X 10-4mg / mlο

[0143] 实施例10 [0143] Example 10

[0144] 1.超支化聚胺酯的制备 [0144] 1. Preparation of hyperbranched polyurethane of the

[0145] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0145] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0146] 在三口瓶中加入8.609g丙烯酸甲酯、10. 514g 二乙醇胺和IOml甲醇,混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇后,得到一种无色透明的油状液体N,N- 二羟乙基-3-胺基丙烯酸甲酯单体。 [0146] methyl acrylate was added 8.609g three-neck flask, 10. 514g IOml diethanolamine and methanol, and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess after methyl acrylate and methanol, to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0147] B.第四代超支化聚胺酯聚合物的制备 [0147] B. The fourth-generation hyperbranched polyurethane polymers prepared

[0148] 在三口瓶中加入5g第三代超支化聚胺酯、6. 60g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 050g四异丁氧基钛为催化剂,应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0148] In the three-neck flask was added 5g third generation hyperbranched polyurethane, 6. 60g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 050g tetraisobutoxy titanium catalyst, under the protection system should N2, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第四代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give a fourth-generation hyperbranched polyurethane.

[0149] 2.第四代超支化聚胺酯-聚(乙交酯-丙交酯)聚合物的合成 Synthesis of polymer [0149] 2. The Fourth Generation hyperbranched polyurethane - - Poly (lactide glycolide)

[0150] 将得到的第四代超支化聚胺酯产物放在真空干燥箱中干燥,将Ig第四代超支化聚胺酯产物与0. 454g丙交酯和4. 546g乙交酯放在单口瓶中,再加入0. 040g的辛酸亚锡, 然后用胶塞将单口瓶塞紧并密封。 [0150] The resulting fourth-generation hyperbranched polyurethane product was dried in a vacuum oven, the fourth Ig-generation hyperbranched polyurethane product with 0. 454g of lactide and glycolide 4. 546g on single-neck flask, stannous octoate was added 0. 040g, and then use the single port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水沉淀。 The purified polymer was dissolved in a small amount of acetone, the precipitate with deionized water. 过滤后得到的产物第四代超支化聚胺酯-聚(乙交酯-丙交酯)聚合物在真空干燥箱中25°C下干燥2天。 The resulting product was filtered after the fourth-generation hyperbranched polyurethane - poly (glycolide - lactide) was dried in a vacuum oven 2 days under Polymer 25 ° C. 通过红外和核磁表征证实第四代超支化聚胺酯-聚(乙交酯-丙交酯)聚合物已经生成,分子量为MOOkDa。 The fourth-generation hyperbranched polyurethane confirmed by IR and NMR characterization - poly (glycolide - lactide) polymer has been generated, a molecular weight of MOOkDa.

[0151] 3.制备第四代超支化聚胺酯-聚(乙交酯-丙交酯)聚合物胶束 [0151] 3. Preparation of fourth generation hyperbranched polyurethane - poly (glycolide - lactide) polymer micelle

[0152] 将0. 2g纯化后的第四代超支化聚胺酯-聚(乙交酯-丙交酯)聚合物溶于6ml 的丙酮中,边搅拌边滴加到Hml去离子水中,最后形成的带蓝光乳液,丙酮通过减压蒸发除去,得到第四代超支化聚胺酯-聚(乙交酯-丙交酯)聚合物胶束。 [0152] The fourth generation of the Purification of 0. 2g hyperbranched polyurethane - poly (glycolide - lactide) polymer was dissolved in 6ml of acetone, was added dropwise with stirring Hml deionized water, and finally the formation of with blue latex, acetone was removed by evaporation under reduced pressure, to give a fourth-generation hyperbranched polyurethane - poly (glycolide - lactide) polymeric micelles. 然后对胶束进行动态光散射、透射电镜及荧光光谱测定观察,结果表明:动态光散色射测定其粒径为198·, 分散指数为0. 08 ;透射电镜观测粒子为规整的圆球形;荧光光谱测定其临界胶束浓度为7. 83X10_4mg/ml。 Then micelle dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy observation, the results showed that: a dynamic light scattering particle size was measured color emitting 198. dispersion was 0.08; TEM observation regular spherical particles; fluorescence spectrometry critical micelle concentration of 7. 83X10_4mg / ml.

[0153] 实施例11 [0153] Example 11

[0154] 1.超支化聚胺酯的制备 [0154] 1. Preparation of hyperbranched polyurethane of the

[0155] A. N, N- 二羟乙基-3-胺基丙烯酸甲酯单体的制备 Preparation [0155] A. N, N- dihydroxyethyl acrylate monomer -3-Aminomethyl

[0156] 在三口瓶中加入8. 609g丙烯酸甲酯,10. 514g二乙醇胺和IOml甲醇混合物在室温和通队情况下搅拌30min后升温至40°C反应4h,然后经过减压蒸馏除去过量的丙烯酸甲酯和甲醇得到一种无色透明的油状液体N,N- 二羟乙基-3-胺基丙烯酸甲酯单体。 [0156] 8. 609g methyl acrylate was added in the three-neck flask, 10. 514g IOml diethanolamine and methanol and the mixture was stirred at rt for 30min on Fleet warmed to 40 ° C the reaction 4h, then subjected to distillation under reduced pressure to remove excess methyl acrylate and methanol to give a colorless transparent oily liquid N, N- dihydroxyethyl -3-Aminomethyl methacrylate monomer.

[0157] B.第四代超支化聚胺酯聚合物的制备 [0157] B. The fourth-generation hyperbranched polyurethane polymers prepared

[0158] 在三口瓶中加入5g第三代超支化聚胺酯,6. 60g N, N-二羟乙基_3_胺基丙烯酸甲酯单体和0. 050g四异丁氧基钛为催化剂,反应体系在N2保护下,120°C恒温反应12h,得到一种黄色粘稠液体。 [0158] In the three-neck flask was added 5g third generation hyperbranched polyurethane, 6. 60g N, N- dihydroxyethyl group _3_ methacrylate monomer and 0. 050g tetraisobutoxy titanium catalyst, the reaction system under N2 protection, 120 ° C reaction temperature 12h, to give a yellow viscous liquid. 将粗产物溶解在无水乙醇中,抽滤、用无水硫酸钠干燥、抽滤、减压蒸馏除去乙醇,然后产物真空干燥,得到第四代超支化聚胺酯。 The crude product was dissolved in absolute ethanol, filtered off with suction, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the ethanol, then the product was dried in vacuo to give a fourth-generation hyperbranched polyurethane.

[0159] 2.第四代超支化聚胺酯-聚己内酯聚合物的合成 [0159] 2. The Fourth Generation hyperbranched polyurethane - polycaprolactone polymer synthesis

[0160] 将得到的第四代超支化聚胺酯产物放在真空干燥箱中干燥,将0.754g第四代超支化聚胺酯产物与5g己内酯放在单口瓶中,再加入0. 040g的辛酸亚锡,然后用胶塞将单口瓶塞紧并密封。 [0160] The resulting fourth-generation hyperbranched polyurethane product was dried in a vacuum oven, the fourth-generation hyperbranched polyurethane 0.754g product with 5g caprolactone in single-neck flask, then added 0. 040g of stannous tin, then the one-port stopper stoppered and sealed. 然后将单口瓶抽真空并加热40°C保持1小时保证体系内无水,然后停止抽真空并将反应体系密闭加热到140°C保持13小时。 Mono vial was then evacuated and heated to 40 ° C over 1 hour held over anhydrous assurance system, vacuum was then stopped and the reaction was sealed was heated to 140 ° C held for 13 hours. 产物溶解在二氯甲烷中,用石油醚沉淀并用石油醚洗三次,然后蒸发石油醚。 The product was dissolved in methylene chloride and precipitated with petroleum ether and washed three times with petroleum ether and then petroleum ether was evaporated. 纯化后的聚合物溶解在少量的丙酮中,用去离子水 The purified polymer was dissolved in a small amount of acetone, deionized water

Claims (2)

  1. [接上页] (51) Int. Cl.A61K 47/34 {2Q>Q)&. 01) [Continued] (51) Int. Cl.A61K 47/34 {2Q> Q) &. 01)
  2. 1. 一种超支化聚合物,该聚合物具有如下式(I)所示结构: A hyperbranched polymer having a structure shown by the following formula (I):
    Figure CN101628970BC00031
    式中D为 Where D is the
    Figure CN101628970BC00032
    D1为 D1 is
    Figure CN101628970BC00033
    η为1-5的正整数,B为脂肪族聚酯,并且该聚合物的分子量为4000kDa-7000kDa ;其中,所述的脂肪族聚酯为具有如下分子式的脂肪族聚酯: η is a positive integer of 1-5, B is an aliphatic polyester, and the molecular weight of the polymer is 4000kDa-7000kDa; wherein said aliphatic polyester is an aliphatic polyester having the formula:
    Figure CN101628970BC00034
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