【作者】 路德待；

【导师】 雷自强；

【作者基本信息】 西北师范大学 ， 高分子化学与物理， 2008， 博士

【摘要】 聚乳酸(PLA)具有优良的生物相容性和可降解性,在许多领域特别是作为医用材料方面备受关注,得到了广泛的应用。然而乳酸均聚物由于结构与性能单一,应用受到很大局限。通过与不同的羟基酸、氨基酸或聚合物如聚乙二醇等进行共聚可以明显改善其强度、韧性、亲水性与降解性等物化性能,并且在改变聚合单元组成的同时也可通过改变共聚物的空间结构,得到诸如线性、梳形、星形或交联以及带有反应性官能团的共聚物,极大的拓宽了乳酸基可降解高分子材料的应用范围。文献综述着重从合成乳酸共聚物的催化剂体系、共聚物组成、结构及其开发应用等方面对最新的研究进展进行了较为详细的阐述。本论文所作研究工作主要包括以下几方面内容:以乳酸-乙醇酸共聚物(PLGA)为研究目标,考察了不同催化剂对产物分子量和收率的影响。在170oC,10h,0.085MPa、分别以金属盐、有机酸酐、无机/有机强酸单独以及金属盐/有机酸酐、金属盐/强酸复合作为催化剂催化乳酸与乙醇酸进行直接缩聚合成乳酸-乙醇酸共聚物,考察了不同催化剂及用量对所得PLGA的粘均分子量及收率的影响,结果显示:浓硫酸、对甲苯磺酸、邻苯二甲酸酐分别与SnCl2·2H2O、ZnCl2、FeCl3和ZnO的复合体系以及浓硫酸和对甲苯磺酸与SnCl2·2H2O复合物的催化效果较好。用凝胶渗透色谱(GPC)对不同粘均分子量的PLGA进行了表征,结果表明所得共聚物不含有小分子化合物,且其分子量分布都比较窄。核磁共振谱(NMR)对产物的结构表征证实所得的共聚物为PLGA。热重分析(TG)发现PLGA的热稳定性随着分子量的增大稍有提高。对所得PLGA进行的W/O/W复乳法制备药物控释微球的研究发现,所得微球表面光滑,呈规则的球形,表明所得聚合物适合作为药物控释包覆材料。为了提高乳酸基聚酯的亲水性和可加工性,又设计合成了一系列臂数和臂长不等的生物可降解共聚物(PLGA)n-PEG-(PLGA)n (n=2, 4, 8)及一系列不同支化密度的生物可降解线性-超支化哑铃形共聚物PLGA-PEG-PLGA。先以二羟基端基聚乙二醇1000、金属钾、环氧氯丙烷及KOH水溶液等先合成出不同数目的羟基端基聚乙二醇,然后与乳酸、乙醇酸在SnCl2·2H2O的催化下进行本体缩聚,得到了一系列臂数和臂长度不同的生物可降解(PLGA)n-PEG-(PLGA)n (n=2,4,8)哑铃形共聚物。核磁共振谱分析结果显示(PLGA)2-PEG-(PLGA)2哑铃形共聚物具有预期的哑铃形结构,其中PLGA链段主要由-GGL-、-LLL-和-GLG-三种类型的微嵌段结构组成。GPC测定的数据显示,共聚物的平均分子量分布都比较窄,并且随着PLGA链长的增加而逐渐变宽,但在保持臂长度不变的情况下随着臂数的增加而减小。同时,GPC测定的数均分子量远小于1H-NMR分析法所得的数值,并且这种差异随着共聚物臂数的增加而进一步增大,也再一次证明了共聚物中预期支化结构的存在。实验所得的哑铃形共聚物在不同的有机溶剂中均有良好的溶解性。特别地,随着共聚物中聚酯含量的逐渐增加,水溶性降低直至完全不溶于水。随着共聚物中聚酯含量的增加或者分支臂的减少其水解降解速率相对变慢。所得到的样品聚合物的热分解温度均高于200°C,且它们的玻璃化转变温度都比较低,并且随着PLGA聚酯臂长度的增加而增大,但当臂长度保持不变而臂数目增加时则下降。AFM对(PLGA)n-PEG-(PLGA)n哑铃形共聚物在单晶硅基质上形成的LB膜的形貌表征结果显示,哑铃形共聚物形成了形态学非均一结构的膜,膜形貌呈现参差不齐、高低不平峰状。上述合成方法由于要制备多羟基端基聚乙二醇中间体,步骤繁琐,产率较低。为简化操作、提高产率,又以二羟基端基聚乙二醇1000、乳酸、乙醇酸及葡萄糖酸在催化剂的作用下进行本体缩聚,得到了一系列不同支化密度的生物可降解PLGA-PEG-PLGA线性-超支化哑铃形共聚物。NMR表征证实产物具有预期的线性-超支化哑铃形结构。GPC测定的数均分子量远小于1H-NMR分析法所得的数值,也说明共聚物中存在预期的超支化结构,且共聚物的平均分子量分布都比较宽。溶解性测定结果显示实验所得的哑铃形共聚物在不同的有机溶剂中均有良好的溶解性。DSC和TG分析结果显示它们的热分解温度均高于200°C,且玻璃化转变温度都比较低。PLGA-PEG-PLGA线性-超支化哑铃形共聚物在单晶硅基质上形成的LB膜的AFM图像表现为形态学非均一结构的膜,其中凸起、明亮的峰形估计为PLGA链段,而不清楚的连续相则为PEG链段。且依PLGA链段倾斜和团聚程度的不同,膜形貌相应呈现参差不齐、高低不平峰状。以有机酸酐与SnCl2·2H2O及Zn或Al复合作为催化剂,采用直接缩聚的方法制备出了较高分子量的乳酸-乙醇酸-己内酰胺共聚物。分子量测定结果表明,酸酐的加入明显提高了所得PLGC的平均分子量。Zn和Al也具有较好的催化效果,但与有机酸酐复合使用时其催化效能改变不大。所得聚酯酰胺PLGC在聚酰胺单元相对较少时其溶解性较好,玻璃化温度较低,降解速率也较快。实验中还发现氨基酸的结构对所得聚酯酰胺的热转变行为影响较大,若氨基酸分子中氨基和羧基之间的碳原子数增加或α碳原子上带有“刚性”基团的氨基酸所得的聚酯酰胺的Tg较高。以乳酸、乙醇酸和L-谷氨酸等合成具有独特支化和环状混杂结构的两亲性可降解聚酯酰胺共聚物PGLG。核磁共振谱分析结果显示:PGLG分子链中含有PLA、PGA以及支化的聚谷氨酸单元,除此之外如果当L-谷氨酸的投料量较大时,可能出现戊二酰亚胺环状结构片段。GPC测定的数据显示,共聚物的平均分子量分布都比较窄,并且Mn随着L-谷氨酸的投料量的增加而减小,而1H-NMR分析法所得的结果正好相反。所得的共聚物在不同的有机溶剂中有较好的溶解性,特别是在碱性水中可以混溶。所得聚合物的热分解温度均高于200°C,且它们的玻璃化转变温度都比较低。以乳酸、乙醇酸和L-酪氨酸等合成了带有酚羟基官能团的两亲性可降解聚酯酰胺共聚物PTLG。核磁共振谱分析结果显示:PTLG分子链中含有PLA、PGA以及聚酪氨酸单元。GPC测定和1H-NMR分析法所得的数据显示,共聚物的平均分子量分布都比较窄,Mn也比较小。所得的共聚物在不同的有机溶剂中有较好的溶解性,特别是在碱性水中可以混溶。所得聚合物的热分解温度均高于200°C,且它们的玻璃化转变温度都比较低。以乙醇酸、乳酸、己内酰胺和淀粉作为原料、水作为介质进行直接缩聚,得到了淀粉接枝乳酸-乙醇酸共聚物(St-g-PLGA)和淀粉接枝乳酸-乙醇酸-己内酰胺共聚物(St-g-PLGC),结构表征结果显示淀粉已与PLGA和PLGC发生了接枝共聚。所得St-g-PLGC在聚酰胺单元相对较少时其溶解性较好,玻璃化温度较低,降解速率也较快。氨基酸的结构对St-g-PLGC的热转变行为影响较大,随着所用氨基酸氨基与羧基之间碳原子数的增加或者α碳原子上带有“硬性”官能团时将会使所得淀粉接枝聚酯酰胺共聚物的Tg增大,反之则减小。力学性能测试结果表明:当ε-己内酰胺单元在St-g-PLGC共聚物中的含量增加时,St-g-PLGC的抗拉强度、弯曲强度以及强度模量均下降,但是断裂伸长率却正好相反,呈现线性增加的趋势。也就是说,ε-己内酰胺的加入显著改善了St-g-PLGA共聚物的韧性。以PLA、β-CD和AGE作为原料,先合成出带有烯丙型双键官能团的可聚合PCD和PPLA大分子单体,然后以甲苯/DMSO作溶剂、AIBN作引发剂进行自由基聚合,得到了可完全生物降解的交联微凝胶。通过改变PCD的烯丙基官能度和其与PPLA的加料比例来控制微凝胶的交联度。单体的结构表征结果显示,PCD和PPLA具有预期结构。PLA-β-CD共聚物微凝胶的热分解温度均在200°C以上。微凝胶在25oC水中的溶胀率随着时间的推移逐渐趋缓,40h后则基本达到溶胀平衡,粒径不再变化。较高交联度和较低β-CD含量的微凝胶的溶胀度较小,反之则溶胀度较大。在PPLA与PCD的加料比例不变的情况下,由平均烯丙基官能度为3的PCD制得的微凝胶的溶胀度最大。微凝胶的交联度越高、β-CD的相对含量越高,其降解速率越慢。若保持PCD的烯丙基官能度不变而增加PCD的相对含量,所得的微凝胶的降解速率随之下降;同样,若保持PCD相对与PPLA的加料比不变而增加PCD的烯丙基官能度,微凝胶的降解速率也随之下降。微凝胶微粒呈球形,且表面比较光滑。当交联度增加时,微粒的粒径相对减小;当PCD相对增加时,粒径则随之增加。更多还原

【Abstract】 Polylactic acid (or Polylactide) (PLA) which was widely used in many field because of its biodegradable and biocompatible properties, have gained enormous attention recently. However, onefold structure and properties limits the applications of PLA homopolymer. The most common strategy to overcome this difficulty is to prepared the copolymers. A wide range of biodegradable copolymers matrices were described in this review with a special emphasis on polylactide because of more eco-friendliness from its origin as contrast to the fully petroleum-based polymers and control of carbon dioxide balance after their composting. Lactic acid (or lactide) copolymerized with hydroxyl acid, amino acid or polymers such as poly(ethylene glycol), starch, etc., can obviously improve the strength, toughness, hydrophilic and controlled-degradable properties of PLA, in the same time, can obtain the linear, comb-like, star-like or cross-linked copolymers. These materials are attracting considerable interest in materials science research. This review aims at highlighting on recent developments in preparation of biodegradable linear, comb-like, star-like or cross-linked PLA copolymers and the catalysts (system) using in copolymerization.The thesis consists of main contents as followings:Poly(lactic acid-glycolic acid) was synthesized from lactic acid and glycolic acid by direct polycondensation using various catalysts in the absence of organic solvents at 170oC. The effect of catalyst and its dosage on molecular weight and yield of PLGA was investigated. As a result, the sulfuric acid (98%), p-toluenesulfonic acid is best. At the same time, the phthalic anhydride is best when it mix with SnCl2·2H2O, ZnCl2, FeCl3 and ZnO, respectively. The phosphorous acid, succinic anhydride and sulfuric acid (98%) also have a good catalytic effect. The PLGA with different viscosity-average molecular weight were characterized by gel permeation chromatography (GPC), the results showed that the copolymer does not contain small molecular compounds, and its molecular weight distribution was narrower. The structure PLGA was confirmed by Nuclear magnetic resonance spectroscopy (NMR). The data of thermogravimetric analysis (TG) showed that the thermal stability of PLGA increased slightly with increasing its molecular weight. The products were suitable for controlled release drug coated materials.A series of multi-hydroxyl (2, 4 and 8) terminated poly(ethylene glycol)s and their biodegradable, bio-compatible, branched barbell-like (PLGA)n-b-PEG-b-(PLGA)n (n=1, 2, 4) copolymers have been synthesized. The lengths of the PLGA arms were varied by controlling the molar ratio of monomers to hydroxyl groups of PEG ([LA+GA]0/[–OH]0=23, 45, 90). Chemical structures of synthesized barbell-like copolymers were confirmed by both 1H and 13C-NMR spectroscopy. Molecular weights were determined by 1H-NMR end-group analysis and gel permeation chromatography (GPC). The result of hydrolytic degradation indicated that the rate of degradation increased with the increase of arm numbers or with the decrease of arm lengths. The thermal properties were evaluated by using differential scanning calorimetry (DSC) and a thermogravimetric analysis (TGA). The results indicated that the thermal properties of barbell-like copolymers depended on the structural variations. The morphology of (PLGA)n-PEG-(PLGA)n copolymers self-assembly films were investigated by atomic force microscope (AFM), the results indicated that the microphase separation existed in (PLGA)n-PEG-(PLGA)n copolymers.A series of biodegradable poly(ethylene glycol)-supported poly(lactic-ran-glycolic acid) (PLGA) linear-hyperbranched barbell-like copolymers were synthesized with poly(ethylene glycol) (PEG), D,L-lactic acid (D, L-LA) aqueous solution, glycolic acid (GA) and gluconic acid (Glu) under bulk condition. The branching density of the hyperbranched section were varied by controlling the molar ratio of gluconic acid to hydroxyl-terminal groups of PEG ([Glu]/[OH]=1, 3.5, 6.0, 8.5). Chemical structures of the copolymers were confirmed by both 1H and 13C-NMR spectroscopy. The molecular weights were determined by 1H-NMR group analysis and gel permeation chromatography (GPC), respectively, and group analysis gave reasonably consistent values. The results of hydrolytic degradation indicated that these copolymers degraded completely not more than three weeks. The thermal properties were evaluated using differential scanning calorimetry (DSC) and by performing a thermogravimetric analysis (TGA). The result indicated that the glass transition temperature (Tg) and melting temperature (Tm) of these copolymers not more than 50°C. The self-assembly behavior of these copolymers on hydrophilic surface was investigated. The morphology of these linear-hyperbranched barbell-like copolymers self-assembly films were investigated by atomic force microscope (AFM), the results indicated that these copolymers could exhibit a more nonhomogeneous, more rough structural orientation films on silicon wafer substrate with increasing the branching densities.High molecular weight poly(lactic acid-glycolic acid-ε-caprolactam) (PLGC) copolymer was synthesized by simply heating a mixture of DL-lactic acid aqueous, glycolic acid andε-caprolactam using organic anhydride and tin (II) chloride dihydrate (SnCl2·2H2O) or metal powder as catalyst without organic solvents. At the same time, in order to investigate the effects of the structure of amino acid on the properties of copolymers, poly(lactic acid-glycolic acid-glycine), poly(lactic acid-glycolic acid-L-alanine), poly(lactic acid-glycolic acid-β-alanine), poly(lactic acid-glycolic acid-γ-aminobutyric acid), poly(lactic acid-glycolic acid-L-phenylalanine) were synthesized under the same conditions, respectively. The structure of PLGC was confirmed by FT-IR and NMR spectra. The average molecular weights of PLGC were determined by Ubbelohde model (corrected by 1H-NMR end-group analysis). The results indicated that compounds of organic anhydride and SnCl2·2H2O were active, and the highest average molecular weights could achieve 9800Da. The thermal properties were evaluated using differential scanning calorimetry (DSC), the results indicated that the glassy-transition temperatures (Tg) of polyesteramide increased with increasing the carbon atom numbers between carboxyl and amino-group of amino acid, also the glassy-transition temperatures (Tg) was higher whenα-carbon atom of amino acid linked with a“rigid”group compared with a“soft”group. The solubility and hydrolytic degradation of PLGC copolymers were investigated.poly(glutamic acid-co-lactic acid-co-glycolic acid) (PGLG), an amphiphilic biodegradable copolymer, was synthesized by simply heating a mixture of L-glutamic acid (Glu), DL-lactic acid and glycolic acid with the present of stannous chloride. The unique branched architecture comprising of glutarimide unit, polyester unit and polyamide unit was confirmed by NMR spectrum. The PGLG was soluble in many organic solvents and aqueous solution of sodium hydroxide (pH≧9.0). The thermal properties were evaluated using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Molecular weights were determined by 1H-NMR end-group analysis and GPC respectively, and the results indicated that the higher Glu content resulted in a decrease of the molecular weight.poly(L-tyrosine-co-lactic acid-co-glycolic acid) (PTLG), an amphiphilic biodegradable polymer, was synthesized by simply heating a mixture of L-tyrosine (Tyr), DL-lactic acid and glycolic acid in the present of stannous chloride. The linear architecture comprising of polyester unit and polyamide unit and hydroxybenzene side-group was confirmed by NMR spectrum. The PTLG was soluble in many organic solvents and aqueous solution of sodium hydroxide (pH≧9.0). The thermal properties were evaluated using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Molecular weights were determined by 1H-NMR end-group analysis and GPC.Starch graft biodegradable poly(lactic acid-co-glycolic acid) (St-g-PLGA) and poly(lactic acid-co-glycolic acid-co-ε-caprolactam) (St-g-PLGC) copolymers were prepared by direct polycondensation from soluble starch, lactic acid, glycolic acid and caprolactam in presence of stannous chloride (SnCl2·2H2O). The chemical microstructure of the resultant copolymers was clarified by NMR spectroscopy and the thermal properties were investigated by differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis. Moreover, the mechanical properties, solubility and degradation velocity were measured. The results indicated that the glassy-transition temperature (Tg) increased with decreasing the contents ofε-caprolactam. The mechanical properties examination demonstrated that the tensile strength and bending strength changed from 32.3Mpa and 69Mpa to 24.2Mpa and 28Mpa with increasing the contents ofε-caprolactam, respectively. The solubility test shown that the copolymers could dissolved in some organic solvents. Because of the poly(ε-caprolactam) is not biodegradable, the rate of degradation of starch-graft-poly(lactic acid-co-glycolic acid-co-ε-caprolactam) copolymers were much slower than that of starch-graft-poly(lactic acid-co-glycolic acid) copolymers.The novel biodegradable polylactic acid-β-cyclodextrin (PLA-β-CD) copolymeric cross-linked microgels were prepared by the radical copolymerization of PLA macromonomer and polymerizableβ-CD derivatives, which theβ-CD derivatives with various numbers of polymerizable vinyl groups were synthesized by 1-allyloxy-2,3-epoxy propane (AGE) andβ-CD. The chemical structures of polymerizable monomers were measured by NMR. The thermal properties, size, morphology, in vitro degradation and swelling behavior of the microgels were investigated. The results indicated that the microgels were stable under thermal condition up to 200°C. The microgels were spherical in aqueous solution. The hydrophilicity of the microgels increased with increasing ofβ-CD contents, while the swelling ratios and rate of degradation decreased. The more vinyl groups onβ-CD the higher cross-linked density, which resulted in a decrease of the swelling ratios and the rate of degradation.更多还原