【作者】 张建华；

【导师】 董岸杰；

【作者基本信息】 天津大学 ， 材料学， 2010， 博士

【摘要】 压敏胶作为经皮给药系统中较为理想的经皮释放用胶粘剂基质,往往既要起到药物及促透剂等的载体或储库作用,还要兼具使经皮给药系统紧密地粘附于皮肤表面的压敏粘附作用,是经皮给药系统中最为关键的组成部分。高分子压敏胶的多层次性结构,比如结构单元组成、分子链长短和形态、侧链、聚集态结构、交联网络结构等,对粘附性以及药物的负载、释放和稳定性有很大的影响,其结构的调控非常重要。近年来发展起来的可逆加成-断裂链转移活性自由基聚合(RAFT)为合成具有特定多层次性结构和功能的高分子压敏胶提供了技术手段。通过RAFT设计和调控聚合物压敏胶多层次性结构、研究压敏胶多层次性结构对药物释放的影响和对药物释放调控作用是本论文的研究工作之一。本文首先以咔唑为原料,通过简单的水相法合成了一系列咔唑基RAFT试剂N-咔唑二硫代甲酸苄基酯、N-咔唑二硫代甲酸α-甲基苄基酯、N-咔唑二硫代甲酸异丙苯酯、N-咔唑二硫代甲酸异丁基酯以及二硫化双(N-咔唑硫代甲酰)中间体,并以此中间体为基础进一步合成了N-咔唑二硫代甲酸异丁腈酯和N-咔唑二硫代甲酸腈基戊酸两种RAFT试剂,研究了它们对自由基聚合的调控作用,并选定性能比较好的N-咔唑二硫代甲酸异丁腈酯为RAFT试剂,分别以丙烯酸乙酯、丙烯酸丁酯、丙烯酸异辛酯为软单体,以丙烯酸甲酯、甲基丙烯酸甲酯以及苯乙烯为硬单体,以甲基丙烯酸β-羟乙酯为改性单体,合成了不同结构的两嵌段或三嵌段丙烯酸酯类嵌段共聚物压敏胶。并通过高效凝胶渗透色谱、核磁等手段对嵌段聚合物进行了表征,还考察了上述压敏胶的初粘力、180°剥离、持粘力等力学性能。以布洛芬、烟酸甲酯和5-氟尿嘧啶为模型药物,考察了这些压敏胶的结构对药物释放的影响和调控作用。研究结果表明RAFT聚合合成的嵌段聚合物压敏胶具有良好的力学性能,而且压敏胶的结构变化对药物释放具有显著的影响,因此,可以利用RAFT聚合调控压敏胶的结构实现对药物释放的调控。本文还以γ-缩水甘油氧丙基三甲氧基硅烷(GPTMS)为偶联剂,通过溶胶-凝胶法,对聚乙烯醇进行化学交联改性,制备了一系列有机-无机杂化凝胶涂膜基质,采用粘度计、红外、光散射、扫描电镜、差热量热等方法研究了杂化凝胶涂膜基质的结构性能,并进行了拉力测试、水蒸汽渗透以及溶胀性能测试,在体考察了杂化膜的使用舒适度和刺激反应;还以布洛芬和5-氟尿嘧啶为模型药物,考察了该涂膜基质对药物释放的影响,结果表明该有机-无机杂化凝胶涂膜基质是一种性能优异的新型经皮给药基质材料。使用化学促透剂是促进药物经皮渗透的有效手段,寻找性能优良的促透剂仍是经皮给药发展的重要方向之一。本文通过酯化反应合成了一系列乳酸酯,并以布洛芬、水杨酸、地塞米松和5-氟尿嘧啶为模型药物,在丙二醇的药物饱和溶液以及亲水性和疏水性压敏胶基质中,考察了该系列乳酸酯对上述药物经皮渗透的促进效率,结果表明乳酸酯的促透效果与乳酸酯的脂肪醇半族碳原子数以及药物的物理化学性质有关,其中乳酸癸酯和乳酸十二酯具有较好的经皮给药促透作用。更多还原

【Abstract】 Pressure sensitive adhesives (PSAs) in transdermal drug delivery system (TDDS) not only are used to bond transdermal drug delivery devices to the outermost layer of the skin, but also are applied to act as a reservoir of drugs or penetration enhancers. As for pressure sensitive adhesives, the multilayer-molecular structures, such as constitutional unit, structure and configuration of the polymer chains, aggregation and crosslinking structure et al., have significant impact on drug release, stability, loading amount and so on. Therefore, the structure control of PSAs is important for TDDS. Fortunately, the reversible addition-fragmentation chain transfer (RAFT) polymerization method has recently been developed to prepare polymers with well-defined structure and low polydispersity.In this paper, RAFT polymerization had been used to prepare a series of PSAs with well-defined structure. First, several carbazyl dithiocarbamates as RAFT agents were prepared by an improved aqueous phase method based on a nucleophilic substitution reaction between sodium carbazole-carbodithioate and alkyl halides at room temperature, including N-carbazole-carbodithioate (BCBD), 1-phenylethyl N-carbazole-carbodithioate (PCBD), cumyl N-carbazolylcarbodithioate (CCBD), tert-butyl N-carbazolecarbodithioate (TBBD), as well as di(thiocarbazolyl) disulfide (DTCD). Then, 2-cyanoprop-2-yl N-carbazolylcarbodithioate (CYCBD) and 4-cyanovalericacid N-carbazolylcarbodithioate (CVCBD) were synthesized based on a substitution reaction between DTCD and azobisisobutyronitrile or azobis(cyanovaleric acid). After the studies on the relative effectiveness of these carbazyl RAFT agents in the RAFT polymerizations, CYCBD with the best control ability was selected as RAFT reagent to initiate copolymerization of acrylate monomers. Ethyl acrylate、butyl acrylate and 2-ethylhexyl acrylate were chosen as the soft monomers, methyl acrylate, methyl methacrylate and styrolene as the hard monomers andβ-hydroxyethyl methacrylate as the crosslink monomers. The structure of the prepared block copolymers were characterized by GPC and 1HNMR. The mechanical properties such as initial bonding strength, cohesion and adhesion were measured according to the related Chinese Standard. At last, ibuprofen, methyl nicotinate and 5-fluorouracil were chosen as drug model to estimate the drug release behavior in the obtained PSAs in vitro and the results show that these PSAs can be used to control drug release.Another objective of this thesis was to develop a novel organic-inorganic hybrid polymeric gel that is suitable for the bioadhesive film applied on skin as TDDS. The film-forming gels were prepared by using poly(vinyl alcohol) as base material,γ-(glycidyloxypropyl) trimethoxysilane (GPTMS) as cross-linker, glycerol as plasticizer and (N-vinyl pyrrolidone) as a tackifier. The mechanical properties, skin adhesion properties, swelling properties and water vapor permeability of the films prepared from different formulations of hybrid gels were studied. The miscibility and the thermal properties of films were investigated by using FT-IR, DSC, SEM and XRD. In addition, release and permeation characteristics of drugs form the resultant films were studied by using hydrophilic 5-fluorouracil and hydrophobic ibuprofen as the model drugs. All results show that the incorporation of GPTMS into the PVA can significantly enhance film mechanical strength and improve film skin adhesion properties of the film, decrease the crystalline regions of PVA and enhance the drug release. Moreover, skin irritation of the hybrid films was investigated in vivo in human subjects, and the results show that the films cause non-irritation to skin after topical application for 120 hours. The organic-inorganic hybrid polymer gel possesses very good properties for application in the skin and may provide a novel and promising formulation for transdermal drug delivery system.Finally, a series of lactate esters was synthesized and their enhancement on the skin permeation of four kinds of drugs with different physicochemical properties in propylene glycol or PSAs was also studied, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10-12 are more effective enhancers.更多还原