经皮给药系统(transdermal drug delivery systems，TDDS)是指药物由皮肤吸收进入体循环并达到有效血药浓度，实现疾病预防或治疗的一类制剂。TDDS是药物新剂型发展的一个重要方向，但TDDS中的关键部分——控释膜的发展已成为TDDS进一步发展的瓶颈。当前制备控释膜的方法主要包括吹塑成型法，压延成型法和流延成型法。这些方法存在着诸多的缺点，如薄膜质量不高，污染环境，薄膜种类少，满足不了更多的药物制成TDDS的需求。 针对目前控释膜的诸多缺点，我们实验室首次利用清洁、无污染的紫外光催化技术制备控释膜。强功率的紫外光照射溶有光引发剂的丙烯酸酯类单体或丙烯酰胺类单体的混合溶液，制备聚合物薄膜。不同物理化学性能的药物作为测试药物，研究聚合物薄膜控制药物释放的性能。 三个丙烯酸酯单体：乙二醇二甲基丙烯酸酯，1，4-丁二醇二丙烯酸酯，和1，6-己二醇二甲基丙烯酸酯，丙烯酰胺单体：N-(1，1-二甲基-3-氧代丁基)丙烯酰胺，制备四个聚合物薄膜A1、A2、A3和A4。实验证实紫外光催化技术可以用于聚合物薄膜的合成。水杨酸、水杨酸甲酯和萘普生作为测试药物。实验发现这四个薄膜能够控制药物零级释放。但这四个薄膜还存在一些缺点，例如薄膜A1、A2和A3缺乏柔软性，不适宜用作TDDS中的控释膜。薄膜A4在合成过程中使用乙醇作为溶剂，导致薄膜厚度不易控制，较难进行重复性实验。 基于薄膜A1、A2和A3的不足，含羟基的丙烯酸酯单体：甲基丙烯酸羟乙酯加入到反应中，用以增强薄膜A2和A3的柔软性，合成了二元薄膜AB1、AB2、AB3、AB4和AB5。水杨酸甲酯作为测试药物。实验发现甲基丙烯酸羟乙酯单体可以增加这五个薄膜的柔性增加。 用含羟基的丙烯酸酯单体：丙烯酸-4-羟基丁酯替换薄膜A4的合成中使用的乙醇，制备薄膜AB6和AB7。实验发现丙烯酸-4-羟基丁酯单体不仅能溶解N-(1，1-二甲基-3-氧代丁基)丙烯酰胺单体，而且参与了反应，使得薄膜的厚度可以控制，而且提高了薄膜的柔软性。 含有不同官能团(羧基、烷氧基、羟基等)的单体两两混合制备聚合物薄膜AB8、AB9、AB10和AB11。1㎎/ml的盐酸可乐定水溶液和水杨酸甲酯作为测试药物。实验发现这些不同类型的聚合物薄膜都能控制药物零级释放。 从上述的薄膜的合成过程中发现含羟基的丙烯酸酯类单体可以促进薄膜的柔软性，因此考虑用两个都含有羟基的丙烯酸酯单体：丙烯酸-4-羟基丁酯和丙烯酸-(2-羟基-3-苯氧基)丙酯，制备薄膜AB12、AB13、AB14和AB15。1㎎/ml的萘普生的水杨酸甲酯溶液和3㎎/ml的盐酸可乐定水溶液作为测试药物。实验发现两个都含羟基的丙烯酸酯单体制备的薄膜具有柔软性的特点，而且能控制药物零级释放。当这两个单体的质量比是1:1时，制备得到的薄膜AB15较易从衬板剥离，较易获得薄膜。 基于薄膜AB15的优点，加入第三个单体进一步调节聚合物薄膜的物理性能和通透性能。甲基丙烯酸异丁酯单体制备薄膜ABC1，甲基丙稀酸异癸酯单体制备薄膜ABC2，甲基丙烯酸环己酯单体制备薄膜ABC3，巴豆酸仲丁基酯单体制备薄膜ABC4，丙烯酸-2-丁氧基乙酯单体制备薄膜ABC5，甲基丙烯酸-2-丁氧基乙酯单体制备薄膜ABC6，甲基丙烯酸-2-苯氧基乙酯单体制备薄膜ABC7，顺丁烯二乙酯单体制备薄膜ABC8，顺丁烯二丁酯单体制备薄膜ABC9，甲基丙烯酸-(2-甲基-2-硝基)丙酯单体制备薄膜ABC10。 盐酸可乐定作为测试药物。从三个方面分析了上述的十种三元聚合物薄膜的通透性能：第三个单体的含量对药物渗透速率的影响，并挑选出最佳单体比例制备的聚合物薄膜作为优选薄膜；优选薄膜的厚度对药物渗透速率的影响；药物的不同浓度对优选薄膜的渗透速率的影响。 实验发现，随着第三个单体的加入，不同种类的薄膜表现出不同的特点：单体C1、C2、C5、C6和C10的含量与薄膜的渗透速率成线性增加的关系；单体C3和C4的含量在20～30%之间变化时，渗透速率无明显差别(显著性水平p > 0.05)；单体C7的含量与渗透速率成线性递减的关系；随着单体C8和C9的含量的增加，渗透速率先增大后减小，当单体含量在20%时具有最大的渗透速率。 实验发现薄膜ABC1、ABC5和ABC7的优选薄膜的渗透速率与测试药物的浓度存在线性递增的关系；薄膜ABC8、ABC9和ABC10的优选薄膜的渗透速率与药物浓度的二次方根存在线性递增的关系；薄膜ABC2、ABC3、ABC4和ABC6的优选薄膜，当药物浓度在某一个范围变化时，渗透速率无明显差别(p>0.05)。 上述的十种三元薄膜的优选薄膜都进行了 FTIR、DSC和SEM的表征。经过24小时以及延长至一个星期的药物通透性实验，发现所有的聚合物薄膜都不存在单体残留的问题。由于不存在残留单体的毒性和刺激性的问题，这些优选薄膜可以安全地用作TDDS中的控释膜。 盐酸地尔硫卓*作为测试药物，进一步分析了其中的八种三元聚合物薄膜(ABC2、ABC3、ABC4、ABC5、ABC6、ABC7、ABC8 和 ABC10)的优选薄膜的通透性能。实验发现随着测试药物的分子尺寸的不同，薄膜的通透性能也不同。 盐酸可乐定作为测试药物，继续研究当上述的十种三元聚合物薄膜的优选薄膜和离体小鼠皮肤共同作用后，药物的通透性能将产生怎样的改变。实验发现薄膜和皮肤共同作用后仍能控制药物零级释放，但会存在时间滞后的问题，而且共同作用的渗透速率小于单独作用的渗透速率。 上述的聚合物薄膜的制备和药物通透性实验都证实紫外光催化技术可用于制备TDDS中的控释膜。通过调节单体的组分、单体的含量可以制备出具有不同理化性质的聚合物薄膜。这些聚合物薄膜对特定的药物具有线性控制其释放的能力。紫外光催化技术有望解决目前TDDS遭遇到的发展瓶颈的问题，成为新的药物制成透皮贴剂的技术平台。 ①*：正确写法是“卓”上有“艹”，由于无法输入，改用“卓”替代，全文如是，特此说明。 关键字：经皮给药系统，控释膜，紫外光催化，制备，表征

 The transdermal drug delivery system (TDDS) is one type of the drug administrations that drug gets into blood circulation by the absorption of skin and reaches effective blood level for the purpose of preventing disease and therapy. TDDS is an important field in development of new types of drug deliveries. However, the controlled release membrane as a key part of TDDS has become the bottle neck of development of TDDS. The traditional methods of preparation of controlled release membrane include boasting plastics molding, pressing spread molding and flowing spread molding. These traditional methods have various shortcomings, such as poor quality, environmental pollution and rare types, so that the traditional methods can't complete the purpose of more and more drugs administering TDDS. Aiming at the shortcomings in the controlled release membrane, a clean and pollution-free technology of ultraviolet light polymerization is introduced to synthesize the controlled release membrane. The mixture of acrylate and acrylamide monomers with photo initiator, were treated under strong power ultraviolet radiations to synthesize the copolymer membrane. The drugs with different properties of physics and chemistry were used as testing drugs in order to analyze the properties of the permeation of the copolymer membranes. Three acrylate monomers: Ethylene glycol dimethacrylate, 1,4-butanediol diacrylate and 1,6-hexanediol dimethacrylate, one acrylamide monomer, diacetone acrylamide, were used to synthesize four copolymer membranes, labeled as A1, A2, A3 and A4, respectively. It was found that the technology of ultraviolet light polymerization could prepare the copolymer membranes. Salylic acid, methyl salicylate and naproxen were used as testing drugs. It was found that these four membranes could control drug zero-order release. However, A1, A2 and A3 had some shortcomings. For example, they lacked soft appearance so they were unsuitable to use as controlled release membrane in TDDS. Ethanol was used as a reagent in the process of preparation of A4, resulted in the difficulties in the preparation of the same thickness of A4. Considered of the lacks of A1, A2 and A3, the monomer, 2-hydroxyethyl methacrylate, which contained hydroxyl group, was fed into the reaction for the purpose of enhancement of soft properties of A2 and A3, and the membranes, labeled as AB1, AB2, AB3, AB4 and AB5 were synthesized. Methyl salicylate was used as a testing drug. It was found that the monomer, 2-hydroxyethyl methacrylate, could enhance the property of flexibleness of the copolymer membranes. The monomer, 4-hydroxybutyl acrylate, which contained hydroxyl group, replaced ethanol in the process of preparation of A4, to synthesize membranes, labeled as AB6 and AB7. It was found that the monomer, 4-hydroxybutyl acrylate could not only dissolve diacetone acrylamide but also participate in the process of preparation; resulted in the possibility of controlling the thickness of the membrane and enhancement the soft property of the membrane. Two different types of monomers, which contained carboxy group, alkoxy group, or hydroxyl group, were mixed to synthesize membranes, labeled as AB8, AB9, AB10 and AB11.1 ㎎/ml clonidine hydrochloride and methyl salicylate were used as testing drugs. It was found that these membranes could control drug zero-order release. Viewing at the above-mentioned membranes, it was found that the monomers containing hydroxyl groups enhanced the property of flexibleness of membranes. Two monomers, 4-hydroxybutyl acrylate and 2-hydroxy-3-phenoxypropylacrylate, both having hydroxyl groups, were used to synthesize membranes, labeled as AB12, AB13, AB14 and AB15.1 ㎎/ml Naproxen and 3 ㎎/ml clonidine hydrochloride were used as testing drugs. It was found that the membranes had the feature of flexibleness and controlled drug zero-order release. When the weight ratio of two monomers was 1: 1, AB15 had more advantages over other membranes, including separation from the plate and acquirement the membrane easily. Based on the advantages of the AB15, the third type of monomer was added to reaction for the purpose of improvements in the properties of physics and permeation of the membrane. Isobutyl methacrylate was used to synthesize membrane ABC1. Isodecy1 methacrylate was used to synthesize membrane ABC2. Cyclohexy1 methacrylate was used to synthesize membrane ABC3. Sec-buty1 tiglate was used to synthesize membrane ABC4. 2-butoxyethy1 acrylate was used to synthesize membrane ABC5. 2-butoxyethy1 methacrylate was used to synthesize membrane ABC6. 2-phenoxy ethyl methacrylate was used to synthesize membrane ABC7. Diethyl maleate was used to synthesize membrane ABC8. Dibutyl maleate was used to synthesize membrane ABC9. 2-methyl-2-nitropropyl methacrylate was used to synthesize membrane ABC10. Clonidine hydrochloride was used as a testing drug. Three aspects of permeation properties of above-mentioned ten membranes were analyzed as follows: the effect of the content of the third monomer on the permeation rate, and the membrane having the optimized properties of plasticity and permeation was selected as an optimized membrane; the effect of the thickness of the optimized membrane on the permeation rate; and the effect of the concentration of drug on the permeation rate. It was found that above-mentioned ten membranes showed different properties with the third monomer feeding: the permeation rates linearly increased with the contents of monomers C1, C2, C5, C6 and C10 increasing; the permeation rates had no significant differences when the contents of monomers C3 and C4 varied in the range of 20-30% (p＞0.05); the permeation rate linearly decreased with the content of monomer C7 increasing; the permeation rates initially increased with the content of the monomers C8 and C9 increasing for up to 20%, then decreased. It was also found that the permeation rates of the optimized membranes ABC1, ABC5 and ABC7, were linearly dependent on the concentration of drug; the permeation rates of the optimized membranes ABC8, ABC9 and ABC10, were linearly dependent on the square root of the concentration of drug; the permeation rates of the optimized membranes ABC2, ABC3, ABC4 and ABC6, had no significant differences when the concentration of drug varied in a range (p＞0.05). Above-mentioned ten optimized membranes were characterized by FTIR, DSC and SEM. No residual monomers were detected in the permeation experiments for 24 hours and extended to one week. All of the optimized membranes were candidates as controlled release membranes in the TDDS without monomers' toxicity and irritation. Diltiazem hydrochloride was used as a testing drug, the permeation properties of eight optimized membranes ABC2, ABC3, ABC4, ABC5, ABC6, ABC7, ABC8 and ABC10, were further analyzed. It was found that the permeation properties of the membranes were varied with the structure of the drug molecule. Clonidine hydrochloride was used as a testing drug, the effects of mentioned-above ten optimized membranes contacted tightly with the ex-vivo skin of rat on the permeation properties were studied. It was found that two layers of membranes, i.e. skin and copolymer membrane, still could control drug zero-order release. However, there was lag time in permeation experiment and the permeation rate of double membranes was lower than the permeation rate of single membrane. From above-mentioned preparations and permeation experiments of the copolymer membranes, it was proved that the technology of ultraviolet light polymerization could synthesize copolymer membranes and these membranes could use as controlled release membranes in TDDS. The properties of physics and chemistry of the copolymer membrane varied with the compositions and contents of the monomers. These membranes controlled the testing drugs zero-order release. The technology of ultraviolet light polymerization was hopeful to break down the bottle-neck of the development of the TDDS, and become a new technological platform in new drugs administering transdermal delivery. KEY WORDS: Transdermal drug delivery system (TDDS), Controlled release membrane, Ultraviolet light polymerization, Synthesis, Characterization