中药经皮给药系统新型基质材料的合成、制备与性能研究
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摘要
经皮给药是一种极具优势的给药方式，其中的压敏胶基质材料作为经皮给药系统的承载体，影响着整个系统的作用效果，在系统中起到十分关键的作用。本文针对现今中药经皮给药系统基质材料的不足和在经皮给药技术上的需求，制备了新型压敏胶基质并对其性能进行了研究。主要工作如下：
以苯乙烯-异戊二烯-苯乙烯嵌段共聚物（SIS）为基础原料，通过甲酸和过氧化氢原位生成过氧甲酸，分别采用非均相与均相工艺进行环氧化反应，合成了不同环氧化程度的环氧化SIS（ESIS），研究了环氧化程度对产物的分子量及其分布、接触角、玻璃化转变温度、吸水率及透湿率的影响，ESIS的热老化和热氧老化行为及机理和SIS环氧化的反应动力学。结果表明，环氧化反应主要发生在1，4-异戊二烯单元，随着环氧化基团的增加，ESIS极性增强，分子量增加而分子量分布变宽，玻璃化转变温度、吸水率和透湿率均提高；ESIS在热氧老化初期，主要是环氧基团发生破坏，而在老化后期，主要是双键发生破坏，并且热老化和热氧老化的机理不同；SIS的环氧化反应总体为二级反应，对过氧化氢生成过氧酸的反应而言反应为一级反应，反应活化能为22.7kJ/mol。
以不同环氧化程度的ESIS为基体树脂，通过选择增粘树脂、增塑剂和抗氧剂制备了ESIS热熔压敏胶，研究了压敏胶与添加剂的相容性，压敏胶的流变性能，压敏胶与不同表面能材料的粘接性能以及皮肤促透剂对压敏胶性能的影响。结果表明，在一定频率区间内，ESIS热熔压敏胶在储能模量(E’)、损耗模量(E’’)和粘度(η)上存在较大差别并具有不同的变化规律，在粘接过程中，频率为0.01Hz左右，E’与热熔压敏胶的初粘性成反比；在剥离过程中，频率为100Hz左右，E”与热熔压敏胶的180°剥离强度呈正比；以η较高的聚合物为基体树脂制备的压敏胶持粘力较大。皮肤促透剂氮酮和二甲基亚砜含量对ESIS压敏胶力学性能有一定影响，随着皮肤促透剂的加入，压敏胶初粘力和剥离强度均先升高再降低。载药量对压敏胶基质影响较大，随着载药量的不断增加，剥离强度和持粘力呈明显下降趋势。
以伤湿祛痛膏中的乌头碱和盐酸麻黄碱为指标成分，进行了大鼠体外渗透实验，研究了不同类型的压敏胶基质的经皮药物释放性能。大鼠体外实验结果表明ESIS热熔压敏胶基质对药物中极性成分的释放效果更好，相对于传统橡胶膏在药物释放度上有很大的改善，其释放度在48小时内符合Higuchi方程，动力学特征方程分别为Q=6.22t1/2-7.41和Q=6.49t1/2-8.98，48小时后，释放为非fick扩散，动力学特征方程分别为Q=44.2t0.6+1.67和Q=25.7t0.6+3.54。在载药量增加的情况下，大幅提高药物释放度，并且对皮肤无刺激性和过敏性，是一种比较理想的橡胶膏基质材料。
对以ESIS热熔压敏胶为基质材料的伤湿祛痛膏进行了质量研究，并制定了伤湿祛痛膏的质量标准，可有效的控制热熔压敏胶伤湿祛痛膏的质量。
Transdermal drug delivery system (TDDS) is drug-loaded adhesivepatches which, when applied to the skin, deliver the therapeutic agent, ata controlled rate, through the skin to the systemic circulation and to thetarget organs. The performance requirements of pressure sensitiveadhesives (PSA) are demanding as they must be able toadhere well to varying skin types (both dry and moist), beremovable without leaving adhesive residue or causing skindamage, and should not irritate the skin. In accordance with the fact oftransdermal drug delivery system currently, in this paper, preparedhot-melt pressure-sensitive adhesives based on ESIS for TDDS. The mainwork was carried out as follow:
The epoxidation of SIS with formic acid and hydrogen peroxide was studied. The microscopic structure of epoxidised SIS (ESIS) wascharacterized by Fourier Transform Infrared(FT-IR),1H nucleal magneticresonance (1HNMR), Gel Permeation Chromatography (GPC) andDynamic Thermomechanical Analysis (DMA). The aging properties andreaction kinetics were also discussed. The experimental results showedthat: the epoxidation reaetion mainly occurred in l,4-isoprene units, andthe molecular weight, the moisture permeability of ESIS and Tg of PIsegment were increased gradually with the increase of the epoxy degree.At the early stage of aging process, the aging reaction occurs mainly onthe epoxy groups, whereas at the later stage, the aging reaction occursmainly on the carbon–carbon double bonds. The epoxy reaction pocesswas the second order reaction, and the reaction activation energy was22.7kJ/mol, however the reaction of process between carbon-carbondouble bond and hydrogen peroxide was the first order reaction.
A kind of hot-melt pressure-sensitive adhesive(HMPSA) was developedwith the synthesized ESIS employed as matric resin, and epoxy soybeanoil as the plasticizer and high-hydrogenation rosin as the tackifier. Theadhesive performance and rheology behaviors of HMPSA were studied.The results indicated that the storage modulus was proportion to thetack(initial adhesion) under the frequency(0.01Hz) condition, the storagemodulus was inverserly proportion to the holding power，and those withgreat values of viscosity, storage modulus give long holding power under the frequency(100Hz) condition. The peel strengths increased firstly andthen decreased with the increase of peel rate in the test. The tack andpeelstrngth of the PSA patch also first increased and then decreased withthe increase of the content of azoe and dimethyl sulfoxide employed astransdermal enhancers. The drug loading is the significant target of PSApatch, which can lower down the adhesion properties.
The transdermal permeation property of the drug in the PSA wasresearched by using aconitine and ephedrine hydrochloride that were themain effective ingridents in Shangshiqutong cataplasm. The vitro testresults showed that the hydrophilicity of ESIS-PSA matrix could improvegreatly the drug-permeation amount in contrast to the traditional rubber.The relationship between cumulative penetration content (Q)and squareroot of release time (t1/2) satisfied with Higuchi equations, which wereQ=6.22t1/2-7.41and Q=6.49t1/2-8.98in48hours, for ESIS and traditionalsystem respectively. After48hours, Q and t1/2equations wereQ=44.2t0.6+1.67and Q=25.7t0.6+3.54respectively, which could beclassified to the non-Fick diffusion process.
The quality standards of Shangshiqutong cataplasm based on ESISHMPSA matrix were studied. This method can effectively control thequality of Shangshiqutong cataplasm.
以苯乙烯-异戊二烯-苯乙烯嵌段共聚物（SIS）为基础原料，通过甲酸和过氧化氢原位生成过氧甲酸，分别采用非均相与均相工艺进行环氧化反应，合成了不同环氧化程度的环氧化SIS（ESIS），研究了环氧化程度对产物的分子量及其分布、接触角、玻璃化转变温度、吸水率及透湿率的影响，ESIS的热老化和热氧老化行为及机理和SIS环氧化的反应动力学。结果表明，环氧化反应主要发生在1，4-异戊二烯单元，随着环氧化基团的增加，ESIS极性增强，分子量增加而分子量分布变宽，玻璃化转变温度、吸水率和透湿率均提高；ESIS在热氧老化初期，主要是环氧基团发生破坏，而在老化后期，主要是双键发生破坏，并且热老化和热氧老化的机理不同；SIS的环氧化反应总体为二级反应，对过氧化氢生成过氧酸的反应而言反应为一级反应，反应活化能为22.7kJ/mol。
以不同环氧化程度的ESIS为基体树脂，通过选择增粘树脂、增塑剂和抗氧剂制备了ESIS热熔压敏胶，研究了压敏胶与添加剂的相容性，压敏胶的流变性能，压敏胶与不同表面能材料的粘接性能以及皮肤促透剂对压敏胶性能的影响。结果表明，在一定频率区间内，ESIS热熔压敏胶在储能模量(E’)、损耗模量(E’’)和粘度(η)上存在较大差别并具有不同的变化规律，在粘接过程中，频率为0.01Hz左右，E’与热熔压敏胶的初粘性成反比；在剥离过程中，频率为100Hz左右，E”与热熔压敏胶的180°剥离强度呈正比；以η较高的聚合物为基体树脂制备的压敏胶持粘力较大。皮肤促透剂氮酮和二甲基亚砜含量对ESIS压敏胶力学性能有一定影响，随着皮肤促透剂的加入，压敏胶初粘力和剥离强度均先升高再降低。载药量对压敏胶基质影响较大，随着载药量的不断增加，剥离强度和持粘力呈明显下降趋势。
以伤湿祛痛膏中的乌头碱和盐酸麻黄碱为指标成分，进行了大鼠体外渗透实验，研究了不同类型的压敏胶基质的经皮药物释放性能。大鼠体外实验结果表明ESIS热熔压敏胶基质对药物中极性成分的释放效果更好，相对于传统橡胶膏在药物释放度上有很大的改善，其释放度在48小时内符合Higuchi方程，动力学特征方程分别为Q=6.22t1/2-7.41和Q=6.49t1/2-8.98，48小时后，释放为非fick扩散，动力学特征方程分别为Q=44.2t0.6+1.67和Q=25.7t0.6+3.54。在载药量增加的情况下，大幅提高药物释放度，并且对皮肤无刺激性和过敏性，是一种比较理想的橡胶膏基质材料。
对以ESIS热熔压敏胶为基质材料的伤湿祛痛膏进行了质量研究，并制定了伤湿祛痛膏的质量标准，可有效的控制热熔压敏胶伤湿祛痛膏的质量。
Transdermal drug delivery system (TDDS) is drug-loaded adhesivepatches which, when applied to the skin, deliver the therapeutic agent, ata controlled rate, through the skin to the systemic circulation and to thetarget organs. The performance requirements of pressure sensitiveadhesives (PSA) are demanding as they must be able toadhere well to varying skin types (both dry and moist), beremovable without leaving adhesive residue or causing skindamage, and should not irritate the skin. In accordance with the fact oftransdermal drug delivery system currently, in this paper, preparedhot-melt pressure-sensitive adhesives based on ESIS for TDDS. The mainwork was carried out as follow:
The epoxidation of SIS with formic acid and hydrogen peroxide was studied. The microscopic structure of epoxidised SIS (ESIS) wascharacterized by Fourier Transform Infrared(FT-IR),1H nucleal magneticresonance (1HNMR), Gel Permeation Chromatography (GPC) andDynamic Thermomechanical Analysis (DMA). The aging properties andreaction kinetics were also discussed. The experimental results showedthat: the epoxidation reaetion mainly occurred in l,4-isoprene units, andthe molecular weight, the moisture permeability of ESIS and Tg of PIsegment were increased gradually with the increase of the epoxy degree.At the early stage of aging process, the aging reaction occurs mainly onthe epoxy groups, whereas at the later stage, the aging reaction occursmainly on the carbon–carbon double bonds. The epoxy reaction pocesswas the second order reaction, and the reaction activation energy was22.7kJ/mol, however the reaction of process between carbon-carbondouble bond and hydrogen peroxide was the first order reaction.
A kind of hot-melt pressure-sensitive adhesive(HMPSA) was developedwith the synthesized ESIS employed as matric resin, and epoxy soybeanoil as the plasticizer and high-hydrogenation rosin as the tackifier. Theadhesive performance and rheology behaviors of HMPSA were studied.The results indicated that the storage modulus was proportion to thetack(initial adhesion) under the frequency(0.01Hz) condition, the storagemodulus was inverserly proportion to the holding power，and those withgreat values of viscosity, storage modulus give long holding power under the frequency(100Hz) condition. The peel strengths increased firstly andthen decreased with the increase of peel rate in the test. The tack andpeelstrngth of the PSA patch also first increased and then decreased withthe increase of the content of azoe and dimethyl sulfoxide employed astransdermal enhancers. The drug loading is the significant target of PSApatch, which can lower down the adhesion properties.
The transdermal permeation property of the drug in the PSA wasresearched by using aconitine and ephedrine hydrochloride that were themain effective ingridents in Shangshiqutong cataplasm. The vitro testresults showed that the hydrophilicity of ESIS-PSA matrix could improvegreatly the drug-permeation amount in contrast to the traditional rubber.The relationship between cumulative penetration content (Q)and squareroot of release time (t1/2) satisfied with Higuchi equations, which wereQ=6.22t1/2-7.41and Q=6.49t1/2-8.98in48hours, for ESIS and traditionalsystem respectively. After48hours, Q and t1/2equations wereQ=44.2t0.6+1.67and Q=25.7t0.6+3.54respectively, which could beclassified to the non-Fick diffusion process.
The quality standards of Shangshiqutong cataplasm based on ESISHMPSA matrix were studied. This method can effectively control thequality of Shangshiqutong cataplasm.
引文
[8]李红强,曾幸荣,吴伟卿,等.热塑性弹性体热熔压敏胶的研究进展[J].中国胶粘剂,2006,15(6):47-50
[9]易严德,热塑性弹性体SIS结构与性能的关系[J].中国胶粘剂,2003,14(2):8-11
[27]杨性坤,宋世林.用SIS及SBS制备热熔压敏胶的工艺研究[J].化学与粘合,2001,3:107
[35]邸明伟,王勃.环氧化SIS热熔型压敏胶的研究[J].粘接,2004,25(5):5-7
[36] Hongqiang Li, Xingrong Zeng, Weiqing Wu. Preparation and Characterization ofEpoxidized Styrene-Isoprene-Styrene Tri-block Copolymer Using Formic Acid-HydrogenPeroxide[J]. JOURNAL OF ELASTOMERS AND PLASTICS,2008,40(4):317-330
[37] Li H Q, Zeng X R, Wu W Q. Epoxidation of styrene-isoprene-styrene block copolymerand its use for hot-melt pressure sensitive adhesive[J]. Polymer-Plastics Technology andEngineering,2008,47:978-983
[90]张睿，张建华，赵胡笳，邓联东，董岸杰.经皮给药用酯化淀粉基压敏胶的制备与性能研究[J].中国胶粘剂，2011，20（11）：30-33
[93]俞振伟，应晓英，梁文权.热熔压敏胶中药物释放性能的研究[J].中国药学杂志,2009,44(24):1878-1882
[98] Jen Ming Yang, Shih Chang Tsai. Biocompatibility of epoxidizedstyrene-butadiene-styrene block copolymer membrane. Materials Science&EngineeringC.2010,30(8):1151-1156
[99] Heping Yu, Zongqiang Zeng, Guang Lu, Qifang Wang. Processing characteristics andthermal stabilities of gel and sol of epoxidized natural rubber[J]. European PolymerJournal2008,44:453–464
[9]易严德,热塑性弹性体SIS结构与性能的关系[J].中国胶粘剂,2003,14(2):8-11
[27]杨性坤,宋世林.用SIS及SBS制备热熔压敏胶的工艺研究[J].化学与粘合,2001,3:107
[35]邸明伟,王勃.环氧化SIS热熔型压敏胶的研究[J].粘接,2004,25(5):5-7
[36] Hongqiang Li, Xingrong Zeng, Weiqing Wu. Preparation and Characterization ofEpoxidized Styrene-Isoprene-Styrene Tri-block Copolymer Using Formic Acid-HydrogenPeroxide[J]. JOURNAL OF ELASTOMERS AND PLASTICS,2008,40(4):317-330
[37] Li H Q, Zeng X R, Wu W Q. Epoxidation of styrene-isoprene-styrene block copolymerand its use for hot-melt pressure sensitive adhesive[J]. Polymer-Plastics Technology andEngineering,2008,47:978-983
[90]张睿，张建华，赵胡笳，邓联东，董岸杰.经皮给药用酯化淀粉基压敏胶的制备与性能研究[J].中国胶粘剂，2011，20（11）：30-33
[93]俞振伟，应晓英，梁文权.热熔压敏胶中药物释放性能的研究[J].中国药学杂志,2009,44(24):1878-1882
[98] Jen Ming Yang, Shih Chang Tsai. Biocompatibility of epoxidizedstyrene-butadiene-styrene block copolymer membrane. Materials Science&EngineeringC.2010,30(8):1151-1156
[99] Heping Yu, Zongqiang Zeng, Guang Lu, Qifang Wang. Processing characteristics andthermal stabilities of gel and sol of epoxidized natural rubber[J]. European PolymerJournal2008,44:453–464