毕业设计（论文）水凝胶贴剂基质的机理和应用研究.pdf

第二军医大学_博士学位论文_水凝胶贴剂基质的机理和应用研究_姓名：侯雪梅_申请学位级别：博士_专业：药剂学_指导教师:高申_20100501水凝胶贴剂基质的机理和应用研究摘要水凝胶贴剂(Hydr ogel Patch)即成型巴布剂(Cataplasm),是以水溶性高分子材 料为主要基质，加入药物，经炼合、涂布、剪切等工序制备而成。与早期的泥状巴布 剂基质相比，组成更为科学合理，工艺条件适合工业化生产，且具有载药量大、给药 剂量准确、使用舒适方便、生产无“三废”、适用范围广和滋润皮肤的优点。但是经 过了几十年的研究和应用，水凝胶贴剂在新产品开发及市场占有率方面远未形成规 模：目前透皮制剂年销售10亿元人民币，水凝胶贴剂所占份额还不足1%。水凝胶贴剂主要由三部分组成：(1)背衬层；(2)水凝胶层，即基质层；(3)防 粘层。其中水凝胶层是水凝胶贴剂的主要组成部分和关键层，决定着贴剂的主要表现 性能。目前水凝胶层主要采用交联型基质，即通过交联组分高价金属离子与水溶性聚 合物(Hydr ophilic polymer s)螯合固化而成。交联型基质主要包括三个部分：(1)交联 骨架材料(Fr ame Mater i叫；(2)交联剂(Cr oss-link ing Agent)；(3)交联调节剂(Adj ustor)；(4)增粘剂(Viscosity Incr easer)；(5)保湿剂(Humectant)；(6)水分。其中交联 骨架材料、交联剂和交联调节剂为基质的交联核心。交联核心的交联程度和交联速度 对贴剂的粘接性能、含水量、药物释放度及透气性等起主导作用。纵观目前水凝胶贴 剂发展的状况，阻碍其产业发展的主要因素在于水凝胶贴剂基质层的基础研究不够深 入，如对基质的交联机理、释放机理、微观机理的研究比较缺乏，对基质中不同组分、不同类型的辅料的性质及特点没有进行系统的考察和研究，从而导致水凝胶贴剂在基 质配方、质量和质量标准、制备工艺包括生产设备等方面缺乏较深层次的技术支持。水凝胶的基质层主要成分是高分子材料，因此具有高分子材料溶于水的主要特 征：粘弹性(Viscoelasticity)。高分子材料在水中溶胀，溶解，并形成高粘度凝胶，稳态下呈半固体状态，表现为粘弹性。水凝胶贴剂基质核心的交联速度和交联程度及 不同基质原料，不同组分的基质配方都是影响水凝胶贴剂基质体系粘弹性的因素。因 此基质的粘弹性是水凝胶贴剂的重要的物理特性。流变特性可迅速和精确的反映材料的内部行为。流变特性通过各种流变参数(弹 性模量G，、粘性模G”量、相位角，如蠕变柔量等)得以体现，也就是说，粘弹性可 通过其各种流变参数值来表征。对于采用交联型基质的水凝胶贴剂来说，其基质核心 的交联速度和交联程度以及基质原料的性能都可通过监测基质体系的流变参数值的 变化得以间接的反映，这为进一步的分析水凝胶贴剂的宏观交联机理和处方筛选提供 数据支持。许多学者认为：基质的流变行为和基质的表面性质(初粘力、剥离强度和内聚力)第二军医大学博士学位论文之间应该存在一种关系。但在实践中，这种想法并没有被深入的研究和广泛的应用。本课题通过流变学法和传统测量粘接力的方法，对这一观点进行了验证，并且建立了 基质各类流变参数和基质粘接力的趋向关系。在此基础上，优化筛选了五类性能良好 的水凝剂贴剂，对其反映粘接力的不同的流变参数进行了监测，以期用各类流变参数 值的范围建立水凝胶贴剂的流变学质量评价。这对水凝胶基质的筛选、优化和建立统 一的、科学的和标准化的测试仪器、测试方法和检测指标，以便对水凝胶贴剂的质量 进行更准确、更客观和更全面的评价，具有极大的意义。水凝胶贴剂作为一种透皮制剂，其稳定性和释放度的考察是保证产品质量的重要 控制手段。然而，建立水凝胶贴剂的稳定性和体外释放度试验方法时面临很大的困难，原因在于水凝胶贴剂是一种特殊的基质（含水量很高和交联反应不断进行）以及释放 机理的研究不够深入。本课题通过流变学的方法监测了水凝胶基质的稳定性和以利多 卡因为模型药物建立流变参数和药物释放之间的关系，以期用流变参数预测水凝胶贴 剂的释放行为。另外，水凝胶贴剂基质的微观形态和微观机理是其一切行为的基础，换句话说，各种基质的不同表面行为都可以从微观形态和微观机理上得以解释上，因此，本课题 借助紫外和红外光谱分析以及扫描电镜对各种水凝胶基质的微观交联机理和微观形 态进行了研究和分析。本文第一部分是对水凝胶贴剂宏观交联机理的研究和分析。首先配制了不同类型 的水凝胶贴剂基质，对其进行流变学的考察（振幅扫描、蠕变实验），通过对不同基 质类型在流变学中表现的性质，推断和分析其交联机理如下：1.通过振幅扫描证明：1）不加交联调节剂时，甘羟铝本身不解离铝离子，不与 聚合物中的较基发生反应；2）相同pH值的交联调节剂对基质的影响各不相同；3）相 同pH值条件下，短时间内，4类有机酸参于的凝胶体系释放铝离子速度按从大到小顺 序排列为；酒石酸 乳酸苹果酸 柠檬酸；4）综合分析结果：a.交联调节剂化 学结构中，羟基（-0H）与股基（-COOH）的存在对体系G*值有影响，在一定的pH 值范围内，竣基可能使体系的弹性或刚性增加，G*值增加，而羟基可以使样品的弹 性降低，体系G*值下降。下降的幅度由羟基（-0H）与按基（-COOH）的个数比决 定，个数比越大，体系G*值下降越多；b.络合物的稳定性来自两种因素：有机酸分 子的化学结构和金属离子与配位体形成络合物的化学结构类型。分子中按基数越多，与金属离子形成的络合物就越稳定；内核配位络合物的稳定性大于外围络合物。2通过单频扫描证明：1）长时间段内，相同pH值有机酸与铝离子形成的络合物 的稳定性从大到小排列为：柠檬酸 苹果酸 乳酸酒石酸。得到的结果与短时间段 内得到的结果一致；2）在4类酸中，乳酸是唯一可单独作为凝胶体系的交联调节剂，水凝胶贴剂基质的机理和应用研究其它有机酸都不宜单独作为凝胶体系的交联调节剂；3）同样的凝胶体系，即使交联 调节剂是相同的pH值，交联速度差异也很大，这说明凝胶体系交联速度的快慢与交 联调节剂的化学结构有很大的关系；4）无论是哪种有机酸，交联反应并不是一步完 成的，凝胶体系的G*值随着时间的增加不断的变化，总体来看，凝胶体系的交联反 应分三个阶段：快速反应阶段，慢速反应阶段和终止阶段。3蠕变实验证明：相同pH值条件下，短时间内，4类有机酸参于的凝胶体系释放铝离 子速度按从大到小顺序排列为：酒石酸 乳酸 苹果酸 柠檬酸；本文第二部分为水凝胶贴剂的微观交联机理的研究和分析。先配制了不同类型的 水凝胶贴剂基质，借助紫外和红外光谱分析，证明了凝胶基质中做为凝胶骨架成分的 高分子材料中的竣基和交联剂铝离子发生了配合反应;然后借助化学和流变学方法证 明：多核羟桥络合金属离子才能具有较高的反应交联活性和效率。最后综合分析交联 反应分可能分4步进行：1）络合物的形成；2）金属离子从络合物中解离出来形成配 位水合离子；3）配位水合离子形成羟桥络合物和多核羟桥络离子；4）活化后的金属 离子与电离后的聚合物进行交联反应；本文第三部分为水凝胶微观形态的研究和微观机理的分析。通过扫描电镜对各种 水凝胶基质的微观形态进行了研究，用微观形态凝胶粒子的大小和形态验证了水凝胶 基质的交联机理。并进一步证明：流变参数的复合粘度是微观形态粒子分散性的外在 表现形式，复合粘度越低，分散性越好。本文第四部分为水凝胶贴剂基质原料的性能考察。首先通过流变学法考察了不同 水凝胶体系的流变行为。这些凝胶体系包括；改变交联调节剂的种类和不同剂量制备 的凝胶体系和改变交联骨架材料、交联剂和增粘剂的种类制备的凝胶体系。然后通过 第一章推断得出的交联机理对各类基质的特点进行分析和验证。得出的结论如下：1交联调节剂1）在短时间段内，有机酸的剂量越大，交联越快；长时间段内，有 机酸剂量越大，交联越慢（除丁二烯酸外）；2）凝胶体系成胶有一定的pH值范围，超过特定值时，体系不成胶；3）有机酸与铝离子形成的络合物的稳定性顺序为：EDTA 丁烯二酸 柠檬酸 苹果酸 乳酸 酒石酸；4）无论哪种有机酸配制的凝胶体系，到一定时间后，凝胶体系就基本稳定；5）每种有机酸在凝胶体系中合适的剂量不同：酒石酸为0.2%,乳酸为1.3%,苹果酸、柠檬酸、丁二烯酸和EDTA不适合单独做交联 调节剂，与其它有机酸合用时，剂量范围或合适剂量分别为：0.08%0.24%、0.2%、0.2%0.26%和 0.01%.2交联剂 1）各类交联剂配制的凝胶体系的交联速度的排序为：氯化铝 甘羟铝 淀粉铝明矶氢氧化铝硫酸钙 氯化钙氢氧化钙；2）除了甘羟铝，淀粉铝适 合单独做凝胶体系的交联剂，其它交联剂都不适合单独做凝胶体系的交联剂；3）交 第二军医大学博士学位论文联剂的合适剂量为0.1%0.4%的范围。3交联骨架1）三种凝胶骨架在相同条件下的交联速度NP600 NP700 NP800；2）NP-600和NP-800不适合单独做透皮制剂基质的凝胶骨架；3）骨架材料的合适剂 量为4%8%。4增粘剂1）CMC使体系的稳定性下降，海藻酸钠、交联装甲基纤维素、U10和西黄 蓍胶易导致凝胶体系失去柔顺性和粘弹性，不适合单独做凝胶基质的增粘剂：2）最 适合的增粘剂为PVPK-90；3）增粘剂的剂量范围应控制在2%。本文第五部分为水凝胶贴剂基质表面性质和内部行为之间的关系研究。通过流变 学法和传统监测水凝胶贴剂表面性质的方法，建立了流变参数和基质粘接能力的关系 如下：a,ir ad/,值与初粘力成正相关5=0.9586）；MGLioo/G*）值与剥离强度 呈正相关（2=0.9388）；1/Jc值与内聚力呈正相关（门=0.9914）；并在前面实验所得 凝胶贴剂基质表面性质和内部行为之间的关系的基础上，通过两种方法考察了基质厚 度和面积对基质粘接力的影响，实验证明：除厚度对基质初粘力的影响不一致外，通 过两套方法得到的结果相同。这个结果是对前面得到的水凝胶贴剂基质表面性质和内 部行为之间的关系结果的进行了进一步的验证。本章实验结果证明：基质表面性质各 指标与流变学参数有相关性，可以通过控制流变学参数调节基质的表面性质。本文第六部分为水凝胶贴剂基质配方研究和流变学质量标准确立。通过通过单因 素考察，确立了水凝胶贴剂基质交联核心各组分剂量的大致范围，然后在确定的范围 内以失水量为考察指标，进行正交设计筛选处方并利用交联机理优化处方。之后，以 优化处方为基础，设计了四类新的处方并对这五类处方（制备完成后第7天）进行流变 学的考察，结果为：瓦也回值（初粘力）为2426,Ggoo/G.值（剥离强度）为57,Jc值（内聚力）为IX10左右。水凝胶贴剂基质参数在满足这些数值的范围 内，贴剂的皮肤追随性良好。本文第七部分为水凝胶贴剂稳定性研究和皮肤刺激性考察。首先通过流变学法考 察流变参数G，goo/G，斫0值在3个月内的变化,观察到这五类水凝胶基质在7天之内变 化最为明显，然后随着时间的增加，G，goo/G，成值逐渐平稳，一个月之后基本稳定。然后通过家兔实验对五类水凝胶基质进行皮肤刺激性实验和按皮肤刺激反应评分标 准进行判断，实验结果为：五类水凝胶贴剂对家兔完整、破损皮肤均无急性毒性反应。本文第八部分为水凝胶贴剂释放性能研究和释放机理分析。以利多卡因为模型药 物，制备了五类水凝胶基质，采用改良的Fr anz扩散池，以生理盐水为接受液，通过 紫外分光法（220nm）测定了利多卡因体外释放度。并对载药的水凝胶基质的流变学 进行了研究。结果证明：水凝胶贴剂的释放具有相同的释放规律，整个释放过程符合 骨架材料的Higuchi方程的扩散模式；水凝胶贴剂的药物释放包括Fick扩散和非Fick扩 4水凝胶贴剂基质的机理和应用研究散。通过流变学法证明：基质的流变参数G，和n*值与释放度相关。G，和n*值越大，释放度越小。本章实验证明：水凝胶基质的流变行为在一定程度上可预测基质的释药 行为。关键词：水凝胶贴剂，流变参数，交联机理，微观形态，微观机理第二军医大学博士学位论文AbstractHydr ogel patch that is for ming Babu(Cataplasm),in which the water-soluble polymer mater ials ar e the main substr ate,its pr epar e pr ocess contains adding dr ugs,r efining together,coating,cutting and so on.Compar ed to the ear ly Muddy Babu base,the composition of hydr ogel patch is mor e scientific and its r easonable pr ocess conditions ar e mor e suitable for industr ial pr oduction,fur ther mor e.It also has many other advantages,such as lar ge dr ug loading-,accur ate dosage,comfor table and convenient for use,no thr ee wastes dur ing pr oduce pr ocess,wide scope of application and nour ishing sk in benefits.However,although after decades of r esear ch and application of hydr ogel patch,its new pr oduct development and mar k et shar e is far fr om being the for mation of scale:pr esently,the tr ansder mal for mulations ar e selling 10 billion yuan ever y year,while the shar e of hydr ogel patch is still less than 1%.Hydr ogel patch mainly consists of thr ee par ts:(1)back lining;(2)hydr ogel layer,namely base layer;(3)anti-adhesive layer.The hydr ogel layer is the maj or components and k ey layer of hydr ogel patch,deter mining its per for mance.Pr esently,hydr ogel layer mainly uses cr oss-link ed base,that is,fbnned by cr oss-link ing components high-value metal ion chelate cur ing with the water-soluble polymer s.Cr oss-link ed base mainly consists of six par ts:(1)cr oss-link ed fr ame mater ial;(2)cr oss-link ing agent;(3)adj ustor s;(4)viscosity incr easer s;(5)humectants,(6)water.In which cr oss-link ed fr ame mater ial cr oss-link ed base mater ial,cr oss-link ed agent and adj ustor s for the cr oss-link ing cor e of substr ate.The cor e cr oss-link ing degr ee and speed play a leading r ole to the patch adhesion,moistur e content,dr ug r elease r ate and per meability,etc.Look ing at the pr esent status of the development of hydr ogel patch,hydr ogel patch base basic r esear ch is not thor ough enough,which was the maj or factor hinder the development of their industr ies,such as lack of the study on the cr oss-link ing mechanism of base,the r elease mechanism,micr o-mechanism of the matix as well as the systematic study and r esear ch about the natur e and char acter istics of differ ent components in base and differ ent types of additive,r esulting in the lack of deeper levels of technical suppor t for the for mulations,quality and quality standar ds of the base and the pr epar ation pr ocess,including pr oduction equipment.The maj or components of hydr ogel base layer is polymer mater ials,so it has the main featur es of water-soluble polymer mater ials：viscoelasticity.Polymer swelling in water 水凝胶贴剂基质的机理和应用研究fir stly,then dissolved and to for m gel with high-viscosity,was a semi-solid state in steady state,showed viscoelastic.The cr oss-link ed r ate and degr ee of hydr ogel base patch cor e,differ ent substr ate mater ials and differ ent components ar e all the factor s that affect the viscoelastic of the base system in hydr ogel patch.Ther efor e,the viscoelastic of base is the impor tant physical pr oper ties of hydr ogel patch.Rheological pr oper ties can r eflect the inter nal behavior of the mater ial r apidly and accur ately.Rheological pr oper ties can be r eflected thr ough a var iety of r heological par ameter s(elastic modulus G,viscous-mode G phase angle,such as the cr eep compliance,etc.),which means viscoelastic could be r epr esented thr ough var ious r heological par ameter s value.For the hydr ogel patches utilizing cr oss-link ed base,its base cor e cr oss-link ed r ate,cr oss-link ed degr ee and behavior s of r aw mater ial can get an indir ect r eflection by monitor ing the the r heological par ameter s change of the base system,so as to pr ovide data suppor t for the fur ther analysis of cr oss-link ed mechanism and for mulation scr eening.Many scholar s believe that:ther e should be a r elationship between the r heological behavior and sur face pr oper ties(tack,peel str ength and cohesion)of base.However,this idea had not been thor oughly studied and widely used in pr actice.In our study,the idea was pr oved by two sets of methods and tr ends in the r elationship between adhesion per for mance and r heological pr oper ties of the base in a hydr ogel patch wer e obtained.On this basis,the five types of hydr ogel patches with good per for mance wer e pr epar ed and the differ ent r heological par ameter s which r eflect its adhesive for ce wer e monitor ed in or der to establish r heological quality evaluation of hydr ogel patch by using the scope of r heological par ameter s,which will be a better tool for optimizing the base for mulation and establishing a unified,scientific and standar dized test instr uments,test methods and test indicator s which could mak e assessment of the quality of the hydr ogel patch mor e accur atly,mor e obj ectively and mor e compr ehensively.Dr ug r elease r ate and stability of hydr ogel patch ar e an impor tant tool for contr oling quality.However,it is ver y difficult to establish a suiable method for monitor ing both of them in vitr o due to the base of hydr ogel patch is a special(high water content and constant the cr osslink ing r eaction)and r elease mechanism not enough in-depth r esear ch.In our study,stability of hydr ogel patches wer e monitor ed thr ough the r heology and the r elationship of dr ug r elease and r heological par ameter s using lidocaine as the model dr ug 7第二军医大学博士学位论文was investigated,which was par ticular ly impor tant for pr edicted dr ug r elease behavior of hydr ogel patch by r heological par ameter s.In addition,the micr oscopic mechanism and the micr o-mor phology of the hydr ogel patch wer e the basis for all its acts,in other wor ds,a var iety of differ ent sur face behavior could be explained on the micr oscopic mechanism and the micr o-mor phology.In our study,UV,infr ar ed spectr oscopy and scanning electr on micr oscopy wer e used to study and analysize micr o-cr oss-link ing mechanismand micr o-mor phology of hydr ogel patch.The fir st par t was the r esear ching and analysising of macr o-cr oss-link ed mechanism of hydr ogel patch.Fir st,the differ ent types of the hydr ogel patch wer e pr epar ed and its r heological behavior s wer e monitor ed by amplitude scanning and cr eep test,and then infer enced and analysised their cr osspoint mechanism accor ding to difier ent r heological pr oper ties of differ ent types of base,as follows:1.Demonstr ated by amplitude scan:1)Aluminum ion itself could be dissociated fr om the Aluminium Glycinate without cr osslink ing r egulator and cor sslink ed r eaction didn t occour between aluminum ion and the car boxyl polymer;2)The effect of the same pH value of the adj ustor s on hydr ogel system was differ ent;3)Under the same conditions of pH value,cr oss-link ed r ate of 4 k inds of hydr ogel patches(differ ent or ganic acids)within a shor t time wer e in or der:tar tar ic acid lactic acid malic acid citr ate;4)Compr ehend-sive analysis of the r esults:a.the hydr oxyl(-OH)and car boxyl(-COOH)in the chemical str uctur e of adj ustor affect the value of G*.In a cer tain r ange of pH values,car boxyl may incr ease the flexibility or r igidity and G*values incr ease.The hydr oxyl can r educe the flexibility of the sample and G*values decr eased.Extent of decr ease of G*values was decided by the r atio of the number of hydr oxyl(-OH)and car boxyl(-COOH).The higher the r atio was,the mor e G*values decr eased;b.The stability of complexes fr om two factor s:chemical str uctur e of or ganic acid and complexes.The mor e the number of car boxyl molecules was,the mor e stable the complexes wer e;The stability of the k er nel complex was gr eater than the exter nal complex.2.Pr oved by single fr equency scanning:1)In a long per iod of time,the stability complexes which wer e for med by or ganic acids with the same pH and aluminum ion wer e or der ed as follows:citr ic acid malic acid lactic acid tar tar ic acid.Results obtained fr om test in a long per iod of time wer e consistent with the r esults obtained fr om test in the shor t per iod of time 2)Lactic acid was the only or ganic acid as a alone adj ustor among 4 k inds acid.3)In the same gel system,even if a百ustor s was the same pH,cr oss-link ing r ate had a gr eat 8水凝胶贴剂基质的机理和应用研究differ ence,indicating that the chemical str uctur e of adj ustor affect the cr oss-link ed r ate;4)Whatever the or ganic acids,cr oss-link ing r eaction was not one step and G*values incr eased with time.On the whole,gel cr osslink ing r eaction was thr ee stages:the r apid r esponse per iod,the slow r eaction per iod and ter mination per iod.3.Cr eep test showed that the r elease r ate of aluminum ions within a shor t time fr om complexes which wer e for med by four k inds of or ganic acids under the same pH and aluminum ions was in or der:tar tar ic acidlactic acidmalic acidcitr ate acid;In the second par t,micr o-cr oss-link ing mechanism of hydr ogel patch was studied and analyzed.Fir st,the differ ent types of hydr ogel bases wer e pr epar ed and the chelation r eaction between the car boxyl gr oup and aluminum ions was demonstr ated by using ultr aviolet and infr ar ed spectr a.Then it was pr oved using chemical and r heological methods that metal ions with Multi-cor e complex had a high activity and efficiency in chelation r eaction.Last,speculate by compr ehensive analysis that the cr osslink ing r eaction may be divided into 4 sub-steps:1)complex for mation;2)metal ion dissociated fr om the complex and the for mation of coor dination;3)coor dination hydr ated ion for m hydr oxyl br idge complex and multi-cor e hydr oxyl br idge complex ion;4)the cr osslink ed r eaction occur between activative metal ions and polymer after ionizating.In the thir d par t,micr o-mor phology and micr o-mechanism of hydr ogel base was studied and analyzed.By scanning electr on,imfor mation of size and micr o-mor phology of gel par ticle can be obtained,w