托特罗定成膜水凝胶制剂及其透皮机理研究
发布时间：2018-08-03 14:13
【摘要】：膀胱过度活动症(Overactive bladder, OAB)是一种常见的泌尿系统疾病，主要症状是尿急、尿频。目前，OAB病因并不清楚，人体无明显组织学病变，通过抑制膀胱中毒蕈碱(Muscarine, M)受体的活性可以有效的治疗OAB。托特罗定是治疗OAB的主导药物，是一种M受体拮抗剂。M受体拮抗剂在人体肝脏内可由P450酶代谢，通常会有一部分生成活性更高的代谢产物，而这些活性代谢产物更易与除膀胱之外的组织中的M受体结合，发生药物不良反应，，如口干、便秘和视力模糊等，这也是目前全球治疗OAB的众多M受体拮抗剂所面临的问题之一。近年来，通过经皮给药M受体拮抗剂的办法，可有效降低药物肝首过效应，使不良反应发生率降低，但成功开发为经皮给药系统并上市的M受体拮抗剂仅有奥昔布宁一例。 大部分M受体拮抗剂不适合开发经皮给药系统，尤其是水凝胶体系，原因有两个：首先，水凝胶往往包含大量极性溶剂，M受体拮抗剂在这些溶剂中溶解度低，尤其是水凝胶基质中含大量水时，药物结晶析出的问题很难解决，而且给药后药物结晶析出会导致疗效低和不稳定，此问题也是导致一些经皮给药系统退市的原因之一；其次，一些M受体拮抗剂自身分子结构复杂，很难透过皮肤角质层，导致透皮能力弱，很难达到较高的血药浓度，导致其水凝胶生物利用度低。托特罗定在开发经皮给药系统时，除了面临上述问题外，还存在由于药物本身是熔点低、粘度高的半固体而导致转移和应用不便的问题。本研究从药物性质出发，在不同的药物转化思路基础上，成功开发托特罗定成膜水凝胶的制备方法，并且科学的获得了最终的优选处方，成膜材料的引入进一步改善了水凝胶的释药行为和应用性，使用时疗效更加稳定，在透皮机理研究中，阐述了托特罗定透皮的分子形态和经过的皮肤途径，并揭示了优选处方高生物利用度的原因。 1、托特罗定理化性质和凝胶材料初步考察。 本部分内容在第2章进行，托特罗定常以其酒石酸盐形式存在，为提高托特罗定透皮量和便于制备水凝胶，需先将酒石酸托特罗定(Tolterodine tartrate， TT)中的酒石酸去除，使其转化为自由碱托特罗定(Tolterodine free base， TB)。TB的溶解度和油水分配系数(logP)是决定其能否成功制备水凝胶的关键因素。由于TB分子中含两个苯环和大量烷烃链，使其在水中极微溶，溶解度仅有107.11μg/ml，当水凝胶基质含水量较高时，托特罗定易析出，有效的药物透皮浓度下降，这是制备高生物利用度托特罗定成膜水凝胶的难点之一。另外，通常认为logP越接近1的药物越易透过生物膜，TB分子中含酚羟基、三级胺结构，使其解离和带电荷情况易受pH影响，且logP远小于1，尤其是在pH7附近时， TB分子易带正负两种电荷，使其logP进一步下降，皮肤渗透性下降，这是制备高生物利用度托特罗定成膜水凝胶的难点二。考虑到TB分子在pH7附近时的可能带电情况，选择了3种与TB相容性好的凝胶材料：阴离子型凝胶材料卡波姆980、中性凝胶材料高取代羟丙基纤维素(H-HPC)和中性凝胶材料羟丙甲基纤维素(HPMC)。初步考察了它们在水和乙醇中的溶胀能力，结果显示除了HPMC在无水乙醇中几乎不溶胀外，其他条件下凝胶材料在水或无水乙醇中均有较好的溶胀能力。 2、水凝胶制备工艺和处方优化 本部分内容在第3章和第4章进行，为了解决TB转移和应用不便的问题开发了乙醇碱液转化法和三乙醇胺转化法两种药物处理方法。不同的药物处理方法获得的TB适合不同的成膜水凝胶制备方案，因此有乙醇碱液转化法对应的后载药法和三乙醇胺转化法对应的先载药法两种水凝胶制备方法。后载药法只是对影响凝胶材料成凝胶能力、TB溶解能力和凝胶成膜能力关键因素的初步筛选，在此基础上先载药法更科学系统的进行了处方优化。 乙醇碱液转化法制备的TB乙醇溶液用于后载药法制备水凝胶。首先，进行了单因素实验，包括处方中卡波姆980含量、H-HPC含量对水凝胶性质影响；基质溶胀时用水量、时间、H-HPC粒径和温度对水凝胶后期保存中药物稳定性的影响；吐温80、乙酸乙酯和有机硅弹性体对于增加药物在基质中溶解度的研究；亲水性成膜材料明胶、聚乙烯醇和HPMC在水凝胶中成膜可行性研究。其次，通过Franz扩散池进行了水凝胶体外透皮实验，考察了水凝胶的体外药物透过量、累积释放率和稳态释放速率。最后，进行了优选处方大鼠体内药代动力学考察。结果显示：在选择HPMCk4m为成膜材料时，后载药法可以制备最高2%载药量的托特罗定成膜水凝胶；吐温80可有效的增加TB溶解度，然而含量较高时影响水凝胶成膜。含20%吐温80的3.54%载药量水凝胶大鼠体内24h绝对生物利用度为21.87%，暗示了吐温80在提高TB透皮速率方面有着明显作用。先载药法是在三乙醇胺转化法前处理药物基础上制备托特罗定水凝胶的方法。根据后载药法确定的处方中关键因素水、乙醇、载药量、吐温80、HPMC，通过三相图的绘制，获得了能成透明水凝胶的处方范围，并且阐述了凝胶基质中水分子类型对药物析出的影响；响应面实验进一步优化了成膜材料、吐温80和载药量的范围，最终获得24h累积释放率最高的成膜水凝胶处方，小鼠鼠皮的体外结果显示，其24h药物累积释放率为86.02%，与预测结果85.42%非常接近。另外，大鼠体内24h绝对生物利用度为24.53%。 3、透皮机理及药效研究 第5章和第6章进行了透皮机理和药效学相关的研究，目的是进一步明确托特罗定透皮能力、透皮的分子形式和透皮经过的角质层途径。 首先考察了托特罗定的皮肤渗透性和在不同皮肤结构中的分布情况，结合优选处方在大鼠全厚度鼠皮、表皮层、真皮层和皮下组织中的药物稳态释放速率分别为15.83，18.55，37.15和81.82μgcm-2h-1，可以肯定托特罗定水凝胶适合于系统给药，即局部涂抹后，药物可透过皮肤入血到达膀胱，从而发挥治疗效果。 优选处方生物利用度高的本质原因是水凝胶使托特罗定更易透过皮肤入血，通过傅立叶变换红外考察了大鼠皮肤角质层中类脂的双分子层氢键变化，以及通过差式量热扫描考查了处方中关键因素吐温80和三乙醇胺对角质层中类脂含量和熔点的影响，两个实验结果均暗示大鼠皮肤角质层中的类脂氢键的改变。优选处方中TB的透皮活化能Ea测得8.638kcal/mol，与氯离子透过人皮肤角质层类脂双分子层时的活化能10.7kcal/mol接近，且水凝胶pH在7.4附近，进一步说明托特罗定是以带一个负电荷的离子形式跨角质层类脂双分子层透皮，并且佐证了角质层中类脂结构氢键的改变而带来的流动性变化。另外，托特罗定带负电时，与卡波姆980的静电排斥作用也有利于其扩散进入皮肤。此部分研究结果可以为3,3-二苯基丙胺类M受体拮抗剂经皮给药系统的开发奠定部分理论基础。 水凝胶药效实验结果显示所优选的托特罗定成膜水凝胶能较好的减少尿失禁大鼠12h累积排尿量，连续给药结果显示，水凝胶制剂可实现OAB长期治疗的目的。
[Abstract]:Overactive bladder (OAB) is a common urinary system disease. The main symptoms are urgency of urine and frequency of urine. At present, the cause of OAB is not clear. There is no obvious histology in the human body. The activity of the Muscarine, M receptor of bladder poisoning can effectively treat the OAB. Tote Luoding as the leading drug for the treatment of OAB. A M receptor antagonist,.M receptor antagonist, can be metabolized by P450 enzymes in the human liver, usually partly to produce more active metabolites, and these active metabolites are more likely to combine with M receptors in tissues outside the bladder and have adverse drug reactions, such as dry mouth, constipation, and blurred vision. This is also a global treatment. A number of M receptor antagonists in OAB are faced with one of the problems. In recent years, percutaneous administration of M receptor antagonists can effectively reduce the head over effect of the drug and reduce the incidence of adverse reactions, but the only case of the M receptor antagonist, which has been successfully developed into the percutaneous drug delivery system, is only oroxicin Bunin.
Most M receptor antagonists are not suitable for the development of the transdermal drug delivery system, especially the hydrogel system. There are two reasons for it: first, the hydrogels often contain a large number of polar solvents, and the solubility of M receptor antagonists in these solvents is low, especially when a large amount of water is contained in the hydrogel matrix, and the crystallization of the drugs is difficult to solve, and the drug is given after the drug. The crystallization of M is one of the reasons for the low and unstable effect. This problem is also one of the reasons for the delisting of some transdermal drug delivery systems. Secondly, some of the M receptor antagonists have complex molecular structures, which are difficult to penetrate the cuticle of the skin, resulting in the weak transdermal capacity and difficult to reach the high blood concentration, resulting in low bioavailability of the hydrogel. Tortero In the development of the percutaneous drug delivery system, in addition to the above problems, there is a problem that the drug itself is a semi solid with low melting point and high viscosity, which leads to the inconvenience of transfer and application. In this study, the preparation method of Ttot Luoding membrane hydrogels was successfully developed on the basis of different drug properties and different drug conversion ideas. The ultimate optimum prescription was obtained. The introduction of film forming material further improved the drug release behavior and application of the hydrogel, and the effect was more stable in use. In the study of the transdermal mechanism, the molecular morphology and the skin pathway of TUTT Luoding transdermal were expounded, and the reasons for the optimization of the high bioavailability of the prescription were also revealed.
1, Tortero's theorized properties and gel materials are preliminarily investigated.
This part is carried out in the second chapter. Tote Luoding is often in the form of tartaric acid. To improve the TUTT Luoding transdermal volume and facilitate the preparation of hydrogels, tartaric acid in the tartaric acid Tote Luoding (Tolterodine tartrate, TT) should be removed to make it converted to the solubility and oil of the free alkali totte Luoding (Tolterodine free base, TB).TB. The distribution coefficient (logP) is the key factor to determine whether the hydrogel can be successfully prepared. Because the TB molecule contains two benzene rings and a large number of alkane chains, it is very soluble in water and the solubility is only 107.11 g/ml. When the water content of the hydrogel matrix is high, TUTT Luoding is easily precipitated and the effective drug permeable concentration is reduced. This is the preparation of high biological use. One of the difficulties in the ditote Luoding membrane hydrogel is that the more likely the logP is the closer to 1 of the drug through the biofilm, the TB molecule contains the phenolic hydroxyl group and the three grade amine structure, which makes its dissociation and charge charge susceptible to pH, and the logP is far less than 1, especially in the vicinity of pH7, and the TB molecules are liable to take two positive and negative charges and make their logP further decline. The decrease of skin permeability is two difficulty in preparing the high bioavailability of Ttot Luoding film hydrogels. Considering the possible electrification of TB molecules near pH7, 3 kinds of gel materials with good compatibility with TB are selected: anionic gel material carbomer 980, neutral gel material high substituted hydroxypropyl cellulose (H-HPC) and neutral gel Material hydroxypropyl methyl cellulose (HPMC). Their swelling ability in water and ethanol is preliminarily investigated. The results show that the swelling ability of gel materials in water or anhydrous ethanol is better than that of HPMC in anhydrous ethanol, except that it is almost non swelling in anhydrous ethanol.
2, optimization of preparation and prescription of hydrogels
This part is carried out in the third and fourth chapters. In order to solve the problem of TB transfer and inconvenient application, two kinds of drug treatment methods are developed by ethanol lye conversion and triethanolamine conversion. Different drug treatment methods are suitable for the preparation of different membrane hydrogels, because of the corresponding post drug loading method for the ethanol conversion method. Two hydrogels were prepared by the first drug loading method corresponding to the triethanolamine transformation method. The post loading method was a preliminary screening of the key factors affecting the gelation ability of the gel material, the solubility of TB and the ability of the gelation of the gel. On this basis, the prescription was optimized in a more scientific system.
The TB ethanol solution prepared by the ethanol lye conversion method was used to prepare the hydrogel by the drug loading method. First, a single factor experiment was carried out, including the content of carbomer 980 in the prescription, the effect of H-HPC content on the properties of hydrogel, the effect of water consumption, time, H-HPC particle size and temperature on the stability of the drug in the later storage of the water. Twain 80, The solubility of ethyl acetate and organosilicon elastomers to increase the solubility of drugs in the matrix; the feasibility study on the film formation of hydrophilic gelatin, polyvinyl alcohol and HPMC in hydrogel. Secondly, the in vitro transdermal experiment of hydrogels was carried out through the Franz diffusion pool, and the drug permeation, the cumulative release rate and the steady state of the gel in vitro were investigated. The release rate. Finally, the pharmacokinetics of the optimized prescription rats were investigated. The results showed that, when the HPMCk4m was selected as the film forming material, the tote Luoding film hydrogel with the maximum dose of 2% was prepared by the post loading method; Twain 80 could effectively increase the solubility of TB, while the high content of the gel could affect the formation of the hydrogel membrane. It contained 20% Twain 80. 3. The absolute bioavailability of 24h in 54% loading hydrogel rats was 21.87%, suggesting that Twain 80 had an obvious effect on improving the transdermal rate of TB. The first drug loading method was the preparation of TUTT Luoding hydrogel on the basis of the triethanolamine conversion process. The key factors for the formulation of the medicine were water, ethanol, and drug loading. Quantity, Twain 80, HPMC, the formulation range of transparent hydrogel was obtained through the drawing of three phase diagram, and the effect of water molecular type on the drug precipitation in the gel matrix was expounded. The response surface experiment further optimized the film forming material, Twain 80 and the range of drug loading, and finally obtained the film formulation with the highest cumulative release rate of 24h. The in vitro results of mouse skin showed that the cumulative release rate of 24h was 86.02%, which was very close to the predicted results of 85.42%. In addition, the absolute bioavailability of 24h in rats was 24.53%.
3, study on transdermal mechanism and efficacy
In the fifth and sixth chapters, the transdermal mechanism and pharmacodynamics related studies were carried out to further clarify the transdermal capacity of TUTT Luoding, the molecular form of transdermal and the cuticle pathway of transdermal passage.
First, the skin permeability and distribution in different skin structures of totte Luoding were investigated. The steady-state release rates of drug homeostasis in rat skin, epidermis, dermis and subcutaneous tissue were 15.83,18.55,37.15 and 81.82 gcm-2h-1 respectively. It was sure that Ttot Luoding hydrogel was suitable for system administration. After topical application, the drugs can reach the bladder through skin and blood, so as to play a therapeutic effect.
The essential reason for the optimization of the bioavailability of the prescription is that the hydrogel makes Tote Luoding more easily permeable through the skin. The hydrogen bonds in the bilayer of the lipid in the cuticle of the rat skin are examined by Fu Liye transform infrared, and the key factors in the cuticle are examined by the differential calorimetry, which are the key factors of Twain 80 and triethanolamine. The effects of the amount and melting point of the two experimental results all suggest the changes in the hydrogen bonds of the lipid in the cuticle of the rat's skin. The optimum prescription of the transdermal activation energy of TB in the prescription Ea is 8.638kcal/mol, which is close to the activation energy 10.7kcal/mol of the chloride ion through the bilayer of the human skin stratum corneum, and the hydrogel pH is near 7.4, further explaining Tote Luoding In the form of a negative charged ion, the transdermal permeation of the lipid bilayer of the stratum corneum is transacted, and the change of the hydrogen bond of the lipid structure in the stratum corneum is confirmed. In addition, the electrostatic repulsion with the carbomer 980 in the totte Luoding belt is beneficial to its diffusion into the skin. The result of this study can be 3,3- two. A theoretical basis for the development of the transdermal drug delivery system of phenylalanine M receptor antagonists is provided.
The results of hydrogel efficacy test showed that the preferred tot Luoding membrane hydrogel could reduce the cumulative urine volume of 12h in urinary incontinence rats. The results of continuous drug delivery showed that the hydrogel could achieve the long-term treatment of OAB.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R943
本文编号：2161995
[Abstract]:Overactive bladder (OAB) is a common urinary system disease. The main symptoms are urgency of urine and frequency of urine. At present, the cause of OAB is not clear. There is no obvious histology in the human body. The activity of the Muscarine, M receptor of bladder poisoning can effectively treat the OAB. Tote Luoding as the leading drug for the treatment of OAB. A M receptor antagonist,.M receptor antagonist, can be metabolized by P450 enzymes in the human liver, usually partly to produce more active metabolites, and these active metabolites are more likely to combine with M receptors in tissues outside the bladder and have adverse drug reactions, such as dry mouth, constipation, and blurred vision. This is also a global treatment. A number of M receptor antagonists in OAB are faced with one of the problems. In recent years, percutaneous administration of M receptor antagonists can effectively reduce the head over effect of the drug and reduce the incidence of adverse reactions, but the only case of the M receptor antagonist, which has been successfully developed into the percutaneous drug delivery system, is only oroxicin Bunin.
Most M receptor antagonists are not suitable for the development of the transdermal drug delivery system, especially the hydrogel system. There are two reasons for it: first, the hydrogels often contain a large number of polar solvents, and the solubility of M receptor antagonists in these solvents is low, especially when a large amount of water is contained in the hydrogel matrix, and the crystallization of the drugs is difficult to solve, and the drug is given after the drug. The crystallization of M is one of the reasons for the low and unstable effect. This problem is also one of the reasons for the delisting of some transdermal drug delivery systems. Secondly, some of the M receptor antagonists have complex molecular structures, which are difficult to penetrate the cuticle of the skin, resulting in the weak transdermal capacity and difficult to reach the high blood concentration, resulting in low bioavailability of the hydrogel. Tortero In the development of the percutaneous drug delivery system, in addition to the above problems, there is a problem that the drug itself is a semi solid with low melting point and high viscosity, which leads to the inconvenience of transfer and application. In this study, the preparation method of Ttot Luoding membrane hydrogels was successfully developed on the basis of different drug properties and different drug conversion ideas. The ultimate optimum prescription was obtained. The introduction of film forming material further improved the drug release behavior and application of the hydrogel, and the effect was more stable in use. In the study of the transdermal mechanism, the molecular morphology and the skin pathway of TUTT Luoding transdermal were expounded, and the reasons for the optimization of the high bioavailability of the prescription were also revealed.
1, Tortero's theorized properties and gel materials are preliminarily investigated.
This part is carried out in the second chapter. Tote Luoding is often in the form of tartaric acid. To improve the TUTT Luoding transdermal volume and facilitate the preparation of hydrogels, tartaric acid in the tartaric acid Tote Luoding (Tolterodine tartrate, TT) should be removed to make it converted to the solubility and oil of the free alkali totte Luoding (Tolterodine free base, TB).TB. The distribution coefficient (logP) is the key factor to determine whether the hydrogel can be successfully prepared. Because the TB molecule contains two benzene rings and a large number of alkane chains, it is very soluble in water and the solubility is only 107.11 g/ml. When the water content of the hydrogel matrix is high, TUTT Luoding is easily precipitated and the effective drug permeable concentration is reduced. This is the preparation of high biological use. One of the difficulties in the ditote Luoding membrane hydrogel is that the more likely the logP is the closer to 1 of the drug through the biofilm, the TB molecule contains the phenolic hydroxyl group and the three grade amine structure, which makes its dissociation and charge charge susceptible to pH, and the logP is far less than 1, especially in the vicinity of pH7, and the TB molecules are liable to take two positive and negative charges and make their logP further decline. The decrease of skin permeability is two difficulty in preparing the high bioavailability of Ttot Luoding film hydrogels. Considering the possible electrification of TB molecules near pH7, 3 kinds of gel materials with good compatibility with TB are selected: anionic gel material carbomer 980, neutral gel material high substituted hydroxypropyl cellulose (H-HPC) and neutral gel Material hydroxypropyl methyl cellulose (HPMC). Their swelling ability in water and ethanol is preliminarily investigated. The results show that the swelling ability of gel materials in water or anhydrous ethanol is better than that of HPMC in anhydrous ethanol, except that it is almost non swelling in anhydrous ethanol.
2, optimization of preparation and prescription of hydrogels
This part is carried out in the third and fourth chapters. In order to solve the problem of TB transfer and inconvenient application, two kinds of drug treatment methods are developed by ethanol lye conversion and triethanolamine conversion. Different drug treatment methods are suitable for the preparation of different membrane hydrogels, because of the corresponding post drug loading method for the ethanol conversion method. Two hydrogels were prepared by the first drug loading method corresponding to the triethanolamine transformation method. The post loading method was a preliminary screening of the key factors affecting the gelation ability of the gel material, the solubility of TB and the ability of the gelation of the gel. On this basis, the prescription was optimized in a more scientific system.
The TB ethanol solution prepared by the ethanol lye conversion method was used to prepare the hydrogel by the drug loading method. First, a single factor experiment was carried out, including the content of carbomer 980 in the prescription, the effect of H-HPC content on the properties of hydrogel, the effect of water consumption, time, H-HPC particle size and temperature on the stability of the drug in the later storage of the water. Twain 80, The solubility of ethyl acetate and organosilicon elastomers to increase the solubility of drugs in the matrix; the feasibility study on the film formation of hydrophilic gelatin, polyvinyl alcohol and HPMC in hydrogel. Secondly, the in vitro transdermal experiment of hydrogels was carried out through the Franz diffusion pool, and the drug permeation, the cumulative release rate and the steady state of the gel in vitro were investigated. The release rate. Finally, the pharmacokinetics of the optimized prescription rats were investigated. The results showed that, when the HPMCk4m was selected as the film forming material, the tote Luoding film hydrogel with the maximum dose of 2% was prepared by the post loading method; Twain 80 could effectively increase the solubility of TB, while the high content of the gel could affect the formation of the hydrogel membrane. It contained 20% Twain 80. 3. The absolute bioavailability of 24h in 54% loading hydrogel rats was 21.87%, suggesting that Twain 80 had an obvious effect on improving the transdermal rate of TB. The first drug loading method was the preparation of TUTT Luoding hydrogel on the basis of the triethanolamine conversion process. The key factors for the formulation of the medicine were water, ethanol, and drug loading. Quantity, Twain 80, HPMC, the formulation range of transparent hydrogel was obtained through the drawing of three phase diagram, and the effect of water molecular type on the drug precipitation in the gel matrix was expounded. The response surface experiment further optimized the film forming material, Twain 80 and the range of drug loading, and finally obtained the film formulation with the highest cumulative release rate of 24h. The in vitro results of mouse skin showed that the cumulative release rate of 24h was 86.02%, which was very close to the predicted results of 85.42%. In addition, the absolute bioavailability of 24h in rats was 24.53%.
3, study on transdermal mechanism and efficacy
In the fifth and sixth chapters, the transdermal mechanism and pharmacodynamics related studies were carried out to further clarify the transdermal capacity of TUTT Luoding, the molecular form of transdermal and the cuticle pathway of transdermal passage.
First, the skin permeability and distribution in different skin structures of totte Luoding were investigated. The steady-state release rates of drug homeostasis in rat skin, epidermis, dermis and subcutaneous tissue were 15.83,18.55,37.15 and 81.82 gcm-2h-1 respectively. It was sure that Ttot Luoding hydrogel was suitable for system administration. After topical application, the drugs can reach the bladder through skin and blood, so as to play a therapeutic effect.
The essential reason for the optimization of the bioavailability of the prescription is that the hydrogel makes Tote Luoding more easily permeable through the skin. The hydrogen bonds in the bilayer of the lipid in the cuticle of the rat skin are examined by Fu Liye transform infrared, and the key factors in the cuticle are examined by the differential calorimetry, which are the key factors of Twain 80 and triethanolamine. The effects of the amount and melting point of the two experimental results all suggest the changes in the hydrogen bonds of the lipid in the cuticle of the rat's skin. The optimum prescription of the transdermal activation energy of TB in the prescription Ea is 8.638kcal/mol, which is close to the activation energy 10.7kcal/mol of the chloride ion through the bilayer of the human skin stratum corneum, and the hydrogel pH is near 7.4, further explaining Tote Luoding In the form of a negative charged ion, the transdermal permeation of the lipid bilayer of the stratum corneum is transacted, and the change of the hydrogen bond of the lipid structure in the stratum corneum is confirmed. In addition, the electrostatic repulsion with the carbomer 980 in the totte Luoding belt is beneficial to its diffusion into the skin. The result of this study can be 3,3- two. A theoretical basis for the development of the transdermal drug delivery system of phenylalanine M receptor antagonists is provided.
The results of hydrogel efficacy test showed that the preferred tot Luoding membrane hydrogel could reduce the cumulative urine volume of 12h in urinary incontinence rats. The results of continuous drug delivery showed that the hydrogel could achieve the long-term treatment of OAB.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R943
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