【作者】 王森；

【导师】 杨明； 朱卫丰；

【作者基本信息】 成都中医药大学 ， 中药学， 2009， 博士

【摘要】 中药复方良肤治疗皮肤瘙痒效果确切,常规乳膏制剂稳定性差,影响临床使用。本文为改善良肤乳膏制剂的稳定性,探索溶度参数理论用于指导中药复方油水分散制剂的设计与评价,对良肤油水分散经皮给药制剂进行研究,并进行了体内外相关评价。本文的具体研究内容和结果如下：1.良肤组分溶度参数及理化性质表征分别采用直接计算法、基团贡献法、IGC、RP-HPLC法测定良肤组分及全方的Hildebrand和Hansen溶度参数,并利用溶度参数表征良肤组分的溶解、分配性质,其结果与经典的饱和溶液法、摇瓶法、RP-HPLC法测定结果相吻合；采用紫外分光光度法、非水滴定法、pH梯度RP-HPLC测定良肤的解离常数,甲醇／pH双梯度同时测定分配系数和解离常数；探讨基于RP-HPLC理论同时表征中药复杂体系多组分的溶度参数及理化参数的方法,结果可行：采用DSC法分析处方混合物中存在的多元低共熔体系,表明丹皮酚与薄荷脑可形成二元低共熔混合物。2.良肤组分经皮渗透性能表征根据良肤组分的溶度参数及理化性质表征良肤有效组分及复方的经皮渗透性,其结果与体外扩散池法测定结果相吻合,丹皮酚、白鲜碱、梣酮在提取物和复方中均容易经皮渗透；进一步考察了pH、丹皮酚—薄荷脑低共熔体系、化学促渗剂等对有效组分经皮渗透性的影响,研究表明提高介质pH值和添加促渗剂能促进有效成分的渗透,从而为良肤经皮给药制剂研究提供依据。3.良肤油水分散制剂的处方和工艺研究以稳定性、经皮渗透性、流变学特性为主要评价指标,根据溶度参数及HLB值理论,进行良肤油水分散制剂的油相、乳化剂、促渗剂的筛选,结果以碳酸二辛酯、Labrafil(?)M 1944 CS为混合油相、GELOT 64为乳化剂、IPM为促渗剂；采用混料设计对乳化剂、油相及水相的配比进行优化,从而确定制剂处方；进而考察了加药方式、乳化方法以及采用空间填充设计优化乳化工艺,从而确定制备工艺,最终制得低能乳化乳膏、高压均质乳膏及凝胶型乳膏三种制剂。4.良肤油水分散制剂的体外评价对三种良肤油水分散制剂：低能乳化乳膏、高压均质乳膏、凝胶型乳膏进行了系统的体外评价,理化性质评价包括：微观形态观察、粒径及粒径分布、Zeta电位、pH值,有效成分含量,流变学特性包括：流变曲线、屈服应力、触变性、动态黏弹性,稳定性,药物释放度,以及体外经皮渗透性等评价。研究表明,三种良肤油水分散制剂均具有较好的质量、稳定性,经皮渗透性良好。5.良肤油水分散制剂的药效学研究采用4-氨基吡啶和右旋糖苷诱发小鼠皮肤瘙痒模型进行止痒实验,结果表明良肤油水分散制剂具有显著的抑制瘙痒的作用；采用二甲苯所致小鼠耳廓肿胀和小鼠棉球肉芽肿模型进行抗炎实验,结果表明良肤油水分散制剂对急性和慢性炎症均有良好的抑制作用,说明良肤油水分散制剂具有良好的止痒和抗炎作用。6.良肤油水分散制剂的药物动力学研究建立了HPLC检测小鼠皮肤中丹皮酚、白鲜碱及梣酮含量的方法,研究良肤油水分散制剂经皮给药后3种有效组分在小鼠皮肤局部滞留的动力学过程。结果表明,3种有效组分在皮肤内T1／2(α)均较小,分别为0.327、0.329、0.262、0.2h,T1／2(β)均大于24h,30min内迅速渗透进入皮肤,并在皮肤局部长时间均有较强的蓄积,与良肤油水分散制剂能够迅速止痒作用相吻合,有利于药物在皮肤深层局部长时间发挥药理作用。建立了HPLC检测大鼠血浆中丹皮酚浓度的方法,研究良肤油水分散制剂经皮给药后丹皮酚在大鼠体内的药物动力学过程。结果表明丹皮酚在大鼠体内过程为二室模型,Tmax为0.5h, Cmax为0.1675μg/ml, T1/2(α)为0.318h,T1／z(p)为6.572h,表明该药达峰时间较短,达峰浓度较高,分布半衰期较短,而消除半衰期较长,可迅速达到治疗目的,且经皮给药后药物丹皮酚的峰谷都不明显,在12h内血药浓度趋于平稳,且能维持稳定血药浓度时间较长,能达到持效、长效的目的。更多还原

【Abstract】 The traditional Chinese herb compound recipe Liangfu has been reported to be effective in treating patients with skin itching. However, due to the poor stability of conventional cream formulations,the clinical use was limited. To improve the stability of Liangfu cream formulations and explore solubility parameter theory to guide the design and evaluation of traditional chinese medicine compound recipe oil-water dispersion formulations,we researched the Liangfu oil-water dispersion transdermal drug delivery formulations and evaluated the system in vitro and in vivo relatively. The dissertation is summarized as follows:1. Study on solubility parameters and properties of components of LiangfuWe use direct calculation and group contribution method, IGC, RP-HPLC method to determine the Hildebrand and Hansen solubility parameters of the components of Liangfu. We use the solubility parameters to study the characterization of dissolvability and distribution of components. The results is coincided with the saturated solution with the classical method, shake-flask method, RP-HPLC determination. We use UV and non-aqueous titration and pH gradient RP-HPLC methods to determine the dissociation constant of Liangfu,and use methanol/pH gradient to determine distribution coefficient and dissociation constant simultaneously.We explore the theory based on the RP-HPLC system to determine solubility parameters and physical and chemical parameters of the complex characterization of TCM.The results is feasible.We use DSC to analyze multi-mixture eutectic system and discover that Paeonol and Menthol formed binary eutectic mixture.2. Characterization of percutaneous penetration of Liangfu componentsWe characterize the percutaneous penetration according to solubility parameters and physical and chemical properties.The results was in accordance with vitro diffusion cell method.Paeonol, Dictamnine and Fraxinellone are easy to penetrate. We study the impact of percutaneous penetration of pH, paeonol-menthol eutectic system, the chemical agent penetration.It shows that raising the pH value of medium and add penetration agent can promote the penetration of active ingredients.This can provide the basis for the research of Liangfu oil-water dispersion formulations.3.The prescription and preparation technique of Liangfu oil-water dispersion formulationsWe use stability, percutaneous permeability and rheological properties as the main evaluation index to filter the oil phase, emulsifier, penetration agents of Liangfu oil-water dispersion formulations according to solubility parameters and HLB values theory.The mixed oil phase compose octyl dimethyl, Labrafil (?) M 1944 CS. The emulsifier is GELOT 64. The penetration is IPM. We use mixture design to optimize the emulsifier, oil phase and water phase ratio,thereby to determine prescription.We study the way of dosing and emulsion method,and use the space-filling design to optimize emulsification process. Thus we determine the preparation process of the low-energy emulsification cream, high-pressure homogenization cream and gel-type cream.4.Quality evaluation of Liangfu oil-water dispersion formulations in-vitroWe evaluate the quality of the low-energy emulsification cream, high-pressure homogenization cream and gel-type cream systematically.The evaluations are consist of physical and chemical properties, active ingredient content, rheological properties, stability, drug release and percutaneous penetration in vitro. Studies have shown that three types of Liangfu oil-water dispersion formulations are better quality, stability, good percutaneous penetration.5.Pharmacodynamics of Liangfu oil-water dispersion formulationsWe use 4-Aminopyridine and Dextran to induce model of mouse skin itching to carry out antipruritic experiments.lt shows that Liangfu oil-water dispersion gormulations can inhibit itching significantly.We use Xylene to induce mouse ear edema and cotton ball granuloma model in mice to carry out experimental anti-inflammatory.It shows that Liangfu oil-water dispersion formulations can inhibit acute and chronic inflammation significantly. These indicated Liangfu oil-water dispersion formulations has a good anti-itching and anti-inflammatory effects.6.Pharmacokinetics of Liangfu oil-water dispersion formulationsWe established a method for the determination of Paeonol, Dictamnine, Fraxinellone in rat skin by HPLC and studied pharmacokinetics of Liangfu oil-water dispersion formulations in rats by transdermal administration.The outcome indicated that four kinds of effective components in the skin with T1/2(α) are 0.327,0.329,0.262,0.2h respectively. T1/2(β) are more than 24h. Liangfu cream penetrate into the skin rapidly in 30min. The skin pharmacokinetics characteristic of four ingriedents in Liangfu cream was lined with the cataplasm long time.We established a method for the determination of paeonol in rat plasma by HPLC and studied pharmacokinetics of pharmacokinetics of Liangfu oil-water dispersion formulations in rats by transdermal administration. The outcome indicated that the patch was a two-compartment model, and its druggery dynamics parameters were:Tmax=0.5h, Cmax 0.1675μg/ml, T1/2(α)= 0.318h, T1/2(β)=6.572h. The above means that this drug has the advantange of lang time keeping stable blood-drug concentration and steady effects.更多还原