Design And Evaluation Of Traditional Chinese Medicine Compound Recipe Liangfu Oil-Water Dispersion Transdermal Drug Delivery Preparations

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.