| Objective: To establish an in vitro method for the analysis of candesartan ester mixed micelles(CC-MMs).The optimum formulation and technological parameters of the mixed micelles of candesartan ester were optimized and their physicochemical properties were characterized.To improve the solubility of candesartan ester.Method: Using Pluronic P123 and Pluronic F127 as drug carriers,the mixed micelles of candesattan ester were prepared by thin film hydration method.Using EE%,DL% and sedimentation rate as indexes,the influencing factors such as P123 mass percentage,P123/F127 dosage,hydration temperature,aqueous volume,rotary evaporation temperature and organic solvent dosage were investigated by single factor method.Combined with central design-response surface method,the optimal formulation of candesartan ester mixed micelles was optimized.By establishing the design space,the feasibility and stability of the production process are improved.Taking appearance and resolubility as comprehensive evaluation indexes,the optimum freeze-drying process of the mixed micelles of candesartan ester was determined.The mixed micellar tablets of candesartan ester were prepared by powder direct compression method.The critical micelle concentration,morphology,particle size,PDI,Zeta potential,stability,redispersion,saturated solubility and other physical and chemical properties of the mixed micelles prepared by using the best formulation and technological parameters were characterized.Thermal analysis(DSC)and infrared spectroscopy(IR)were used for phase identification.The release characteristics of the mixed micelles of candesartan ester in vitro were determined by dialysis bag diffusion method.The mixed micelles of P123/F123 were compared with those of P123 and F127 using DL%,EE%,sedimentation rate,particle size,PDI and Zeta potential as indexes.Results: The established method for in vitro analysis of the mixed micelles of candesartan ester is stable and feasible.The best preparation method for the mixed micelles of candesartan ester is thin film hydration method.The optimal formulation and process parameters were as follows: the amount of organic solvent was 3 ml,the rotary evaporation temperature was 45℃,the hydration temperature was 40℃,the hydration time was 45 min,the mass percentage of P123 was 66.7%,the amount of P123/F127 was158.2 mg,and the volume of water phase was 8.40 ml.Microcrystalline cellulose was used as filler,talc powder and magnesium stearate(1:1)were used as lubricant,and the dosage was 2%.The CMC value of CC-MMs was 0.0059 g/100 ml,the average particle size,PDI and Zeta potential were(26.39±0.22)nm,0.210±1.49 and(-21.57±0.71)m V,respectively.Under the microscope,the morphology is regular spherical with uniform distribution,and there is no aggregation.The results of DSC and IR indicated that candesartan ester existed in amorphous form in the mixed micelles.After the preparation of CC into CC-MMs,the solubility of CC in purified water and p H 6.8 buffer was increased by 1100 times and 781 times,respectively,indicating that CC-MMs could significantly improve the solubility of CC.The redispersity and stability of the mixed micelle lyophilized powder of candesartan ester were investigated.In vitro drug release studies showed that the mixed micelles of candesartan ester had a certain sustained release effect.Conclusion: The preparation process of candesartan ester mixed micelles and tablets is simple,stable and feasible,which can effectively improve the solubility of candesartan ester,and has a certain slow-release effect.Compared with P123 micelle or F127 micelle,the mixed micelle system formed by P123 and F127 is more stable,and has higher encapsulation rate and drug loading,smaller particle size and PDI.The combination of Pluronic P123 and Pluronic F127 can make up for their shortcomings and give full play to their advantages. |
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