Preparation Of Fenofibrate Solubilization System By Mechanical Ball Milling And The Mechanism Study

Fenofibrate?FNB?,also known as proulrine which has an irreplaceable status in clinical applications as a potentional lipid-lowering drug,is a pro-drug of fenofibrate acid.It is widely used in the treatment of hypertriglyceridemia and mixed hyperlipidemia.Fenofibrate is a typical drug of Biopharmaceutics Classification System?BCS?class II compounds with a high permeability and low solubility.Mechanical ball milling technology can improve the wettability and the dissolution of insoluble drugs by reducing its crystallinity and increasing its surface area.In this paper,fenofibrate was prepared by mechanical ball milling,which can reduce the particle size of the drug,and then improve the water solubility and the dissolution rate of the drug.The contents were as follows:The analysis methods for fenofibrate content and its in vitro dissolution rate were established.The results showed that the analytical methods were feasible,moreover,it has a high degree of accuracy and reproducibility.The methods could meet the requirements of this subject.Theinclusioncompoundoffenofibrateand hydroxypropyl-?-cyclodextrin was prepared by ball milling.The factors which has an effect of the compound were investigated such as milling time,milling speed and the mole ratio of fenofibrate and hydroxypropyl-?-cyclodextrin.The preparation method was that mixture of fenofibrate and hydroxypropyl-?-cyclodextrin with a molar ration of1:1 was continuous grinding for 90 min under the speed of 200 rpm.The dissolution and solubility experiments in vitro showed that the dissolution rate and water solubility were greatly improved.The results showed that fenofibrate was exist as the amorphous state in the co-grinding complex.The stability study of the co-grinding complex and fenofibrate shows that the stability of the inclusion complex is obviously enhanced compared with the pure fenofibrate.Appropriate amount of water-soluble excipients were added in the inclusion compound to enhance the inclusion efficiency and inclusion constant.The best conditions for preparing three element ball milling material were determined by the same method of preparing inclusion compound.The ternary system was prepared with the condition of 200rpmand120min,themassratiooffenofibrate,hydroxypropyl-?-cyclodextrin and hydroxypropyl methylcellulose was 1:4.5:0.5.The ternary system has better dissolution rate than binary system,moreover,the inclusion efficiency and stability constant has been enhanced.Fenofibrate and glycyrrhizic acid solid dispersion was prepared by roller ball milling.The solubility and in vitro dissolution of fenofibrate and glycyrrhizic acid solid dispersion were investigated,moreover,the stability and oral bioavailability of fenofibrate and glycyrrhizic acid solid dispersion was investigated.Cumulative dissolution of fenofibrate could reached to 80%at 5 min in the solid dispersion.The AUC_0^?and C_maxax of fenofibrate in plasma could reached to 563.69±170.96?g/mL and 90.68±1.12?g/mL respectively.Moreover,the solid dispersion has high bioavailability and stability.