Preparation And Pharmacokinetics Of Megestrol Acetate Nanosuspension

Megestrol acetate is a synthetic progestin that is clinically used in the treatment of advanced breast and endometrial cancers and is used as an appetite stimulant for the most commonly prescribed medicines for the treatment of cancer or AIDS patients with anorexia,weight loss and cachexia,improving patient quality of life.However,megestrol acetate belongs to the Biopharmaceutics Classification System Class II drug,and its poor water solubility limits drug absorption and bioavailability.In this parper,megestrol acetate nanosuspension was preparated using drug nanocrystal technology,with the expectation of increasing drug solubility and dissolution,and then improving absorption and bioavailability.The UV and HPLC methods were established respectively in this paper for the analysis of the dissolution and the assay of megestrol acetate.The methodological study showed that the established method were accurate,reliable and stable to meet the test requirements.A media milling method was employed to prepared megestrol acetate nanosuspension,and the technological conditions were also optimized.Taking drug particle size and PDI as examining indexes,the process parameters,such as the kinds and concentrations of stabilizers,grinding time,size and weight of grinding bead,grinding speed and other kinds and dosage of supplements,were investigated via single factor test.On this basis,the process conditions were optimized in an orthogonal experiment of four factors and three levels.And the results indicated that the optimized process parameters were as follows: drug concentration was 125 mg/m L,the concentrations of stabilizers SDS and PVPK30 were 1% and 2%(relative to the drug amount),Zr O2 beads(φ=0.5 mm)were 35 g,grinding speed was 150 r/min,grinding time was 10 h,citric acid was 0.5%,sodium citrate was 0.5%,sodium benzoate was 0.1%,sucrose was 25%(m/v).This paper evaluated the quality of self-made megestrol acetate nanosuspension.The results showed that the particle shape of megestrol acetate nanocrystals were bullet crystals as well as the mean particle size was 233.3 nm with an uniform particle size distribution;the p H,sedimentation volume ratio and redispersibility of megestrol acetate nanosuspension were in accordance with the USP;after milling the crystalline state and chemical structure of megestrol acetate were not changed;the dissolution rate in the four dissolution medium was also obviously improved compared to the crude suspension and the commercial dispersible tablets(P<0.05);and the content of megestrol acetate nanosuspension was in line with the USP regulations.The analytical method of megestrol acetate in vivo of wistar rats was established and the pharmacokinetics in vivo of it was studied.Self-made megestrol acetate nanosuspension was test preparation,and megestrol acetate physical mixture and commercial dispersible tablets were reference preparation,this paper studied the blood concentration at different time after intragastric administration.Pharmacokinetic parameters were calculated by DAS 3.0 pharmacokinetic software.The results showed that the peak concentration(Cmax)of self-made megestrol acetate nanosuspension,megestrol acetate physical mixture and the commercial dispersible tablets were599.10±145.30 ng/m L,151.11±22.87 ng/m L and 269.16±42.51 ng/m L,respectively;the peak time(Tmax)were 2.67±0.52 h,3.17±1.17 h and 3.8±0.45 h,respectively;the AUC(0-∞)were 7415.53±1211.64 ng?h/m L,2118.48±1098.51 ng·h/m L and 4102.08±1355.94ng?h/m L,respectively.The relative bioavailability of self-made megestrol acetate nanosuspension was 350.04% and 180.77%,indicating that the preparation of megestrol acetate nanosuspension could improve the drug absorption in vivo and bioavailability.