Preparation And Characterization Of Megestrol Acetate Nanoformulation

In recent years,among female cancers,breast cancer and endometrial cancer have become important killers threatening women's health.Megestrol acetate is the main drug for breast cancer and endometrial cancer.However,because megestrol acetate is a typical BCS(Biopharmaceutics Classification System)class II drug,its low solubility in water results in poor bioavailability in the body.Nanometerization of poorly soluble drugs can increase the specific surface area of the drug,thereby increasing its dissolution rate and dissolution rate and improving the bioavailability of the drug in the body.In this paper,the bottom-up method and the top-down method are used to nanometerize megestrol acetate,and the effect of experimental conditions on the particle size of megestrol acetate is discussed.The obtained nanopowder was prepared into a suspension of megestrol acetate and its properties were characterized.At the same time,a dry suspension of megestrol acetate was prepared on the basis of the suspension.The main contents are as follows:Bottom-up was used for nanometerization of megestrol acetate,in which acetone was used as the solvent,water was used as the anti-solvent,and mannitol was used as the surfactant in the beaker.The solvent concentration,rotation speed,solvent anti-solvent ratio and mannitol content were discussed respectively.Univariate experiments were conducted to explore the optimal conditions for the preparation of megestrol acetate micropowder,and finally the preparation of MA micropowder with an average particle size of 1.5 ?m.And to explore the effect of other surfactants on particle size,the combination of HPMC and SDS and HPMC and sucrose were used to obtain micropowders with an average particle size of 2 ?m and 1.6?m,respectively.The crystal forms of the three micropowders and the drug substance were compared with the in vitro dissolution.It was found that the crystal form of the micropowder did not change compared with the drug substance,but the crystallinity was significantly weakened.The in vitro dissolution experiment shows that the dissolution rate of the micropowder can reach 80%,and that of the API is 60%,and the dissolution rate is improved.The obtained megestrol acetate micropowder was prepared as an MA suspension.The effects of CMC and xanthan gum concentration in the aqueous solution on the stability of the suspension were also discussed.A stable MA suspension was prepared when the content of xanthan gum was 3 mg/mL and the content of CMC was 0.6 mg/mL.It was allowed to stand at room temperature for 5 days without obvious precipitation and delamination,and the upper concentration of the suspension No significant changes.The dissolution of the obtained suspension was characterized.The experimental results showed that the dissolution of the suspension was 90%at 210 minutes,and the commercially available tablets were 59%at the same time.The suspension liquid phase was more soluble than the domestic tablets.The degree has improved.The top-down method was used for the nanometerization of megestrol acetate.Separately,the high-speed shearing method of fixed rotor and sand grinding method were used to prepare megestrol acetate suspension,and the preparation conditions were optimized.Using HPMC and TPGS as surfactants,megestrol acetate suspensions with an average particle size of 206 nm and 325 nm can be prepared respectively.The static settlement and redispersibility of megestrol acetate suspensions are in line with national Pharmacopoeia regulations.The in vitro dissolution experiment showed that the final dissolution rate was 98%,which was higher than 60%of the domestic marketed drugs.Cytotoxicity experiments were performed on megestrol acetate suspension using Human breast cancer cells(mm231).The experimental results showed that when the megestrol acetate concentration was 5 ?g/mL,the mm231 cell survival rate decreased with the increase of the action time.The mm231 cell survival rates at 2h,12h,and 24h were 76%,60%,and 53%,respectively.As the concentration of megestrol acetate increased,the mm231 cell survival rate gradually decreased.When the megestrol acetate concentration changed from 5 ?g/mL to 50 ?g/mL,the mm231 cell survival rate changed from 76%to 45%after two hours of action.The cytotoxicity of the aqueous solution without megestrol acetate was much lower than that of the suspension.Under the same conditions,the mm231 cell survival rate of the suspension was 76%,and the mm231 cell survival rate of the aqueous solution with the drug was 97%.Further preparation and characterization of megestrol acetate dry suspension,the crystal form of the dry suspension did not change compared with the API,but the intensity of the diffraction peak decreased and the crystallinity decreased.The dry suspension is dispersed in water to form a suspension,and after standing for 3 hours,there is no precipitation and delamination.The cytotoxicity experiment of dry suspension showed that the cell survival rate of the dry suspension dropped from 97%to 34%as the megestrol acetate concentration changed from 5?g/mL to 50?g/mL after 2 hours of addition.Increased toxicity.When the megestrol acetate concentration was 50 ?g/mL,as the dry suspension addition time increased from 2 h to 24h,its cell survival rate decreased from 34%to 21%,and as the dry suspension addition time increased,cytotoxicity increased.