Preparation And Evaluation Of Abiraterone Acetate Tablets Based On Lipid Matrix

Abiraterone is an oral administrated cytochrome oxidase P450（CYP450）c17inhibitor that can decrease the androgen levels by inhibiting the key enzyme in the androgen synthesis,and is used to treat advanced prostate cancer.Abiraterone belongs to the biopharmaceutical classification system（BCS）class IV category,and its bioavailability is 5%;however,since 92%of abiraterone is metabolized to inactive metabolites in vivo,the actual utilization rate is only 0.4%,which is a very low bioavailability.Therefore,to improve the solubility and bioavailability of abiraterone is the key to the research of abiraterone preparation.In order to solve these problems,this project uses lipid-based preparation as the drug delivery carrier.Lipid-based formulations（LBFs）are a new drug delivery carrier.Its purpose is to enhance the solubility of insoluble drugs in the intestinal tract and improve their absorption and bioavailability.LBF not only has the advantages of traditional carrier system,but also improves the disadvantages.There are a variety of preparation methods,can be oral,transdermal,mucous membranes and other ways of administration,has its special advantages.After oral preparation of LBF according to the prescription of classⅢ,under the force provided by gastrointestinal peristalsis and the interaction with gastric and intestinal fluid,self-microemulsification can be produced into microemulsion with fine and uniform particle size.LBF can increase drug dissolution by reducing drug particle size and increasing contact area,thus increasing in vivo absorption and bioavailability.The purpose of this study is to develop abiraterone acetate into a kind of LBF.LBF is a solid powder obtained by spray drying after incubating abiraterone acetate SMEDDS from microemulsion and mesoporous silica,which can improve the dissolution and stability of the preparation.This paper determined the equilibrium solubility of abiraterone in different oil phase,surfactant and co-surfactant;self-drew tenary phase diagram through the appearance of the emulsion;selected self-microemulsifying prescription according to the size of the emulsifying area;optimized the prescription with the standard of maximum equilibrium solubility and minimum particle size and through central composite design-response surface methodology,and screened out the best proportion.The particle size and potential of the prepared abiraterone LBF was observed by Malvin particle size analyzer and the morphology was observed by transmission electron microscope.The self-microemulsion was combined with the commonly used solid adsorbents,and the adsorbents with the maximum absorbance were screened through adsorption capacity test.The LBF powder was prepared by spray drying of abiraterone LBF and the carrier,and was analyzed and identified by scanning electron microscopy,differential scanning calorimetry and powder X-ray diffraction analysis methods.The tablets were prepared by dry granulation and direct tablet compression,the effects of different speed,diluent and dilution on the dissolution of tablets were determined,and the dissolution rates of self-made tablets and commercial tablets in different dissolution media were investigated.The pharmacokinetic characteristics of self-made preparation and reference preparation were studied with beagle dogs as experimental animals.The pharmacokinetic time curve was drawn and the pharmacokinetic parameters were calculated by pharmacokinetic software.The oil phase of the optimizedself-microemulsifying prescription was Medium chain triglycerides,surfactant was Cremophor EL,and co-surfactant was Isopropano.Transmission electron microscopy showed that the self-microemulsion was spherical without agglomeration,similar in appearance and size,and with the average particle size of 21.35±0.22 nm,PDI of 0.078±0.039,Zeta potential of about-9.44±0.51 m V,and drug loading of 66.51±13.62 mg/g.The results show that the prepared self-microemulsion has small particle size and uniform dispersion.The Mesoporous silica nanoparticles was selected as the best solid carrier for the maximum adsorption capacity of liquid self-microemulsion.The ratio of Mesoporous silica nanoparticles to self-microemulsion was1:3.Spray drying conditions were selected by single factor and orthogonal experiments.DSC and X-ray powder diffraction analysis showed that abiraterone existed in amorphous state in LBF after spray drying.SEM showed that LBF were absorbed or coated by pores of mesoporous silica.HPMC-603 was selected as diluent and CCMC-NA as disintegrating agent by dissolution in simulated gastric juice and simulated intestinal juice.The dissolution rate of homemade tablets was significantly better than that of reference preparations,and the dissolution rate was more than 90%.Solid self-emulsifying tablets were prepared by direct tablet compression method,and the basic properties of abiraterone LBF tablets were measured,which all met the requirements of Chinese Pharmacopoeia（2020 edition）for tablets.The preliminary quality evaluation of results were all in accordance with the pharmacopoeia.To verify whether abiraterone LBF tablet can improve the bioavailability,this study included the abiraterone acetate tablets as the reference preparation,and oral administration was adopted for beagle dogs.The half-life(T_1/2)values of abiraterone acetate LBF tablets samples（75 mg/tablet）and reference tablets（250 mg/tablet）after oral administration were 3.42 and 4.27 h,respectively,while area under the concentration time curve(AUC^0-1)（h*ng/m L）values were 107.71 and 52.83,respectively.The F value of the relative bioavailability was 704.80%.The pharmacokinetic test results showed that the bioavailability of abiraterone acetate LBF tablets was significantly higher than that of commercial reference preparations.The preparation method of LBF can significantly improve the bioavailability of abiraterone,and provide a reference basis for improving the bioavailability of BCS-IV drugs.