Preparation And Evaluation Of Progesterone Nanocrystal Injection

Objective:This subject aims to use the emulsification method combined with freeze-drying technique to prepare progesterone nanocrystal injection.By screening out the optimum preparation process and formulation to obtain the progesterone nanocrystal injection with uniform particle size and good stability.Besides,the prepared progesterone nanocrystal injection was evaluated in vitro and in vivo.Method:The progesterone microemulsion was prepared by emulsification method,and then the solvent of emulsion was removed by freeze-drying technique to obtain progesterone nanocrystal powder injection.Formulations and processes were optimized with particle size,polydispersity index(PDI),and?-potential as indicators.While the structure and crystal form of progesterone nanocrystalline were determined by differential scanning calorimetry(DSC),X-ray powder diffraction(XRD),scanning electron microscopy(SEM)and Fourier transform infrared spectroscopy(FT-IR).Besides,high-performance liquid chromatography was employed to measure the content of progesterone in the in vitro dissolution test.While the concentrations of progesterone in plasma were determined by LC/MS.Commercial progesterone injection and progesterone nanocrystal injection were administrated to SD rats at the same dose by intramuscular injection respectively,to study the pharmacokinetics behavior of both formulations.In this study,the progesterone nanocrystal injection is prepared by emulsification and freeze-drying,compared with the wet milling method,which can avoid pollution and prevent degradation.Result:Progesterone powder injection prepared with optimized formulation and process was porous and well formed,which could be easily dispersed with physiological saline.The particle size of the nanocrystalline was found to be uniform at 700nm with PDI value of about 0.28 and has a certain ?-potential at about-6.0.The stability studies performed under room temperature of 25?showed that the nanocrystal injection maintained stable within 6 days.However,the freeze-dry powder can maintain good dispersibility after being stored at 4? for 3 months.Differential scanning calorimetry analysis showed that progesterone nanocrystalline has a melting endothermic peak similar to API.The results of X-ray powder diffraction revealed that the characteristic diffraction peak of progesterone nanocrystalline and API basically agree.Infrared spectroscopy illustrated that the two compounds have similar chemical structure and functional groups,and no new chemical bonds generated in progesterone nanocrystalline.The above results demonstrates that the crystal form of progesterone nanocrystalline is stable,which is the same as API.However,in vitro dissolution tests showed that the dissolution rate of the nanocrystalline significantly increased compared with API,which could be released over 94%within 0.083 hour.While in vivo pharmacokinetic studies have shown that the peak time of progesterone nanocrystal injection was 0.50±0.39 h and the peak concentration was 93.35±28.28 ?g/L.The peak time of progesterone nanocrystal injection was significantly shorter than that of commercially available progesterone injection,which Cmax and AUC0-? were 3.76 and 1.85 times of the latter,respectively.Finally,the safety evaluation indicated that the pH value of the progesterone nanocrystal injection was in the range of 4-9,which meet the quality requirements of the injection.Conclusion:The progesterone nanocrystal injection prepared by emulsification combined with freeze-drying technique obtained a uniform particle size at 700 nm with single stable crystal,which has a certain stability with ?-potential at about-6.0.In vitro dissolution test and in vivo pharmacokinetics studies demonstrated that dissolution rate of the nanocrystal injection has been significantly improved compared to API.The preparation process possess the advantages of low energy consumption,simple process,which is suitable for industrial mass production.This study provides references and ideas for improving the dissolution rate and bioavailability of poorly soluble drugs.