In Vivo And In Vitro Study Of Testosterone Undecanoate Crystal Suspension

Objective: In order to reduce the adverse reaction and improve the bioavailability of testosterone in the market with testosterone undecanoate injection oil sold in the market,the nanocrystalline technique was used to prepare and compare the differences in the release behavior of three different particle sizes of testosterone undecanoate nano/micro-crystal suspension and the market,so as to provide experimental basis for the preparation of testosterone undecanoate long-acting preparation.Methods: The formulation and process of testosterone undecanoate nanoscale suspension were studied.Particle size,particle size distribution,main drug loss rate and preparation time were taken as the main evaluation indexes,and different preparation methods,high pressure homogenization and wet grinding,were selected.The size and stability of the testosterone undecanoate nanoscale suspension were used as evaluation indicators to screen the prescription.Three different sizes of testosterone undecanoate suspension were prepared by changing the preparation process.The particle size and potential of different crystal size suspension were measured by scanning electron microscope,nanoparticle size analyzer and Mastersizer 2000 laser particle size analyzer.The X ray powder diffraction method was used to determine whether the crystallization type of the main drug was changed during the preparation process.The equilibrium solubility of testosterone undecanoate suspension in different media and the release rate in different media were measured.To establish a method for the determination of testosterone LC-MS/MS in rat plasma,the female SD rats were used as animal model,and the intramuscular injection method was used to compare the pharmacokinetics parameters of the testosterone undecanoate market and testosterone undecanoate crystal suspension with different particle sizes.A rabbit local muscle stimulation test was conducted to evaluate the safety of crystal suspension.Results: In order to ensure the initial stability of the suspension,0.1% poloxamer and0.2% polysorbate 80 were selected as stabilizers to maintain the stability of the suspension nanoparticles.Crystal suspensions with particle size of 0.34 μm(A),1.2 μm(B)and 4.8 μm(C)were obtained respectively.Nanocrystals can be observed as irregular and prismatic crystals.X ray powder diffraction method has been used to determine the crystalline typesof the main drugs during preparation.The equilibrium solubility of testosterone undecanoate crystal suspension with different particle sizes in different media was measured.The results showed that the equilibrium solubility of nanocrystalline suspensions in water was nearly 10 times higher than that of the raw material.The dissolution of the injection is carried out in order to control the particle size of the suspension.In the drug test,SD rats were injected intramuscularly,and the suspension of C was continuously released for more than 3 weeks,and the AUC of water suspension was higher than that of the oil solution,indicating that the bioavailability of the suspension was improved to a certain extent.The local irritation test of rabbit muscle showed that the biocompatibility of the aqueous suspension was better than that of the commercially available oil solution.Conclusions: In this study,the pharmacokinetic parameters of rats with a particle size of about 4.8 μm(C)were obtained by the method of high pressure homogenization,and the pharmacokinetic parameters of the rats were the closest to the marketed oil solution preparation.The bioavailability was improved,and the biocompatibility was better than the market preparation.Therefore,the particle size of the new release injection prepared by the nanocrystalline technology could be controlled in 5 μm.