| Dasatinib(DAS)is a potent oral multikinase inhibitor for the treatment of chronic myeloid leukemia,and Dasatinib is a hydrophobic drug,which faces the problem of limited absorption due to poor water solubility.Drug nanonization is an effective technical means to improve the dissolution and absorption of hydrophobic drugs by reducing their particle size.In this study,DAS nanoemulsion and DAS nanocrystals were prepared by rotating packed bed(RPB),the formulation and preparation process of the system were optimized,and the products were characterized and evaluated.The main research contents are as follows:(1)Through the determination of drug solubility,the drawing of pseudo-ternary phase diagram,and the investigation of nanoemulsion particle size distribution,oleic acid was selected as oil phase,Cremophor RH 40 was selected as surfactant,1,2-propanediol was selected as co-surfactant,and the optimum ratio of the system was determined.The nanoemulsion with particle size of 17.69±0.62 nm and PDI of 0.171±0.048 was prepared under the optimum emulsification condition of beaker.The effect of RPB parameters on the emulsification was investigated,the nanoemulsion with particle size of 16.15±0.42 nm and PDI of 0.122±0.021 was continuous prepared at the high-gravity level ?=47,and the yield was about 48 L/h.After being stored at 4?,25? and 40? for 14 days,the appearance,particle size and drug content of the nanoemulsion remained stable.And after being stored at strong light exposure(4500 lx)for 14 days,the Dasatinib content of nanoemulsion decreased by 25.65%.In long-term experiment(4 months),freeze-thaw experiment and dilution experiment,DAS nanoemulsion showed good stability.(2)DAS nanocrystals were prepared by high-gravity antisolvent recrystallization method,and the influence of excipient types and RPB parameters on recrystallization was investigated.With mannitol as an excipient,continuous preparation with high-gravity level ?=188,the recrystallization dispersion was freeze-dried to obtain DAS nanocrystals with short diameter of about 200 nm and long diameter of about 750 nm.The solubility of DAS nanocrystals can reach 28.20 ?g/mL in PBS at 37?,pH=6.8,which is 4.18 times before recrystallization.XRD analysis indicated that the nanocrystals were AH N-6 crystal form.(3)In the PBS release medium with 1%Triton X-100,the release amount of DAS nanoemulsion in 24 h is 56.96%,the release amount of DAS nanocrystals can reach 48.38%,and the release amount of raw drug is only 4.72%,both nanoemulsion and nanocrystals significantly improved dissolution and release properties of Dasatinib.In the anti-digestion experiment of nanoemulsion,96.18%of Dasatinib was retained in the non-precipitation phase after the nanoemulsion was digested in lipolysis solution for 2 h.The results of cytotoxicity experiments showed that the nanoformulation improved the anti-tumor performance of Dasatinib in vitro,and the anti-tumor ability:nanoemulsion>nanocrystals>raw drug,with a concentration of 10 ?g/mL Dasatinib toward MDA-MB-231 cells,after 24 h of administration,the activity inhibition rate of the DAS nanoemulsion group was 30.38%,the DAS nanocrystals group was 22.33%,and the raw drug group was only 11.51%.In the permeability study of Caco-2 cells as absorption model,the apparent permeability coefficients of DAS nanoemulsion and DAS nanocrystals in the absorption direction were 1.63 times and 1.35 times of the raw drug,respectively,indicating that nanoemulsion and nanocrystals can effectively improve the absorption of Dasatinib. |
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