| Objective: To study the preparation of nano-realgar, optimize the process parameters to get nano-realgar particles; To study the pharmacokinetics of arsenic of nano-realgar in rats and compare the differences of pharmacokinetics between nano-realgar and traditional realgar for the purpose of development of a new drug.Methods: (1)Realgar powder was milled in a plenary mill in the operating condition of nitrogen. To optimize process parameters by changing the mass ratio of steel balls to realgar,the temperature of ball milling,the velocity of revolution,the milling time, et al under the arrangement of orthogonal design of experiment. Determination of the diameter and the distribution of realgar nano-particles was done by laser scattering particle size distribution analyzer,scanning electron microscopy and atomic force microscopy. (2)170 rats were divided into two groups by random, and then a single ig dose of 2.062 mg/mL of nano-realgar and traditional realgar were given to the two groups,0.5mL respectively .To collect serum samples after ig of drugs in rats at certain time as follows: 0,0.5,0.75,1,1.5,2,3,4,5,6,8,10,12 h. The concentration of arsenic in samples were determined by ICP-MS. (3)The pharmacokinetics parameters were processed with 3P97 software and statistics were performed with SPSS.Results: (1)The optimum parameters in the preparation of nano-realgar are as follows: the mass ratio of mill balls to realgar is 16:1, the temperature is -20℃, the velocity of revolution is 38Hz, the ball milling time is 12h and adding 50 mL H2O as surfactant. About 90% of realgar nano-particles which size is under 100 nm can be obtained under the optimum parameters in preparation of nano-realgar. The results of SEM and AFM showed that the bigger particles were made up of 5~30nm nano-particles. (2) After single ig dose of nano-realgar and traditional realgar to rats, the serum concentration-time curves were all fit to one-compartment model. The main parameters of nano-realgar group and traditional realgar group:Tmax(0.8083±0.1185 h 1.3300±0.3467 h respectively), Cmax(0.6230±0.1928 mg/L,0.1833±0.0512 mg/L respectively),AUC0→∞(2.4238±0.6542(mg/L)h,1.5601±0.3349 (mg/L)h respectively),CL/F(0.4254±0.0912 L/(kg﹒h) 0.6609±0.1233 L/(kg﹒h) respectively),Vd/F( 75.8299±9.1087 L/kg,264.3590±46.5237 L/kg respectively). Between nano-realgar group and traditional realgar group, the ratio of Ka was 3.6:1,T1/2Ka was 1:5.5,Ke was 1:3 ,T1/2Ke was 1.5:1. (3) There was a significant difference in pharmacokinetics parameters between nano-realgar group and traditional realgar group. Tpeak, Cmax and AUC in nano-realgar group were better than traditional realgar, t1/2Ke of arsenic in nano-realgar group was longer.Conclusion:(1) Optimizing process parameters by changing the mass ratio of steel balls to realgar, the temperature , the velocity of revolution, the milling time, et al. About 90% of realgar nano-particles which size is under 100 nm can be obtained. (2) The pharmacokinetics parameters of arsenic of nano-realgar and traditional realgar in rats were all fit to one-compartment model. (3)Tmax, Cmax and AUC in nano-realgar group were better than traditional realgar group obviously. Differences between the two groups were prominent. (4) Compared with traditional realgar, arsenic of nano-realgar distributed more quickily but eliminated slowly. Nano-reaglar had better pharmacokinetics parameters in-vivo. The studies we had done could accelerate the development of nano-realgar.
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