Research And Preparation Of Sorafenib Tosylate Nano Tablet

Sorafenib tosylate(SFN)is a multi-kinase inhibitor primarily used to treat advanced renal cell carcinoma and hepatocellular carcinoma.Sorafenib tosylate is a Biopharmaceutics Classification System(BCS)class Ⅱ drug with very low solubility in water,resulting in poor bioavailability.The solubility and bioavailability of SFN can be improved by nano-chemical method.In this paper,sorafenib tosylate nano powder was prepared by high-gravity technology combined with solvent-antisolvent precipitation,and then the powder was made into nano tablet.The process of preparing sorafenib tosylate nano powder by RPB was optimized.The changes of morphology,particle size and crystal form of nano powder in simulate gastric juice and intestinal juice was investigated,and the stability of nano powder was studied.At last a better formulation of sorafenib tosylate nano tablet was selected,then the quality and performance of the tablets were characterized.The main conclusions are as follows:The preparation process in RPB is as follows:the mixture of N,N-dimethyl formamide(DMF)and anhydrous methanol were used as the solvent(VDMF:V methanol=1:9),water was used as the antisolvent,the solvent/antisolvent volume ratio is 1:10,drug concentration is 20 mg/mL,polyvinylpyrrolidone(PVP)was used as the stabilizer(WSFN:WPVP=1:0.1).The average particle size of prepared SNF spherical particles was 150 nm.Amorphous nano powder(250 nm)were obtained after lyophilization,and its structure did not change compared with that of API,while its dissolution performance is good and can reach 95%in 30 min.The SFN nano powder changed from amorphous to crystallized and its particle size over 1 μm after entering the simulate gastric juice.The nanoparticles appeared self-assembly phenomenon when entering the simulate intestinal juice.The cytotoxicity test showed that the cytotoxicity of nano powder was 133%higher than that of API at the optimal administration time and concentration.The high temperature and strong light conditions did not affect its dissolution performance in the factor stability experiment of nano powder.However,the nano powder agglomerate into large particles over 10 μm under high humidity condition,and it only dissolved 15%at 30 minutes.So the SFN nano powder need to be preserved in the dark,avoiding humidity and low temperature conditions.When placed at room temperature for 270 days,the average particle size of SFN nano powder was still below 300 nm,and the solubility is similar to that of the freshly prepared nano-powder.When placed for 360 days,the powder showed serious agglomeration,the average particle size increased to 1.4 μm,and the dissolution performance decreased significantly.The formulation of nano tablet is as follows:the filling agent is pregelatinized starch,the bonding agent is polyvinylpyrrolidone,the disintegrating agent is crosslinked polyvinylpyrrolidone,the wetting agent is sodium lauryl sulfate,the lubricant is magnesium stearate.The quality of nano tablet meets the standard of Chinese pharmacopoeia.In the hydrochloric acid solution with a pH of 1,the dissolution performance of the nano tablets was similar to that of the commercially available tablets,while in the buffer solution with a pH of 6.8,the dissolution of the nano tablets was 20%higher than that of the commercially available tablets.In the pharmacokinetic studies in rats,the blood drug concentration of the nano tablets after entering the rats was 34.8%higher than that of the physical-mixed tablets.The nano tablets did increase the bioavailability by reducing the drug particle size.The dissolution performance of nano tablets was not affected when placed in high temperature and strong light for 3 months,but the properties of nano tablets were seriously affected by high humidity,and the preservation condition of nano-tablets was the same as that of nano powders.