Study On The Membrane Tablet Of A New Generation Of Tyrosine Kinase(BCR-ABL)T315I Inhibitor Procyclotinib CY03529B

CY03529B is a novel parent nuclear structure compound,a tyrosine kinase inhibitor against imatinib T315 I mutant strain,which with imatinib as lead compound and modified by computer-aided drug design.CY03529 B has good pharmacological activity.Preliminary studies have shown that this compound can be used to treat chronic myelogenous leukemia(CML).Currently,CY03529 B is in the stage of pre-clinical research and development.In this paper,we studied the preformulation of the raw material of CY03529 B.The HPLC conditions of the raw material were established,and the chromatographic conditions were validated by methodology.Meanwhile,we investigated the liquid characterization,solid characterization,compatibility and stability of the raw material of CY03529 B,which provided a basis for the selection of the dosage form of CY03529 B.HPLC was used to determine the content of the raw material in vitro.The physical properties of the bulk drug CY03529 B were investigated and we found that CY03529 B had strong moisture absorption.Therefore,film coating was carried out on the basis of tablets,which not only improve the stability,but also cover up the bad odor and improve the patient compliance.The basic prescription of the chip core was determined by single factor investigation,and the optimal prescription of the chip core was determined by the appearance,hardness and disintegration time of the chip core.In the same way,orthogonal test was used to determine the optimal preparation technology of thin film coating with disintegration time limit and coating qualification rate as indicators.The quality standard of CY03529 B thin film coated tabelt was investigated in accordance with the quality standard of Chinese pharmacopoeia.And the inspection items included weight difference,hardness,brittleness,dissolution,content determination and so on,inspection of CY03529 B film coated tabelt,in the study of the stability of thin film coating,the influence factor test,accelerated test and long-term test were carried out,and the results all met the quality standard requirements.In order to investigate the absorption of CY03529 B thin film coating tablets in mice,pharmacokinetic and tissue distribution tests were performed by oral gavage.In the pharmacokinetic experiment,we investigated the pharmacokinetic parameters of the drug in mice,such as elimination half-life,peak time,and maximum blood concentration,so as to provide a basis for the study of the oral interval time required for the drug to achieve steady-state blood concentration in the next clinical trial.In the experimental study of tissue distribution,the results showed that after intragastric administration of CY03529 B thin-film coating tablets,the drug was widely distributed in mice,especially in the gastrointestinal tract.Pharmacokinetic studies have shown that CY03529 B can be excreted from the body through feces,with a cumulative excretion rate of 16.7%,without causing cumulative poisoning.In vivo intestinal absorption experiments of rats showed that the absorption of CY03529 B in the small intestine was not related to the concentration,and the absorption mechanism was passive diffusion.The micronucleus test of mouse bone marrow cells on CY03529 B thin film coating showed that CY03529 B had no mutagenicity and was of high safetyand the plasma drug concentration curve and pharmacokinetic parameters were obtained,providing a basis for further studies.It can be concluded from the above experiments that CY03529 B has hygroscopicity,and its stability can be improved by preparing it into thin film coating.The quality and stability of thin film tablet are in accordance with pharmacopoeia.Thin film film can be quickly absorbed in the mouse body,the distribution is wide,in the gastrointestinal tract absorption is good.Can be excreted through the excrement outside the body,will not cause accumulative poisoning,safe to higher.