Study On Deferiprone Oral Sustained - Release Tablets For Adriamycin - Induced Myocardial Toxicity

Doxorubicin（DOX） is one of the anthracycline antibiotics widely used in cancer chemotherapy.However,it is limited by severe and cumulative cardiotoxicity despite its effectiveness.Deferiprone（DEF） is the first orally iron chelator,which is economical and has good compliance.As we all know,there is no publications reported the study of its effect on the anti-tumor effect of DOX and its extended release formulation.The aim of this project is to investigate the effect of DEF on the anti-tumor effect of DOX with in vitro and in vivo studies,then,to develop 12-hour extended release tablets of DEF.The MTT results showed DEF could affect the anti-tumor effect of DOX as well as protecting the normal cells.However,its protection of normal cells is stronger than of tumor cells.The results also suggested that low dose DEF treated after the concentration of DOX reached 8μmol/L would not affect the anti-tumor effect of DOX and still be protective to normal cells,which was demonstrated by our in vivo studies that low dose DEF and administration delayed DEF would not affect the suppression effect of DOX on transplanted human gastric cancer in nude mice.The intestinal transport of DEF was performed by applying everted intestinal sacs method.The absorption of DEF was passive diffusion and had no significant difference in different gut regions（P＞0.05）.Adding verapamil in the everted gut sacs did not affect the absorption of DEF（P＞0.1）.A three-factor-five-level uniform design was performed to sift screening the formulation in which the three factors were HPMC K100M,Compritol 888 and MCC while the levels were different contents of these matrix materials.The final optimal formula was that the content of HPMC K100M was 15mg,Compritol 888 15mg and MCC 35mg.The drug release in vitro of the DEF extended release tablets prepared according to this optimal formulation is good and the quality is stable.A random two-way crossover study in 6 dogs was adopted.The drug serum concentration was determined by internal standard HPLC method.The pharmacokinetic parameters were calculated by moment method.The results indicated that the t_max and MRT of extended release tablets（ER） were longer than those of immediate release tablets（IR）（P＜0.05）,and theρ_max of ER was lower than that of IR（P＜0.01）.The bioavailability of ER relative to IR was（99.06±7.10）%. The method is proved to be simple,sensitive and rapid.The two formulations have the same absorption extent.Comparing with IR,the ER exhibited good extended release tendency.