| Isradipine,a new dihydropyridine calcium antagonist,is clinically used for the treatment of hypertension.In order to improve the compliance of patients,a novel sustained-release（SR）tablets containing isradipine（5mg）have been successfully developed.（1）In the preformulation study,analysis methods of dissolution,drug content and related substances were established by a high performance liquid chromatography（HPLC）.The linear regression equation for dissolution test was A=31.005C-2.918（R2=0.9999）at the concentration range of 0.1-10μg/mL.The linear regression equation for determination of drug content was A=33063C+190000（R2=0.9999）at the concentration range of100-800μg/mL,and the intraday and interday precision,accuracy and stability of this method meet the requirements.Isradipine has five distinct related substances,including related substance A,B,C,D and E.The relative retention time of these peaks are 0.52,0.73,0.81,0.85 and 2.17,respectively.The solubility of active ingredient showed no remarkable changes at various pH conditions.The drug-excipients compatibility study showed that the contents of related substances were significantly increased when CMS-Na,Eudragit RS PO and Eudragit RS RL PO were used as excipients.（2）In the formulation study,the release of isradipine from the SR capsule marketed overseas was evaluated.Isradipine SR tablets were prepared using a wet granulation method,and the effects of formulation and process factors（the ratio of HPMC with different viscosity,the ratio of diluents,and the hardness of tablet）on the release behaviors were also investigated using the single factor study.The optimal core tablets were further coated with Opadry?03B28796 as a film coating material.There was no significant difference of release rate between the core and coated tablets.The f2 value between the optimized SR tablet and marketed SR capsule was higher than 50,indicating that the release rates of two products were similar.（3）Three batches of optimized SR tablets were prepared and the qualities of products were also assessed.For all three batches of products,the weight variations of tablets were lower than 5%,the drug contents were 95-105%,and the total related substances were not more than 0.2%,respectively.（4）The stabilities of three batches of SR tablets were studied.The results of stress test showed that the drug contents（95-105%）and related substances（<0.4%）meet the requirements of USP even under high temperature（60℃）,high humidity（RH 92.5%）and strong light（4500 Lux）.However,the contents of related substances were slightly increased under high temperature and high humidity,and remarkably increased under strong light.（5）The preliminary pharmacokinetic study of developed SR tablets（Test）was carried out compared to the commercial SR capsule as a reference after a single oral administration in rabbits.The pharmacokinetic parameters of Test and Reference were as follows:The values of Cmax were 95.25 and 102.30 ng/mL,the values of AUCINF were1721.65 and 1107.41 ng/mL·hr,and the values of Tmax were 6 and 8h,respectively.The developed SR tablets showed a sustained release manner and a good correlation between in vitro and in vivo. |
