Preparation And Study Of Mesalazine And Metrmidazol Colon Specific Pellets

Objective: Chronic ulcerative colitis was one of the diseases which were more difficult to cure generally acknowledged at present. The clinical therapeutic alliance of mesalazine and metrmidazol could keep patients at remission behavior who were at episode phase and active phase and was employed very extensively. Mesalazine and metrmidazol colon specific pellets (CSP)were prepared to make medication conveniently, release drug in lesion region of colon directly, bring local therapeutical effect into full play and be more effective, avoid release and absorption of drug in upper digestive tract to decrease adverse reaction incidence effectively. Method: Mesalazine and metrmidazol CSP were prepared respectively. The cores of CSP were prepared by extrusion-spheronization with microcrystalline cellulose(MCC)and coated with Eudragit S-100 by flow bed. The factors of prescription(dose of MCC, excerption and dose of adhesive )were inspected which influenced formation and release of pellets. The orthogonal experiment was designed to screen technique in which the speed of extrusion, speed of spheronization and the time of spheronization were taken as three influential factors and three different levels were selected to part , each conformation of technique was selected refer to the L9(34) orthogonal design table. By analysis of range, the optimization of technique were definited with the colligation evaluation of formation and release of pellets. The suitable coat weight was definited though evaluating the release percentage of CSP coated with different weight. The uniform experiment was designed to screen technique in which the concentration of coating liquor, temperature of in air, pressure of spray and speed of transfuse were taken as four influential factors and three different levels were selected to part , each conformation of technique was selected refer to the U884 uniform design table. By multi-factors regression , the optimization of technique were definited with the colligation evaluation of recovery and release of CSP. The stability of technique was inspected through the recovery and dissolution test of three batch CSP prepared according to the optimization of prescription and technique. According to the literature, HPLC method was established to determine the content of mesalazine and metrmidazol in CSP. Chromatograph condition: Hypeysil-ODS C18 column; mobile phase: pH6.5 phosptat buffer-methanol 80:20 (including 0.01M quadributyl ammonium bromide);flow rate: 1ml/min; wave-length of detector: 240nm. The dissolution test of CSP was established refer to the dissolution test of colon specific tablet recorded in C.P. HClsolutons(9-1000),pH6.8 and pH7.8 phosphate buffer were taken as release medium by turns. Mesalazine and metrmidazol in sample was determined by HPLC method. The sampling time was 2th hour in HCl solutons(9-1000);4th hour in pH6.8 phosphate buffer; 1th hour in pH7.8 phosphate buffer. The factors involving high temperature, high humidity and radiancy was investigated which influence the stability of CSP. The stability in accelerating condition was inspected by estimating the character, content and release percentage of samples deposited 1 month, 2 month, 3month, 6month at temperature 40℃±2℃and relative humidity 75%±5%. After oral administration of mesalazine CSP(200mg) and mesalazine tablet(250mg) to rabbits respectively, the concentration of mesalazine in rabbits plasma at certain sampling times were determined with high performance liquid chromatograph (HPLC). The pharmacokinetics parameters were calculated by the method of noncompartmental model. The character of colon specific release in vivo of mesalazine CSP was evaluated by comparison of the main pharmacokinetics parameters of two preparation including T_lag ,C_max ,T_max,AUC_0-∞with pairing t check. Results: By analysis range of the orthogonal experiment result, the optimization of technique were definited: speed of extrusion 30r/min, speed of spheronization 40r/min, the time of spheronization 4 min. The optimization of prescription and technique of mesalazine and metrmidazol core of CSP:Prescription: 1: metrmidazol 100g , MCC 20g, distilled water 42ml 2: mesalazine 500g, MCC 75g, distilled water 200ml Technique: the drug and accessories were sieved past 80 category to mix well-distributed and made into soft stuff. The pellets were prepared by extrusion-spheronization: speed of extrusion 30r/min, speed of spheronization 40r/min, the time of spheronization 4 min. The pellets at 18-24 category were recovered after desiccation three hours at 45℃.The pellets prepared had good spheronization, the critical angle of pellets was 12.3゜, the recovery was 93.9%, release percentage was more than 95% in 30 minutes. By the multi-factors regression , the optimization of technique were definited: concentration of coating liquor 6%, temperature of in air 45℃, pressure of spray 0.5kg , speed of transfuse 2ml/min.The data of release percentage in vitro of three batch mesalazine and metrmidazol CSP prepared according to the optimization of prescription and technique had not significant discrepancy (p>0.05), the recovery was more than 90%.The stability of technique was proved. The result of the system serve experiment of the HPLC method to determine the content of mesalazine and metrmidazol in CSP coincided with the specify of C.P: the reserve time of mesalazine and metrmidazol were about 3min and 7min, the separate degree was more than 1.5, the theory number of plate was more than 4000, the recovery were 99.84% and 99.77%, theprecision was 3.21% and 3.49%. The method could determine the content of mesalazine and metrmidazol in CSP accurately and precisely. The result that the release percentage of mesalazine and metrmidazol CSP at 2th hour in HCl solutons(9-1000) and 4th hour in pH6.8 phosphate buffer were less than 5%, at 1th hour in pH7.8 phosphate buffer more than 95% coincided with the specify of colon specific tablet in C.P. It proved the transparent character of colon specific release in vitro of CSP. The increased weight owing to absorbing humidity of mesalazine and metrmidazol CSP was 2.63% which were deposited 10days at relative humidity 95%. The result that the character, content and release percentage of CSP had not significant discrepancy at the condition of high temperature, high humidity and radiancy proved that mesalazine and metrmidazol CSP were stable at high temperature, high humidity and radiancy condition. The result that the character, content and release percentage of samples had not significant discrepancy which were deposited 6month at accelerating condition proved the term of validity could be two years with routine package. By the pharmacokinetics study of rabbits in vivo, the pharmacokinetics parameters of mesalazine CSP and mesalazine tablet : T_lag (h) 7.83±0.56 0.58±0.14 Cmax(ug/ml) 4.064±0.3518 5.401±1.504...