Methylprednisolone 嵌段式聚合微膠體劑型在家兔之藥物動力學研 究
Pharmacokinetic studies of Methylprednisolone in Rabbits by Polymeric Micelle Formulation
中文摘要
利用兩種嵌段式共聚合物微膠體(polymeric micelles, PM):PM1, PM2 為載體以物 理性包覆(physical entrapment)方式製備，改善水難溶性皮質類固醇藥物
methylprednisolone(MP)的溶解度，延長 MP 於血中的半衰期，並增加 MP 於脊髓 的蓄積，為本次實驗的目的。
在嵌段式共聚合物的物理化學性質方面，分別測試臨界膠質體濃度並評估嵌段式 共聚合物的 MP 的溶解度及其粒徑大小與釋放速率。並利用紐西蘭白兔之十二指 腸，以體外實驗方式研究藥物與 PM1 及 PM2 穿透的情形。動物實驗方面，以雄 性紐西蘭白兔為實驗動物，以兩種給藥途徑分別是靜脈注射與口服給藥，給與單 一劑量的 MP，分別溶於水或嵌段式共聚合物水溶液中，於不同時間點採血與脊 髓分析其濃度。
由實驗結果顯示， PM1、 PM2 臨界膠質體濃度分別是 0.1% (w/w)、0.01%(w/w)，
溶解度從 60?g/ml(MP/H2O)增加到 220?g/ml(MP/PM1)及 110?g/ml(MP/PM2)，粒 徑大小分別是 60nm(PM1)及 10nm(PM2)，嵌段式共聚合物的 MP 的藥物釋放速 率在 MP/PM1 劑型有緩釋的效果。而 MP 的穿透會受到 P-glycoprotein 影響，分 別加入 PM1 或 PM2 後，可增加 MP 穿透量。本次實驗動物檢品使用高效液相層 析儀(HPLC)分析，建立兩種分析條件，分析血漿檢品與脊髓檢品。動物之血漿 檢品與脊髓檢品在經高效液相層析儀分析後之結果，嵌段式共聚合物的 MP 有半 衰期延長與增加脊髓的藥物蓄積的結果。藥物動力學參數方面，分別以靜脈注射 MP/H2O，MP/PM1， MP/PM2 後，排除半衰期分別為 76.1±8.0 min，514.3±70.0 min，428.5±100.2 min、清除率(Cl) 分別為 26.3±3.0，8.8±1.5，12.6±1.2 mL/min、
AUC 分別為 42.6±7.9， 140.0±34.3，83.3±8.1 min‧?g/mL。而分別口服 MP/H2O，
MP/PM1， MP/PM2 後，半衰期分別為 79.0±1.7 min，416.4±55.9 min，428.0±39.9 min、清除率分別為 24.3±2.1，8.1±1.1，12.8±1.4 mL/min、AUC 分別為 19.2±1.6，
75.5±13.5，82.3±11.3 min‧?g/mL。在統計上以 ANOVA 分析之結果均有差異。
以口服投藥後，嵌段式共聚合物包覆 MP 對靜脈注射 MP/H2O 之身體可用率分 別是 0.8 (MP/PM1)及 1.2 (MP/PM2)。
英文摘要
The purpose of thesis study was used two polymeric micelles (PM1, PM2)
formulation for methylprednisolone (MP) to developed (1) prolong circulation of MP
in blood and (2) enhancement of accumulation of MP in spinal cord. In
physicochemical properties of two formulations (MP/PM1, MP/PM2): solubility, CMC, particle size and release rate was tested. In addition, in vitro permeations of MP/PM1 and MP/PM2 were evaluated on duodenal of rabbit. Male New Zealand rabbits received oral and a IV bolus dose of MP (MP/PM1, MP/PM2, MP/H2O).
The critical micelle concentration of two formulation of PM1 and PM2 values were 0.1% and 0.01%, respectively. The solubility of MP was also observed increasing from 60?g/ml (MP/H20) to 220?g/ml (MP/PM1) and 100?g/ml (MP/PM2). Particle size was found 60nm and 10nm for PM1, PM2, respectively. MP/PM1 show slow release rate by cellulose membrane tested. After incubation of P-gp inhibitor and concentration-dependence, we found that PM1, and PM2 could modify the MP transport of duodenum from Apical to Basical direction.
After IV administration of three formulation (MP/H20, MP/PM1, MP/PM2): terminal half-life (t1/2β)was increased from 76 to 514 and 428 min; clearance, from 26 to 9 and 13 mL/min; AUC0→∞, from 42 to 140 and 83.3 min‧?g/mL, respectively. After oral delivery of three formulation the terminal half-life (t1/2β) was increased from 79 (MP/H20) to 416 (MP/PM1) and 428 min(MP/PM2); clearance was decreased from 24 to 8 and 13 mL/min; AUC0→∞ was increased from 19 to 75 and 82 min‧?g/mL, respectively. After oral administration of MP/PM1 and MP/PM2 the absolute bioavailability was found 0.8 and 1.2, respectively. Finally, we could observed that PM1, PM2 could prolong the blood circulation time and enhancement of MP in spinal cord.
