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系統識別號 U0007-1704200714554289
論文名稱(中文) Methylprednisolone嵌段式聚合微膠體劑型在家兔之藥物動力學研究
論文名稱(英文) Pharmacokinetic studies of Methylprednisolone in Rabbits by Polymeric Micelle Formulation
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 93
學期 2
出版年 94
研究生(中文) 李克繼
研究生(英文) Daniel Lei
學號 M301090016
學位類別 碩士
語文別 中文
口試日期
論文頁數 0頁
口試委員 指導教授-廖嘉鴻
中文關鍵字 嵌段式聚合微膠體劑型 
英文關鍵字 Methylprednisolone (MP) 
學科別分類
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.
論文目次 目錄 附表目錄.........................................................................................I-II 流程目錄........................................................................................II-II 附圖目錄........................................................................................III- IV 中文摘要........................................................................................ V-VI 英文摘要........................................................................................VII-VIII 第一章. 緒論..............................................................................1 1. 皮質類固醇藥物(glucocorticoids)之臨床應用...........................1 2. 皮質類固醇藥物之作用機轉......................................................2 3. 急性脊髓損傷(Acute Spinal Cord Injury, ASCI)........................3 4. 治療急性脊髓損傷之藥物..........................................................4 5. Methylprednisolone之物化性質.................................................6 6. Methylprednisolone分析方法之報告.........................................6 7. Methylprednisolone之藥物動力學.............................................8 8. 嵌段式共聚合物藥物輸送系統..................................................9 9. 實驗目的....................................................................................13 第二章. 實驗部分..........................................................................14 一. 實驗材料及儀器..........................................................................14 1. 實驗試藥...................................................................................14 2. 儀器...........................................................................................14 3. 試藥之配製...............................................................................16 3.1 Methylprednisolone working 溶液的配製……………....16 3.2 Dexamethasone working溶液的配製………………..….16 3.3 Cortisone working溶液的配製………………………….16 3.4 Phosphate buffer solution(PBS)的配製……………….....16 3.5 6% PM1溶液的配製………………………………….…17 3.6 0.01% PM2溶液的配製…………………………………17 3.7 Pyrene儲備溶液之配製…………………………………17 二. 實驗方法………………………………………………………...18 1. 嵌段式共聚合物臨界膠質體濃度之測定……………………18 2. 嵌段式共聚合物膠質體粒子大小之測定………………...….18 3. 嵌段式共聚合物的methylprednisolone的溶解度之測定…..18 4. 嵌段式共聚合物的methylprednisolone的釋放速率之分析..18 5. Methylprednisolone之分析條件……………………………...19 5.1血液檢品之分析條件……………………………..….19 5.2脊髓檢品之分析條件……………………………20 6. 檢品的處理………………………………………………20 6.1血液檢品之處理…………………………………20 6.2脊髓檢品之處理…………………………………21 7. 標準檢量線的製作………………………………………22 7.1血漿檢品標準檢量線的製作……………………22 7.2脊髓檢品標準檢量線的製作……………………22 8. 分析方法之精確性與準確性試驗……………………….23 9. 回收率試驗…………………………………………….…24 9.1血漿回收率試驗……………………..………..…24 9.2脊髓回收率試驗……………………………….…25 10. 動物實驗……………………………………….…..…25 10.1實驗家兔之準備…………………………………25 10.2靜脈注射methylprednisolone之方法……….….26 10.3口服投與methylprednisolone之方法……….….26 11. 動物實驗數據之處理…………………………………27 11.1靜脈注射methylprednisolone之數據處理……..27 11.2口服投與methylprednisolone之數據處理……..27 12. 十二指腸黏膜穿透實驗……………………………...28 12.1十二指腸之處理………………………………...28 12.2十二指腸黏膜穿透實驗之方法…………….......28 12.3 十二指腸黏膜導電度測量……………………..29 第三章. 結果與討論………………………………………30 1. 嵌段式共聚合物臨界膠質體濃度之測定…………………..30 2. 嵌段式共聚合物膠質體粒子大小……. …………………….31 3. 嵌段式共聚合物的methylprednisolone溶解度測定結果….32 4. 嵌段式共聚合物的methylprednisolone的藥物釋放速率之結果討論…………………………………………………………..33 5. 檢品分析方法………………………………………………...34 5.1分析方法之標準檢量線…………………………………....38 5.1.1血漿檢品分析方法之標準檢量線…………………...38 5.1.2脊髓檢品分析方法之標準檢量線……………………38 5.2分析方法之精確性與準確性試驗 ………………………40 5.2.1血漿檢品分析方法之精確性與準確性……………..40 5.2.2脊髓檢品分析方法之精確性與準確性 ……………41 5.3分析方法之回收率(Recovery test) ……………………….43 5.3.1血漿檢品分析方法之回收率………………………..43 5.3.1脊髓檢品分析方法之回收率……………………..….43 6.動物實驗之結果與討論………………………………………...…44 6.1.靜脈注射methylprednisolone之藥物動力學結果與討論…….44 6.2脊髓methylprednisolone含量分析之結果與討論…………….48 6.3口服投與methylprednisolone之藥物動力學結果與討論….....49 7. 十二指腸黏膜穿透實驗之結果與討論………………………..52 7.1 十二指腸黏膜穿透實驗之結果與討論. …………………52 7.2 十二指腸黏膜導電度測量之結果與討論………………53 肆. 結論………………………………………………………………..56 伍. 參考文獻…………………………………………………………..58
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