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研究生： 劉國盛
Liu, Kuo-Sheng
論文名稱： 丁基原啡因及其前驅藥新型長效製劑在止痛及戒癮之研究
NOVEL LONG-ACTING FORMULATIONS OF BUPRENORPHINE AND ITS PRODRUGS IN THE TREATMENT OF PAIN AND OPIOID DEPENDENCY
指導教授： 王志中
Wang, Jhi-Joung
桂椿雄
Kuei, Chun-Hsiung
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2006
畢業學年度： 94
語文別： 中文
論文頁數： 121
中文關鍵詞： 前驅藥 、長效 、丁基原啡因 、戒癮 、止痛
外文關鍵詞： dependence, buprenorphine, pain, prodrug, long-acting
相關次數： 點閱：93  下載：1 
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    • 中文摘要

    丁基原啡因為強效之止痛劑，同時它也被用來做為藥物成癮之減癮或戒斷藥物，由於在臨床這類疾病的治療上，正期待有著一個長效的藥物出現，因此若將這個藥物衍生製成長效製劑，將對於臨床的醫療作出貢獻。本論文的目的為研發一系列新型長效的丁基原啡因及其衍生物的製劑，作為止痛及戒癮之用。

    本論文研究中主要之工作分為下列四項： 1. 設計及製成丁基原啡因及其前驅藥之長效製劑。 2. 評估丁基原啡因及其前驅藥長效製劑在止痛上之療效。 3. 探討丁基原啡因及其前驅藥長效製劑作用機轉。 4. 探討丁基原啡因及其前驅藥長效製劑對於誘發嗎啡身體依賴性動物在戒斷上之療效。

    本論文主要之研究成果可歸納為下列四點： 1. 完成丁基原啡因及其前驅藥長效製劑之設計及製成。 2. 完成丁基原啡因及其前驅藥長效製劑在止痛上之評估，其中丁基原啡因癸酸酯之長效製劑在大鼠上之止痛效果最長。 3. 完成丁基原啡因及其前驅藥長效製劑作用機轉之探討，並証實此類前驅藥在體內會完全換成丁基原啡因，而其長效機轉在於藥物由注射處緩慢釋出。 4. 完成丁基原啡因及其前驅藥長效製劑對於誘發嗎啡身體依賴性動物在戒斷上之評估，証實丁基原啡因丙酸酯在小鼠上可快速達到戒斷效果，並有長效作用達171小時。

    ABSTRACT

    Buprenorphine, an opioid analgesic, is used not only for the treatment of pain but also for the treatment of physical dependence to opioids. Because, in clinical practice, a long-acting drug is inspired, extending the duration of buprenorphine would make it more valuable for clinical use.The aim of this dissertation was to design and develop a series of novel long-acting formulations of buprenorphine and its derivatives for the treatment of pain and opioid dependence.

    The major works included in this study were: 1. design and development of novel formulations of buprenorphine and its prodrugs, 2. evaluation of the analgesic effect of these formulations, 3. study the mechanism of their actions, 4. evaluation of the effect of these formulations on physical dependence to morphine.

    The results of the dissertation included: 1. the long-acting formulations of buprenorphine and its prodrugs were developed, 2. the analgesic effects of long-acting formulations of buprenorphine and its prodrugs were confirmed. Among these formulations, buprenorphine decanoate demonstrated the longest duration of action, 3. in in vivo study, buprenorphine prodrugs were completely converted to buprenorphine and the mechanism of their long-acting effect was due to the slow release of prodrugs from the injection site, and 4. the long-acting formulations of buprenorphine and its prodrugs were effective in the management of physical dependence to morphine. Buprenorphine propionate demonstrated a rapid onset and long-duration of action of 171 hours.

    目錄 頁 導言 ----------------------------------------- 1 第一節、研究動機 ----------------------------- 4 壹、強效且長效止痛劑之臨床醫療需求性 --------- 4 貳、強效且長效戒斷藥物之臨床醫療需求性 ------- 5 第二節、研究目的 ----------------------------- 6 第三節、丁基原啡因簡介 ----------------------- 7 第四節、研究主要方法 ------------------------- 10 壹、研究設計之思維過程 ----------------------- 10 貳、本研究之具體作法(步驟) ------------------- 13 第一章、丁基原啡因及其酯類衍生物之設計與製作 - 15 第一節、緒言 ------------------------------------------------- 15 第二節、材料與方法 ------------------------------------------- 16 壹、材料 ----------------------------------------------------- 16 貳、丁基原啡因鹼之製備 --------------------------------------- 17 參、丁基原啡因酯類衍生物之合成 ------------------------------- 17 一、丁基原啡因丙酸酯之合成 ----------------------------------- 17 二、丁基原啡因庚酸酯、丁基原啡因癸酸酯之合成 ----------------- 18 肆、丁基原啡因酯類衍生物之純化 ------------------------------- 18 一、丁基原啡因丙酸酯之純化 ----------------------------------- 18 二、丁基原啡因庚酸酯、丁基原啡因癸酸酯之純化 ----------------- 21 第三節、結果 ------------------------------------------------- 21 第四節、討論 ------------------------------------------------- 32 第五節、結論 ------------------------------------------------- 33 第二章、探討丁基原啡因及其酯類衍生物在止痛上之療效 ---------- 34 第一節、緒言 ------------------------------------------------- 34 第二節、材料與方法 ------------------------------------------- 35 壹、動物 ----------------------------------------------------- 35 貳、藥物 ----------------------------------------------------- 36 參、丁基原啡因在大鼠上之止痛效果 ----------------------------- 36 一、評估鹽酸丁基原啡因之止痛效果 ----------------------------- 36 二、評估丁基原啡因及其酯類衍生物之止痛效果 ------------------- 37 肆、統計分析 ------------------------------------------------- 38 第三節、結果 ------------------------------------------------- 38 第四節、討論 ------------------------------------------------- 43 第五節、結論 ------------------------------------------------- 46 第三章、丁基原啡因及其酯類衍生物長效作用機轉之探討 ---------- 47 第一節、緒言 ------------------------------------------------- 47 第二節、材料與方法 ------------------------------------------- 49 壹、分析方法之建立 ------------------------------------------- 49 一、高效率液相層析儀組件 ------------------------------------- 49 二、化學試劑 ------------------------------------------------- 50 三、樣品前處理步驟 ------------------------------------------- 50 四、層析法 --------------------------------------------------- 51 五、再現性、精準性及正確性 ----------------------------------- 52 六、回收率 --------------------------------------------------- 52 貳、丁基原啡因酯類衍生物長效作用機轉之探討 ------------------- 52 一、靜脈注射丁基原啡因酯類衍生物於白兔體內之藥動學研究------- 52 1. 動物 ------------------------------------------------------ 52 2. 藥物 ------------------------------------------------------ 53 3. 動物模式 -------------------------------------------------- 53 二、肌肉注射丁基原啡因酯類衍生物於大鼠上之藥動學研究 -------- 54 1. 動物 ------------------------------------------------------ 54 2. 藥物 ------------------------------------------------------ 55 3. 動物模式 -------------------------------------------------- 55 三、資料分析與統計 ------------------------------------------- 56 第三節、結果 ------------------------------------------------- 57 壹、分析方法之建立 ----------------------------------------------- 57 一、層析圖譜 ------------------------------------------------- 57 二、藥物於管柱之滯留時間及可測得之最低定量濃度 --------------- 59 三、再現性、精準性及正確性 ----------------------------------- 59 四、回收率 --------------------------------------------------- 63 貳、丁基原啡因酯類衍生物長效作用機轉之探討 ------------------- 63 一、靜脈注射丁基原啡因酯類衍生物於白兔體內之藥動學研究 ------ 63 二、肌肉注射丁基原啡因酯類衍生物於大鼠上之藥動學研究 -------- 67 第四節、討論 ------------------------------------------------- 72 壹、分析方法之建立 ------------------------------------------- 72 貳、丁基原啡因酯類衍生物長效作用機轉之探討 ------------------- 72 一、靜脈注射丁基原啡因酯類衍生物於白兔體內之藥動學研究 ------ 72 二、肌肉注射丁基原啡因酯類衍生物於大鼠上之藥動學研究--------- 73 第五節、結論 ------------------------------------------------- 74 第四章、探討丁基原啡因及其前驅藥對於誘發嗎啡身體依賴性動物在戒斷上之療效 ------------------------------------- 76 第一節、緒言 ------------------------------------------------- 76 第二節、材料與方法 ------------------------------------------- 78 壹、探討丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之療效 -- 78 一、動物 ----------------------------------------------------- 78 二、藥物 ----------------------------------------------------- 79 三、動物模式 ------------------------------------------------- 79 1. 誘發嗎啡身體依賴性之動物模式 ------------------------------ 80 2.戒斷反應之評估 --------------------------------------------- 81 3.評估不同劑量之鹽酸丁基原啡因、不同劑型之丁基原啡因、不同劑量及不同油性緩釋劑型之丁基原啡因鹼，對於嗎啡身體依賴性動物在戒斷上之療效 ------------------------- 81 貳、探討丁基原啡因前驅藥對於誘發嗎啡身體依賴性動物在戒斷上之療效 --------------------------------------------- 82 一、動物 ----------------------------------------------------- 82 二、藥物 ----------------------------------------------------- 83 三、動物模式 ------------------------------------------------- 84 1. 誘發嗎啡身體依賴性之動物模式 ------------------------------ 84 2. 戒斷反應之評估 -------------------------------------------- 85 3. 評估不同劑量之鹽酸丁基原啡因、不同劑型之丁基原啡因、不同劑量之丁基原啡因前驅藥，對於嗎啡身體依賴性動物在戒斷上之療效 --------------------------------------- 85 參、統計分析-------------------------------------------------- 86 第三節、結果 ------------------------------------------------- 86 壹、探討丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之療效 -- 86 貳、探討丁基原啡因前驅藥對於誘發嗎啡身體依賴性動物在戒斷上之療效 ----------------------------------------------- 97 第四節、討論 ------------------------------------------------- 97 壹、探討丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之療效 -- 97 貳、探討丁基原啡因前驅藥對於誘發嗎啡身體依賴性動物在戒斷上之療效 -------------------------------------------- 103 第五節、結論 ------------------------------------------------ 104 總結 -------------------------------------------------------- 107 參考文獻 ---------------------------------------------------- 109 附錄、已發表之相關著作--------------------------------------- 120 表目錄 表 1-1. 丁基原啡因及其酯類衍生物之基本性質 ------------------- 22 表 1-2. 丁基原啡因及其酯類衍生物之紅外線光譜分析一覽表 ------ 23 表 1-3. 丁基原啡因及其酯類衍生物之核磁共振氫譜一覽表 -------- 24 表 1-4. 丁基原啡因及其酯類衍生物之核磁共振碳譜一覽表 -------- 26 表 1-5. 丁基原啡因及其酯類衍生物之質譜分析一覽表 ---------- 31 表 2-1. 大鼠肌肉注射鹽酸丁基原啡因、丁基原啡因鹼及其酯類衍生物後產生之止痛性效果 ----------------------------- 40 表 3-1. 各種分析丁基原啡因之方法 ----------------------------- 48 表 3-2. 丁基原啡因和丁基原啡因丙酸酯在大鼠、兔、狗、豬、人之全血中最低定量濃度 ------------------------------- 60 表 3-3. HPLC方法分析丁基原啡因之精準性及正確性 --------------- 61 表 3-4. HPLC方法分析丁基原啡因丙酸酯之精準性及正確性 -------- 62 表 3-5. HPLC方法分析丁基原啡因、丁基原啡因丙酸酯和丁基原啡因癸酸酯 (內標準品) 之回收率 ----------------------- 64 表 3-6. 白兔靜脈注射丁基原啡因或丁基原啡因丙酸酯之藥動學參數 66 表 3-7. 大鼠肌肉注射鹽酸丁基原啡因、丁基原啡因鹼及其酯類衍生物之藥動參數 ------------------------------------- 69 表 4-1. 不同劑型之丁基原啡因之溶解度及其作用時間 ---------- 89 圖目錄 圖 0-1. 新藥研究開發與上市的流程圖 --------------------------- 2 圖 0-2. 主要研究流程圖 --------------------------------------- 3 圖 0-3. 丁基原啡因之化學結構 --------------------------------- 8 圖 1-1. 丁基原啡因鹼及其酯類衍生物之化學結構 ----------------- 19 圖 1-2. 丁基原啡因酯類衍生物之合成反應 ----------------------- 20 圖 1-3. 丁基原啡因鹼核磁共振碳譜各別碳之化學位移 ---------- 27 圖 1-4. 丁基原啡因丙酸酯核磁共振碳譜各別碳之化學位移 -------- 28 圖 1-5. 丁基原啡因庚酸酯核磁共振碳譜各別碳之化學位移 -------- 29 圖 1-6. 丁基原啡因癸酸酯核磁共振碳譜各別碳之化學位移 -------- 30 圖 2-1. 大鼠肌肉注射鹽酸丁基原啡因後產生之止痛性效果 -------- 41 圖 2-2. 大鼠肌肉注射鹽酸丁基原啡因、丁基原啡因鹼及其酯類衍生物後產生之止痛性效果 ----------------------------- 42 圖 3-1. 層析圖 ----------------------------------------------- 58 圖 3-2. 白兔靜脈注射丁基原啡因或丁基原啡因丙酸酯之血中藥物濃度圖 --------------------------------------------- 65 圖 3-3. 大鼠肌肉注射不同劑量之鹽酸丁基原啡因之血中藥物濃度圖 68 圖 3-4. 肌肉注射鹽酸丁基原啡因所得之AUCs (3-4A) 或末端半衰期(3-4B) 與劑量之相關性 ---------------------------- 70 圖 3-5. 大鼠肌肉注射丁基原啡因鹼及其酯類衍生物之血中藥物濃度圖71 圖 4-1. 小鼠對嗎啡產生之身體依賴性 (七天) ------------------- 88 圖 4-2. 肌肉注射鹽酸丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之劑量反應圖 --------------------------------- 90 圖 4-3. 肌肉注射不同劑型之丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之反應圖 ------------------------------- 91 圖 4-4. 肌肉注射丁基原啡因鹼對於誘發嗎啡身體依賴性動物在戒斷上之劑量反應圖 ----------------------------------- 92 圖 4-5. 肌肉注射溶於不同油中之丁基原啡因鹼對於誘發嗎啡身體依賴性動物在戒斷上之反應圖 ------------------------- 94 圖 4-6. 小鼠對嗎啡產生之身體依賴性 (十一天) ----------------- 95 圖 4-7. 肌肉注射鹽酸丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之劑量反應圖 --------------------------------- 96 圖 4-8. 肌肉注射不同劑型之丁基原啡因對於誘發嗎啡身體依賴性動物在戒斷上之反應圖 ------------------------------- 98 圖 4-9. 肌肉注射不同劑量之丁基原啡因丙酸酯對於誘發嗎啡身體依賴性動物在戒斷上之反應圖 ------------------------- 99

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