臺灣博碩士論文加值系統

口服威而剛錠劑是在勃起功能障礙治療上，最為廣泛使用的藥物；然而，其仍存在著必須於需求前一小時服用，以及其較低的生體可用率的缺點。舌下路徑給藥方法提供快速吸收、高生體可用率及快速的藥效作用，因此本研究將藉由這些優點，發展sildenafil的舌下噴劑及舌下錠劑劑型。
本研究所用的Sildenafil舌下噴劑，其溶媒載體系統分別為油酸、丙烯乙二醇及微乳劑 (微乳劑由油相-油酸、界面活性劑¬-聚山梨醇酯80、輔助界面活性劑-聚乙二醇600或丙烯乙二醇組成)。 將所製備的舌下噴劑投與動物進行體內研究。實驗結果顯示，以0.53毫克劑量的sildenafil於丙烯乙二醇的舌下噴劑作用最為迅速，開始作用時間為1.33±0.57分鐘且藥效時間能達1.5小時。
Sildenafil 舌下錠劑的製備是先將上述sildenafil的舌下噴劑溶媒載體系統吸附於不同吸附劑 (FLORITE® R、Neusilin®US2、AEROSIL®200、SYLOID®244 FP及 AEROPERL® 300/30) 而成固態顆粒，再與結合劑 (EMDEX® 或Cyclocel® ) 及崩散劑 (Ac-Di-Sol ® 或 Kollidon®CL) 所搭配而成。先進行測量各種吸附劑吸附溶媒系統後的粉末流動性，再對錠劑溶離率、硬度及崩散時間進行評估；最後，將不同處方組成的舌下錠劑，投予動物進行體內動力學研究。其體內研究得知，sildenafil於丙烯乙二醇中，與吸附劑FLORITE® R進行1:1重量比例吸附，再與結合劑- Cyclocel®及崩散劑- Ac-Di-Sol ®所製備出的舌下錠劑，於0.52毫克劑量下，開始作用時間最快為1.94±0.41分鐘並藥效時間能達1小時。

Oral sildenafil (Viagra®) is the most popular drug to treat erectile dysfunction. However, it should be taken 1 hour before sexual intercourse and lower bioavailability. It is well known that sublingual delivery of drugs offers rapid absorption and high bioavailability, with subsequent almost immediate onset of pharmacological effect. Due to these superiorities, we developed sildenafil sublingual spray and tablet.
Sildenafil in oleic acid, propylene glycol and microemulsion prepared by water phase (H2O), oil phase (oleic acid), surfactant (Tween 80) and cosurfactant (PEG600 or propylene glycol) were developed for rapid-onset sublingual spray of sildenafil. Sildenafil sublingual spray was administered sublingually to rabbits and in vivo sublingual absorption of sildenafil from different solvent systems was investigated. Sublingual absorption of sildenafil from propylene glycol was found to be fairly rapid. At 0.53 mg dose, the mean onset of action was 1.33±0.57 min and lasted for an average of 1.5 hour.
The sildenafil sublingual tablets containing the composition of various granulated sublingual spray adsorbed onto different silicate adsorbants (FLORITE® R, Neusilin®US2, AEROSIL®200, SYLOID®244FP and AEROPERL®300/30), binder (EMDEX® or Cyclocel® ) and disintegrant (Ac-Di-Sol ® or Kollidon® CL) were prepared. The powder rheometry and characteristics (dissolution, hardness and distegration) of sublingual tablets were characterized and in vivo sublingual absorption of sildenafil from different sublingual tablets was investigated in rabbits. In vivo studies showed that sildenafil in propylene glycol formulation adsorbed on FLORITE® R by 1:1 weight ratio mixed with Cyclocel® and Ac-Di-Sol ® , the onset of action was fast at 1.94±0.41 min and lasted for 1 hour at 0.52 mg.

目錄 I
附表目錄 V
附圖目錄 VII
中文摘要 X
Abstract XII
第一章 緒論 1
第一節 Sildenafil研究背景介紹 2
壹、基本性質 2
一. 物化特性 2
二. 藥理機轉 3
三. 副作用 4
貳、劑型之發展 4
一. 口服劑型 4
二. 外用軟膏劑型 8
三. 鼻噴劑型 9
1. 鼻腔生理構造 9
2. 鼻噴劑型發展 10
四. 舌下劑型 12
1. 舌下生理構造 12
2. 舌下劑型發展 21
第二節 研究動機 34
第二章 研究材料與實驗方法 35
第一節 實驗材料與儀器設備 35
壹、實驗材料 35
貳、儀器設備 37
第二節 分析方法之確效 39
壹、Sildenafil標準品分析方法之確效 39
一. 分析條件 39
二. 內部標準品 (internal standard) 溶液之配製 39
三. Sildenafil檢量線標準品溶液之配製 39
四. 溶液標準品之確效 40
貳、血漿中Sildenafil檢品分析方法之確效 40
一. Sildenafil 血漿標準品之配製 40
二. 血漿中Sildenafil 萃取方法 41
三. 血漿中Sildenafil 的萃取回收率 41
四. 血漿標準品之確效 41
第三節 舌下噴劑 42
壹、舌下噴劑製備 42
第四節 舌下錠劑 43
壹、舌下錠劑製備 43
一. 粉末安息角試驗 43
二. 處方設計 45
貳、舌下錠劑特性測量 48
一. 硬度測試 48
二. 崩散時間觀察 48
三. 體外溶離試驗 48
第五節 動物投予sildenafil舌下噴劑及舌下錠劑之動力學研究 50
壹、動物試驗 50
一. 實驗動物 50
二. Sildenafil舌下噴劑及舌下錠劑處方及劑量 50
三. 試驗方法 51
貳、血漿檢品之檢測 52
參、藥物動力學數據分析 52
第三章 結果與討論 55
第一節 Sildenafil高效液相層析之分析方法 55
壹、Sildenafil標準品分析方法之確效 55
貳、血漿中Sildenafil檢品分析方法之確效 58
第二節Sildenafil舌下噴劑 63
壹、舌下噴劑製備 63
貳、動物投予舌下噴劑之動力學研究 65
第三節Sildenafil舌下錠劑 69
壹、舌下錠劑製備 69
貳、舌下錠劑特性測量 72
一. 硬度測試 72
二. 崩散時間觀察 72
三. 溶離度試驗 75
參、動物投予sildenafil舌下錠劑之動力學研究 87
結論 101
參考文獻 102

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