臺灣博碩士論文加值系統

口服藥物為目前最普遍的給藥途徑，它的優點包括給藥安全方便、忍受度高、消除注射的不舒服、製程上較為經濟、病患不需要醫療人員從旁協助等，但口服藥物由於藥物本身分子的結構，疏水性的藥物有溶解度問題的限制，而親水性的藥物有穿透腸壁吸收的限制，如何在這兩者間取得一個平衡，是口服藥物劑型的重要課題。而本研究使用HP-β-CD(2-Hydroxypropyl-β-cyclodextrin)，為一種修飾過的環狀醣類分子，它具有特殊的雙極性的構造，環狀空洞處為親脂性，能夠包覆親脂性藥物，使難溶性藥物的溶解度提高，並且可以減少藥物和水的作用，以延長藥物的保存時間，同時增加生物有效率；實驗中使用兩種脂溶性的藥物，分別為Tolbutamide和Estradiol，Tolbutamide為一降血糖口服藥物，而Estradiol為一固醇類藥物，他們的特性都是非常難溶於水。
本實驗主要分析藥物本身及劑型相關的化學、物理特性，第一部分藉由物理混合、共同揮發來製作inclusion complex；第二部分則使用兩種相關儀器: Differential scanning calorimetry、Fourier transform infrared spectroscopy來分析藥物與HP-β-CD可能的作用機制；第三部分使用UV-VIS定量分析藥物在加入HP-β-CD後的溶解程度與溶離率差異。本實驗主要嘗試證明藥物溶解度如何被提升與利用，並期望能當作日後研究難溶性藥物賦形劑的參考模型。

Oral administration of drugs is the most common dosage. The advantages include safety, convenience, comfort, and low cost. However, limitations of oral drugs are due to the structure of the drug molecules. Hydrophobic drugs exhibit low solubility whereas the hydrophilic have diffusion limit through the intestinal wall. It is important to obtain a balance between the two properties for oral drugs. In this study, the HP-β-CD(2-Hydroxypropyl-beta-cyclodextrin) was used as a solubility enhancer due to modified cyclic carbohydrate molecules. HP-β-CD has a special bipolar structure and hydrophobic circular hole. Hence, the solubility of poorly water soluble drugs can be increased. According by stability and bioavailability of drugs, can be increased.
Two hydrophobic drugs in the experiments were Tolbutamide and Estradiol. Tolbutamide is oral hypoglycemic drug and Estradiol is a steroid drug. They are very insoluble in water. In this study, we analyzed chemical and physical characteristics of the drugs associated to HP-β-CD. The first part was to prepare the physical mixtures by physical mixing and the inclusion complex by co-evaporated method. The second part was to analyze physicochemical properties using two analytical instruments : Differential scanning calorimetry, Fourier transform infrared spectroscopy. The third part was to quantitatively analyze solubility and dissolution differences of drugs after adding the HP-β-CD by UV-VIS. A possible binding of drugs to HP-β-CD was proposed.

致謝 I
中文摘要 II
Abstract IV
目錄 V
表目錄 VIII
圖目錄 IX
第一章 緒論 1
第二章文獻回顧 3
2.1藥物動力學(Pharmacokinetic) 3
2.1.1給藥途徑 4
2.1.2口服製劑 5
2.1.2藥物與賦形劑的物理化學特性 6
2.2 pH值對藥物的吸收與溶解度影響 8
2.3藥物介紹 13
2.3.1糖尿病與藥物Tolbutamide 13
2.3.2 Estradiol 17
2.3.3 Cyclodextrin 環糊精 20
2.3.4 HP-β-CD(2-Hydroxypropyl-β-cyclodextrin) 23
第三章 研究目的 25
第四章 藥品與儀器 27
4-1藥品與儀器 27
儀器: 28
第五章 實驗方法與步驟 31
5.1 製作藥物與HP-β-CD之物理混合 31
5.2 製作兩種藥物與HP-β-CD之inclusion complex 31
5.3 DSC(Differential Scanning Calorimeter) 33
5.4 FT-IR(Fourier Transform Infrared Spectrometer) 34
5.4.1 FTIR試片製作 34
5.4.2 樣品分析 34
5.5 Phase-solubility 35
5.5.1製作兩種藥物與不同HP-β-CD濃度及pH值之檢量線 35
5.5.2 Estradiol溶解度測試 36
5.5.3 Tolbutamide溶解度測試 36
5.6 Phase dissolution 37
5.6.1 Tolbutamide 溶離測試 37
5.6.2 Estradiol溶離測試 38
第六章 結果與討論 39
6.1 DSC熱力學分析 39
6.2 FTIR圖譜分析 43
6.2.1 TB+ HP-β-CD:物理混和與inclusion complex圖譜比較 43
6.2.2 Estradiol+ HP-β-CD:物理混和與inclusion complex圖譜比較 45
6.3溶解度(phase solubility) 47
6.3.1 溶解度探討 47
6.3.2 Tolbutamide溶解度探討 49
6.3.3 Estradiol溶解度探討 52
6.4 溶離度(phase dissolution) 55
6.4.1 Tolbutamide 溶離探討 55
6.4.1 Estradiol溶離探討 56
第七章 結論 57
第八章 參考文獻 61

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