臺灣博碩士論文加值系統

傳統難溶性藥物的口服劑型設計傾向立即釋放系統，服用次數通常為一天三次以上，而這樣的情形導致了藥物的血中濃度具有明顯的波動性以及造成藥物毒性副作用。因此，對於降低藥物副作用及增加病患服藥順從性有必要發展出新穎的控釋劑型。但是藥物的溶解度和溶離速率不佳的情況之下常導致像較低的血中濃度與難以預測之生體可用率及不良副作用之產生，此原因之產生常因缺乏投與劑量的等比性與藥量經不同的生理環境條件造成過多的喪失，以及食物的影響性等，為最主要因素。
此研究使用的模式藥物為cilostazol，它是合成的抗凝血製劑並具有血管舒張的作用。文獻指出，cilostazol會因高脂性食物的影響提升血中濃度與生體可用率並增加副作用的發生頻率；若降低藥物分子大小和提高藥物溶解度有助於降低食物的影響性並可增加生體可用率。
本研究目的是以親水性賦形劑為載體與製程改良，開發出難溶性藥物之控釋劑型並改善藥物的溶解度以降低因食物影響導致的不良副作用。實驗以新穎性熱黏附造粒法（thermal adhesion granulation，TAG）之製程並比較固體分散系統（溶媒法、熱融法）之差異。
實驗結果顯示，根據掃描式熱分析儀判圖，cilostazol的結晶體型態轉變為非晶型；就物理性方法評估粉末及錠片特性，安息角與硬度於不同製程所製備的錠片並無顯著差異。然而，於藥物溶離試驗結果中，當處方加入Kollidon VA64時，隨添加量增加顯著地改善藥物的溶離速率。於TPGS和vitamin E系統中，增加TPGS和vitamin E的比例均會提昇藥物的溶解度與溶離速率。研究顯示了利用固體分散系統與熱黏附造粒法開發新穎的控釋劑型可以顯著地增加cilostazol的溶解度並將食物影響性降至最低。

Traditional immediate-release oral solid dosage forms of poorly soluble drugs have to be administered three times a day, which results in a significant fluctuation in the plasma drug concentration and drug toxic side effects. Therefore, development of controlled-release dosage forms is desirable for side effect reduction and for patient compliance. However, the poor aqueous solubility and dissolution rate lead to several problems such as low and unpredictable (or variable) physiological availability and therapeutic response, lack of dose proportionality, excessive loss of an administration dose, and food effect.
Cilostazol, the model drug of this study, is a synthetic antiplatelet agent with vasodialating effect. The frequencies of headache and other side effects are increased with the administration dose of cilostazol. It is also suggesting that the oral bioavailability (BA) of cilostazol could be enhanced due to the improvement of dissolution by food. Data shows the reduction of particle size is found to be efficient to improve the oral BA of cilostazol and to avoid the food effect on the absorption.
The purpose of this study is to develop a controlled release dosage form using hydrophilic excipients and different approaches of preparations to improve the solubility of poorly soluble drug with minimization of food effect.
It is shown that using approaches of solid dispersion (solvent method, hot melt method, and thermal adhesion granulation) could change the crystalline state of cilostazol to form an amorphous state that could be detected by the differential scanning calorimetry (DSC). Different method of preparations has no significant difference from the data of angle of repose and hardness of tablets. However, the dissolution rate is increased in the Kollidon VA64 system. Solubility and dissolution rate of cilostazol are increased when increasing the ratio of TPGS and vitamin E. In conclusion, these findings clearly indicate that the solubility of cilostazol can be maximized and the food effect may be minimized by using solid dispersion and thermal adhesion granulation technology to develop a controlled release dosage form.

目錄 I
附表目錄 III
附圖目錄 V
中文摘要 IX
Abstract XI
第壹章 緒論 1
第一節 難溶性藥物之控釋劑型的開發 1
第二節 藥物溶解度與食物之關係 5
第三節 Cilostazol簡介與其相關之研究 7
第四節 改善溶解度之方法介紹 19
ㄧ、固體分散系統之簡介 21
二、熱黏附造粒法之簡介 22
第五節 研究動機與目的 27
第貳章 研究材料與方法 28
第一節 實驗材料及儀器設備 28
ㄧ、實驗材料 28
二、儀器設備 29
第二節 實驗方法 30
ㄧ、處方設計 30
二、粉末造粒及錠劑製備 33
三、分析方法 35
四、示差掃描式熱分析儀分析 36
五、粉末安息角測定 36
六、硬度測試 37
七、溶離度試驗 37
第參章 結果與討論 40
第一節 分析方法之確立 40
第二節 示差掃描式熱分析 46
第三節 安息角測定 55
第四節 硬度測試 58
第五節 溶離度試驗 63
第肆章 結論 89
參考文獻 90

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