臺灣博碩士論文加值系統

自發性微乳化藥物傳輸系統通常是由油相、界面活性劑系統及藥物以適當比例所組成。此一系統若接觸到水溶液或腸胃道液體，經由消化管壁的蠕動，會自發性乳化形成微乳化透明澄清之液體，因此可以有效的作為難溶性藥物的傳輸載體。在本研究中，選擇一種難溶性藥物Fenofibrate(降血脂藥物)作為模式藥，利用中鏈型三酸甘油脂Myritol 318作為油相及非離子型界面活性劑D-α-Tocopheryl polyethylene glycol 1000 succinate(TPGS)和Polysorbates(Tween系列)製備成自發性微乳化藥物傳輸系統。溶離試驗結果顯示原廠處方在水中幾不溶解；而使用適當的界面活性劑系統在特定的重量比例時，可以得到具適宜溶離速率的配方組成。然而人體試驗結果卻顯示其生體可用率較原廠處方為低。
為了進一步探究影響此配方吸收的可能影響因素，並依據三相圖選擇配方組成，試著開發出提高生體可用率之配方。實驗設計在界面活性劑系統上稍作調整，選出數個不同組成比例之配方，觀察其在pH1.2鹽酸水溶液，10、25以及50 rpm三種轉速下之溶離曲線，藉以模擬藥物於胃中不同收縮張力下釋放的情形；同時紀錄不同配方溶離液外觀及量測粒徑大小，找尋溶離後可形成較小粒徑者，期望可藉改變配方比例組成及提高藥物釋放後總表面積以增加吸收效果。
由體外實驗結果篩選出一組擁有最小平均粒徑、外觀澄清度最高以及適宜溶離速率的配方，分別作成膠囊以及水溶液兩種劑型；另外選定一組平均粒徑較大、外觀較渾濁但也具適宜溶離速率配方做成膠囊劑型，進行人體單向平行試驗。體外實驗結果顯示配方在不同界面活性劑組成下會影響溶離液的顆粒大小與外觀透明澄清度；體內實驗結果顯示溶離液顆粒大小在一定範圍內，降低顆粒大小並無法有效提升生體可用率；而在適當的組成比例下，可得到與原廠對照處方生體可用率相當之配方。最後依據體內及輔以體外實驗結果，針對溶離速率、溶離液粒子大小以及配方組成，在藥物經由口服自發性微乳化劑於人體吸收作相關探討。
由本研究的結果顯示自發性微乳化藥物傳輸系統可有效作為難溶性藥物的載體( Fenofibrate為例)，並已初步開發出與市售藥品生體可用率相當之新劑型配方。

Self-microemulsifying drug delivery systems (SMEDDSs), which are self-emulsified into a clear and translucent fluid in aqueous medium under gentle digestive motility in the gastrointestinal tract, usually consisting of a mixture of oils, surfactant systems and drugs, represent a possible alternative to traditional oral formulations of poorly-water soluble. In the present study, a model lipophilic compound, Fenofibrate (an effective agent for the treatment of various types of dyslipidemia), was formulated in a medium chain triglyceride oil (MCT) and nonionic surfactant mixtures of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and polysorbates (Tween 20 and Tween 80). Previous dissolution study showed Fenofibrate was hardly released from reference drug, Tricor®, in water medium (less than 1.5% in 60mins); While using TPGS/Tween 20 as the mixture of surfactant (Smix) at a Km value of 1/4 was found to yield the desired SMEDDSs for Fenofibrate (almost completely released within half hour). However, results of clinical trial showed the bioavailability was lower in SMEDDS formulation than in Tricor®. In order to figure out the reason and with an attempt to develop a formulation that could improve the bioavailability, we change the composition on surfactant system. In vitro dissolution studies from formulations of different compositions under rotation speed of 10, 25 and 50rpm were used to simulate the release of drugs in stomach under different digestive motility. Besides, we looked for formulations that produce small particle size in dissolution medium for their formation of large surface area for absorption. At last, 3 formulations in 2 dosage form were prepared for another clinical trial. In vitro experiments results showed the particle size and the outcome of dissolution medium were influenced by the compositions of surfactant systems. In vivo results revealed that within specific range, lower the particle size of dissolution medium could not efficiently improve the bioavailability. In appropriate formulation composition, the bioavailability could be comparably attained with that of Tricor®. Moreover, several possible factors affecting the absorption of formulations were also in further discussion in the study.
Our study indicated that the potential use of SMEDDS for oral delivery of Fenofibrate can be an alternative to improve its systemic availability. The development of SMEDDS is promising for improving the oral bioavailability of poorly soluble drugs

目錄I
中文摘要III
AbstractV
附表目錄VII
附圖目錄IX

第壹章 緒論1

第一節 研究背景介紹1
一、口服劑型簡介1
二、微乳劑系統3
三、自發性微乳劑系統(SMEDDS)7
四、模式藥物：Fenofibrate10

第二節 研究動機18

第貳章 研究材料與實驗方法19

第一節 實驗材料及儀器設備19
一、實驗材料19
二、儀器設備20

第二節 分析方法的確立21
一、Fenofibrate(FFB)之紫外分光光度計之體外分析方法21
二、Fenofibric acid(FFBA)高效液相層析之體內分析方法21

第三節 配方開發及體外試驗25
一、配方開發與製備 25
二、體外溶離試驗28
三、配方粒徑分析28

第四節 臨床人體試驗31
一、臨床人體試驗31
二、血漿檢品之檢測 32
三、藥物動力學數據分析32

第參章 結果與討論33

第一節 分析方法的確立33
一、FFB紫外可見分光光度計之體外分析方法33
二、FFBA高效液相層析之體內分析方法33

第二節 配方開發及體外溶離試驗43
一、配方開發與製備 43
二、體外溶離試驗53
三、配方粒徑分析70

第三節 臨床人體試驗83

第肆章 結論92

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