臺灣博碩士論文加值系統

微乳劑系統是由水相、油相以及兩性物質（通常為界面活性劑與輔助界面活性劑的混合物）所組成，具有均一的外觀，且為熱力學上的穩定系統。由於微乳劑系統是屬於熱力學上的穩定分散系統，因此在適當的條件下，無須外加能量的幫助即可自然形成並穩定存在。微乳劑系統除了有傳統乳劑的W/O與O/W等型態之外，在適當的條件下也會有油、水兩相皆貫通整個系統的雙連續相構造。本論文的目的即研究將雙連續相微乳劑之油相以聚合反應固化後，所得到的多孔性固體對於藥物釋放的影響。
本論文所選擇的微乳劑系統是由水-sodium bis(2-ethylhexyl)phosphate (NaDEHP)-苯乙烯—甲苯等四種成分所組成。其中NaDEHP為系統中唯一的界面活性劑，苯乙烯與甲苯（體積比1：1）則共同組成系統之油相。選擇苯乙烯與甲苯作為系統之油相是希望聚合過程中，甲苯能提供新生成的聚合物較好的溶解環境，以增加系統的穩定性，降低聚合物分子對微乳劑系統結構的破壞。
在建立微乳劑系統之相圖的過程中，我們研究了NaDEHP的自由態bis(2-ethylhexyl) phosphoric acid（DEHPA）與Cu(OH)2之間的反應機制，並以此反應為基礎建立了一個利用分光光度計測定溶液吸光值的NaDEHP定量方法。在此反應機制的研究過程中我們以流動注入法即時監測反應的進行，並以由不同反應模式所導出之方程式對所得到的反應曲線作曲線揉合。研究結果發現，當DEHPA / n-heptane溶液與Cu(OH)2接觸時，兩者會先形成一中間產物Cu(OH)DEHP。此高活性的中間產物會很快的繼續與溶液中的DEHPA或另一Cu(OH)DEHP分子反應成為終產物Cu(DEHP)2。在本論文的反應條件下，第一個反應步驟為整個反應的速率決定步驟，整個反應也可簡化為擬似一次反應，其速率方程式為：
其中K1為Cu(OH)2與反應溶液之接觸面積固定時結合Cu(OH)2變因的擬似一次反應速率常數。研究中我們也發現Cu(DEHP)2分子在n-heptane溶液中會與水分子形成一比一的複合物Cu(DEHP)2·H2O。此複合物的最高吸收波長約在805 nm，與未形成複合物的Cu(DEHP)2（755 nm）明顯不同。由於Cu(DEHP)2·H2O在水分濃度極低的情況下就會形成，而且反應中每生成一分子Cu(DEHP)2就會有二分子的水生成，因此定量時應該以805 nm作為定量波長較為適當。
利用以上關於界面活性劑的定量方法，以及對油相（測定吸光值）及水相（費氏滴定法）的定量方法，我們建立了此系統在25℃下的相圖。關於微乳劑系統的性質分析，我們分別測定了各檢品的導電度、黏度、擴散係數等性質，並以光學顯微鏡分別觀察微乳劑檢品在毛細管中與油相或水相接觸的情形，以判別各相是屬於W/O，O/W，或是雙連續相型態的微乳劑。至於一般研究微乳劑型態常用的電子顯微鏡取像的部分則因檢品揮發性過高，以致在進行冷凍蝕刻的步驟時就失敗而無法進行。依據定性分析的結果，我們發現此相圖系統在本論文研究的範圍內（NaDEHP濃度小於55 %），相圖可以區分為五個主要區域，其中至少包含了一個雙連續相的區域，一個W/O及一個O/W型態的微乳劑部分。另外兩個低油相比例的區域具有極高的黏度，推測可能為具有液晶型態結構，但尚無法證實。
在以上的相圖中我們從雙連續相的區域中選取了一個具有較高油相比例的組成（水相：界面活性劑：油相 = 25.2：35.5：39.3重量比）進行聚合試驗。聚合時分別在檢品中加入油溶性及水溶性的起始物（2,2-dimethoxy-2-phenylacetophenone與K2S2O8），並以紫外線照射以加速反應進行。實驗結果顯示反應速率並無法達到預期的目標，微乳劑檢品在約30分鐘的反應之後由原先的透明外觀轉變成白色混濁，並出現分層而無法形成多孔性的聚合體。檢討其原因，除了可能是因為聚合條件的為最佳化之外，也可能是因為油相中單體比例偏低所致。
為了繼續探討多孔性固體對藥物釋出的影響，我們另外參考了文獻中的作法，以methyl methacrylate — acrylic acid — sodium dodecyl sulfate — H2O微乳劑系統聚合出具多孔性質的固體。所得之聚合物具有吸水膨脹的性質，其平衡吸水量與所處溶液之酸鹼值有關。當溶液之pH值偏鹼時，聚合物會因為分子結構上的羧基解離而吸水膨脹；當聚合物置於酸性環境中時，羧基不帶電，所以聚合物呈現厭水狀態而將內部的水分排出。此吸水膨脹的機制對於藥物的釋出也會有影響。如果聚合物檢品在不同pH值的環境中吸附藥物，所得到的含藥檢品在不同pH值的溶媒中也會有不同的溶離曲線。溶離試驗的結果顯示，本論文中所製備的多孔性聚合物檢品雖然可以對藥物的溶離有延緩釋出的效果，但其效率顯然並未達於原先預期的效果。此結果可能與孔洞的結構以及聚合物分子的特性有關，確實的影響變因則仍須進一步研究才能加以確定。

This thesis was focused on the application of microemulsion systems in the field of pharmaceutical solid dosage forms. Microemulsions are isotropic dispersed systems composed of water and oil phases, and surfactant mixtures, which were mainly composed of a surfactant and a medium-chain alcohol. Unlike traditional emulsions, or macroemulsions, which needed extra energy to disperse the systems, microemulsion systems were thought to be thermodynamically stable and can be formed spontaneously when properly formulated. In addition to the two common types of dispersions, W/O or O/W, microemulsions are characteristic of the bicontinuous state in which both water and oil phases form interconnected network percolating the whole system, with the surfactant molecules forming the interface between them. It is interesting to investigate the polymerization of a bicontinuous state to form a porous solid in which drug molecules can be incorporated to delay its release from the dosage.
We chose H2O, sodium bis(2-ethylhexyl)phosphate (NaDEHP), styrene, and toluene as the components of the microemulsion system. The oil phase components, styrene and toluene (1:1, v/v), were chosen for the ability of styrene to polymerize and the relative good solubility of polystyrene in toluene. NaDEHP was chosen as the sole surfactant for its ability to form microemulsions without the aid of cosurfactants, thus simplifying the complexity of the system.
The quantification method was developed upon NaDEHP by introducing the reaction between Cu(OH)2 and the free form of NaDEHP, bis(2-ethylhexyl)phosphoric acid, DEHPA. Although both NaDEHP and DEHPA showed no absorbance above 400 nm, the salt Cu(DEHP)2 showed absorption peak around 755 nm in n-heptane solution, but around 805 nm when forming 1-to-1 complex with water molecules. This change in photometrical property enables NaDEHP to be quantified spectrophotometrically. To justify the quantification procedure, we also investigate into the reaction mechanism of DEHPA and Cu(OH)2. Although the whole reaction was stoichiometrically found to be 2nd-order reaction with respect to DEHPA, the results of kinetic study showed that the reaction was actually consecutive reaction. The Cu(OH)2 molecule was first brought into the oil solution by one molecule of DEHPA to give the reactive intermediate Cu(OH)DEHP, which was the limiting step of the whole reaction. The Cu(OH)DEHP was then reacted into the final product Cu(DEHP)2 by reacting with another molecule of DEHPA or Cu(OH)DEHP. The whole reaction can be simplified as a pseudo-first order reaction, and can be expressed mathematically as
in which the apparent first-order reaction constant K1 included the factor of Cu(OH)2 when the contact area was kept constant between Cu(OH)2 and the reaction solution.
A microemulsion phase diagram was constructed under 25℃. Qualitative analyses were conducted including electrical conductivity, viscosity, diffusion coefficient, and the continuity of the microemulsion samples were examined in a capillary by optical microscopy. However, the freeze fracture electric microscopic examination was failed due to the high volatility of the oil phase. Five regions were found in the phase diagram, in the region of NaDEHP concentration less than 55 %. Three of them were identified to be W/O, O/W, and bicontinuous microemulsions, respectively. The other two, with relatively high viscosity, were suspected to be liquid crystal in nature.
Among the phase diagram, a bicontinuous sample of high oil content (water phase : surfactant : oil phase = 25.2 : 35.5 : 39.3 w/w) was selected as the sample of polymerization reaction test. Oil-soluble and water-soluble initiators (2,2-dimethoxy-2-phenylacetophenone and K2S2O8) were both simultaneously used in the polymerization reaction. Unfortunately, polymerization was not successful and no porous solid was obtained even under UV irradiation. The initially transparent samples turned opaque and showed phase separation after about 30 minutes of reaction. The failure to achieve porous solid may be caused by the low concentration of the monomer, styrene. The low volume fraction of the monomeric styrene might lead to poor polymerization results if the reaction condition was not optimized.
In order to complete the investigation on the influence of porous solid on the drug release, another microemulsion system of methyl methacrylate — acrylic acid — sodium lauryl sulfate — H2O was referenced from the literature. Porous solids were successfully prepared according to the literature and dissolution tests were performed. However, since the carbonyl group derived from acrylic acid after polymerization was sensitive to the H+ concentration of the solution, the hydrophilicity of the porous solid was therefore influenced tremendously by the pH value of the surrounding liquid and the solid showed significant swelling behavior in buffer solutions. A water-soluble compound phenol red was employed as the model drug. We prepared different drug-containing porous solids by equilibrating the solid with drug containing buffer solutions of different pH values. The results showed that the swelling behavior of the porous solid influenced the dissolution profiles to some extent. The fastest dissolution profile was obtained from the basic sample (porous solid soaked in pH 6.14 drug-containing buffer solution) to release drug in acidic medium (pH = 3.0), while the slowest one was the result of acid sample (porous solid soaked in pH 3.0 drug-containing buffer solution) in an acidic dissolution medium (pH = 3.0).
The slow release effect of the solid was not as efficient as expected, however, more detailed investigations should be performed before making further conclusions.

封面
中文摘要
英文摘要
目錄
圖表目錄
壹、緒論
一、微乳劑系統簡介
1.微乳劑的基本性質
2.微乳劑性質之測定
液滴大小
導電度
黏度
擴散係數
界面張力
二、微乳劑的應用
貳、研究目的
參、O/NaDEHP/styrene/toluene分散系統之研究
一、文獻探討
1.微乳劑系統的選擇
2.多孔性固體與藥物溶離速率之關係
二、研究步驟
1.各成分之純化與製備
<1>DEHPA之純化
<2>NaDEHP之製備
<3>聚合物單體之純化
2.各成分之基本性質分析
<1>NaDEHP之界面活性
<2>DEHPA之pKa及對水溶解度之測定
3.建立相圖
<1>微乳劑檢品之製備
<2>定量分析
<3>微乳劑檢品之定性分析
4.聚合反應
5.溶離試驗
6.數據分析
三、各成分之性質及分析方法之研究
1.NaDEHP之性質及定量方法之研究
<1>NaDEHP之界面活性
<2>DEHPA之解離常數及溶解度
(i)理論推導
(ii)實例測試
(iii)DEHPA的測定結果
<3>NaDEHP之製備及純化
<4>DEHPA衍生物以及定量相關化合物的光學性質研究
(i)DEHPA衍生物的光學性質
(ii)Sudan Ⅲ之光學性質
<5>DEHPA與Cu(OH)2之反應機構及反應動力學之研究
(i)反應動力學之理論推導
(ii)實驗設計及數據之曲線揉合
<6>NaDEHP定量方法的探討
(i)利用DEHPA與Cu(OH)2之反應進行定量分析
(ii)利用NaDEHP與CuSO4之反應進行定量
2.苯乙烯與甲苯之定量方法
3.水分含量之測定
4.相圖之組成
四、分散系統各相之定性分析
1.擴散係數
2.導電度
3.黏度
4.光學顯微鏡之觀察
五、相圖之綜合討論
1.擴散係數
2.黏度
3.導電度
4.電子顯微鏡
5.相圖之結論
六、聚合試驗之測試結果
七、結論
肆、O/SDS/MMA/AA雙連續相微乳劑之聚合試驗及其在控釋劑型上應用之可行性評估
一、文獻探討及研究目的
二、雙連續相微乳劑之聚合反應
三、多孔性聚合物之藥物載入及溶離試驗
1.聚合物的藥物載入
2.聚合物之解離及其平衡吸水量
3.溶離試驗
四、結論
伍、總結
參考文獻

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