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研究生:許家禎
研究生(外文):Chia-chen Hsu
論文名稱:以微乳劑製備奈米膠囊其體外釋離與降解之研究
論文名稱(外文):In vitro release and degradation of poly(ethyl 2-cyanoacrylate) nanocapsules prepared from w/o microemulsion
指導教授:高純琇高純琇引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:120
中文關鍵詞:聚氰基丙烯酸乙基酯奈米膠囊藥物釋離聚合物降解微乳劑
外文關鍵詞:polyethyl cyanoacrylatenanocapsulemicroemulsionpolymer degradationin vitro drug release
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以聚氰基丙烯酸烷基酯(polyalkyl cyanoacrylate,PACA)為材質之奈米顆粒,由於具有生體相容性及生體可分解性,且聚合過程簡便,因此在近年來已被廣泛地研究,希望能成為有效之藥物載體系統。微乳劑系統屬於熱力學上的穩定分散系統,因此在適當的條件下,無須外加能量即可自發性形成並穩定存在。經由微乳劑系統之界面聚合反應可以合成具空心結構的奈米膠囊。本研究室之前的研究,已成功地利用甲苯、水及界面活性劑NaDEHP所組成的w/o型態微乳劑系統,以氰基丙烯酸乙酯(ethyl 2-cyanoacrylate,ECA)單體進行界面聚合反應,合成包覆水溶性藥物的PECA奈米膠囊,並利用減壓濃縮法純化。本研究中比較不同單體配方對膠囊藥物包覆率之影響。另外探討溶離環境pH值、製劑上的變因及添加酯解酶對nicardipine HCl奈米膠囊之降解產物甲醛與乙醇產生及藥物釋離情形的影響。
分散在反應媒液之奈米膠囊以粒徑分析儀分析其粒徑大小結果比經純化步驟後在掃瞄式電子顯微鏡(SEM)下觀察的膠囊粒徑大,此顯著的差異可能來因純化過程使顆粒縮小有關。
在探討奈米膠囊藥物之包覆率發現,加入相同的單體量但較低的單體濃度或提高所加入之單體量,均可增加藥物包覆率。然而增加單體量卻會使奈米膠囊之載藥率下降,故製備奈米膠囊時,選擇適當的單體量是相當重要的。
PECA奈米膠囊之降解研究中,當溶離液之pH值增加,降解產物甲醛和乙醇產生速率及總產生量均增加。不同配方之PECA奈米膠囊在三個pH下(3.0、7.4、9.0)下之降解結果,單體加入量較低之配方(配方1)相較於單體加入量高的配方(配方2),其甲醛和乙醇的產生量及速率較高。在加入之單體量對膠囊粒徑及厚度之影響有限的情況下,PECA膠囊壁緻密度的改變可能是影響降解速率之因素。此外,添加酯解酶時,會降低甲醛產生之速率及量,卻增加乙醇產生之速率及量。
Nicardipine HCl奈米膠囊之藥物釋離研究中,不論哪一種配方製得之奈米膠囊,對照於nicardipine HCl藥物溶液,均具有延遲藥物釋放的效果。溶離液的酸鹼度對於nicardipine HCl從PECA膠囊中釋放有顯著影響。在較高的pH值有較高的藥物釋離速率。在配方1,其168小時在不同pH值(3.0、7.4、9.0)的總釋出量無顯著差異,皆可達到85%以上。但是配方2,在pH 9.0時,nicardipine HCl的釋放有被抑制的現象。原因可能是nicardipine HCl與PECA膠囊之交互作用造成nicardipine HCl不可逆之吸附於膠囊表面所導致。在所有pH值下(3.0、7.4、9.0),配方1均較配方2有較快之釋離速率,可能與膠囊壁緻密度有關。添加酯解酶影響PECA奈米膠囊藥物釋離之結果,在配方1,無論是否加入酯解酶,48小時之藥物總釋離量並沒有顯著不同。而配方2,無添加酯解酶與添加不同酯解酶量之三個組別間,其藥物釋離均有顯著差異,且在高酯解酶添加量時,藥物釋出速率較快。可能由於添加酯解酶時對於PECA性質之改變,並不顯著影響配方1之藥物釋離,但對於膠囊壁較緻密之配方2的藥物釋離卻具有顯著影響。
Poly (alkyl cyanoacrylate) (PACA) nanoparticles have gained extensive interest as drug carriers because of the biocompatibility and biodegradability of the polymer and the simplicity of the polymerization process. Microemulsions are thermodynamically stable systems and can be formed spontaneously when properly formulated. Nanocapsules can be prepared by interfacial polymerization of water-in-oil microemulsions. In the previous study, poly (ethyl 2-cyanoacrylate) (PECA) nanocapsules were successfully prepared by adding ECA monomers into a water-in-oil microemulsion system, which was composed of toluene, water and sodium bis (2-ethylhexyl) phosphate (NaDEHP) as the surfactant. After polymerization, evaporation under reduced pressure was used to the purification of nanocapsules. The aim of present study is to study the effects of monomer concentration and monomer mass adding to polymerization on the encapsulation efficiency. Furthermore, the effects of pH, formulation variables and esterase on the release profiles of degradation products (formaldehyde and ethanol) and drugs are also investigated.
Particle size of nanocapsules suspended in reaction media were measured by dynamic light scattering (DLS), which were significantly higher than the particle size of PECA nanocapsules purification by scanning electron microscopy (SEM). This may be due to the shrinking effect after the process of nanocapsule purification.
The efficiency of nicardipine HCl entrapment within PECA nanocapsules was influenced by the concentration of monomer solution and the mass of monomer used in the polymerization. The monomer solution of lower concentration and the increase of monomer mass resulted in higher drug encapsulation efficiency.
The PECA nanocapsule degradation study showed that the polymer would degrade faster in higher pH phosphate buffer solution (PBS). The degradation of polymer was faster in formulation 1(the volume ratio of monomer added to water phase 1:20) as compared with formulation 2 (the volume ratio of monomer added to water phase 1:10). The enzymatic degradation of PECA by esterase increased the production of ethanol but decreased the production of formaldehyde.
The drug release study of nicardipine HCl nanocapsule also showed that the two formulations provided products with a potential for controlling the drug release. Drug release rate was faster in higher pH PBS. After 168 hours, there was no significant difference in total release % of the three groups (pH 3.0, 7.4 and 9.0) in formulation 1 (about 85%). However, the release of nicardipine HCl was suppressed under basic conditions (pH 9.0) in formulation 2. The existence of drug-polymer interactions may lead to some of the drug remaining in the nanocapsules, and drug can not completely release. Formulation 1 had a faster drug release rate then formulation 2 may also attribute to the less tightness of polymer wall. When PECA nanocapsules were exposed to esterase, the drug release pattern would be changed.
中文摘要 i
Abstract iii
目錄 v
圖表目錄 vii

壹、緒論 1
一、奈米藥物載體 1
二、聚氰基丙烯酸烷基酯 2
1. 物理化學特性 3
2. 單體的用途 4
3. 聚氰基丙烯酸烷基酯奈米顆粒 6
三、聚氰基丙烯酸烷基酯之降解反應與其毒性 11
1. 聚氰基丙烯酸烷基酯之降解反應 11
2. 聚氰基丙烯酸烷基酯之毒性 19
四、微乳劑系統 21
1. 微乳劑之特性 21
2. 微乳劑與乳劑之比較 23
3. 微乳劑系統之應用 25
4. 實驗所使用之微乳劑系統 26
5. 以微乳劑系統進行界面聚合反應 28
五、模式藥 Nicardipine HCl 30
六、酯解酶 32
七、物性測量方法之理論 34
1. 粒徑測量 34
2. 電子顯微鏡技術 35
八、藥物釋放動力學探討 36
貳、研究目的 38
參、實驗方法 39
一、實驗藥品及儀器 39
1. 實驗藥品 39
2. 實驗器材 40
二、實驗步驟 41
1. 界面活性劑(NaDEHP)的製備 41
2. 微乳劑的製備 41
3. 奈米膠囊的製備 42
4. 奈米膠囊之物化特性 43
5. 奈米膠囊載藥包覆率測量 45
6. 含藥奈米膠囊之藥物釋放與聚合物降解試驗 49
肆、結果與討論 58
一、奈米膠囊的製備研究 58
1. 奈米膠囊粒徑與型態分析 58
2. 影響奈米膠囊藥物包覆率的因素探討 62
二、PECA奈米膠囊之降解試驗 66
1. 溶離液的酸鹼度對PECA奈米膠囊降解之影響 66
2. 製備上之變因對PECA奈米膠囊降解之影響 74
3. 酯解酶對PECA奈米膠囊降解之影響 82
三、奈米膠囊之藥物釋放研究 89
1. 溶離液的酸鹼度對PECA奈米膠囊藥物釋離之影響 89
2. 製備上之變因對PECA奈米膠囊藥物釋離之影響 96
3. 添加酯解酶酵素對PECA奈米膠囊藥物釋出之影響 100
4. PECA奈米膠囊藥物釋離數學模式之探討 104
伍、結論 110
參考文獻 112
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