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研究生:賴美冠
研究生(外文):Mei-Kuan Lai
論文名稱:應用不同乳化溶劑揮發法及奈米金於微粒包覆技術之研究
論文名稱(外文):Application of Different Emulsion Solvent-evaporation Methods and Gold Nanoparticles to Microencapsulation
指導教授:蔣見超
指導教授(外文):Raymond Chien-Chao Tsiang
學位類別:博士
校院名稱:國立中正大學
系所名稱:化學工程所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:185
中文關鍵詞:奈米金微粒包覆微粒膠囊乳化溶劑揮發法
外文關鍵詞:MicroencapsulationmicrocapsulesEmulsion Solvent-evaporation MethodsGold Nanoparticles
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本論文第一階段(第四章)乃是利用微粒包覆技術中之O/W型乳化溶劑揮發法將acetaminophen(APAP)包覆於poly(L-lactide)(PLLA)中。由熱重損失分析和微差掃瞄熱卡計數據可證實APAP被包覆於PLLA中並可知APAP是均勻分佈於PLLA微粒膠囊中。於乳化過程無論是添加明膠或聚乙烯醇作為保護膠體,對所製備得之微粒膠囊皆會有顯著的影響。隨著增加分散介質中任一種保護膠體之濃度,會提高所製備得微粒膠囊之回收率及其APAP之釋放速率,但微粒膠囊之粒徑大小及負載效果會降低。當使用明膠當作保護膠體時,其所製備得之微粒膠囊的表面是較平坦的,而當使用聚乙烯醇當作保護膠體時,所製備得微粒膠囊的表面變為較崎嶇不平且有一些小峰生成。

本論文第二階段(第五章)主要研究以O/W型、O/W共溶劑型及W/O/W型乳化溶劑揮發法製備含APAP藥物之PLLA微粒膠囊。微粒膠囊之平均粒徑及表面型態會隨著使用不同的乳化溶劑揮發法而有所變化。於O/W共溶劑型乳化溶劑揮發法,使用不同的醇類或烷類共溶劑會對微粒膠囊產生顯著的影響,當使用較疏水性之共溶劑如庚烷時可提高藥物包覆效率,且其提高之藥物包覆效率將近是O/W型乳化溶劑揮發法的兩倍。於W/O/W型乳化溶劑揮發法,當使用較少量之水作為內部水相時所得之藥物包覆效率將近是O/W型乳化溶劑揮發法的三倍。以W/O/W型乳化溶劑揮發法所製備得微粒膠囊不僅具有較高的藥物包覆效率且亦具有不錯的控制釋放行為(如同以O/W型乳化溶劑揮發法所製備得之微粒膠囊)。以O/W型及O/W(醇類)共溶劑型乳化溶劑揮發法所製備得微粒膠囊之釋放動力學是較符合Higuchi間質動力模式(非儲主式),即APAP是均勻分佈於PLLA微粒膠囊中。然而,以O/W(烷類)共溶劑型及W/O/W型乳化溶劑揮發法所製備得微粒膠囊之釋放動力學是較符合一階釋放動力模式,即其是屬於儲主式之微粒膠囊。

本論文第三階段(第六章)的第一部份將探討以W/O/W型乳化溶劑揮發法製備含thioridazine(TH)及奈米金之ethyl cellulose(EC)微粒膠囊。所使用之奈米金被證實是安全無虞可應用於微粒包覆技術,且藉由二次離子質譜儀證實TH吸附於奈米金上是屬於無破壞的物理吸附。含TH及Au之微粒膠囊(ETA)具有較延長的控制釋放行為,且其藥物包覆效率比僅含TH不含奈米金的ET微粒膠囊之藥物包覆效率來得高,且高於1.6倍。ET微粒膠囊之釋放數據較符合一階釋放動力模式,即ET微粒膠囊是屬儲主式,而ETA微粒膠囊之釋放數據較符合Higuchi間質動力模式,即TH藥物是均勻分佈於ETA微粒膠囊(非儲主式)。

本論文第三階段(第六章)的第二部份將探討以W/O型乳化溶劑揮發法製備含TH及奈米金之EC微粒膠囊,並探討使用不同濃度(100、500及1000ppm)之奈米金乙醇溶液對所製備得之微粒膠囊的影響。微粒膠囊之藥物釋放會隨著是否添加奈米金及使用不同濃度奈米金乙醇溶液而變化,且皆可達到良好控制釋放的效果。而含TH及Au之微粒膠囊(ETA)具有較延長的控制釋放行為,且使用1000ppm之奈米金乙醇溶液所製備得ETA1000微粒膠囊之藥物包覆效率比僅含TH不含奈米金的ET微粒膠囊之藥物包覆效率來得高,且高於1.7倍。以W/O型乳化溶劑揮發法製備得ET微粒膠囊之釋放數據較符合一階釋放動力模式,即ET微粒膠囊是屬儲主式,而ETA微粒膠囊之釋放數據較符合Higuchi間質動力模式,即ETA微粒膠囊是屬非儲主式。
The first section of paper describes the microencapsulation of acetaminophen (APAP) in poly(L-lactide) (PLLA) via the oil-in-water emulsification solvent-evaporation method. The thermogravimetric analysis and differential scanning calorimetry data indicated that the acetaminophen was encapsulated and uniformly distributed in the poly(L-lactide) microcapsules. The addition of either gelatin or polyvinyl alcohol as the protective colloid to the emulsion was found to have a significant impact on the resulting microcapsules. Increasing the concentration of either protective colloid in the dispersing medium increased the recovery and the release rate of acetaminophen, but reduced the particle size and loading efficiency of the microcapsules. While gelatin imparted a smooth topography to the surface of the microcapsules, PVA made the surface of the microcapsules bumpy and humped.

PLLA microcapsules containing APAP were prepared by three emulsion solvent-evaporation methods including an O/W-emulsion method, an O/W-emulsion co-solvent method and a W/O/W-multiple-emulsion method at the second section of paper. The average size and morphology of the microcapsules varied substantially among these three preparation methods. Various alcohol and alkane co-solvents were found to exert significant impact on the O/W-emulsion co-solvent method and a more lipophilic co-solvent such as heptane appeared to enhance drug encapsulation with an efficiency nearly double of the O/W-emulsion method. When a small amount of water was added as the internal aqueous phase in the W/O/W-multiple-emulsion method, the encapsulation efficiency was found nearly triple of that for the O/W-emulsion method. While having a higher encapsulation efficiency, the microcapsules prepared by the W/O/W-multiple-emulsion method had as good controlled release behavior as those prepared by the O/W-emulsion method. The release kinetics of microcapsules prepared by the O/W-emulsion method and the O/W-emulsion co-solvent (alcohol) method fitted the Higuchi model well in corroboration with the uniform distribution of APAP in PLLA matrix, i.e. the monolithic type microcapsules. However, the release kinetics of microcapsules prepared by the O/W-emulsion co-solvent (alkane) method and the W/O/W-multiple-emulsion method fitted the first-order model better, indicating the reservoir type microcapsules.

In the last section (part I) thioridazine-containing ethyl cellulose (EC) microcapsules were prepared in the presence of gold nanoparticles via the W/O/W emulsification solvent-evaporation method. The gold nanoparticles have been verified as human safe and the nondestructive physisorption of thioridazine on gold nanoparticles was corroborated with the time-of-flight second ion mass spectrometry measurements. The morphology of the formed microcapsules (ETA) changed substantially because of the presence of gold nanoparticles. In addition to a prolonged controlled release, these ETA microcapsules had an enhanced thioridazine (TH) encapsulation with an efficiency over one and half times that of the microcapsules (ET) containing no nanogold particles. While data of the release kinetics for ET microcapsules fitted the first-order model suggesting the microcapsules be of the reservoir-type, corresponding data for ETA microcapsules agreed better with the Higuchi model indicating a uniform distribution of TH in the monolithic-type microcapsules.

In the last section (part II) EC microcapsules containing TH were prepared in the presence of gold nanoparticles via the W/O emulsification solvent-evaporation method and the effects of the different concentrations (100、500 and 1000ppm) of the alcoholic nanogold solution on properties of ETA microcapsules were discussed. The drug release of the all microcapsules varied significantly depending on whether gold nanoparticles were present and the different concentrations of the alcoholic nanogold solution during the microencapsulation; all microcapsules could achieved the well-controlled release. In addition to a prolonged controlled release, these ETA1000 microcapsules had an enhanced TH encapsulation with an efficiency over one and half times that of the microcapsules (ET) containing no nanogold particles. While data of the release kinetics for ET microcapsules fitted the first-order model suggesting the microcapsules be of the reservoir-type, corresponding data for ETA microcapsules agreed better with the Higuchi model indicating a uniform distribution of TH in the monolithic-type microcapsules.
中文摘要…………………………………………………………………............Ⅰ
英文摘要…………………………………………………………………………Ⅲ
目錄………………………………………………………………………………Ⅵ
表目錄……………………………………………………………………………Ⅹ
圖目錄……………………………………………………………………………XⅡ
符號說明…………………………………………………………………….......XVⅢ

第一章 緒論………………………………………………………………….......1
1-1 研究緣由……………………………………………………………….…….1
1-2 研究動機與目的……………………………………………………………..3

第二章 原理介紹…………………………………………………………….….12
2-1 凝膠相分離法……………………………………………………………….12
2-2界面活性劑與乳化安定劑…………………………………………………..14
2-3藥物控制釋放之傳輸機構…………………………………………………..16
2-4 藥物釋放動力模式………………………………………………………….18

第三章 實驗內容………………………………………………………………..24
3-1實驗藥品……………………………………………………………………..24
3-2實驗設備與分析儀器……………………………….....................26
3-3微粒膠囊之製備……………………………………………………………..28
3-3-1 含Acetaminophen之PLLA微粒膠囊………………………………….28
3-3-1-1 O/W型乳化溶劑揮發法……………………………………….……..28

3-3-1-2 O/W共溶劑型乳化溶劑揮發法…………………………………...…29
3-3-1-3 W/O/W型乳化溶劑揮發法………………………………………..…30
3-3-2 含Thioridazine之EC微粒膠囊…………………………………….......30
3-3-2-1 W/O/W型乳化溶劑揮發法…………………………………………...31
3-3-2-2 W/O型乳化溶劑揮發法…………………………………………..…..31
3-4藥物於溶離液中之檢量線製作……………………………….………….….33
3-5微粒膠囊分析………………………………………………………………...34
3-5-1 藥物含量測定………………………………………………………….…34
3-5-2 藥物溶離試驗……………………………………………………….……34
3-5-3 掃瞄式電子顯微鏡(SEM)分析…………………………………….…….34

第四章 以不同保護膠體製備PLLA微粒膠囊之研究………………………...45
4-1 熱性質分析…………………………………………………………………..47
4-2 粒徑分佈……………………………………………………………………..47
4-3負載效果及回收率…………………………………………………………...48
4-4 表面微觀觀察………………………………………………………………..50
4-5 藥物釋放研究………………………………………………………………..50
4-6 結論…………………………………………………………………………..52

第五章 以三種不同乳化溶劑揮發法製備PLLA微粒膠囊之研究………….....66
5-1 O/W型及O/W共溶劑型乳化溶劑揮發法…………………………………68
5-2 O/W型與O/W (醇類)共溶劑型乳化溶劑揮發法之比較………………….69
5-3 O/W型與O/W (烷類)共溶劑型乳化溶劑揮發法之比較………………….70
5-4 O/W (醇類)共溶劑型與(烷類)共溶劑型乳化溶劑揮發法之比較…………71
5-5 W/O/W型乳化溶劑揮發法…………………………………………………72
5-6 釋放動力學………………………………………………………………….73
5-7 三種不同乳化溶劑揮發法之比較………………………………………….75
5-8 結論………………………………………………………………………….77

第六章 應用奈米金於微粒包覆Thioridazine藥物……………………………96
6-1 W/O/W型乳化溶劑揮發法………………………………………………….98
6-1-1 奈米金水溶液…………………………………………………………....98
6-1-1-1 奈米金水溶液之性質………………………………………………..98
6-1-1-2 兔子之皮膚刺激性測試…………………………………….……….99
6-1-1-3 老鼠之口服毒性測試………………………………………………..99
6-1-2 Thioridazine藥物吸附於金……………………………………………...99
6-1-2-1 熱重損失分析儀(TGA)……………………………………..100
6-1-2-2 紫外-可見光譜分析儀………………………………………100
6-1-2-3 二次離子質譜儀(SIMS)……………………………….…...101
6-1-3 微粒膠囊之特性……………………………………………….102
6-1-3-1 回收率………………………………………………………102
6-1-3-2 平均粒徑……………………………………………………103
6-1-3-3 藥物包覆效率……………………………………………...103
6-1-3-4 表面微觀觀察……………………………………………………..104
6-1-3-5 藥物釋放研究……………………………………………………..104
6-1-3-6 藥物釋放動力模式研究…………………………………………..105
6-1-4 結論……………………………………………………………..106

6-2 W/O型乳化溶劑揮發法………………………………………………….…108
6-2-1 奈米金乙醇溶液………………………………………………………....108

6-2-2 Thioridazine藥物吸附於金………………………………………………109
6-2-2-1 熱重損失分析儀(TGA)………………………………………109
6-2-2-2 二次離子質譜儀(SIMS)………………………………….…110
6-2-3 微粒膠囊之特性……………………………………………….111
6-2-3-1 回收率…………………………………………………….…111
6-2-3-2 平均粒徑………………………………………………….…112
6-2-3-3 藥物包覆效率……………………………………………….112
6-2-3-4 表面微觀觀察……………………………………………………...113
6-2-3-5 藥物釋放研究……………………………………………………...114
6-2-3-6 藥物釋放動力模式研究……………………………………….…..114
6-2-4 結論……………………………………………………………...116

第七章 總結...........................................................................................................151

參考文獻…………………………………………………………………….……153
發表論文………………………………………………………………………….165
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