含水溶性藥物之乙基纖維素微膠囊的製備

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蔡燕鈴(Yian-Lin Tzai) 查詢紙本館藏

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論文名稱

含水溶性藥物之乙基纖維素微膠囊的製備

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摘要(中)

本研究利用二次包覆法與O/W乳化溶劑揮發法製備乙基纖維素微膠囊，採用之核心物質為茶葉鹼，溶劑為二氯甲烷。二次包覆法係利用有機溶液添加非溶劑相分離法製備核物質，再利用乳化添加非溶劑相分離法完成微膠囊包覆。
變化二次包覆法之核物質與第二次包覆之乙基纖維素比值，改變以O/W乳化溶劑揮發法製備微膠囊時共溶劑共溶劑之種類。並對於這些不同變數造成的微膠囊粒徑變化、表面形態、藥物損失、藥物釋放速率與微膠囊之溶出動力學加以比較分析。
微膠囊之粒徑變化受高分子溶液黏度、相分離速率、高分子液滴與水相之界面張力影響。二次包覆之微膠囊不管核物質為何種系列，其總EC/TH之比值為最高時(1.0)，粒徑皆較其餘比值為小，這是由於高的高分子溶液黏度造成高分子鏈過快沉析所致。以O/W乳化溶劑揮發法製備微膠囊時，大部份極性共溶劑的添加會減低高分子液滴與水相間之界面張力，使微膠囊粒徑減小，但添加量較多時溶劑擴散速率較快，使包覆溶液黏度較大而有較大之粒徑。烷類溶劑的添加則會降低包覆溶液的黏度，使微膠囊粒徑因而減小。
以二次包覆法製備微膠囊與以O/W乳化溶劑揮發法製備微膠囊共溶劑的添加均有減少藥物損失趨勢，其以O/W乳化溶劑揮發法中添加烷類對藥物損失減少約20％最有效用。由於二次包覆法兩層EC膜厚度與殼質結構的變化，使微膠囊溶出速率呈現較多變化，而有較寬廣的藥物溶出速率範圍。以O/W乳化溶劑揮發法製備微膠囊時，影響微膠囊藥物溶出速率因素為：1.微膠囊在水相中之硬化時間，2.高分子鏈之伸展程度， 3.殘餘溶劑的量。由於這三種因素競爭的結果，使得微膠囊藥物溶出速率範圍廣泛。以非溶劑添加相分離法製備微膠囊時，其T20範圍從2.7到7.7小時，但以二次包覆法變化不同EC/TH比值所製備之微膠囊，T20範圍則從2小時拓展到35.4小時，藥物制放範圍明顯增大。共溶劑所製備微膠囊之T20的變化，可自4小時延長至71.3小時，其對藥物溶出範圍之增廣效果更佳。
在溶出動力學方面，因二次包覆之微膠囊呈不均齊形態之藥物分佈，故可符合零階溶出模式。無論添加何種醇類製備微膠囊，其藥物釋放量皆有至少30％符合零階溶出模式。而添加烷類製備微膠囊時，由於正己烷、正庚烷等較低碳數烷類之沸點較低，其添加造成較疏鬆的微膠囊殼層使藥物由內溶出時受到的孔道阻力較低，故其較添加正辛烷、正壬烷、正癸烷等高碳數烷類有較多百分比符合零階溶出模式。但當添加正辛烷、正壬烷、正癸烷為25％時由於有較多的溶劑殘留，使得微膠囊於後處理時形成較多之孔洞而減少孔道阻力，而有更高之百分比符合零階溶出模式。

摘要(英)

The double-encapsulated microcapsules were prepared by the non-solvent addition phase-separation method to form the first encapsulated microcapsule and, then, were encapsulated again using the O/W emulsion non-solvent addition method to mitigate drug loss and achieve zero-order sustained-release. The O/W emulsion solvent evaporation method was also used to prepare the microcapsules for mitigating drug loss and achieve zero-order sustained-release. Theophylline and ethylcellulose were used as the core material and shell material, respectively. The effects of the total TH/EC ratios of the double-encapsulation emulsion non-solvent addition method on particle size, surface morphology, drug loss, release rate and release behavior of microcapsules were investigated.
The particle size of microcapsules was affected by the viscosity of the polymer solution, the rate of phase-separation and the interface-tension between the polymer solution droplet and water phase. In the double-encapsulated process, the particle size of the microcapsules was the smallest when the total EC/TH ratio was 1.0. This was due to the high viscosity of the polymer solution causing the polymer chain to precipitate too quickly. In the O/W emulsion solvent evaporated process, because the interface-tension between the polymer solution droplet and water phase was reduced so that the particle size of microcapsules was small by adding the polar co-solvent. When the added amount of polar co-solvent was over a specific level, the viscosity of the polymer solution could be increased to cause a large particle size. The particle size of the microcapsules could be reduced when an amount of alkane co-solvent added to the polymer solution was decreased.
The drug loss could be mitigated whenever microcapsules were prepared by the double-encapsulation method or O/W emulsion solvent evaporation method. The drug loss could be especially mitigated by about 20% when the microcapsules were prepared by adding an alkane co-solvent during the O/W emulsion solvent evaporated process. The range of the drug-release rate of the double-encapsulated microcapsules was broad due to the change in the thickness and construction of the double EC film. When the microcapsules were prepared by the O/W emulsion solvent evaporation method, the factors affecting the drug-release rate of the microcapsules were : 1. the time the microcapsules hardened in the water phase, 2. the extent to which the polymer chain stretched, 3. the amount of non-solvent remaining. The range of the drug-release rate of the microcapsules was also influenced by these three factors. The range of T20 could be drastically extended from 2.7 — 7.7 hours that of single-encapsulated microcapsules to 2 — 35.4 hours. In the O/W emulsion solvent evaporation process, the T20 of the microcapsules prepared by adding a co-solvent could be extended from 4 hours to 71.3 hours. Thus, the range of the drug-release rate was broader than the others.
As for dissolution kinetics, the double-encapsulated microcapsules could fit a zero-order release model due to its nonuniform drug distribution dosage form. At least the first 30% of the drug released fit a zero-order release model whenever any kind of alcohol co-solvent was added to prepare the microcapsules. The release behavior of the microcapsules prepared by adding n-hexane and n-heptane in the O/W emulsion solvent evaporated process was closer to zero-order than that of the microcapsules prepared by adding n-octane, n-nonane and n-decane. This was because the boiling points of n-hexane and n-heptane are lower than those of the other three alkane co-solvents resulting in their microcapsules possessing a more porous structure. When the added amount of n-octane, n-nonane and n-decane was 25%, more co-solvent remained so that when the remained co-solvent was removed by after treatment, the porosity increased, and, therefore, the resistance to the drug release was decreased. This resulted in their released behavior fitting more closely to a zero-order released model.

關鍵字(中)

★ 乙基纖維素

關鍵字(英)

論文目次

中文摘要……………………………………………………….Ι
表索引………………………………………………………….
圖索引………………………………………………………….
第一章緒論…………………………………………………..1
第二章二次包覆法製備乙基纖維素微膠囊………………..9
2-1前言…………………………………………………………………9
2-2實驗…………………………………………………………………10
2-2-1實驗材料………………………………………………………….10
2-2-3核物質之製備…………………………………………………….11
2-2-4微膠囊之製備…………………………………………………….11
2-2-5藥物損失與藥物含量之測定…………………………………….12
2-2-6微膠囊內茶葉鹼含量測定……………………………………….13
2-2-7藥物溶出試驗……………………………………………………13
2-2-8掃描式電子顯微鏡觀察………………………………………….16
2-3結果與討論………………………………………..…………….….16
2-3-1核物質之性質………………………………………………...…..16
2-3-1-1產率和粒徑分佈……………………………………………….16
2-3-1-2表面形態……………………………………………………….18
2-3-1-3釋放速率……………………………………………………….18
2-3-2微膠囊的性質…………………………………………………….22
2-3-2-1粒徑大小………………………………………………………..22
2-3-2-2藥物損失……………………………………………………….23
2-3-2-3藥物釋放速率…………………………………………………..23
2-3-2-4表面形態……………………………………………………….25
2-4結論…………………………………………………………………26
第三章以O/W乳化溶劑揮發法製備乙基纖維素微膠囊…29
3-1前言…………………………………………………………………29
3-2實驗…………………………………………………………………30
3-2-1實驗材料………………………………………………………….30
3-2-2微膠囊之製備…………………………………………………….30
3-2-3藥物含量測定…………………………………………………….32
3-2-5掃瞄式電子顯微鏡觀察………………………………………….33
3-3結果與討論………………………………………………..………..33
3-3-1 PVA含量………………………………………………………....33
3-3-2系統溫度…………………………………………………………34
3-3-3高分子溶液濃度…………………………………………………42
3-3-4結論………………………………………………………………50
第四章共溶劑的添加製備乙基纖維素微膠囊………....…..51
4-1前言…………………………………………………………………51
4-2實驗…………………………………………………………………51
4-2-1實驗材料………………………………………………………….51
4-2-2微膠囊之製備…………………………………………………….52
4-2-3藥物損失與藥物含量測定……………………………………….52
4-2-4藥物溶出試驗…………………………………………………….53
4-2-5掃描式電子顯微鏡觀察………………………………………….53
4-3結果與討論…………………………………………………………53
4-3-1丙酮/二氯甲烷系列之探討………………………………………53
4-3-2異丙醇/二氯甲烷系列之探討……………………………………59
4-3-3四氯化碳/二氯甲烷系列之探討…………………………………63
4-4結論……………………………………………………...………….67
第五章添加醇類共溶劑的對乙基纖維素微膠囊性質之影響
…………………………...……………………………………71
5-1前言………………………………………………………………..71
5-2實驗………………………………………………………………..71
5-2-1實驗材料………………………………………………………..71
5-2-2微膠囊之製備…………………………………………………..72
5-2-3藥物損失與藥物含量測定………………………………….….73
5-2-4藥物溶出試驗……………………………………………….….73
5-2-5掃描式電子顯微鏡觀察…………………………………….….73
5-3結果與討論…………………………………….…………………73
5-3-1甲醇/二氯甲烷系列……………………………………………73
5-3-2乙醇、丙醇/二氯甲烷系列……………………………………79
5-3-3丁醇、戊醇/二氯甲烷系列……………………………………79
5-4結論………………………………………………………………95
第六章添加非極性共溶劑對乙基纖維素微膠囊性質之影響
………………………………………………………………100
6-1前言………………………………………………………………100
6-2實驗………………………………………………………………100
6-2-1實驗材料……………………………………………………….100
6-2-2微膠囊之製備………………………………………………….101
6-2-3藥物損失與藥物含量測定…………………………………….101
6-2-4藥物溶出試驗………………………………………………….101
6-2-5掃描式電子顯微鏡觀察…………………………………….....101
6-3結果與討論…………………………………………………..……101
6-3-1正己烷/二氯甲烷系列…………………………………………..101
6-3-3正庚烷、正辛烷、正壬烷、正癸烷/二氯甲烷系列…………..103
6-4結論…………………………………………...…………………...126
第七章藥物釋放動力學探討與零級釋放模式之追求....…127
7-1前言……………………………………………………………….127
7-2理論……………………………………………………………….130
7-3二次包覆微膠囊之溶出動力學………………………………….132
7-4以共溶劑製備而得微膠囊之溶出動力學……………………….141
7-5結論……………………………………………………………….149
第八章總結…………………………………………………150
參考文獻………………………………………………………………154
發表文獻………………………………………………………………168

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指導教授

陳暉(Hui Chen)

審核日期

2000-7-10

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