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研究生：	楊國明 Yang, Guo-Ming
論文名稱：	藥物釋放之親疏水性乙基纖維素/羥丙基纖維素摻合微粒的製備與其藥物釋放之研究 Drug release behavior and preparation of microspheres composed of hydrophilic/hydrophobic blends of ethylcellulose and hydroxypropylcellulose
指導教授：	吳逸謨 Woo, Eamor M. 郭人鳳 Kuo, Jen-Fung
學位類別：	博士 Doctor
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2006
畢業學年度：	94
語文別：	中文
論文頁數：	159
中文關鍵詞：	控制釋放、微粒、微粒膠囊、兩階段、乙基纖維素、羥丙基纖維素
外文關鍵詞：	microsphere, controlled release, hydroxypropylcellulose, two stages, microcapsule, ethylcellulose
相關次數：	點閱：187 下載：3
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　　本論文是以微粒包覆技術來製備微粒膠囊以求達到藥物控制釋放，本研究採用新式oil/oil懸浮蒸發法成功製得不同基材疏水性乙基纖維素 (EC) 和親水性羥丙基纖維素 (HPC) 適當的微粒膠囊。並且探討水溶解性藥物captopril (CAP) 微粒膠囊及難溶解性藥物isosorbide dinitrate (ISDN) 的不同釋放機制。
　　首先是以oil/oil懸浮蒸發法製備EC和HPC為基質的水溶解性藥物CAP微粒膠囊，探討微粒膠曩粒徑及大小分佈的影響便變因，並尋找製備EC/HPC/CAP微膠囊粒徑250-425μm最多產量的操作條件。接著再以X射線及接觸角試驗和紫外線光譜鑑定微膠囊特性。用以研究藥物延遲釋放的微膠囊粒徑250-425μm，並加以探討不同EC/HPC組成的微膠囊釋放模式。以累計溶離試驗測定各時間微粒膠囊的CAP釋放行為，其結果前0.7小時遵守一階釋放動力模式，而釋放時間從2到10小時則是零階釋放動力。其一階釋放及零階釋放動力的速率常數與EC/HPC組成呈線性關係。
　　接著再探討難溶性藥物ISDN以oil/oil懸浮蒸發法製備延遲釋放的微膠粒。以EC和HPC作基材製備成含ISDN的微膠粒。四種EC/HPC不同比例(EC的重量組成為 1, 0.833, 0.67 and 0.5)和三種粒徑(100-150, 250-300, and 400-450 μm)作為微粒膠曩基質的ISDN釋放行為探討。EC/HPC組成在接觸角試驗的結果中，以EC/HPC組成3:3為分界，分為兩段的直線分別探討之。首先分析沒有明顯膨潤部份的EC:HPC= 6:0，5:1，4:2，3:3，比較不同顆粒大小及高分子組成的ISDN顆粒作體外試驗( in vitro ) 的累計釋放量關係，粒徑大小對於藥物釋放行為的影響比高分子組成明顯。在高HPC組成和較小粒徑顯示較多藥物殘留量和釋放速度較快。400-450μm粒徑的微粒膠曩顯示較慢的藥物釋放速率和較大的藥物殘留量，所以藥物釋放動力與粒徑大小和高分子組成有關。粒徑在100-150μm時，顯示藥物呈單一階段的擴散控制機制，另一方面，其他250-300μm及400-450μm這兩種粒徑微粒膠曩則顯示兩階段的Higuchi平方根時間帶有遲滯時間的釋放機制。
　　探討難溶性藥物ISDN以oil/oil懸浮蒸發法製備延遲釋放的微膠粒系統，以高成份HPC和低成份 EC為速度控制的基材。研究的主要目的是探討高成份的HPC (EC:HPC=2:4,1:5,0:6)的微粒膠囊基材對難溶性藥物ISDN釋放速率的影響及藥物釋放機制。以微粒和薄膜兩種製備方法探討藥物釋放的模式。在以具有明顯膨潤部份的EC:HPC=2:4，1:5，0:6作基材製備成含ISDN的微粒膠曩，其釋放行為是零階模式釋放且沒有明顯的遲滯時間。而模擬組成薄膜則出現兩個階段的釋放模式，前段是零階釋放模式，而後段是Higuchi平方根時間帶有遲滯時間的釋放機制，依照SEM照片及動力模式可探知薄膜的外層積存的藥量較多，故EC/HPC/ISDN薄膜前段可得到零階釋放模式；而內部ISDN分佈則因為有濃度梯度發生，所以後段釋放則以Higuchi平方根時間擴散模式，如此說明依本系統製備的EC/HPC/ISDN微膠囊是還是屬於核-殼型態的擴散模式，只是當高的HPC/ EC比值時，顆粒吸水太快，則藥物釋放的溶蝕速率和基質吸水膨潤剛好達到平衡，形成只有單一階段釋放溶離模式。且微粒膠囊的皮層相對於膜太薄，故很快地整個玻璃狀態部分立刻被水攻擊而成微粒膠囊內部濃度均勻，且遠大於外界濃度，所以微粒膠囊內ISDN的釋放是單一階段零階的機制，而膜呈現較大厚度，水的滲透和基質的膨潤需時較久，所以會有兩段式的釋放模式。

　In this work, the technology of microencapsulation is adopted to prepare the microspheres to obtain the controlled drug release. The study adopts the novel system of oil in oil suspention evaporation method to obtain various matrixes of microspheres successfully by hydrophobic ethylcellulose (EC) and hydrophilic hydroxypropylcellulose (HPC), and to approach various mechanisms from water-soluble drug captopril (CAP) and poorly soluble drug isosorbide dinitrate (ISDN).
　First, the microcapsules were prepared using the oil in oil suspention evaporation method for sustained release of water-soluble drug CAP from microcapsules composed of EC and HPC. Factors affecting the size and size distribution of microcapsules were investigated. The optimum conditions on the maximum products of 250-425μm of EC/HPC/CAP microspheres particle size were fined as well. The 250-425μm microcapsules were characterized using an x-ray diffractometer, static contact angle instrument and UV/visible spectrophotograph. The microcapsules for the sustained release were studied on the various EC/HPC compositions. The cumulative releases of CAP from the microcapsules at various times were measured. The results could be well described by a first order release kinetics for the first 0.7 hours and zero order release kinetics for the release time from 2 to 10 hours. The rate coefficients of first and zero-order stages linearly depended upon the EC/HPC composition.
　Therefore, microcapsules for sustained release of poorly soluble isosorbide dinitrate (ISDN) were prepared based on EC and/or HPC as matrix materials using the oil in oil suspention evaporation method. The release behaviors of microspheres were studied by four EC/HPC compositions (1, 0.833, 0.67 and 0.5 weight fraction EC) and three-mode sizes (100-150, 250-300, and 400-450 μm). The result of the static contact angle of EC/HPC composition was obtained with further respective discussion by dividing the lines of demarcation into two parts as EC/HPC = 3/3. Above all, the part of non-obvious swelling EC: HPC= 6:0, 5:1, 4:2, 3:3 was analyzed. The cumulative amounts of ISDN releasing from the microspheres as functions of mode fractions size and polymer compositions were measured in vitro. It was observed that the microspheres’ size influenced the release behavior of drug more obviously than the polymer composition. The higher hydrophilic HPC content and the smaller size reveal that the faster release rate of drug and the smaller amount of drug residue. The microspheres of 400～450 μm exhibit a slow drug release rate and larger fraction of drug residues. The kinetics of drug release depends on the size and polymer composition. The microspheres with 100-150 μm, of all polymer compositions, present one-stage diffusion kinetic with a lag period for drug release. On the other hand, the microspheres with the other 250-300μm and 400-450μm sizes exhibit two-stage diffusion kinetic with a lag period.
　The novel system of microencapsulation for sustained release of poorly soluble isosorbide dinitrate (ISDN) was prepared by using the oil/oil suspension evaporation method. More content Hydroxypropyl cellulose (HPC) and poorer content ethylcellulose (EC) were used as a rate-controlled matrix. The aim of this study was to investigate the effect of the more content HPC (EC: HPC= 2:4, 1:5, 0:6) of microspheres matrix on the release rate of an incorporated ISDN drug and drug release kinetics. In vitro drug release models, the preparation methods of microspheres and films were measured. The ISDN microspheres of the more content HPC of microspheres matrix present one-stage diffusion kinetic with no clear lag period for drug release. On the other hand, the films with oil/oil suspension evaporation method exhibit two-stage diffusion kinetic for drug release. The former release stage exhibits zero-order dissolution model while the latter release stage exhibits Higuchi square time diffusion model. According to SEM picture and the kinetic model, the outer layer with a large amount of drug is obtained. Therefore, the former mechanism of EC/HPC/ISDN is zero order kinetics. Nevertheless, the gradient concentrations are occurred in the inner part, thus the latter release part is Higuchi square time diffusion model. The microspheres obtained are still surmised to have a core-shell morphology but the skin of the microsphere is a very thin wall allowing high release rates to present one-stage release model. However, when the high ratio EC/HPC matrix of microsphere water uptake too fast, the erosion rate of drug release and matrix water uptake to swell and reach the equilibrium. The outer skin is so thin that the release rate is too fast, so there is only a zero-order release model while the microsphere is too small and the outer layer is too thin. The water immediately uptakes the whole glassy state, so the inner part concentration of microspheres is homogeneous. Because the concentration is larger than the outer part, the ISDN release from the microspheres belongs to zero order mechanism. Also the skin layer of microsphere is comparatively much thinner than the film, so the water immediately attacked the whole glassy state to form the homogeneous inner concentration of the microsphere, which is far larger than the outer concentration. So the ISDN release kinetics of the microsphere is one stage of zero-order kinetics. However, the film presents larger thickness than microsphere that it needs more time for the penetration of water and the swelling of matrix, so the kinetics is two stages controlled release.

摘要								  I
Abstract 								 IV
誌謝								 IX
目錄 								 XI
表目錄								XIV 
圖目錄								 XV 
符號說明								XXI
第一章	緒論	         						  1
第二章	原理與文獻回顧						  4
	2-1控制釋放系統	  	 				  4
	2-2控釋系統之分類						  5
	2-2-1擴散控制系統						  5
	2-2-2基質擴散系統						  7
	2-2-3膨脹控制系統						  9
	2-2-4溶蝕控制系統						  9
	2-2-5化學控制系統						 10
	2-2-6化學固定系統						 11
	2-2-7滲透壓幫浦						 12
	2-3控釋系統之應用						 13
	2-3-1農業之應用	 					 13
	2-3-2生物殺蟲劑						 14
	2-3-3船用塗料						 14
	2-3-4醫藥之應用						 15
	2-3-5其他應用						 18
	2-4控制藥物釋放傳輸					 19
	2-4-1貯藏室系統	 					 20
	2-4-2均質分散式系統					 21
	2-4-3侵蝕性系統						 21
	2-5微粒膠囊						 25
	2-6微粒包覆						 26
	2-6-1微粒包覆技術						 26
	2-6-2微粒膠囊的特點					 29
	2-6-3微粒膠囊化法						 31
	2-6-3-1物理化學方法					 32
	2-6-3-2化學方法						 33
	2-6-3-3.機械方法						 34
	2-6-4 微膠囊之藥物釋放數學模式				 35
第三章	實驗							 41
	3-1實驗藥品						 41
	3-2實驗儀器與設備						 43
	3-3 實驗方法						 44
	3-3-1EC/HPC/CAP微膠囊的製備					 44
	3-3-2EC/HPC/ISDN微粒製備					 44
	3-3-3製備所得微粒膠囊的大小分佈				 44
	3-3-4藥物溶出量						 45
	3-3-5溶離試驗						 45
	3-3-6薄膜的製備						 46
	3-3-7 顆粒特性測試						 47
	3-3-8人工胃液的製備					 47
	3-3-9人工腸液的製備					 47
第四章	結果與討論						 48
	4-1水溶解性藥物captopril (CAP) 在EC/HPC微粒膠囊的釋放機制	 50
	4-1-1前言							 50
	4-1-2 結果與討論						 52
	4-1-3 結論						 58
	4-2高比率EC/HPC為疏水性基材之isosorbide  dinitrate
           微膠粒製備與釋放機制之研究	 			 75
	4-2-1前言							 76
	4-2-2結果與討論					 	 77
	4-2-2-1顆粒的特徵						 77
	4-2-2-2 ISDN 製備顆粒的溶離試驗				 79
	4-2-2-3 藥物釋放動力					 80
	4-2-3 結論						 84
	4-3難溶解性藥物isosorbide dinitrate (ISDN) 在EC/HPC親水部
           分較多之微膠囊粒的釋放機制				 96
	4-3-1 前言						 96
	4-3-2 結果與討論						 97
	4-3-3 結論						102
第五章	總結							135
	參考文獻							138
	作者簡介							157

表目錄
Table 2-1 Polymer materials for controlled release		 	 23
Table 4-1 Composition of EC/HPC/CAP microcapsules			 58
Table 4-2 Weight fraction of mode fraction sizes and drug 
	 concentration of microspheres				 85
Table 4-3 Drug residue and diffusion parameters of the drug 
	 release from the microspheres obtained as functions 
	 of size and polymer composition				 86
Table 4-4 Composition of EC/HPC/ISDN microcapsules 			104
Table 4-5 Drug residue and diffusion parameters of the drug 
	 release from the microspheres and films obtained 
	 as functions of the polymer composition. 
	 (m) microsphere  (f) film					105
Table 4-6 Behaviors of water uptake of EC and/or HPC blends 
	 membranes without ISDN					106
Table 4-7 Behaviors of water uptake of EC and/or HPC blends 
	 membranes with ISDN					107

圖目錄	
Figure 2-1  Cross-section of spheres or cylinder of reservoir devices 	  6
Figure 2-2  Matrix diffusion system（a）cross-section of matrix 
            diffusion systems （b）various ratio drug dispersed 
            in polymer matrix					  8
Figure 2-3  Swelling-controlled systems				  9
Figure 2-4  Erosion-controlled systems				 10
Figure 2-5  Biodegradable systems					 11
Figure 2-6  Chemical bonding systems					 12
Figure 2-7  Structure of the osmotic pump systems			 13
Figure 2-8  Comparison of the drug concentration after using 
            the various pesticides					 14
Figure 2-9  Degradation diffusion mechanism				 15
Figure 2-10 Drug level vs. time (a) tradition drug formula 
            (b) controlled release drug formula (c) injection		 16
Figure 2-11 Mechanism and model of controlled drug release		 20
Figure 2-12 Application of microencapsulation				 27
Figure 2-13 Various types of microcapsule				 29
Figure 2-14 Effect of drug stability for microcapsules			 30
Figure 4-1  Effect of stirring rates on microcapsule size distribution	 60
Figure 4-2  Effect of polymer concentration on microcapsule 
            size distribution					 61
Figure 4-3  Effect of non-solvent adding rate on microcapsule 
            size distribution					 62
Figure 4-4  Effect of drug/polymer ratio on microcapsule 
            size distribution					 63
Figure 4-5  Plot of degree of crystallinity and contact angle vs. 
            matrix composition for microcapsules			 64
Figure 4-6  In vitro release profiles of CAP microcapsules 
            (A1-A7 in Table 4-1)					 65
Figure 4-7  Plot of first-order release shorter than 0.7 hr
            (A1-A7 in Table 4-1)					 66
Figure 4-8  Plot of release drug wt% vs. square root of dissolution 
            time for the release shorter than 0.7 hr 
            (A1-A7 in Table 4-1)					 67
Figure 4-9  Relation of K1, tlag, and composition			 68
Figure 4-10 Relation of K2, residue drug and composition		 69
Figure 4-11 X-ray diffraction of microspheres				 70
Figure 4-12 SEM pictures of various composition (A1-A7 in Table 4-1)	 74
Figure 4-13 Wide angle x-ray diffraction of (A) isosorbide dinitrate 
            (B) microspheres with various polymer compositions: 
            A1 = E0.5H0.5; A2 = E0.67H0.33; A3 = E0.83H0.17.		 87
Figure 4-14 Static contact angles of water on films of EC/HPC polymer 
            blend with various compositions				 88
Figure 4-15 SEM illustration for microspheres, 
            (A)E0.83H0.17 and (B)E0.5H0.5				 89
Figure 4-16 Dissolution curve of ISDN in water at 37oC and 100 rpm.	 90
Figure 4-17 Plots of cumulative release drug wt% vs. time of the 
            microcapsules obtained as functions of size and 
            polymer composition of microspheres. 
            L(i), M(i) & S(i) is indicated in Table 4-3.		 91
Figure 4-18 Plots of cumulative release drug wt% vs. the 
            square root of time for ISDN releasing from the 
            small microspheres.  
            S1 E0.5H0.5, S2 E0.67H0.33, S3 E0.83H0.17, S4 EC.		 92
Figure 4-19 Plots of cumulative release drug wt% vs. 
            square root of time for ISDN releasing from the 
            medium microspheres. 
            M1 E0.5H0.5, M2 E0.67H0.33, M3 E0.83H0.17, M4 EC.		 93
Figure 4-20 Plots of cumulative release drug wt% vs. the square root 
            of time for ISDN releasing from the large microspheres.  
            L1 E0.5H0.5, L2 E0.67H0.33, L3 E0.83H0.17, L4 EC. 		 94
Figure 4-21 Cumulative release wt% vs. square root of time lines of 
            ISDN released from ethyl cellulose–made microspheres 
            replotted from Fig. 9 of Dinarvand et al. (2000).		 95
Figure 4-22 Schematic representation of the solvent dissolution 
            process of a polymer slab				108
Figure 4-23 General schematic profile for the release of a 
            dispersed solute from an erodible polymer matrix		109
Figure 4-24 Schematic drawing of observed swelling boundaries and 
            dimensional changes during drug release in relation to 
            drug solubilities					110
Figure 4-25 Plots of cumulative release ISDN wt% vs. time from 
            the microcapsules with various compositions		111
Figure 4-26 Plots of cumulative release ISDN wt% vs. time from 
            the microcapsules with various films			112
Figure 4-27 Water uptake of HPC film with or without ISDN		113
Figure 4-28 Water uptake of E1H5 film with or without ISDN		114
Figure 4-29 Water uptake of E2H4 film with or without ISDN		115
Figure 4-30 Plots of cumulative release ISDN wt% vs. time for Films 
            obtained shorter than 1 hour				116
Figure 4-31 Plots of cumulative release ISDN wt% vs. square time for 
            films obtained after 2 hour				117
Figure 4-32 SEM picture of surface of E2H4 film			118
Figure 4-33 SEM picture of cross-section of HPC film			119
Figure 4-34 SEM picture of cross-section of E1H5 film			120
Figure 4-35 SEM picture of cross-section of E2H4 film			121
Figure 4-36 Photographs of apparent changes of HPC films with and 
            without ISDN as functions of immersion time of water	125
Figure 4-37 Photographs of apparent changes of E1H5 films with and 
            without ISDN as functions of immersion time of water	129
Figure 4-38 Photographs of apparent changes of E2H4 films with and 
            without ISDN as functions of immersion time of water	133
Figure 4-39 Photographs of apparent changes of E2H4 dry films with 
            and without ISDN					134
                                    

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