藥物與人類是密不可分的，不論是醫藥、農藥等產品，都與日常生活息息相關，有些藥物若投藥過量會產生副作用或造成農作及環境的傷害，而藥量太少則失去藥效，因此藥物控制釋放遂成為藥物應用重要的一環；本實驗以超臨界二氧化碳為工具藉以製備藥物控制釋放粒子，一方面減少有機溶劑的使用，一方面則可藉其絕佳的滲透性來去除藥劑中殘留的有機溶劑而避免投藥所造成的傷害。
超臨界流體製造微奈米級粒子技術常被應用在兩個方面：一為製造高表面積比的微粒子，此類粒子多應用在反應的催化；另一為雙物質系統，利用超臨界流體所製備出的多孔性微粒子(microspheres)吸附揮發性物質，或以基質包覆藥物形成微膠囊(microcapsules)，以達到控制釋放之效果。
由超臨界製程所製備出的催化劑粒子，具有相當大的孔洞體積，因而增大其表面積以增強催化效果，並能減少用量，降低成本。所製得之多孔性高分子可使藥物均勻分佈在內而緩解釋出。此外，超臨界流體可經由特殊的設計來製造微膠囊；如超臨界流體增大╱分散溶液－Solution Enhanced Dispersion by Supercritical fluids (SEDS)所製造出來的微膠囊粒子可應用在藥物遞送元件中，並提供多方面的研究。
本論文主要分為兩部份探討：一為SEDS製程中各變因對製得粒子尺寸的影響，其中包含膨脹槽的壓力及溫度、藥物及基質的質量比以及藥物及基質溶液的流速等；另一則為所製得之阿司匹靈╱乙基纖維素粒子在模擬胃液中控制釋放的研究及其釋藥動力模式，其中包括粒子尺寸、藥物基質質量比及其流速快慢對所得粒子在模擬胃液中的釋藥行為及釋藥模式的影響並做一系列的探討。

Medicines are important for human beings. Both medical and chemical products are related as closely as each breath to the daily live. Some drugs would induce side effect or damage the crops and environment by overdosing or cumulating, but lose its effect by not enough dosing. To overcome the situation, controlled-release of drugs becomes an important issue. This study is to producing controlled-release drug by supercritical carbondioxide process which has the benefit of decreasing the consuming of organic solvent.
The techniques of making sub-micro particles by supercritical fluid process are applicated in two territories: one is to make micro particles with high surfacing area to catalyze reactions; the other is composite system for microspheres or microcapsules; the former can absorb vaporous compounds, the latter are medicine-encapsulate by polymeric matrixes. Both of them have controlled release behavior.
Catalytic particles made by supercritical fluids have quite large pore volume to induce its catalytic power, reduce the necessary amounts of catalysis and lower the costs. Drug releasing for microspheres could also be controlled. Besides, microcapsules can be made by supercritical fluid techniques such as solution enhanced/dispersion by supercritical fluids (SEDS).
This thesis contains two parts: one is the studying on each factor in SEDS that could influences on particle size such as the pressure and the temperature of expansion vessel, the ratio of drug/matrix and the flow rate of drug and matrix solution. The other is the controlled-release behaviors of aspirin/ethyl cellulose sub-micro particles in synthetic gastric juice. The factors which affect the conditions and the mode of drug releasing include the particle size, drug/matrix ratio and the flow rate of solutions would be discussed.

誌謝……………………………………………………………………..Ⅰ
摘要…………………...…………………………………………...…....Ⅲ
英文摘要……………………………………………………………….Ⅴ
目錄……………………………………………………………………..Ⅶ
表目錄…………………………………………………………………..Ⅹ
圖目錄………………………………………………………….…...ⅩⅠ
第一章　緒論……………………………………………………………1
第二章　控制釋放技術…………………………………………………3
2-1 藥物控制釋放技術…………………………………………….3
2-2 傳統藥劑與控制釋放藥劑釋藥途徑的比較………………….5
2-3 控制釋放微粒釋藥情形……………………………………...10
2-4 藥物控制釋放動力模式……………………………………...16
第三章　微粒包覆技術………………………………………………..20
　　3-1 微粒包覆技術…………………………….…………………..20
　　3-2 微粒包覆製程簡介……………………….…………………..22
第四章　超臨界流體製備微奈米粒子………………………………..25
　　4-1 超臨界流體的定義…………………………………………...25
　　4-2 超臨界流體的特性…………………………………………...27
　　4-3超臨界二氧化碳………………..…………………………...27
4-4 超臨界流體製備微奈米粒子技術…………………………28
第五章　實驗內容…………………………………………………….37
　　5-1 實驗設備……………………………………………………...37
5-1-1 超臨界流體增大╱分散溶液(SEDS)實驗裝置………...37
5-1-2 模擬胃液控制釋放實驗………………………………37
5-1-3 藥品及溶劑……………………………………………...39
　　5-2 實驗架構……………………………………………….……..39
5-2-1 膨脹槽壓力與溫度……………………………………...41
5-2-2 藥物基質比及溶液流速………………………………...41
5-3 分析部份……………………………………………………...43
5-3-1 檢量線的配製…………………………………………...43
5-3-2 模擬胃液的組成……...…………………………………43
5-3-3 粒子中的藥物分析...…………………………………44
5-3-4 模擬胃液實驗...…………………………………………44
5-3-5 粒子尺寸分析...…………………………………………45
第六章　結果與討論…………………………………………………..46
6-1溫度與壓力對粒子尺寸之影響………………………………46
6-1-1膨脹槽壓力對粒子尺寸之影響…………………………52
6-1-2膨脹槽溫度對粒子尺寸之影響…………………………52
6-2藥物基質比與溶液流速對粒子尺寸之影響…………………56
6-2-1藥物基質比對粒子尺寸之影響……….…..……………56
6-2-2溶液流速對粒子尺寸之影響…………….……………61
6-3流速與藥物基質比對模擬胃液實驗之影響…………………63
6-4模擬胃液實驗之動力模式探討………………………………69
6-5 膨脹槽內徑大小對粒子尺寸及模擬胃液…………………...79
第七章　結論…………………………………………………………..84
參考文獻………………………………………………………………..85
表　目　錄
表一 氣體、超臨界流體與液體的一般物理性質…………………….27
表二 各種化合物的超臨界性質………………………………………29
表三 藥品列表………………………………………………………....39
表四 實驗設計(1)……………………………………………………...42
表五 實驗設計(2)……………………………………………………...42
表六 各實驗條件所得之粒子尺寸……………………………………51
表七 各製程的粒子尺寸………………………………………………62
表八 不同膨脹槽尺寸所得之粒徑大小………………………………79
圖 目 錄
圖1　一般藥劑釋放的輸送途徑………………………………………..6
圖2　控制釋放劑型的輸送途徑………………………………………..6
圖3　藥物釋放濃度與時間之關係……………………………………11
圖4　儲主式形狀及其藥物釋放速率與時間之關係…………………12
圖5　非儲主式形狀及其藥物釋放速率與時間之關係………………12
圖6　理想的零階釋放動力模式 (a)釋藥速率與時間的關係圖；(b)釋
藥總量與時間的關係圖…………………..……………………14
圖7　時間延遲及突釋效應……………………………………………15
圖8　一般純物質之三相…………………………………………...….26
圖9　RESS製程流程…………………………………………………32
圖10　GAS/SAS製程流程…………………………………….………34
圖11　SEDS製程流程圖……………………………………………...36
圖12　SEDS三套管設計圖…………………………………………...36
圖13 自組SEDS裝置流程圖……………………………………….…38
圖14 實驗架構…………………………………………………………40
圖15 在藥物基質比(D：M = 1：1)及高流速條件下膨脹槽溫度為40 ℃、膨脹槽壓力分別為 (a) 800 psi；(b) 1200 psi；(c) 2000 psi；(d) 3000 psi所製得之粒子…..…………………………………47
圖16 在藥物基質比(D：M = 1：1)及高流速條件下膨脹槽溫度為50 ℃、膨脹槽壓力分別為 (a) 800 psi；(b) 1200 psi；(c) 2000 psi；(d) 3000 psi所製得之粒子……………….….…………………48
圖17 在藥物基質比(D：M = 1：1)及高流速條件下膨脹槽溫度為60 ℃、膨脹槽壓力分別為 (a) 800 psi；(b) 1200 psi；(c) 2000 psi；(d) 3000 psi所製得之粒子………………...….…………………49
圖18 在藥物基質比(D：M = 1：1)及高流速條件下膨脹槽溫度為70 ℃、膨脹槽壓力分別為 (a) 800 psi；(b) 1200 psi；(c) 2000 psi；(d) 3000 psi所製得之粒子………………...….…………………50
圖19 粒子尺寸與膨脹槽壓力之關係圖…….…………….…………..53
圖20 粒子尺寸與膨脹槽溫度之關係圖…………..…………………..55
圖21 D：M＝1：2高流速製程製得粒子之光學顯微鏡圖….....……..57
圖22 D：M＝1：2低流速製程製得粒子之光學顯微鏡圖….....……..58
圖23 D：M＝1：1高流速製程製得粒子之光學顯微鏡圖….....……..59
圖24 D：M＝1：1低流速製程製得粒子之光學顯微鏡圖….....……..60
圖25　D：M＝1：2中高低流速釋藥總量與時間的關係圖…….……..64
圖26　D：M＝1：1中高低流速釋藥總量與時間的關係圖…….……..65
圖27　D：M＝2：1中高低流速釋藥總量與時間的關係圖…….……..66
圖28　高流速中不同藥物基質比釋出阿司匹靈總量…………….….67
圖29　低流速中不同藥物基質比釋出阿司匹靈總量…………….….68
圖30　藥物基質比1：2高流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..70
圖31　藥物基質比1：1高流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..72
圖32　藥物基質比2：1高流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..74
圖33　藥物基質比1：2低流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..75
圖34　藥物基質比1：1低流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..77
圖35　藥物基質比2：1低流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..78
圖36 D:M = 1：1大槽製程；膨脹槽壓力(P = 1200 psi)、膨脹槽溫度(T = 60 ℃)……………………………………………………....80
圖37　大槽製程製得粒子之阿司匹靈釋放總量與時間的關係圖…..81
圖38　不同膨脹槽尺寸所製得粒子之阿司匹靈釋放總量與時間的關
係圖（◆）5/4 in” id.（□）1/2 in” id. …..……………………….82

1.朱自強, 超臨界流體技術－原理和應用, 化學工業出版社, 北京, 1999.
2.A. C. Tanquary and R. E. Lacey, Ed. “Controlled Release of Biologically Active Agent.” Plomum, 1974.
3.J. C. Colbert, Ed. “Action Drug Forms.” Noyes Data Corporation, 1974.
4.R. L. Kronenthal, Ed. “Polymeriu Medicine and Surgery.”
5.H. P. Gregor, Ed. “Biomedical Application of Polymer.” Polenum, 1973.
6.D. Andrade, “Hydrogels for Medical, "and Related Application.” ACS Symposium 31, 1976.
7.J. Cardarell, “Controlled Release Pesticides Formulation.” CRC, 1976.
8.R. Powell, “Controlled Release, Fertilizer.” NDC, 1968.
9.W. Harris, “Proceedings 1974 International Controlled-Release Pesticide Symposium.”
10.W. Harris, “Proceedings 1975 International Controlled-Release Pesticide Symposium.”
11.W. Harris, “Proceedings 1977 International Controlled-Release Pesticide Symposium.”
12.D. R. Paul and F. W. Harris, “Controlled Release Polymeric Formulation. ACS Symposium Series (33).
13.J. Folkman and D. M. Doug Jr., J. Surg. Res., 4, 139, 1964.
14.沈宗禮, 制放技術與微粒包覆, 高立圖書有限公司.
15.R. Baker, “Controlled Release of Biologically Active Agents.”
16.J. Crank, “The Mathematics of Diffusion.” Oxford University Press, London, 1956.
17.F. A. Kincl and H. W. Rudel, “Acta Endocrinologica Supplementum.” 1970.
18.C. F. Lerk, W. J. Bolink, and K. Zuurman, “Solid Dosage Form with Constant Release.” Pharm. Ind., 38, 561, 1976.
19.J. G. Wagner, “Interpretation of Percent Dissolved-time Plots Derived from in Vitro Testing of Conventional Tablets and Capsules.” J. Pharm. Sci., 58, 1253, 1969.
20.T. Higuichi, “Mechanism of Sustained-action Medication: Theoretical Analysis of Rate of Release of Solid Drugs Dispersed in Solid Matrices.” J. Pharm. Sci., 52, 1145, 1963.
21.B. de Jong and H. Grant, Proc. Acad. Sci., Amsterdam 41, 646, 1938.
22.B. de Jong, and H. Grant, Biochem. Zeit., 232, 338, 1931.
23.B. K. Green, U.S. Reissue 24899, 1960.
24.B. K. Green and L. Sohleicher, U.S. Pat. 2800457~8 and 2730457, 1960.
25.J. A. Bakan, U.S. Pat. 3436355, 1969, and 2712507, 1955.
26.C. Brynko, and J. A. Scarpelli, U.S. Pat. 3190837, 1965.
27.I. L. Yrkowitz, U.S. Pat. 3533958, 1970.
28.C. Brynko, U.S. Pat. 3341466, 1967.
29.E. H. Jensen, U.S. Pat. 3265630, 1966.
30.C. Brynko, U.S. Pat. 3401123, 1966.
31.L. A. Lnzzi, Ph. D. Dissertation, Univ. of Rhode Island, Kingston, R. I., 1966.
32.H. G. Bungenberg de Jong in “Collid Science” Vol. 11, H. R. Kruyt Ed. Elsevier Publishing, Co. Amsterdam, 1949.
33.A. Dobry and F. Boyer-Kawenoki, “Phase Separation in Polymer Solution.” J. Poly. Sci., 90, 1974.
34.T. C. Powell, U.S. Pat. 3415758, 1965.
35.R. E. Miller and J. L. Anderson, U.S. Pat. 3155590, 1964.
36.H. L. Rowe, U.S. Pat. 3336155, 1967.
37.G. O. Fanger, U.S. Pat. 3531418, 1970.
38.J. L. Anderson, U.S. Pat. 3341416, 1967.
39.G. L. Gardner, Chem. Eng. Prog., 62, 4, 83-91, 1966.
40.Development of Multipurpose Capsular Adhesives, Pica Tinny Arsenal, U.S. Gov. Report No. DAAA 21-68C-0581.
41.Z. Reyes, U.S. Pat. 3173878, 1965 and U.S. Pat. 3405070, 1968.
42.A. E. Vassiliades, U.S. Pat. 3418656 and U.S. Pat. 3418650, 1968.
43.U. W. Matson, U.S. Pat. 3516846, 1970.
44.G. B. Robert, U.S. Pat. 3674704, 1972.
45.British Pat. 907284 to The National Cash Register Company.
46.P. W. Morgan and S. L. Kuclek, J. Ploy. Sci., 40, 299, 1959.
47.J. E. Vandegaer and F. G. Meyer, U.S. Pat. 3464926, 1969.
48.A. W. Doyle, U.S. Pat. 3160686, 1964.
49.R. M. Jolkovski, U.S. Pat. 3270100, 1966.
50.J. E. Sato and J. E. Vandegaer, U.S. Pat. 3492380, 1970, Br. Pat. SP. 1091141.
51.L. S. Richen and M. H. Arlesheim, U.S. Pat. 3778383. 1973 and U.S. Pat. 3514328. 1971.
52.E. V. Anthony, U.S. Pat. 3418656, 1970.
53.M. P. Powell, U.S. Pat. 3779941, 1973.
54.M. Ruus, U.S. Pat. 3429827, 1970.
55.Z. Kan, U.S. Pat. 3432327, 1970.
56.J. E. Vandegaer, U.S. Pat. 3886084, 1975.
57.W. F. Gorham, U.S. Pat. 3300332, 1966.
58.J. A. Herbig and J. F. Hanny, U.S. Pat. 3161602, 1964.
59.K. Stephan and K. Lucas, “Viscosity of Dense Fluid.” Plenum Press, New York, 1979.
60.E. Klesper, Angew. Chem. Int. Engl., 17, 738, 1978.
61.J. C. Giddings, M. N. Meyers, L. Mclaren and R. A. Keller, Science, 162, 37, 1968.
62.D. W. Matson, J. L. Fulton, R. C. Petersen and R. D. Smith, Ind. Eng. Chem. Res., 26, 2298, 1987.
63.P. G. Debenedetti, AIChE J., 36, 1289, 1990.
64.J. Jung and M. Perrut, J. Supercritical Fluids, 20, 179-219, 2001.
65.M. Hanna and P. York, Patent WO 95/01221, 1994.
66.M. Hanna and P. York, Patent WO 96/00610, 1995.
67.L. Sze Tu, F. Dehghani, A. K. Dillow and N. R. Forster, Proceedings of The 5th Meeting on Supercritical Fluids, Tome L., M. Perrut, P/ Subra (Eds.), ISBN 2-905-267-28-3, 23-25 March, Nice,263-270, 1998.
68.楊景堯, 實驗計劃法在製備控制釋放型藥物微膠囊之應用與研究, 國立成功大學化學工程研究所博士班論文, 2000.