臺灣博碩士論文加值系統

口服藥物傳輸系統（ODDS），主要的目標都是為了達到控制釋放，使藥物在血液中濃度固定，使其發揮最大療效。藥物控制釋放常見的方式，一般多以將藥物用特殊的化學材質包覆，使藥物在某一種狀態下適時適量釋出，例如：PH值改變、延長釋放時間等。膠囊則是最早、最常見也最方便的一種藥物包覆方式。本研究針對常見的膠囊變因，例如：填充量、大小、釋放環境探討其釋放行為，更進一步探討目前硬膠囊足以取代軟膠囊的技術-腰帶（sealing），以及藥物走向控制釋放的關鍵-膜衣（coating）。將實驗結果配合數值模型量化出藥物的擴散係數。並由實驗結果知膠囊此類特殊構形之釋放行為。使用電導度法做定量，避免了一般光學儀器容易因為色素造成的影響，且其精確度與高效能液相層析儀定量法在同一數量級，又攜帶方便、實用。

The Oral Drug Delivery System (ODDS) is designed to control drug release by maintaining the drug concentration constant in blood and reaching the optimal efficacy. The most effective implementation of control release is to coat the drug with designed material which is sensitive to certain conditions e.g., pH values, release time, etc. Among the variety of coating methods, capsulation is the mostly employed. This work investigate the common manipulated parameters of capsulation, including drug filling amount, capsule size, conditions of bulk solution, sealing, and coating. The electrical conductivity method was used to determine the drug concentration for its satisfactory accuracy, convenience and relatively low cost compared to High Performance Liquid Chromatography (HPLC). With the mathematical model, the quantification of the drug release from capsules is thus feasible.

目錄

摘要 i
ABSTRACT ii
目錄 iii
表目錄 v
圖目錄 vi
第一章 緒論 1
第一節 前言 1
第二節 研究目的 1
第二章 文獻回顧 4
第一節 藥物傳輸系統 4
一、 原理 4
二、 藥物傳輸類型 4
第二節 口服劑介紹 7
一、 常見的口服藥物劑型 7
二、 膠囊的由來 9
三、 膠囊的分類 10
第三節 膠囊腰帶 17
第三章 實驗設計 19
第一節 實驗流程 19
一、 實驗方法 19
二、 膠囊之填充處理 25
三、 膠囊藥物釋放實驗步驟 25
四、 膠囊填充物含水量測定步驟 27
第二節 實驗藥品 28
第三節 實驗儀器 28
第四章 研究結果 29
第一節 標準曲線 29
第二節 膠囊釋放釋放累積濃度 30
一、 膠囊填充飽滿度實驗數據 30
二、 膠囊大小實驗數據 34
三、 膠囊釋放環境實驗數據 39
四、 膠囊腰帶實驗數據 43
五、 膠囊膜衣實驗數據 48
六、 水分含量測定實驗數據 52
第三節 量化膠囊擴散係數 55
一、 量化後數值 55
二、 最小根均方誤差法 56
三、 數據擬合結果 57
第五章 討論 60
第一節 膠囊填充飽滿度 60
第二節 膠囊大小 61
第三節 膠囊釋放環境 62
第四節 膠囊腰帶 63
第六章 結論與未來展望 66
第七章 參考文獻 67

1.北醫藥訊 中華民國九十七年一月一日 出刊 第 40 期
2.Allen, T. M., and Cullis, P. R. (2004). Drug delivery systems: entering the mainstream. Science 303, 1818.
3.Anderson, M. P., and Woessner, W. W. (1992). Applied groundwater modeling: simulation of flow and advective transport.
4.Banker, G. S., and Rhodes, C. T. (2002). Modern pharmaceutics. Informa HealthCare.
5.BOWMAN, B. J., and OFNER, C. M. (2002). Hard gelatin capsules. Protein-based films and coatings, 367.
6.Brown, J., Madit, N., Cole, E., Wilding, I., and Cade, D. (1998). The effect of cross-linking on the in vivo disintegration of hard gelatin capsules. Pharmaceutical research 15, 1026-1030.
7.Cade, D., Cole, E., Mayer, J. P., and Wittwer, F. (1986). Liquid filled and sealed hard gelatin capsules. Drug Development and Industrial Pharmacy 12, 2289-2300.
8.Casey, D., Beihn, R., Digenis, G., and Shambhu, M. (1976). Method for monitoring hard gelatin capsule disintegration times in humans using external scintigraphy. Journal of Pharmaceutical Sciences 65, 1412-1413.
9.Chang, H. C., Wu, S. S., Wang, Y. F., and Wang, H. M. Quantification of porcine skin permeability in transdermal diffusion with a numerical model. Journal of the Taiwan Institute of Chemical Engineers 41, 136-142.
10.Charman, S. A., and Charman, W. N. (2003). Oral modified-release delivery systems. DRUGS AND THE PHARMACEUTICAL SCIENCES 126, 1-10.
11.Chien, Y. W. (1992). Novel drug delivery systems. Informa Healthcare.
12.Chin, W., and Kroontje, W. (1961). Conductivity method for determination of urea. Analytical Chemistry 33, 1757-1760.
13.Chin, W., and Kroontje, W. (1962). Urea Hydrolysis, Conductivity Method for Estimation of Urease Activity. Journal of Agricultural and Food Chemistry 10, 347-348.
14.Cole, E., Cade, D., and Benameur, H. (2008). Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Advanced Drug Delivery Reviews 60, 747-756.
15.Cole, E., Scott, R., Connor, A., Wilding, I., Petereit, H., Schminke, C., Beckert, T., and Cade, D. (2002). Enteric coated HPMC capsules designed to achieve intestinal targeting.International Journal of Pharmaceutics 231, 83-95.
16.Erlich, L., Yu, D., Pallister, D., Levinson, R., Gole, D., Wilkinson, P., Erlich, R., Reeve, L., and Viegas, T. (1999). Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules. International Journal of Pharmaceutics 179, 49-53.
17.Ewart, T. (2000). Liquid filled and sealed hard gelatin capsules.Capsugel Library, 1-12.
18.Frenning, G., Tunon, A., and Alderborn, G. (2003). Modelling of drug release from coated granular pellets. Journal of controlled release 92, 113-123.
19.Grass, G. (1997). Simulation models to predict oral drug absorption from in vitro data. Advanced Drug Delivery Reviews 23, 199-219.
20.Gullapalli, R. (2010). Soft gelatin capsules (softgels). Journal of Pharmaceutical Sciences 99, 4107-4148.
21.Guo, M., Kalra, G., Wilson, W., Peng, Y., and Augsburger, L. (2002). Hard Gelatin Capsule Formulation Development. Pharmaceutical Technology, 44-60.
22.Hoffman, A. (1998). Pharmacodynamic aspects of sustained release preparations. Advanced drug delivery reviews 33, 185-199.
23.Ishibashi, T., Hatano, H., Kobayashi, M., Mizobe, M., and Yoshino, H. (1998). Design and evaluation of a new capsule-type dosage form for colon-targeted delivery of drugs. International journal of pharmaceutics 168, 31-40.
24.Ishibashi, T., Ikegami, K., Kubo, H., Kobayashi, M., Mizobe, M., and Yoshino, H. (1999). Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted delivery capsule (CTDC). Journal of controlled release 59, 361-376.
25.Jannin, V., Musakhanian, J., and Marchaud, D. (2008). Approaches for the development of solid and semi-solid lipid-based formulations. Advanced drug delivery reviews 60, 734-746.
26.Koizumi, T., Ritthidej, G. C., and Phaechamud, T. (2001). Mechanistic modeling of drug release from chitosan coated tablets. Journal of controlled release 70, 277-284.
27.Marques, M. R. C., Cole, E., Kruep, D., Gray, V., Murachanian, D., Brown, W. E., and Giancasproa, G. I. (2009). Liquid-filled gelatin capsules, pp. 1029-1041.
28.McCall, T. W., Baichwal, A. R., and Staniforth, J. N. (2003). TIMERx oral controlled-release drug delivery system. DRUGS AND THE PHARMACEUTICAL SCIENCES 126, 11-20.
29.Muraoka, M., Hu, Z., Shimokawa, T., Sekino, S., Kurogoshi, R., Kuboi, Y., Yoshikawa, Y., and Takada, K. (1998). Evaluation of intestinal pressure-controlled colon delivery capsule containing caffeine as a model drug in human volunteers. Journal of controlled release 52, 119-129.
Pasic, M. (2008). Study to design stable lansoprazole pellets.
30.Podczeck, F. (2004). Pharmaceutical capsules. Pharmaceutical Pr.
31.Podczeck, F., and Jones, B. (2004). Pharmaceutical capsules (second ed.). Pharmaceutical Pr.
32.Pope, C. (2001). Qualitative research methods: A health focus. International Journal of Epidemiology 30, 185.
33.Saharan, V., Kukkar, V., Kataria, M., Gera, M., and Choudhury, P. (2009). Dissolution enhancement of drugs. part i: technologies and effect of carriers. International Journal of Health Research 2, 107-124.
34.Serajuddin, A. (1999). Solid dispersion of poorly water soluble drugs: early promises, subsequent problems, and recent breakthroughs. Journal of Pharmaceutical Sciences 88, 1058-1066.
35.Sherry Ku, M., Li, W., Dulin, W., Donahue, F., Cade, D., Benameur, H., and Hutchison, K. (2010). Performance qualification of a new hypromellose capsule: Part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus , Quali-V and gelatin capsules. International Journal of Pharmaceutics 386, 30-41.
36.Siepmann, F., Muschert, S., Flament, M., Leterme, P., Gayot, A., and Siepmann, J. (2006). Controlled drug release from Gelucire-based matrix pellets: Experiment and theory. International journal of pharmaceutics 317, 136-143.
37.Sood, A., and Panchagnula, R. (2003). Design of controlled release delivery systems using a modified pharmacokinetic approach: a case study for drugs having a short elimination half-life and a narrow therapeutic index. International journal of pharmaceutics 261, 27-41.
38.Stegemann, S., and CAPSUGEL. (1999). Hard Gelatin Capsules Today-and Tomorrow. Capsugel Library.
39.Sternberg, R. J., and Zhang, L. (2001). Perspectives on thinking, learning, and cognitive styles. Lawrence Erlbaum.
40.Tang, B., Cheng, G., Gu, J. C., and Xu, C. H. (2008). Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Discovery Today 13, 606-612.
41.Thombre, A., Cardinal, J., DeNoto, A., and Gibbes, D. (1999). Asymmetric membrane capsules for osmotic drug delivery II. In vitro and in vivo drug release performance. Journal of controlled release 57, 65-73.
42.Verma, R. K., and Garg, S. (2001). Drug delivery technologies and future directions. Pharmaceutical Technology, 1.
43.Verma, R. K., Krishna, D. M., and Garg, S. (2002). Formulation aspects in the development of osmotically controlled oral drug delivery systems. Journal of controlled release 79, 7-27.
44.Vilivalam, V., Illum, L., and Iqbal, K. (2000). Starch capsules: an alternative system for oral drug delivery. Pharmaceutical Science & Technology Today 3, 64-69.
45.Wittwer, F. (1985). New developments in hermetic sealing of hard gelatin capsules. Pharm. Manuf 2, 24.
46.Wu, C., and Benet, L. (2005). Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharmaceutical Research 22, 11-23.
47.Yang, G. M. (2006). Drug release behavior and preparation of microspheres composed of hydrophilic/hydrophobic blends of ethylcellulose and hydroxypropylcellulose.
48.Yu, L. X., Lipka, E., Crison, J. R., and Amidon, G. L. (1996). Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Advanced drug delivery reviews 19, 359-376.
49.2000Ó Torpac Inc. All rights reserved. Torpac is a registered trademark of Torpac Inc.
50.吳信賢（2008），利用數值模型定量尿素經皮吸收之滲透係數，中興大學化工碩士論文
51.王怡芳（2009），藥物分子結構在經皮吸收過程中所扮演的角色：以水楊酸和阿斯匹靈為例，中興大學化工碩士論文
52.http://www.lsbu.ac.uk/water/hygel.html