臺灣博碩士論文加值系統

本研究目的利用親水性聚合物褐藻膠 (alginate) 和鹿角菜膠
(carrageenan) 與交聯劑( 氯化鈣和幾丁聚醣) 進行交聯反應
(cross-linking)，使錠劑水合時形成膠層，進而達到藥物持續釋放
(sustained-release) 的效果。以示差掃描熱量分析儀 (differential
scanning calorimetry; DSC) 檢測賦型劑與主成份沒有交互作用。配方設計以單方膠體、兩種膠混合及膠體與交聯劑作用，進行配方試製配合
體外溶離試驗與紫外光分光光度計執行快速檢測，得聚合物褐藻膠和
鹿角菜膠與交聯劑 (氯化鈣和幾丁聚醣) 比例為1：1：1：1 最佳，藥
物持續釋放可達20 至24 小時。放大製程其粉體特性：安息角 (angle of
repose) 為42 度、總體密度 (bulk density) 與敲擊密度 (tapped density)分別為0.41 及0.46 g/cm3 、水份含量為3.59%和粉體含量為98.21 ±0.95%。以此粉體製錠成每顆重250 mg，含主成份120 mg 之錠劑。重量均一度為250.54 ± 0.59 mg，平均厚度為4.63 mm，硬度為80.5 N；以高效液相層析方法分析，得錠劑含量為99.07 ± 0.97%、含量均一度
為97.10 ± 0.97%，體外溶離試驗結果為0.1 N 鹽酸、pH 4.5 磷酸緩衝
溶液和pH 6.8 磷酸緩衝溶液分別在24 小時、22 小時及20 小時達到完
全釋出。

This study is to use hydrophilic polymers (sodium alginate and carrageenan) and crosslink agents (calcium chloride and chitosan) to crosslinking reaction. When the tablets were dissolved with water, surface gel was performed and showed drug sustained release. The differential scanning calorimetry analyzer proved no mutual effect between excipients and acetaminophen. To prepare hydrogel matrix sustained release, tablets containing acetaminophen with alginate, carrageenan and chitosan were as the matrix material. The optimal formulation was examined by using in
vitro dissolution test and UV spectrophotometer test. The result showed that the test ratio of drug sustained release sodium alginate, carrageenan and crosslink agents (calcium chloride and chitosan) 1:1:1:1 which had up to 20-24 hr. After amplification of process, the powder characteristics were as follows: angle of repose, 42 degrees; crude density, 0.41 g/cm3; tapped density, 0.46 g/cm3; the water content, 3.59%; and the powder content, 98.21 ± 0.95%. Each tablet was 250.54 ± 0.59 mg, containing main
components 120 mg, and the average thickness was 4.63 mm, and the hardness was 80.5 N. The content of tablets tested by high performance liquid chromatography method was 99.07 ± 0.97%, the content uniformity for each tablet was 97.10 ± 1.17%. In vitro dissolution in 0.1 N HCl, pH 4.5 phosphate buffer solution and pH 6.8 phosphate buffer solution, the complete release of content was 24 hr, 22 hr and 20 hr.

目錄
摘要 ···································································································1
英文摘要 ···························································································2
研究背景 ···························································································3
壹、文獻整理
一、錠劑的分類 ······································································· 5
二、錠劑製造流程 ··································································· 6
三、藥物的吸收 ······································································· 7
四、間質型釋放原理 ······························································· 7
五、常見的間質型錠劑材料 ··················································· 8
六、Acetaminophen 的特性 ····················································· 9
七、膠體特性 ·············································································11
貳、研究內容
一、前言 ······················································································15
二、材料與方法
(一) 材料
1. 配方原料與賦形劑 ····················································16
2. 試劑 ···········································································16
3. 實驗儀器 ···································································17
3. 市售品 ·······································································18
(二) 方法
1. 實驗架構 ···································································19
2. 原料測試 ···································································20
3. 配方試製 ···································································20
II
4. 配方分析 ···································································20
5. 最佳配方製程管制試驗 ···········································22
6. HPLC 分析方法確校 ·················································25
7. 體外溶離試驗 ···························································29
參、結果與討論 ················································································32
肆、結論 ···························································································39
伍、圖表 ···························································································41
陸、參考文獻 ····················································································63
柒、附錄 ···························································································69
謝誌 ···································································································75

田蔚城、王志鵬、王盛世、白壽雄、呂淑彬、邱明善、沈重光、李淑
妃、林山陽、周文智、洪昭竹、馬海怡、施凱翔、陳正、陳巧文、
陳思豐、郭怡玲、皺先岩、劉博文、盧曉華。1999。生物產業與
製藥產業(下冊) 。九州圖書。台北。pp.170-180。
劉正雄。2006。藥物劑型與遞藥系統。九州圖書。台北。pp.227-275。
許桂森、林明忠、蕭哲志、張美姬。1997。簡明圖解藥理學。藝軒圖
書出版社。台北。pp.6-8，491-492。
行政院衛生署。2000。現行法規優良製造規範-分析確效作業指導手冊。
行政院衛生署。台北。
張為憲、張永和、陳怡宏、林志城、李敏雄、陳昭雄、張基郁、林慶
文、呂政義、孫璐西、顏國欽。1996。食品化學。華香園出版社。
台北。pp.62-69。
王靜瓊、莊武璋、張正欽。2008。藥物分析原理。江山出版有限公司。
台北。pp.26-37。
AOAC (Association of Official Analytical Chemists) 2000. Official Methods of Analysis 17th edition. AOAC, Arlington, VA, USA.
Black, M. 1984. Acetaminophen hepatotoxicity. Annual Review of Medicine 35: 577-593.
Cekmen, M., Ilbey, Y. O., Ozbek, E., Simsek, A., Somay, A. and Ersoz, C. 2009. Curcumin prevents oxidative renal damage induced by acetaminophen in rats. Food and Chemical Toxicology 47: 1480-1484.
Chen, S. C., Wu,Y. C., Mi, F. L., Lin, Y. H., Yu, L. C. and Sung ,H. W. 2004. A novel pH-sensitive hydrogel composed of ,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery. Journal of Controlled Release 96: 285-300.
Chenite, A., Chaput,C., Wang, D., Combes, C., Buschmann, M. D., Hoemann, C. D., Leroux, J. C., Atkinson, B. L., Binette, F. and Selmani, A. 2000. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 21: 2155-2161.
Fernandez-Perez, M., Villafranca-Sanchez, M., Flores-Cespedes, F. and Daza-Fernandez, I. 2011. Ethylcellulose and lignin as bearer polymers in controlled release formulations of chloridazon. Carbohydrate Polymers 83: 1672-1679.
FDA (Food and Drug Administration) 1997. Guidance for Industry:
Bioavailability a d Bioequivalence Studies for Orally Administered
Drug Products — General Considerations. FDA. Washington. USA.
George, M. and Abraham, T. E. 2006. Polyionic hydrocolloids for the
intestinal delivery of protein drugs:Alginate and chitosan — A
review. Journal of Controlled Release 114: 1-14.
González-Rodríguez, M. L., Holgado, M. A., Sánchez-Lafuente, C., Rabasco, A. M. and Fini, A. 2002. Alginate/chitosan particulate systems for sodium diclofenac release. International Journal of Pharmaceutics 232: 225–234.
Inghelbrecht, S. and Remon, J. P. 1998. Reducing dust and improving granule and tablet quality in the roller compaction process. International Journal of Pharmaceutics 171: 195-206.
Kulkarni, R. V., Baraskar, V. V., Setty, C. M. and Sa, B. 2011. Interpenetrating polymer network matrices of sodium alginate and carrageenan for controlled drug delivery application. Fibers and Polymers 12: 352-358.
Kuo, C. K. and Ma, P. X. 2001. Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: Part 1. Structure, gelation rate and mechanical properties. Biomaterials 22: 511-521.
Michael, S. L., Pumford, N. R., Mayeux, P. R., Niesman, M. R. and Hinson, J. A. 1999. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology 30: 186-195.
Mitsumata, T., Suemitsu, Y., Fujii, K., Fujii, T., Taniguchi, T. and Koyama, K. 2003. pH-response of chitosan, k-carrageenan, carboxymethyl cellulose sodium salt complex hydrogels. Polymer 44: 7103–7111.
Moyer, A. M., Fridley B. L., Jenkins G. D., Batzler, A. J.,
Pelleymounter, L. L., Kalari, K. R., Ji, Yuan, Chai, Y. Nordgren, K. K. S. and Weinshilboum, R. M. 2011. Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicological Sciences 120: 33-41.
Piyakulawat, P., Praphairaksit, N., Chantarasiri, N. and Muangsin, N. 2007. Preparation and evaluation of chitosan/carrageenan beads for controlled release of sodium diclofenac. The American Association of Pharmaceutical Scientists Pharmscitech 8: 120-130.
Ravi Kumar, M. N. V. 2000. A review of chitin and chitosan applications. Reactive and Functional Polymers 46: 1-27.
Savides, M, C. and Oehme, F. W. 1983. Acetaminophen and its toxicity. Journal of Applied Toxicology 3: 96-111.
Sankalia, J. M., Sankalia, M. G. and Mashru, R. C. 2008. Drug release and swelling kinetics of directly compressed glipizide sustained - release matrices: Establishment of level A IVIVC. Journal of Controlled Release 129: 49-58.
Sung, K. C., Nixon, P. R., Skog, J. W., JU, T. R., Gao, P., Topp, E. M. and Patel, M. V. 1996. Effect of formulation variables on drug and polymer release from HPMC-based matrix tablets. International Journal of Pharmaceutics 142: 53-60.
Talukdar, M. M. and Kinget, R. 1995. Swelling and drug release behaviour of xanthan gum matrix tablets. International Journal of Pharmaceutics 120: 63-72.
Tønnesen, H. H. and Karlsen, Jan. 2002. Alginate in Drug Delivery Systems. Drug Development and Industrial Pharmacy 28: 621–630.
USP (United States Pharmacopeia) 2012. Acetaminophen in United States Pharmacopeia (USP 35). The United States Pharmacopeial Convention. Rockville, MD, USA. pp. 255-265, 295-301, 801-804, 2029-2033.
Valero, E., Carrion, P., Varon, R. and Garcia-Carmona, F. 2003. Quantification of acetaminophen by oxidation with tyrosinase in the presence of Besthorn’s hydrazone. Analytical Biochemistry 318: 187-195.
Viriden, A., Wittgren, B. and Larsson, A. 2011. The consequence of the chemical composition of HPMC in matrix tablets on the release behaviour of model drug substances having different solubility. European Journal of Pharmaceutics and Biopharmaceutics 77: 99-110.
Wang, Q., Hu, X., Du, Y. and Kennedy, J. F. 2010. Alginate/starch blend fibers and their properties for drug controlled release. Carbohydrate Polymers 82: 842-847.
Watson, D. G. 2005. Pharmaceutical Analysis. Elsevier Pte Ltd. 2th edition. Singapore. pp. 38-41.
Zhao, Y. L., Zhou, G. D., Yang, H. B., Wang, J. B., Shan, L. M. Li, R. S. and Xiao, X. H. 2011. Rhein protects against acetaminophen - induced hepatic and renal toxicity. Food and Chemical Toxicology 49: 1705-1710.