臺灣博碩士論文加值系統

近年來，口服固體劑型可藉由配方設計以改良藥物之釋放及吸收。藥物控制釋放製劑具有多項之優點，除了可以維持藥品的血中濃度以提高治療效率外，也可減少投藥次數以改善傳統口服劑型的投藥之不便性，所以藥物製劑配方與技術對於藥物釋放影響之各項研究就顯得相當重要。
本實驗使用治療消化性潰瘍之藥物雷貝拉唑 (Rabeprazole) 及治療膀胱過動症之藥物奧昔布寧 (Oxybutynin) 作為模式藥物，製備不同比例高分子之處方製劑和不同比例之腸溶包衣包覆，以探討在製劑中控釋高分子與腸溶包衣材質比例對 Rabeprazole 及 Oxybutynin 釋放之影響；並探究腸溶包衣對 Rabeprazole 延遲釋放劑型化學安定性之影響。
研究結果顯示，在相同 pH 值之溶離試驗下，Rabeprazole 隨著內包衣層厚度的增加而降低其溶離速率。而在酸性的溶離液底下，若腸溶包衣層包覆足夠，就可保護主成份不受酸性環境的影響而產生降解。
在 Oxybutynin 的部分，親水性高分子的黏度及使用量的選擇是主要影響藥物核心釋放速率的關鍵。而在包衣包覆組成中調整羥丙基甲基纖維素與腸溶包衣高分子之比例，在溶媒 pH1.2 中亦可達到不同之釋放速率。由上述研究內容顯示，應用腸溶包衣系統的方式來製備具有控制釋放效果的口服 Rabeprazole 和 Oxybutynin 製劑是確實可行的。

In recent years, scientific and technological advancements have been made in the development of controlled drug delivery system. Controlled drug delivery technology has many advantages, such as improve effectiveness, convenience and reduce side effects. It also helps to improve quality of life. In order to obtain optimum formulation to ensure efficacy and safety profiles, the effect of formulation variables on drug release and stability are crucial.
Rabeprazole and oxybutynin are used in the present study as the model drugs.
Formulations with different polymer amount and enteric coating ratios were designed to evaluate their effects on drug release as well as chemical stability.
The results demonstrate rabeprazole dissolution rates decreased with the increased in inner coating level. As in the acid dissolution media, no significant degradation was observed if enough enteric polymer has been coated.
For oxybutynin, the hydrophilic polymer viscosity and amount added can affect the drug release rates. Adjusting the ratios of HPMC and Eudragit L100-55 amounts contributed to different release rates in pH1.2 medium. The study clearly shows that the application of enteric coating systems to obtain optimum release rates of rabeprazole and oxybutynin is feasible.

中文摘要................................................................................................................I
Abstract.................................................................................................................II
致謝.....................................................................................................................III
目錄.....................................................................................................................IV
圖目錄.................................................................................................................VI
表目錄..............................................................................................................VIII
第一章 緒論.......................................................................................................1
第二章 文獻回顧...............................................................................................9
第一節 模式藥物Rabeprazole之簡介.......................................................9
第二節 Rabeprazole研究中所使用聚合物之介紹..................................18
第三節 模式藥物Oxybutynin之簡介......................................................23
第四節 Oxybutynin研究中所使用聚合物之介紹...................................32
第三章 研究目的.............................................................................................40
第四章 儀器、材料及方法.............................................................................41
第一節 儀器...............................................................................................41
第二節 材料...............................................................................................43
第三節 實驗方法.......................................................................................45
第五章 結果與討論.........................................................................................56
第一節 不同配方之Rabeprazole 製劑對藥物溶離之影響....................56
第二節 不同配方之Oxybutynin 製劑對藥物溶離之影響.....................64
第六章 結論.....................................................................................................73
第七章 參考文獻.............................................................................................75

1.楊國明. 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. 國立成功大學化學工程學系. 2006;博士論文.
2.World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th ed. 2007.
3.Thomas C. Chitosan/Polyethylene glycol-alginate microcapsules for oral delivery of hirudin. J appl Poly Sci. 1998;70(11):2143-2153.
4.Conte U, Maggi L, Colombo P, Manna A.L. Multi-layered Hydrophilic matrices as constant release devices. J. Control. Rel. 1993;26:39 - 47.
5.Deasy PB, Brophy MB, Ecanow B, Joy MM. Effect of Ethyl Cellulose Grade and Sealant Treatments on the Production and in Vitro Release of Microencapsulated Sodinm Salicylate. J. Pharm. Pharmacol. 1984;32(1):15-20.
6.Banker GS, Rhodes CT. Modern Pharmaceutics. 4th ed. 2002.
7.Zhan X, Yin G, Wang L, Ma B. Exponential heating in drug stability experiment and statistical evaluation of nonisothermal and isothermal prediction. J Pharm Sci. Jun 1997;86(6):709-715.
8.Takka S, Rajbhandari S, Sakr A. Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets. Eur J Pharm Biopharm. Jul 2001;52(1):75-82.
9.Suneel Gupta GS. Providing Constant Analgesia with OROS® Hydromorphone. Journal of Pain and Symptom Management. 2007;33(2).
10.Kreitz MR, Domm JA, Mathiowitz E. Controlled delivery of therapeutics from microporous membranes. II. In vitro degradation and release of heparin-loaded poly(D,L-lactide-co-glycolide). Biomaterials. Dec 1997;18(24):1645-1651.
11.Vinay Kumar, S k Prajapati, Girish C Soni, Mahendra Singh, Neerajkumar. Sustained release matrix type drug delivery system: a review. World Journal of Pharmacy and Pharmaceutical Sciences. 2012;1(3):934-960.
12.Chem C.P, Gujarat A. Formulation, process parameters optimization and evaluation of delayed release tablets of rabeprazole sodium. Int J Pharmacy Pharm Sci. 2010;2:144-155.
13.Muthukumaran M SenthilKumar K L, Ratnam B C. Formulation and evaluation of delayed release pellet of rabeprazole sodium. J. Pharm &Ind. Res. 2011;1(3):182.
14.陳昭姿. Rabeprazole-作用快速的質子幫浦抑制劑. 當代醫學.27(7).
15.Dott AG, Johnson L. Rational prescribing: practice audit and drug switch in dyspepsia management. Int J Clin Pract. Dec 1999;53(8):599-603.
16.Earnest DL, Robinson M. Treatment advances in acid secretory disorders: the promise of rapid symptom relief with disease resolution. Am J Gastroenterol. Nov 1999;94(11 Suppl):S17-24.
17.Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc (Wash). Jan-Feb 2000;40(1):52-62; quiz 121-123.
18.http://w3.tyh.com.tw/medweb/upload/emed/emed_012.htm.
19.莊宗憲. 氫離子幫浦阻斷劑藥物之比較. 家庭醫學與基層醫療.27(2).
20.Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil. Jan 2013;19(1):25-35.
21.Jagannath M, Mallikarjuna Gouda M, Somashekar Shyale, Shanta kumar S.M. Development and evaluation of novel compression coated tablets of levofloxacin and rabeprazole used in the treatment of peptic ulcer disease. International Research Journal of Pharmaceutical and Applied Sciences. 2012;2(5):109-116.
22.Carswell CI, Goa KL. Rabeprazole: an update of its use in acid-related disorders. Drugs. 2001;61(15):2327-2356.
23.Stafford J. Enteric film coating using completely aqueous dissolved hydroxypropyl methl cellouse phathalate spray solution. 1982;8(4):513-530.
24.Wade A, Waller P. Handook of pharmaceutical excipient. 1994.
25.http://cht.a-hospital.com/
26.http://fdaforum.net/.
27.Mukharya, S.A. Chaudhary, A. Bheda, A. Mulay, N.Mansuri, N. Laddha, A.K. Misra. Stable and Bioequivalent Formulation Development of Highly Acid Labile Proton Pump Inhibitor: Rabeprazole. International Journal of Pharmaceutical Research and Innovation. 2011;2:1-8.
28.張谷維. Narcotics類藥品間質及間質膜衣控釋系統之研究. 私立嘉南藥理科技大學生物科技研究所. 2005;碩士論文.
29.Ozturk A.G, Ozturk S.S, Palsson B.O, Wheatley T.A, Dressman J.B. Mechanism of release from pellets coated with an ethyl cellouse-base film. Journal of Controlled Release. 1990;14:203-213.
30.Raymond C Rowe. Handbook of pharmaceutical excipient:pharmaceutical press and American pharmacists association. 6th ed. 2006.
31.Garcia CV, Paim CS, Steppe M, Schapoval EE. Development and validation of a dissolution test for rabeprazole sodium in coated tablets. J Pharm Biomed Anal. Jun 7 2006;41(3):833-837.
32.Andersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol. Jan 2004;3(1):46-53.
33.Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. Jan 2003;61(1):37-49.
34.雷建邦, 溫軒琳, 項怡平. 膀胱過動症的藥物研發新趨勢. Chang Gung Journal of Pharmacy. 2012;19:2.
35.Mukerji G, Yiangou Y, Grogono J, et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol. Jul 2006;176(1):367-373.
36.Matsumoto Y, Miyazato M, Furuta A, et al. Differential roles of M2 and M3 muscarinic receptor subtypes in modulation of bladder afferent activity in rats. Urology. Apr 2010;75(4):862-867.
37.Andersson KE. The concept of uroselectivity. Eur Urol. 1998;33 Suppl 2:7-11.
38.郭漢崇. 膀胱過動之藥物治療. 台灣尿失禁防治協會.
39.陳昭姿. Oxybutynin-老少咸宜的尿失禁治療劑. 當代醫學. 1993;20(1).
40.Athanasopoulos A, Perimenis P. Pharmacotherapy of urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. Apr 2009;20(4):475-482.
41.Fernandes E, Vernier R, Gonzalez R. The unstable bladder in children. J Pediatr. Jun 1991;118(6):831-837.
42.Thuroff JW, Bunke B, Ebner A, et al. Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol. Apr 1991;145(4):813-816; discussion 816-817.
43.Ouslander JG. Management of overactive bladder. N Engl J Med. Feb 19 2004;350(8):786-799.
44.http://www.rxlist.com/script/main/hp.asp.
45.http://www.synmosa.com.tw/.
46.Aulton M, Abdul M, Hogan J. The mechanical properties of HPMC films derived from aqueous system : The influence of plasticzers. Drug Dev Indus Pharm. 1981;7:649-668.
47.莊素卿. Phenyltriazine類抗癲癇藥物控釋製劑之釋放及安定性研究. 私立嘉南藥理科技大學藥物科技研究所. 2011;碩士論文.
48.李維揚. Alfuzosin間質性以及間質性膜衣包覆錠劑之製備與藥物釋放研究. 私立嘉南藥理科技大學藥物科技研究所. 2009;碩士論文.
49.Katzhendler I, Azoury R, Friedman M. Crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets based on hydroxypropyl methylcellulose. J Control Release. Jun 1998;54(1):69-85.
50.Gebelein C, Cheng T, Yang C. Pharmaceutical and Medical Polymers. Polymeric Materials Science and Engineering. 1990;63:401-405.
51.http://eudragit.evonik.com/.
52.林山陽. 膜衣包覆技術. 九州圖書文物有限公司.
53.詹雅雯. 使用擠壓搓圓技術於Didanosine和Doxycycline Hyclate腸溶性圓粒劑型之研究. 私立嘉南藥理科技大學生物科技研究所. 2007;碩士論文.
54.Brostrom S, Hallas J. Persistence of antimuscarinic drug use. Eur J Clin Pharmacol. Mar 2009;65(3):309-314.
55.顏兆熊. 台灣醫界雜誌. 台灣醫界. 2006;49(10).
56.Birns J, Lukkari E, Malone-Lee JG. A randomized controlled trial comparing the efficacy of controlled-release oxybutynin tablets (10 mg once daily) with conventional oxybutynin tablets (5 mg twice daily) in patients whose symptoms were stabilized on 5 mg twice daily of oxybutynin. BJU Int. May 2000;85(7):793-798.