臺灣博碩士論文加值系統

以鹽酸多西環素腸溶微粒為例，研究以不同溶解特性之腸溶包衣材料HPMC-P與EUDRAGIT® L30D-55，搭配不同的包衣製程，進行微粒之包覆並檢驗，0.06M HCl溶液與pH 5.5緩衝液中溶離度、圓整度及脆碎度之差異，探討強光、高溫及高濕對產品之影響以及加速安定性。初步結果顯示HPMC-P和EUDRAGIT® L30D-55的處方下，0.06M HCl溶液與pH 5.5緩衝液中溶離度並無太大的差異。比較以底噴流動床包衣所包覆之微粒，酸中溶離度以及其圓整度與脆碎度數據均優於側噴，因此選擇底噴，結合不同處方試製樣品，進行安定性以及虐待試驗研究。

相關實驗結果顯示在高溫下，有關物質及含量兩個指標中，EUDRAGIT® L30D-55表現比HPMC-P微粒更佳，且在強光、高溫及高濕環境下，皆具有良好的穩定性，樣品在0.06M HCl溶液中溶離度小於2%，故選擇為優化處方。

以EUDRAGIT® L30D-55為腸溶材料，配合底噴流動床包覆，是最符合質量穩定，兼具降低成本和環境無害之最佳選擇。

Coat hydrochloric acid doxycycline enteric-coated pellets with different dissolution characteristics enteric coating, HPMC-P and EUDRAGIT® L30D-55, in different coating process; identify their dissolution, roundness, and friability in 0.06M HCl solution and pH 5.5 buffer solution as well as impact of intense light, high temperature and high humidity on the product and its accelerated stability. Initial results suggest HPMC-P and EUDRAGIT® L30D-55 based products make no significant difference in acid and pH5.5 buffer solution in terms of dissolution. Particles coated by fluid bed granulation end up with better acid dissolution, roundness, and friability than their side granulation counterparts. We then take samples made by bed granulation and different formula for stability and puncture tests.

Test results suggest EUDRAGIT® L30D-55 based pellets outperm the HPMC-P ones with respect to substance and concentration while maintaining the same good stability in environment of intense light, high temperature and high humidity as well as less than 2% dissolution in 0.06M HCl solution. EUDRAGIT® L30D-55 is then poised the optimum prescription.

Coating EUDRAGIT® L30D-55 enteric material with fluid bed granulation is the best option in terms of reliable quality, lower costs and environment friendliness.

壹、緒論 1
一、鹽酸多西環素 1
(一)鹽酸多西環素作用機轉 2
(二)多西環素使用禁忌 3
(三)鹽酸多西環素中國藥典檢驗標準 4
二、微粒 5
(一)微粒製劑優勢 5
(二)微粒製備工藝簡敘 7
(三)粉末上藥法 7
(四)溶液及懸浮液上藥法 8
(五)流動床噴霧法 9
(六)擠出滾圓法 10
(七)球型凝聚法 11
(八)噴霧乾燥與噴霧凝結 12
(九)冷凍制丸法 13
(十)熔融制丸法 13
三、微粒包衣與控釋工藝 14
(一)糖衣鍋包衣 14
(二)底噴式流動床包衣 15
(三)側噴式流動床包衣 18
(四)流動床底噴與側噴式包衣機設備 19
四、腸溶膜包衣液組成 20
(一)腸溶包衣材料 20
1.有機腸溶包衣材料HPMC-P 21
2.水性腸溶包衣材料EUDRAGIT® 23
(二)可塑劑 25
(三)抗黏劑 25
(四)溶劑 26
(五)色素 26
貳、研究動機以及研究設計 27
參、材料與方法 29
一、材料與設備 29
(一)儀器設備 29
(二)試藥與材料 30
二、包衣液處方配置及處方篩選 32
(一)HPMC-P有機包衣液處方以及配製 32
(二)EUDRAGIT® L30D-55包衣液處方及配製 33
(三)處方篩選 34
三、製程以及操作參數 35
(一)糖衣鍋包衣製程參數 35
(二)流動床製程參數 36
四、物理試驗與外觀性狀 38
(一)物理性質 38
(二)外觀性質與微粒切面觀察 39
五、檢驗方法 39
(一)溶離度檢驗方法 39
(二)含量與相關物質檢驗方法 41
(三)檢量線製備 44
六、鹽酸多西環素腸溶微粒虐待性試驗 45
(一)強光試驗 45
(二)高溫試驗 45
(三)高濕試驗 45
七、加速安定性試驗 46
肆、結果與討論 47
一、處方篩選方法與製程篩選研究結果 47
(一)HPMC-P包衣處方增量研究結果 48
(二) EUDRAGIT® L30D-55包衣處方增量研究結果 50
二、物理性質與外觀性狀結果 51
(三)物理性質結果 51
(二)溶出後微粒外觀性質與微粒切面 52
三、檢驗結果與HPLC圖譜 54
(一)系統適用性 54
(二)含量檢測圖譜 54
(三)有關物質檢測 56
(四)檢量線 57
四、鹽酸多西環素載藥丸芯含量以及有關物質數據 58
五、虐待性試驗結果 59
六、安定性試驗結果 63
伍、結論 65
參考資料 66

[1] U.S.F.a.D. Administration, Doxycycline Hyclate Delayed-Release Tablets, 1967.

[2] I. Chopra, M. Roberts, Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance, Microbiology and molecular biology reviews, 65 (2001) 232-260.

[3] A.E. Czeizel, M. Rockenbauer, Teratogenic study of doxycycline, Obstetrics & Gynecology, 89 (1997) 524-528.

[4] N.P. Commission, Pharmacopoeia Of The People''s Republic Of China, china medical science press, Beijing, 2015.

[5] H. Bechgaard, G.H. Nielsen, Controlled-Release Multiple-Units and Single-Unit Doses a Literature Review, Drug Development and Industrial Pharmacy, 4 (1978) 53-67.

[6] K. Lavanya, V. Senthil, V. Rathi, Pelletization technology: a quick review, International Journal of Pharmaceutical Sciences and Research, 2 (2011) 1337.

[7] S.P. Sharma K, A Review On Formulation And Evaluation Aspects Of Enteric Coated Pellets, pharmatutorjournal, (2016).

[8] N. Hampel, A. B?佟k, M. Peglow, E. Tsotsas, Continuous pellet coating in a Wurster fluidized bed process, Chemical engineering science, 86 (2013) 87-98.

[9] S. Bhaskaran, P. Lakshmi, Extrusion spheronization—a review, Int. J. Pharm. Tech. Res, 2 (2010) 2429-2433.

[10] W.G. Chambliss, Conventional and specialized coating pans, Marcel Dekker, Inc.: New York1989.

[11] J.A. Lindlof, D.E. Wurster, Apparatus for coating particles in a fluidized bed, Google Patents, 1964.

[12] S. Srivastava, G. Mishra, Fluid bed technology: overview and parameters for process selection, International Journal of Pharmaceutical Sciences and Drug Research, 2 (2010) 236-246.

[13] A.U. Alam, Y. Qin, S. Nambiar, J.T. Yeow, M.M. Howlader, N.-X. Hu, M.J. Deen, Polymers and organic materials-based pH sensors for healthcare applications, Progress in Materials Science, (2018).

[14] R.C. Rowe, P.J. Sheskey, S.C. Owen, Handbook of pharmaceutical excipients, Pharmaceutical press London2006.

[15] S. Mori, Hypromellose Phthalate Enteric Coating Material, in: S.C.P.E. Department (Ed.), ShinEtsu, Tokyo, 2002.

[16] K. Nollenberger, J. Albers, Poly (meth) acrylate-based coatings, International journal of pharmaceutics, 457 (2013) 461-469.

[17] R.S. Berger, A Double?錉lind, Multiple?鋻ose, Placebo?錀ontrolled, Cross?隩ver Study to Compare the Incidence of Gastrointestinal Complaints in Healthy Subjects Given Doryx R and Vibramycin R, The Journal of Clinical Pharmacology, 28 (1988) 367-370.

[18] I.C.O.H.O. TECHNICAL, R.F.R.O.P.F. HUMAN, USE, STABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
Q1A(R2), European Union, 2003.