臺灣博碩士論文加值系統

控釋劑型為一種在固定時間以一定速率將藥物有效的傳遞到作用部位，產生預期效果的一種劑型。而本研究的目的乃是製備Nicardipine長時間釋放劑型。
在初步篩選數種賦形劑之後以HPMC來當做載體，並以Avicel®及Sodium alginate來當做修飾藥物溶離速率之添加劑。
為快速獲得具有理想釋出速率之Nicardipne extended release錠劑，本實驗利用Response surface methodology(RSM)之技術來尋求符合多項目標在第3、6和12小時之藥物釋放百分比分別為不可大於30％，介於40~65％和大於80％之合適化處方。其中以HPMC、Avicel®、Sodium alginate的含量設為indepensent factor，依限制性混合實驗法來設計一系列模式配方，所有配方依pH change溶媒進行藥物釋出試驗，以藥物在第3、6和12小時釋出量為dependent facto利用一次多項式方來分析independent factor及dependent factor之關係並找出符合理想之配方。
結果顯示，所得合適化處方在第3、6和12小時之預估溶離率值與與實際實驗觀察值經由RE％來評估，發現其RE％≦5％，因此確認了RSM的可用性；而且Nicardipine間質型長期釋放錠之釋出機轉則近似零級模式。

Controlled release may be defined as a technique by which drug are made available to a target at a fixed rate and duration to produce a desirable therapeutic effect. The purpose of the study was to prepare nicardipine matrix for extended release.
HPMC was selected as carrier to prepare nicardipine tablets and Sodium alginate and Avicel® were used to confer the release of drug.
The response surface methodology (RSM) and multiple responses optimization polynomial equation were used to obtain optimal nicardipine matrix for extended release. First of all the release rate at 3, 6, 12 hr were not more than 30%, not less than 40~65% and not less than 80%, respectively. The amounts of HPMC, Avicel® and Sodium alginate were defined as independent factors. Limit mixture method was used to design an array of formulations. Dissolution test with pH change buffer was used to obtain the release percentages at the 3, 6 and 12 hr. Multiple responses optimization polynomial equation was used to analyze the relationship between independent factor and dependent factor to obtain an optimal formulation.
The result showed the optimized formulation provided a dissolution profile equivalent to that of predict and its RE%±5% was not more than 5%, indicating that the optimal formulation could be obtained by using response surface methodology.
The mechanism of drug release from optimal nicardipine matrix tablets was found to follow quasi Zero-order model.

表次目錄-------------------------------------------------- Ι
表次目錄-------------------------------------------------- Π
圖次目錄-------------------------------------------------- Ⅲ
中文摘要-------------------------------------------------- Ⅳ
英文摘要-------------------------------------------------- Ⅴ
壹、 緒論------------------------------------------------- 1
一、 前言------------------------------------------------- 1
二、 口服控制劑型之背景----------------------------------- 2
三、 間質型錠劑釋出情形與機轉----------------------------- 4
四、 Nicardipine HCl基本之概述--------------------------- 6
(一) 物化特性-------------------------------------------- 6
(二) 藥效藥理-------------------------------------------- 7
(三) 臨床使用--------------------------------------------
8
(四) 藥物動力學------------------------------------------ 8
五、 各賦形劑之基本概述----------------------------------
六、
七、 ---------------------------- 13
24
六、 實驗設計法 (experimental design)--------------------
七、 Nicardipine HCl物化性質實驗------------------------------ 18
貳、 研究目的--------------------------------------------- 23
參、 材料與儀器設備--------------------------------------- 24
一、 材料(Material)--------------------------------------- 24
(一) 藥品(Drug)------------------------------------------- 24
(二) 賦型劑(Excipients)與化學試藥(Chemical reagents)------ 24
二、 儀器設備(Apparatus)---------------------------------- 25
肆、 實驗方法--------------------------------------------- 26
一、 Nicardipine HCl間質型控釋錠之製備---------------- 26
(一) 濕式造粒法---------------------------------------- 26
(二) 壓錠方法------------------------------------------ 26
(三) Nicardipine HCl配方------------------------------- 26 Nicardipine HCl配方
(四) Nicardipine HCl處方設計--------------------------- 29
二、 體外溶離試驗------------------------------------- 31
三、 體外實驗檢品分析方法--------------------------------- 33
四、 資料分析方法----------------------------------------- 34
五、 示差掃描熱分析法------------------------------------- 35
伍、 結果與討論------------------------------------------- 36
一、 定性定量方法之結果-----------------------------------
一、 ------------------------------------------------ 36
二、 體外溶離試驗-----------------------------------------二、 39
(一) Nicardipine配方溶離之影響----------------------------
1. ----------------------------------------------- 39
(二) 添加Avicel對藥物釋出之影響--------------------------
2. ---------------------- 43
(三) 添加Sod.Alginate對藥物釋出之影響-------------------- 45

三、 實驗設計法檢測之結果--------------------------------- 51

四、 式差掃描熱分析法(Differential Scanning Calorimetry)-- 62

陸、 陸、結論-------------------------------------------------- 68
柒、參考文獻---------------------------------------------- 69

Akitoshi, Y., Takayama, K., Machida, Y., Nagai, T., Computer optimization of the formulation of acrylic plaster. Chem. Phqrm. Bull., 1985; 33: 4536-4543.
Ahmed, J. H., Grant, A. C., Rodger, R. S. C., Murry, G. R., Elliot, H. L., Inhibitory effect of ureamia on the hepatic clearance, and metabolism of nicardipine. Br. J. Clin. Pharmacol., 1991; 32: 57-62.
Atkinson, A. C., Experiments with mixture: Design, Models and the Analysis of Mixture Data., John Wiley and Sons, Inc. 1996.
Braybrook, J. H., Hall, L. D., Review: Polymeric controlled release system. Drug Des. Deliv., 1990; 6: 73-86
Campbell, B. C., Kelman, A. W., Hillis, W. S., Noninvasive assessment of the haemodynamic effect of nicardipine in normotensive subject. Br. J. Clin. Pharmacol., 1985; 20(suppl.1): 55s-61s.
Cook, E., Clifton, G. G., Vargas, R., Bienvenu, G., Williams, R., Pharmacokinetics, pharmacodynamics and minimum effective clinical dose of intravenous nicardipine. Clin. Pharmacol. Ther., 1990; 47: 766-778.
Chien, Y. W., Novel drug delivery system, 2th ED., 1992
Feely, L. C., Davis, S. S., The influence of polymeric excipients on drug release from hydroxypropylmethylcellulose matrices. Int. J. Pharm., 1988; 44: 131-139.
Ford, J. L., Rubinsyein, M. H., Hogan J. E., Formulation of sustained release promethazine hydrochloride tablets using hydroxypropyl methylcellulose matrices. Int. J. Pharm., 1985; 24: 327-338.
Glossmann, H., Activation of chromaffin cell Ca2+ channels by novel dihydropyridine. Nature. 1985; 313: 503-504
Hong, J. E., Hydroxypropylmethylcellulose sustained release technology. Drug Des. Deliv., 1989; 15: 975-999.
Howard C. Ansel, Loyd V. Allen, Jr., Nicholas G. Popovich., Pharmaceutical osage forms and drug delivery system, 7th ED. 1999; 229-235
Kim, H., Fassihi, R., A new ternary polymeric matrix delivery of highly soluble drug. Pharm. Res., 1997; 14: 1415-1421.
Jun, H. W., The roles of drug delivery systems in pharmacology therapeutics. Pharm. Technol., 1995; 19: 42-50
Jover, I., Poodczeck, F., Newton, M., Evalation, by a statistically designed experiment, of an experimental grade of microcrystalline cellulose, Avicel, as a technology to aid the production of pellets with high drug loading. J. Pharm. Sci., 1996; 85: 700-705.
Lee, P. I., Kinetics of drug release from hydrogel matrices. J. Control. Release., 1985; 2:277-288..
Mura, P., Manderioli, A., Bramanti, G., Furlanetto, S., Pinzauti, S., Utilization of differential scanning calorimertry as a screening technique to determine the compatibility of ketoprofen with excipients. Int. J. Pharm., 1995; 199:71-79.
Merk Index, 12th Ed., Merck and Co. Inc., Rahway., 1996, p1115
Montgomery, D. C., Design and Analysis of Experiments. 5th ed. Canada: John Wiley and Sons, Inc., 2001; 218-233
O''Connor, R. E., Schwartz, J. B., Extrusion and spheronization technology. J. Pharm. Sci. Technol., 1989; 9: 187-216.
Peppas, N. A., Sahlin, J. J., A Asimple equation for description of solute release. Ⅲ. Coupling of diffusion and relaxation. Int. J. Pharm., 1989; 57: 169-172.
Ristschel, W. H., Biopharmaceutic and pharmacokinetic aspects in the design of controlled release peroral drug delivery system. Drug Dev. Ind. Pharm., 1989; 15: 1073-1103
Sorkin, E. M., Clissold S. P., A review of its Pharmacodynemic and pharmacokinetic properties, and therapeutic efficacy in the cardiovascular disorders. Drug., 1987; 33: 296-345.
Schoors, D. F., Vercruysse, I., Musch G., Masser, D.L., Dupont, A. G., Influence of nicardipine on pharmacokinetics, and pharmacodynamics off propanolol in healthy volunteer. Br. J. Clin. Pharmac., 1990; 29: 497-501.
Stevenson, W. T.. Sefton M. V., Graft copolymer emulsions of sodium alginate with hydroxyalkyl methacrylates for microencapsulation. Biomaterials. 1987; 8(6): 449-57.
Sako K. Sawada T. Nakashima H. Yokohama S. Sonobe T. Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release. J. Control. Release., 2002; 81(1-2):165-72
Visor, G. C., Bajk, E., Benjamin, E., Intranasal delivery of nicardipine in the rat. J. Pharm. Sci., 1990; 75: 44-46.
Wan, L. S. C., Heng, P. W. S., Wong, L. F., Matrix swelling: A simple model describing extent of swelling of HPMC matrices. Int. J. Pharm.,1995; 116: 159-168
Wingard, L. B., Brody, T. M., Larner, J., Schwartz, A., Human pharmacology. Mosby Year Book, 1991; 213-222.
Wade, A., Weller, P. J., Handbook of Pharmaceutical Excipients, 2nd Ed. J. Am. Pharm. Assoc. 1994; 229-232