臺灣博碩士論文加值系統

　　Nifedipine為一鈣離子阻斷劑，廣泛用於缺鐵性心臟疾病及高血壓之治療，然半衰期短約為2-3小時，可藉助服用長效控釋劑型來延長藥物作用時間，並避免血中濃度變化幅度大的危險性。
　　本研究主要目的在以非均一藥物濃度方式（non-uniform drug concentration distribution），製備Nifedipine零級持續釋出之口服劑型。實驗方法為使用兩臺蠕動幫浦，乙臺將A槽中聚合物包衣溶液輸送至B槽之含藥及聚合物包衣溶液中均勻混合（幫浦速率為Ki），另乙臺則同時將B槽之均勻混合溶液輸送至離心式流動床內進行糖珠包衣步驟（幫浦速率為Ko）。
　　處方設計中，主要探討因素為(1)乙基纖維素（ethyl cellulose）之含量(2)研入水溶性物質蔗糖（sucrose）之含量(3)幫浦速率比值[Ki/(Ko-Ki)]。每批處方製劑進行體外溶離釋出分析，係根據美國藥典第23版所載，以擬胃酸（不含酵素）另添加1.5%(w/v)之Tween 80為溶媒，以確保在溶離度測定中維持“sink condition”。以藥物溶離釋出曲線中，表示零級釋出的直線關係之r（correlation coefficient）值，及12小時後藥物釋出百分比，來做為最佳處方之篩選標準。
　　首先固定幫浦速率比值[Ki/(Ko-Ki)=1]，使用不同重量之包衣聚合物，當包衣溶液中含有6 gm之 ethyl cellulose時，得到較佳之藥物溶離釋出曲線（r=0.97826、藥物釋出91%）；並發現當ethyl cellulose含量增加時，其溶離釋放速率常數（release rate constant）變小了。接著觀察分別研入2 gm及6 gm的sucrose於此處方中之影響，所得結果為藥物釋出分別增至91.5%及93%，然對其零級釋出的直線關係影響不大（r值為0.97705及0.93250）。當固定使用6 gm的ethyl cellulose，改變Ki/(Ko-Ki)之比值，發現release rate constant隨幫浦速率比值之增高而降低，並選擇出Ki/(Ko-Ki)比值為1.07之較佳處方（r=0.99088、藥物釋出71%）。由前得知可藉助研入sucrose增加藥物的釋出，且不影響零級釋出的直線關係，故研入不同量的sucrose觀察之，結果製得乙批處方，研入sucrose為0.3 gm，藥物釋出提高至85%，釋出曲線之r值為0.99055。
　　本實驗證明以質粒梯度濃度法製備Nifedipine口服零級持續釋出劑型之可行性，並以最佳處方製劑（N18處方）進行動物實驗，發現產生一般平緩的血中藥物濃度的變化，同時證明此處方具有持續控釋之作用。

　　Nifedipine, a calcium channel-blocking agent, has widely been used for the treatment of hypertention and coronary heart disease. Because it's half-life is 2-3 hours, we can take the long-term sustained release dosage form to increase the duration and avoid the suddenly change of plasma drug concentration.
　　The objective of this study was to use the non-uniform drug concentration method for preparing oral dosage form of nifedipine with zero-order release. We use two peristaltic pumps, one pumps the matrix solution of vessel A to vessel B, which contains the nifedipine and matrix solution (the pump rate is Ki). The other one pumps drug solution from vessel B to the rotary fluid-bed (the pump rate is Ko).
　　The main formulation parameters we discuss are (1) the content of ethylcellulose (2) the incorporate amount of water soluble sucrose (3) the change of pump ratio Ki/(Ko-Ki). The dissolution test follow the USP X X III paddle method and use 1.5% (w/v) Tween 80 in the dissolution medium to maintain "sink condition". From the drug dissolution profile, we use the zero-order fitting model and the final release percent of nifedipine within 12 hours as the criteria to optimize the formulation.
　　The data indicate that (1) Increase of ethylcellulose amount will decrease the dissolution release rate constant when we fix the pump ratio. (2) Incorporation of water soluble sucrose will increase the total drug release percent, and the zero-order linearity is not change significantly. (3) Increase of pump ratio will decrease the release rate constant. Finally, we successfully select a formulation which correlation coefficient is 0.99055 and the final release percent is up pto 85%. In animal tests, proved that our sustained release formulation was successfully.