- 學位論文
Theophylline控釋劑型設計與體內體外相關性研究
Design of Controlled Release Dosage Form and In Vivo-In Vitro Correlations Study for Theophylline
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摘要
本研究探討間質型態(matrix type)錠劑中聚合物含量對體外溶離與體內吸收的影響；錠劑以theophylline為模式藥物及HPMC為控制釋放之聚合物製成。錠劑中HPMC的濃度分別為5%、15%、30%，實驗結果發現，HPMC含量較低的劑型具有較快速的溶離速率，且三種不同的劑型依據f1、f2數值判斷其溶離曲線是不相同的。 體內藥動試驗方面，當劑型中含有較低的HPMC濃度，則會有較高的Cmax，表示體內的表現可自體外溶離試驗反應得知。同時藉由In Vivo-In Vitro Correlation (IVIVC)的應用，更進一步發現體內體外相關性試驗中，含5% HPMC、15% HPMC、30% HPMC的三個不同劑型配方在level A correlation中，只有5% HPMC之配方有較好的體內體外相關性(Fa與Fd以線性回歸分析，R2 >0.95以上)。而在level B、level C correlation方面，都可以得到不錯的相關性。 若討論一級穿透速率常數(Kp)相對一級溶離常數(Kd)的α比值(α=Kp/Kd)，α值會隨HPMC含量的增加而增加，顯示當HPMC含量愈高時，整個吸收步驟受到溶離速率所限制，速率決定步驟為藥物之溶離速率。
並列摘要
In this study, theophylline was used as a model drug to illustrate how the relative rates of in vitro dissolution/ in vivo absorption may be affected by the HPMC concentration in the matrix tablets. The various HPMC concentrations used in the matrix tablets were 5%, 15% and 30%; a wet granulation method was utilized to fabricate the matrix tablets. The lower HPMC concentration formulation had faster release rate. The results showed that the in vitro dissolution rates of various formulations were a function of HPMC concentration. Both f1 and f2 values indicated the in vitro dissolution profiles for various formulations were not similar. The in vivo pharmacokinetic studies using humans showed that higher Cmax was observed for lower HPMC concentration formulation, demonstrating the in vivo performance of various formulations may be reflected by their in vitro dissolution. In the IVIVC studies, level B and C correlation methods got good linear relationships for all the tested formulations, and level A correlation only worked for the one with 5% HPMC. As the HPMC concentration increased, the alpha value increased; the fact indicated that dissolution was the rate limiting step.
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