- 學位論文
穿心蓮內酯固體分散劑型之製備及其性質評估
Preparation and characterization of andrographolide solid dispersion formulation
摘要
本篇研究目的為利用固體分散劑型，改善穿心蓮內酯之低水溶解度、低通透性質及提高其口服生體可用率。固體分散劑型製備方式採取溶劑揮發法，而最佳處方進一步觀測固體分散劑型之結晶型態及主成分及載體間之鍵結，再藉由體外腸道通透性試驗證實固體分散對於通透性之改善，而最後再以大鼠藥物動力學試驗驗證其生體可用率之提升。而其中於優化劑型步驟中，初步會先選擇載體，以PEG 6000、Poloxamer 407、PVP K30、PVP K15及PVP K90進行篩選，而於溶離釋放結果以PVP K30具最佳之效果，篩選載體後再進行界面活性劑篩選，於PVP K30處方中加入Cremophor EL或Tween 80進行優化，結果以1:7:1（w/w/w）比例之穿心蓮內酯:PVP K30:Cremophor EL具最佳之溶離釋放效果，其於5分鐘內能達約80%釋放，相較於穿心蓮內酯粉末之第5、120及溶離效率之溶離度分別提升約16、2及4倍。優化處方進行水溶解度試驗證實相較於穿心蓮內酯及其物理混合物，其水溶解度分別提升約1.5及1.3倍。再以差示掃描量熱分析確認穿心蓮內酯固體分散劑型為非晶型形態存在，而以傅立葉轉換紅外光譜進行分析，證實以PVP K30及Cremophor EL製備為固體分散劑型並不會與穿心蓮內酯產生新之化學鍵結。於體外腸道通透性試驗，固體分散劑型於十二指腸、空腸及迴腸分別相較於穿心蓮內酯通透性提升約2、3及3倍。而進一步於大鼠體內藥物動力學試驗中，固體分散劑型可以提高2.99倍之相對生體可用率，且大鼠口服服用100 mg之穿心蓮內酯固體分散劑型與口服服用300 mg之穿心蓮內酯於t1/2、Cmax、AUC0-t及AUC0-∞具有相似之藥物動力學數值。綜合以上結果，穿心蓮內酯之固體分散劑型成功克服穿心蓮內酯本身低水溶解度及通透性之性質且於體內能夠成功提高生體可用率。
並列摘要
The study aimed to develop solid dispersion system of andrographolide (AG) to improve the dissolution and oral bioavailability. Solid dispersions were prepared by solvent evaporation method. And the optimized formulation of solid dispersion would be observed the crystal state and the chemical bonding between active ingredient and carriers. The permeability properties would be checked by everted intestinal test. Finally, the pharmacokinetics studies of rats would be conduct to prove the promotion of oral bioavailability. To optimized the formulation of solid dispersion, PEG 6000, Poloxamer 407, PVP K30, PVP K15 and PVP K90 were chosen as the carrier to evaluate the drug releasing. From the results of dissolution, the AG with PVP K30 demonstrated the best dissolution rate and was chosen for further formulation optimizing study. In the optimizing experiment, Cremophor EL or Tween 80 was added to the PVP K30 formulation. From the dissolution result, the 1:7:1 (w/w/w) of AG:PVP K30:Cremophor EL was the optimized formulation. The optimized one showed about 80% release of AG at 5 minute. In addition, comparing to AG powder, the release performance of the optimized formulation was about 16-, 2- and 4-fold higher at 5, 120 minutes and dissolution efficiency, respectively. And the results of solubility test, the optimized formulation improve the solubility about 1.5- and 1.3-fold comparing with AG and physical mixture. Moreover, differential scanning calorimetry analysis showed the optimized formulation presented amorphous state. And Fourier transform infrared spectroscopy analysis showed that there was no interaction between AG, PVP K30 and Cremophor EL. In everted intestinal test, the results showed the optimized formulation improve the permeability properties about 2-, 2- and 3-fold of duodenum, jejunum and ileum comparing with AG. At last, the pharmacokinetic studies showed solid dispersion improved relative bioavailability to 2.99-fold. And 100 mg of the optimized formulation had the similar t1/2, Cmax, AUC0-t and AUC0-∞ comparing with AG. To sum up, the solid dispersion of AG successfully overcame the solubility and permeability, also improved the oral bioavailability.
參考文獻
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