膨脹型胃滯留傳遞系統的開發與特性探討
Development and Characterization of Expandable Gastroretentive Delivery System (GRDS)
中文摘要
本實驗的目的是希望能發展出一個新穎的膨脹型胃滯留藥物傳輸系統。我們主要 是以具膨脹特性的聚合物為主，再添加不同的輔助性賦型劑來製備出理想的劑 型。本研究中，主要將處方的設計分為以下五大分類來進行膨脹特性的探討，包 括：不同聚合物的組合、帶電型聚合物的添加、不同離子複合物的組合、滲透壓 物質的添加和導水物質的添加。從不同的聚合物或賦型劑的組成，依錠劑之物化 性質可以評估不同的錠劑膨脹特性，包括重量的差異或可見的膨脹程度觀察，
作為對於錠片膨脹的程度有更完整的了解。
實驗結果顯示單獨比較高分子量的PEO（M.W.8,000,000）和 HEC 250HHX 發
現PEO 的膨脹特性較顯著。然而，當等量的 NaCMC 分別添加到上述兩種聚合
物中，卻發現NaCMC 的添加使 HEC 250HHX 能達到較 PEO 更優越的膨脹效果。
此外，從不同離子複合物的添加量中，發現膨脹程度只有微量的加強效果。另外 滲透壓物質或是導水物質的添加對於膨脹特性的影響性並沒有顯著的加強效果。
最後，從五大類的處方設計中我們發現HEC 250HHX 和 NaCMC 450 cps 以 60：40 的混合比例能夠得到最佳的膨脹效果。
接著添加三種不同溶解度的藥物到膨脹型的處方中（HEC 250HHX:NaCMC 450 cps = 60:40）以探討不同濃度的氯化鈉溶液（A：0，B：0.1，C：0.5，D：
0.9％）對於藥物釋放模式的影響性。結果顯示，易溶藥物 Metformin 在各溶液中 的釋放速率順序為D>C>A>B，這現象可以 Metformin 在 0.1％的氯化鈉溶液中 的溶解度相較於其他濃度的溶液下確實明顯地偏低來解釋。可溶藥物
Ciprofloxacin 在各溶液中的釋放速率順序為 D>C>B>A。這主要是因為
Ciprofloxacin 在高濃度氯化鈉溶液中的溶解度較偏低，而溶解度較低的藥物有 可能會阻礙膠體層的形成因而藥物可以藉由聚合物的溶蝕較快速地從高濃度氯
化鈉溶液中釋放出來。而微溶藥物Esomeprazole 在各溶液中的釋放速率順序為
A>C>D>B。因為 Esomeprazole 在各溶液中的藥物釋放速率並沒有顯著的差異，
因此認為氯化鈉溶液濃度對於Esomeprazole 藥物釋放的影響性不大。在從實驗
結果我們也得知，Metformin 主要是藉由水份滲透速率來控制藥物的釋放，而 Ciprofloxacin 和 Esomeprazole 則是利用水份滲透和膨脹速率來控制藥物的釋放。
結果顯示此製備錠片之特性在胃內能有更明顯延長胃滯留時間的效果，且具有 控釋藥物之效能。
英文摘要
The aim of the study was to develop a novel expandable gastroretentive drug delivery system. We have been interested in developing the devices based on swellable
polymers combining with several functionalities in the unit. In our studies, the investigation of different formulation factors included the following five categories, i.e. different combination of swellable polymers, the addition of chargable polymers, different combination of ionic complexes of polymers, the addition of osmogents and the addition of wicking agents on the swelling behavior was conducted. Physical characterizations of the tablets including swelling index based on weight variation and visual swelling observations were carried out to have comprehensive understanding of the swelling properties for different combination of polymers and excipients with different functionalities.
Results demonstrate that the swelling ability of higher molecular weight PEO
(M.W.8,000,000) was greater than HEC 250HHX alone. However, when NaCMC 450 cps were added in the same ratio to both swellable polymer, it was interesting to found that the swelling size of the combination with HEC 250HHX were much larger than the combination with PEO M.W.8,000,000. On the other hand, the addition of polyionic complexes showed only slightly improvement in swelling index. However, the addition of both osmogents and wicking agents did not show significant
improvement in swelling index compared to HEC 250HHX alone. Among the five categories, we found that the combination of HEC 250HHX and NaCMC 450 cps in the ratio of 60:40 exhibited the greatest swelling index.
Subsequently, three different solubility drugs were incorporated in the expandable formulations (HEC 250HHX:NaCMC 450 cps = 60:40) to investigate the influences of the drug solubility on the drug release pattern and swelling behaviors in the medium containing various NaCl concentration (A: 0, B: 0.1, C: 0.5, D: 0.9%).
Results reveal that the rank order of decreasing release rate for freely water soluble drug Metformin was D>C>A>B, in which the solubility of Metformin in 0.1% NaCl was exactly much lower than the others. The rank order of decreasing release rate was D>C>B>A for water soluble drug Ciprofloxacin. Due to its highly soluble in various NaCl concentration, this might be caused by the extent of the hindrance in the formation of gel layer increased with increasing NaCl concentration leading to the faster release rate. However, the rank order of decreasing release rate was A>C>D>B for slightly soluble drug Esomeprazole, in which the difference of release rate was not significant pronounced that the influence of NaCl concentration on the release profile of Esomeprazole could be neglected. Furthermore, it was elucidated that the release
mechanism of Metformin was mainly by diffusion controlled release, while the release mechanism of Ciprofloxacin and Esomeprazole were mainly by anomalous diffusion release.
In conclusion, the developed gastroretentive device composed of HEC and NaCMC possessed significantly excellent swelling potential for longer gastric retention with sustained drug release characteristics.
