- 學位論文
嵌段式共聚合物對難溶性藥物助溶能力之探討
Solubilization of hydrophobic drugs by copolymers
摘要
利用嵌段式共聚合物改善兩個類似之水難溶性藥物(compound A與B)之水溶解度，評估水難溶性藥物在嵌段式共聚合物包覆後之增溶效果。並利用結構上與compound A、B不同之藥物compound C、prednisolone、dexamethasone及fluorometholone pivalate確認此評估方式之可行性。此compound A與B之水溶解度測試後分別為124.48 ± 26.08 ng/ml及4.90 ± 0.28 μg/ml。在使用八個同系列不同長度之嵌段式共聚合物來改善添加後，在單一嵌段式共聚合物的情況下，以PM6 (41.50 ± 10.47 μg/ml, 49.20 ± 0.62 μg/ml)及PM7 (58.45 ± 0.15 μg/ml, 54.73 ± 2.37 μg/ml)助溶效果最好。故分別對PM6及PM7與其他共聚合物進行混合式溶解度試驗。同時利用嵌段式共聚合物臨界微膠體濃度之測定、混合前後粒徑大小及溶解度提升的程度，篩選出最佳之嵌段式共聚合物組成。實驗結果顯示，共有7個混合處方(PM1+PM6、PM8+PM6、PM4+PM2+PM6 、PM8+PM7+PM6、PM5+PM2+PM7、PM4+PM3+PM7、PM5+PM3+PM7)，同時具有降低臨界微膠體濃度，降低粒徑大小，且對compound A之溶解度具有協同作用，而其中以8 % PM8+PM7+PM6提升compound A溶解度最顯著(1.09 ± 0.05 mg/ml)。而這六種混合處方(PM2+PM7、PM5+PM7、PM6+PM7、PM3+PM1+PM6、PM8+PM7+PM6、PM6+PM2+PM7) 對compound B也有降低臨界微膠體濃度，降低粒徑大小，溶解度具有協同作用，其中以12%之PM3+PM1+PM6混合，可以提升compound B溶解度最顯著(753.73 ± 139.05 μg/ml)。利用線性迴歸之R2值評估compounds A與B與嵌段式共聚合物之物理化學相關性。其中發現以Compounds A與B在各嵌段式共聚合物下之溶解度，與嵌段式共聚合物疏水端之重量、疏水端莫耳數及compound A、B在共聚合物下三個因子之擬分配係數具有較佳的相關性。其次compound C, dexamethasone, prednisolone and fluorometholone pivalate在此類嵌段式共聚合物下，均可增加溶解度，並且極性較差的藥物，溶解度提升倍率較極性較佳的藥物大。
並列摘要
The main propose of this study was to improve the solubility of hydrophobic drugs (compound A and compound B) by copolymers. Compound C、prednisolone、dexamethasone and fluorometholone pivalate were used further evaluate the feasibility of the increasing solubility. The water solubility of compound A and B were found in 124.48 ± 26.08 ng/ml and 4.90 ± 0.28 μg/ml, respectively. Among these 8 different length of copolymer, the solubility of compounds A and B in PM6 and PM7 were increased to 41.50 ± 10.47, 58.45 ± 0.15, 49.20 ± 0.62, and 54.73 ± 2.37 μg/ml, respectively. Therefore, PM6 and PM7 were used to combine with another seven copolymers to further evaluate the synergistic solubilization effect for compounds A and B. The opimization combinations of mixed copolymer were screened by decreased the critical micelle concentration of copolymers, decreased the particle size after mixing with compound A or B, and the increased solubility of copolymers for compound A an B. Our results indicated that 7 combination of copolymers (PM1+PM6、PM8+PM6、PM4+PM2+PM6 、PM8+PM7+PM6、PM5+PM2+PM7、PM4+PM3+PM7、PM5+PM3+PM7) were lower critical micelle concentration, reduced particle size and, synergistic solubilization for compound A. Among of them, 8 % PM8+PM7+PM6 was significantly increased the solubility of compound A to 1.09 ± 0.05 mg/ml. For compound B, 6 combination of copolymers (PM2+PM7、PM5+PM7、PM6+PM7、PM3+PM1+PM6、PM8+PM7+PM6、PM6+PM2+PM7), could lower critical micelle concentration, reduced particle size, and synergistic solubilization for compound B. 12% PM3+PM1+PM6 was significantly increased the solubility of compound B to 753.73 ± 139.05 μg/ml. Using the liner simple regression to evaluate the correlation between compound A or B with physicochemical properties of block copolymers, the results were found that the solubility of compound A or B in copolymers was correlated with the hydrophobic mole, hydrophobic weight of copolymers and the partition coefficient of compound A or B in copolymers. Furthermore, compond C, dexamethasone, prednisolone and fluorometholone pivalate were all enhanced solubility by copolymers. In addition, the more hydrophobicity of drugs could be more increased solubility by these types of block copolymers.