Thoma K, Ziegler I
Ludwig-Maximilians-University Munich, Germany.
Eur J Pharm Biopharm. 1998 Jul;46(1):105-13. doi: 10.1016/s0939-6411(97)00164-1.
Various ratios of succinic acid to fenoldopam mesylate, ranging from 0:1 to 18:1 were incorporated in pellets and coated with 1.5-12% w/w Surelease. Even though the coating level did influence the rate and amount of fenoldopam release, the influence of the succinic acid to drug ratio was much more important and evident at all coating levels. Being a weakly basic drug, fenoldopam release ceased when testing in SIF for succinic acid to drug ratios of 0:1-4:1, with the end of release being more abrupt for the 0:1 than for the 4:1 ratio. Only for a succinic acid to drug ratio of > or =5 was fenoldopam release constant for 6-8 h and independent of the pH-value of dissolution media. For a thin coat of about 2.5% w/w Surelease, those pellets showed an ideal controlled release behaviour with release rates of about 5-10%/h and a total release of almost 80% in 8 h. The dissolution profiles of Surelease coated pellets with high succinic acid to drug ratios (> or =5) and different coating levels, were evaluated for best fits to commonly used kinetic models. Sustained release mechanisms are discussed according to best fit models. The quantification of the pH-adjuster succinic acid, released from pellets with an acid to drug ratio of < or =1 showed, that despite their failure as a controlled release system for fenoldopam, the investigated coats could control the release of succinic acid effectively at optimized coating levels. For increasing succinic acid to drug ratios (< or =4) succinic acid was released at an ever more constant rate and release rates, though still faster than the release rates of fenoldopam, decreased steadily for increasing ratios. At a 5:1 ratio finally release rates of succinic acid and fenoldopam were almost identical. Therefore those pellet cores were almost completely emptied during dissolution testing, with both fenoldopam and succinic acid leaving at a constant rate and a total release of about 80% each for a 2.5% Surelease coat, while lower succinic acid to drug ratios had failed to show any sustained release for such thin Surelease coats. A similar formulation with fumaric acid instead of succinic acid failed to show the desired release pattern, indicating that it is the presence of a sufficiently high amount of succinic acid rather than the presence of an acidic compound in general, that ensures fenoldopam solubility at higher pH-values.
将不同比例（范围从0:1至18:1）的琥珀酸与甲磺酸非诺多泮制成微丸，并包衣1.5 - 12% w/w的Surelease。尽管包衣水平确实会影响非诺多泮的释放速率和释放量，但在所有包衣水平下，琥珀酸与药物的比例影响更为重要且明显。作为一种弱碱性药物，当在模拟肠液（SIF）中测试琥珀酸与药物比例为0:1 - 4:1时，非诺多泮的释放停止，0:1比例时释放结束比4:1比例时更突然。仅当琥珀酸与药物比例≥5时，非诺多泮的释放才在6 - 8小时内保持恒定且与溶出介质的pH值无关。对于约2.5% w/w Surelease的薄包衣，这些微丸呈现出理想的控释行为，释放速率约为5 - 10%/小时，8小时内总释放量接近80%。评估了具有高琥珀酸与药物比例（≥5）和不同包衣水平的Surelease包衣微丸的溶出曲线，以确定其与常用动力学模型的最佳拟合情况。根据最佳拟合模型讨论了缓释机制。对酸与药物比例≤1的微丸中释放的pH调节剂琥珀酸进行定量分析表明，尽管它们作为非诺多泮的控释系统失败，但在所研究的包衣在优化的包衣水平下能够有效控制琥珀酸的释放。随着琥珀酸与药物比例增加（≤4），琥珀酸以越来越恒定的速率释放，且释放速率虽仍快于非诺多泮的释放速率，但随着比例增加而稳步下降。最终在5:1的比例下，琥珀酸和非诺多泮的释放速率几乎相同。因此，在溶出测试过程中，这些微丸芯几乎完全排空，对于2.5% Surelease包衣，非诺多泮和琥珀酸均以恒定速率释放，各自的总释放量约为80%，而较低的琥珀酸与药物比例对于如此薄的Surelease包衣未能显示出任何缓释效果。用富马酸代替琥珀酸的类似制剂未能显示出所需的释放模式，这表明是存在足够高量的琥珀酸而非一般的酸性化合物的存在，确保了非诺多泮在较高pH值下的溶解度。
