Kaukonen A M, Lennernäs H, Mannermaa J P
Department of Pharmacy, University of Helsinki, Finland.
J Pharm Pharmacol. 1998 Jun;50(6):611-9. doi: 10.1111/j.2042-7158.1998.tb06894.x.
Water-soluble derivatives of beta-cyclodextrin have been considered for solubilization of spironolactone in the formulation of a safe liquid preparation for premature infants. The oral absorption of spironolactone was studied in rats to evaluate the need to adjust spironolactone dosage in prospective clinical studies. Spironolactone was administered in solutions of sulphobutyl ether beta-cyclodextrin (SBE7) or dimethyl-beta-cyclodextrin (DM-beta-CyD) and also as spironolactone-containing powder papers (reference preparation). Spironolactone in SBE7 solution was administered intravenously to assess the extent of intestinal absorption from the different formulations. Spironolactone and the metabolites 7alpha-thiospirolactone, 7alpha-thiomethylspirolactone and canrenone were determined in rat serum after intravenous administration of spironolactone. Half-lives for spironolactone, 7alpha-thiomethylspirolactone and canrenone were 0.72 +/- 0.17, 1.5 +/- 0.3 and 2.2 +/- 0.3 h, respectively. Although, according to Cmax values, 7alpha-thiomethylspirolactone was the major serum metabolite in rats, higher AUC (area under the serum concentration-time curve) values were obtained for canrenone. After oral administration of spironolactone the bioavailabilities evaluated from the AUC values of 7alpha-thiomethylspirolactone were 27.5 +/- 9.3%, 81.3 +/- 28.8% and 82.8 +/- 28.6% for powder papers, DM-beta-CyD and SBE7 solutions, respectively. The oral absorption of spironolactone by rats was better after administration of spironolactone in SBE7 and DM-beta-CyD solutions than after administration as powder papers. Both cyclodextrin formulations enhanced spironolactone bioavailability to a similar extent despite some deacetylation of spironolactone in the presence of SBE7. A reduction of spironolactone dosage would be recommended during clinical studies with premature infants. These results indicate that SBE7 could be a safe and suitable excipient for the solubilization of spironolactone in paediatric formulations.
β-环糊精的水溶性衍生物已被考虑用于使螺内酯增溶，以配制一种适合早产儿的安全液体制剂。在大鼠中研究了螺内酯的口服吸收情况，以评估在未来临床研究中调整螺内酯剂量的必要性。螺内酯以磺丁基醚β-环糊精（SBE7）或二甲基-β-环糊精（DM-β-CyD）溶液的形式给药，也以含螺内酯的粉末纸（参比制剂）形式给药。将SBE7溶液中的螺内酯静脉给药，以评估不同制剂的肠道吸收程度。静脉注射螺内酯后，测定大鼠血清中的螺内酯及其代谢产物7α-硫代螺内酯、7α-硫代甲基螺内酯和坎利酮。螺内酯、7α-硫代甲基螺内酯和坎利酮的半衰期分别为0.72±0.17、1.5±0.3和2.2±0.3小时。虽然根据Cmax值，7α-硫代甲基螺内酯是大鼠血清中的主要代谢产物，但坎利酮的AUC（血清浓度-时间曲线下面积）值更高。口服螺内酯后，根据7α-硫代甲基螺内酯的AUC值评估，粉末纸、DM-β-CyD和SBE7溶液的生物利用度分别为27.5±9.3%、81.3±28.8%和82.8±28.6%。大鼠口服螺内酯后，在SBE7和DM-β-CyD溶液中给药后的吸收情况比以粉末纸形式给药更好。尽管在SBE7存在的情况下螺内酯会发生一些脱乙酰化，但两种环糊精制剂均在相似程度上提高了螺内酯的生物利用度。在对早产儿进行临床研究期间，建议减少螺内酯的剂量。这些结果表明，SBE7可能是儿科制剂中使螺内酯增溶的一种安全且合适的辅料。
