Narisawa S, Stella V J
Department of Pharmaceutical Chemistry and Higuchi Biosciences Center for Drug Delivery Research, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
J Pharm Sci. 1998 Aug;87(8):926-30. doi: 10.1021/js980041h.
Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values <8 during long term storage; phenytoin readily precipitates when formed from fosphenytoin due to its limited aqueous solubility. The objective of this study was to develop stable formulations of fosphenytoin in the pH range of 7.4-8. 0 by inhibiting the phenytoin precipitation through complexation with a parenterally safe cyclodextrin, (SBE)7m-beta-CD. Phase solubility studies at 25 degreesC revealed that phenytoin could be effectively solubilized by (SBE)7m-beta-CD both in the presence and absence of 80.6 mg/mL fosphenytoin (as its dihydrate). The binding constants for the phenytoin/cyclodextrin complex were found to be 1073 and 792 M-1 at pH 7.4 and pH 8.0, respectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)7m-beta-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41-45 M-1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 degreesC in the presence of 0.03 or 0.06 M (SBE)7m-beta-CD. It was projected from the solubility of phenytoin and the kinetic information that fosphenytoin shelf lives as high as nine years at 25 degreesC and pH 7.4 in the presence of 60 mM of (SBE)7m-beta-CD might be possible while longer shelf lives might be possible at pH 8.
磷苯妥英是苯妥英的水溶性前体药物，在长期储存期间，当pH值小于8时主要降解为苯妥英；由于苯妥英的水溶性有限，其由磷苯妥英形成时很容易沉淀。本研究的目的是通过与肠外安全的环糊精（SBE）7m-β-CD络合来抑制苯妥英沉淀，从而开发出pH值范围在7.4至8.0之间的磷苯妥英稳定制剂。25℃下的相溶解度研究表明，无论有无80.6mg/mL磷苯妥英（其二水合物形式），苯妥英都能被（SBE）7m-β-CD有效增溶。发现苯妥英/环糊精络合物在pH7.4和pH8.0时的结合常数分别为1073和792M-1。由于磷苯妥英和苯妥英与（SBE）7m-β-CD之间存在竞争性包合，正如预期的那样，即使磷苯妥英/环糊精络合物的结合常数相对较小（41 - 45M-1），在存在磷苯妥英的情况下，苯妥英的增溶程度仍低于不存在磷苯妥英时。采用初始速率来跟踪磷苯妥英生成苯妥英的过程。在所研究的所有条件下均观察到零级动力学。在存在0.03或0.06M（SBE）7m-β-CD的情况下，在25、37和50℃下跟踪苯妥英的生成速率。根据苯妥英的溶解度和动力学信息推测，在存在60mM（SBE）7m-β-CD的情况下，磷苯妥英在25℃和pH7.4时的货架期可能高达9年，而在pH8时可能有更长的货架期。
