Case Study: Fosphenytoin: A Prodrug of Phenytoin
Fosphenytoin was designed to be a water-soluble, parenterally safe form of phenytoin, or 5,5-diphenylhydantoin, a sparingly water-soluble (20–30 µg/mL), weakly acidic drug (pKa 8.3) useful in the treatment of epilepsy. To achieve an aqueous solution suitable for parenteral administration, phenytoin was originally formulated as its sodium salt (sodium phenytoin) in a vehicle consisting of 40%propylene glycol and 10% ethanol with a final pH of 12. This formulation can be very toxic, causing severe irritation and pain at the local site of injection and occasional fatalities if injected too rapidly. Sodium phenytoin cannot be administered by intramuscular (IM) injection. Its water-soluble prodrug, fosphenytoin, is formulated in a purely aqueous solution at a pH of about 8.5; it has shown superior safety compared to sodium phenytoin while also permitting IM dosing. Two patents covering fosphenytoin (Stella and Sloan, 1979, 1981) have expired, but two formulation patents are still valid (Herbranson et al., 1990; Stella 2000). An extensive review of the history of fosphenytoin has been published; it includes other examples of prodrugs of phenytoin (Stella, 1996).
KeywordsFormulation Patent Severe Irritation Phosphate Prodrug High Total Body Clearance Phosphate Ester Prodrug
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