Development and testing of an improved parenteral formulation of phenytoin using 2-hydroxypropyl-beta-cyclodextrin.
The objective of this study was to increase the solubility of phenytoin by complexing it with varying concentrations of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and create an entirely aqueous formulation with a pH significantly closer to physiologic pH (7.4). The phenytoin-HPBCD complexation was characterized using phase-solubility analysis at HPBCD concentrations ranging from 10 to 50% w/v over the pH range of 7.4-11.0. The two most promising formulations, i.e., a formulation consisting of 40% HPBCD at pH 10.4, and a second formulation consisting of 20% HPBCD at pH 11.0, were selected for further study. Both formulations were entirely aqueous and had a significantly decreased pH compared to the original commercial formulation (Parke-Davis, pH 12.0). These formulations also exhibited a significantly decreased tendency to precipitate in vitro. The tissue irritation potential of the 20% w/v HPBCD formulation at pH 11.0 was found to be reduced considerably compared to the commercial injection in a BALB/c mouse model.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721, USA. Blanchard@pharmacy.arizona.edu
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Blanchard
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Ugwu
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Bhardwaj
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Dorr
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000008:administration & dosage*; D005260:Female; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D010672:Phenytoin / Q000008:administration & dosage* / Q000633:toxicity; D012867:Skin / Q000187:drug effects; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D010672:Phenytoin