Platform-Technology Based on Prodrug/Enzyme Systems for Rapid Absorption of Hydrophobic Drugs: Toward Intranasal Treatment of Seizure Emergencies

Poor water solubility of novel drugs is a key challenge in drug discovery and development as it results in low drug bioavailability upon local or systemic administration. The prodrug approach is commonly utilized to enhance solubility of hydrophobic drugs. However, for rapid drug absorption, supersaturated solutions need to be employed. In this work, a platform technology based on prodrug/enzyme systems was developed wherein prodrug and enzyme are co-administered at the point of absorption (e.g. nasal cavity) to form in situ supersaturated drug solutions for enhanced bioavailability. This accelerated absorption was demonstrated by developing prodrug/enzyme systems for two seizure emergency drugs - phenytoin (fosphenytoin/alkaline phosphatase) and diazepam (avizafone/A.O. protease). Enzyme kinetics was performed in assay buffer pH 7.4 at 32oC. In vitro permeability studies were performed using Madin Darby canine kidney II-wildtype (MDCKII-wt) monolayers as a nasal epithelia model. Results indicated that drug absorption with prodrug/enzyme system increased proportionately to the degree of supersaturation; this flux was 1.5 to 6- fold greater and 2-17.6 fold greater compared to saturated phenytoin and diazepam, respectively. The experimental data fitted reasonably well to a two compartment pharmacokinetic model with first order conversion of prodrug to drug. The developed prodrug/enzyme systems remarkably enhanced drug (phenytoin, diazepam) transport across model membrane. This strategy could be particularly useful when fast action is required, for example for intranasal therapy of seizure emergencies.