Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs

Purpose. To study the utility of the nasal route for the systemic delivery of L-dopa using water soluble prodrugs of L-dopa and to examine if this del ivery method will result in preferential delivery to the CNS. Methods. Several alkyl ester prodrugs of L-dopa were prepared and their phy sicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, rat brain homogenate, rat CSF, and rat nasal berfus ate were determined by HPLC. In vivo nasal experiments were carried out in rats. Levels of L-dopa and dopamine in plasma, CSF, and olfactory bulb were determined using HPLC method with electrochemical detection. Results. All the prodrugs showed improved solubility and lipophilicity with relatively fast in vitro conversion in rat plasma. Absorption was fast fol lowing nasal delivery of the prodrugs with bioavailability around 90%. Dopa mine plasma levels did not change significantly following nasal administrat ion of the butyl eater prodrug. Olfactory bulb and CSF L-dopa concentration were higher following nasal delivery of the butyl ester prodrug compared t o an equivalent intravenous dose. Conclusions. Utilization of water soluble prodrugs of L-dopa via the nasal route in the treatment of Parkinson's disease may have therapeutic advantag es such as improved bioavailability, decreased side effects, and potentiall y enhanced CNS delivery.