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Enhancement of the Systemic and CNS Specific Delivery of L-Dopa by the Nasal Administration of Its Water Soluble Prodrugs

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Abstract

Purpose. To study the utility of the nasal route for thesystemic delivery of L-dopa using water soluble prodrugs of L-dopa and toexamine if this delivery method will result in preferential delivery to theCNS.

Methods. Several alkyl ester prodrugs of L-dopa wereprepared and their physicochemical properties were determined. Invitro hydrolysis rate constants in buffer, rat plasma, rat brainhomogenate, rat CSF, and rat nasal berfusate were determined by HPLC. Invivo nasal experiments were carried out in rats. Levels of L-dopa anddopamine in plasma, CSF, and olfactory bulb were determined using HPLCmethod with electrochemical detection.

Results. All the prodrugs showed improved solubility andlipophilicity with relatively fast in vitro conversion in ratplasma. Absorption was fast following nasal delivery of the prodrugs withbioavailability around 90%. Dopamine plasma levels did not changesignificantly following nasal administration of the butyl ester prodrug.Olfactory bulb and CSF L-dopa concentration were higher following nasaldelivery of the butyl ester prodrug compared to an equivalent intravenousdose.

Conclusions. Utilization of water soluble prodrugs ofL-dopa via the nasal route in the treatment of Parkinson's disease may havetherapeutic advantages such as improved bioavailability, decreased sideeffects, and potentially enhanced CNS delivery.

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Authors and Affiliations

  1. Endo Pharmaceuticals, Garden City, New York, 11530

    Huaihung Danny Kao

  2. Procter and Gamble Pharmaceuticals, Mason, Ohio, 45040

    Ashraf Traboulsi

  3. Osaka University, Osaka, 565-0871, Japan

    Soichi Itoh

  4. Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, 40536

    Lewis Dittert

  5. Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, 40536

    Anwar Hussain

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  1. Huaihung Danny Kao
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  2. Ashraf Traboulsi
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  4. Lewis Dittert
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  5. Anwar Hussain
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Kao, H.D., Traboulsi, A., Itoh, S. et al. Enhancement of the Systemic and CNS Specific Delivery of L-Dopa by the Nasal Administration of Its Water Soluble Prodrugs. Pharm Res 17, 978–984 (2000). https://doi.org/10.1023/A:1007583422634

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