Lipid nanocarriers containing a levodopa prodrug with potential antiparkinsonian activity

• Formulation of nanocarriers (LN) containing antiparkinsonian L-dopa prodrug (LD-PD)
• DSC showed that the loaded LD-PD interacts with the lipid phase.
• Controlled prodrug release from LD-PD loaded LN confirmed by in vitro studies.
• LD-PD loaded LN reduced parkinsonian disabilities and shows a longer lasting action.

This paper describes the production, characterization and in vivo activity of lipid nanocarriers (LN) containing a levodopa prodrug (LD-PD) with therapeutic potential in Parkinson's disease. LD is the mainstay of the pharmacotherapy of Parkinson's disease. However, after a good initial response, motor fluctuations, dyskinesia and loss of efficacy, develop over time, partly due to oscillations in plasma and brain levels of the drug. LD-PD was produced with the aim of prolonging the pharmacological activity of LD. To improve solubility, and simultaneously provide a long lasting release and therapeutic efficacy, the prodrug was formulated in tristearin/lecithin LN.The obtained formulation was homogeneous in particle size and remained stable for up to 2 months from preparation. For the three different tested LD concentrations, namely 1.25, 2.5 and 5.0 mg/ml, the morphological characterization revealed no substantial differences between unloaded and LD-PD loaded LN. The calorimetric test showed an interaction between the lipid phase and the loaded prodrug. In vitro studies using the dialysis method and enzymatic degradation procedure showed that the LD-PD loaded LN provided a controlled prodrug release. Finally, two behavioural tests specific to akinesia (bar test) or akinesia/bradykinesia (drag test) performed in 6-hydroxydopamine hemilesioned mice (a model of Parkinson's disease) demonstrated that the LD-PD loaded LN attenuated parkinsonian disabilities, showing a slightly reduced maximal efficacy but a longer lasting action (up to 24 h) than an equal dose of LD. We conclude that LD-PD loaded LN may represent a future LD formulation useful in Parkinson's disease therapy.

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