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Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure

Dimiou, Savvas; Lopes, Rui M; Kubajewska, Ilona; Mellor, Ryan D; Schlosser, Corinna S; Shet, Manjunath S; Huang, Hugh; ... Uchegbu, Ijeoma F; + view all (2022) Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure. International Journal of Pharmaceutics , 618 , Article 121658. 10.1016/j.ijpharm.2022.121658.

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Abstract

Levodopa (L-DOPA) is an oral Parkinson's Disease drug that generates the active metabolite - dopamine (DA) in vivo. However, oral L-DOPA exhibits low oral bioavailability, limited brain uptake, peripheral DA-mediated side effects and its poor brain bioavailability can lead to long-term complications. Here we show that L-DOPA forms stable (for at least 5 months) 300 nm nanoparticles when encapsulated within N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ). A nano-in-microparticle GCPQ-L-DOPA formulation (D50 = 7.2 µm), prepared by spray-drying, was stable for one month when stored at room and refrigeration temperatures and was capable of producing the original GCPQ-L-DOPA nanoparticles upon aqueous reconstitution. Nasal administration of reconstituted GCPQ-L-DOPA nanoparticles to rats resulted in significantly higher DA levels in the brain (Cmax of 94 ng g-1 above baseline levels 2 h post-dosing) when compared to nasal administration of L-DOPA alone, with DA being undetectable in the brain with the latter. Furthermore, nasal GCPQ-L-DOPA resulted in higher levels of L-DOPA in the plasma (a 17-fold increase in the Cmax, when compared to L-DOPA alone) with DA undetectable in the plasma from both formulations. These data provide evidence of effective delivery of DA to the brain with the GCPQ-L-DOPA formulation.

Type: Article
Title: Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure
Location: Netherlands
DOI: 10.1016/j.ijpharm.2022.121658
Publisher version: https://doi.org/10.1016/j.ijpharm.2022.121658
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Chitosan, GCPQ, Levodopa, Nano-in-microparticles, Nose-to-brain, Parkinson’s Disease
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10146203
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