%0 Journal Article
%A Dimiou, Savvas
%A Lopes, Rui M
%A Kubajewska, Ilona
%A Mellor, Ryan D
%A Schlosser, Corinna S
%A Shet, Manjunath S
%A Huang, Hugh
%A Akcan, Ozgur
%A Whiteside, Garth T
%A Schätzlein, Andreas G
%A Uchegbu, Ijeoma F
%D 2022
%F discovery:10146203
%I Elsevier
%J International Journal of Pharmaceutics
%K Chitosan, GCPQ, Levodopa, Nano-in-microparticles, Nose-to-brain, Parkinson’s Disease
%T Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure
%U https://discovery-pp.ucl.ac.uk/id/eprint/10146203/
%V 618
%X 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.
%Z This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.