Design and Development of Levodopa Loaded Polymeric Nanoparticles for Intranasal Delivery

Abstract

Intranasal delivery is an alternative administration route to deliver levodopa (L-Dopa) to the brain. This drug delivery route offers high drug permeability across the nasal epithelium and rapid absorption into the central nervous system (CNS) while bypassing first-pass metabolism. In this study, we developed a library of polymeric nanocarrier systems for L-Dopa utilising poly(lactic-co-glycolic acid) (PLGA) and chitosan. A total of three PLGA nanoparticles formulations (P1, P2 and P3) were prepared using a modified water-in-oil-in-water (W/O/W) solvent evaporation technique, while four formulations of chitosan nanoparticles (C1, C2, C3 and C4) were prepared by ionic gelation method with sodium tripolyphosphate (TPP) as a cross-linking agent. Upon characterising nanocarriers developed, it was discovered that C2 demonstrated the best results with regard to droplet size (553 ± 52 nm), polydispersity index (0.522), zeta potential (+46.2 ± 2.3 mV), and encapsulation efficiency (82.38% ± 1.63). Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) further corroborated the particle size analysis highlighting that C2 displayed uniform particle size with spherical morphology. Additionally, X-ray diffraction analysis (XRD) revealed that C2 was in an amorphous state while Fourier transform infrared (FTIR) analysis showed that there were no chemical interactions that might change the chemical structure of L-Dopa within the polymeric nanoparticle matrix. Lastly, an in-vivo intranasal study in male Wistar rats showed that the absorption of L-Dopa when formulated as chitosan nanoparticles was significantly enhanced (p < 0.05) by approximately two-fold compared to unmodified L-Dopa. Therefore, this work illustrates that formulating L-Dopa into chitosan nanoparticles for intranasal delivery is a potentially viable formulation strategy to improve the bioavailability of the drug for the treatment of Parkinson’s disease.

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

“…and formulations including drug in solution or bulk drug. This is true for FDA approved therapies like L-Dopa, paclitaxel, carmustine, lamotrigine, carbamazepine, desvenlafaxine, almotriptan, naloxone, experimental immunotherapies, and natural products, including ferulic acid (FA), isoflavonoids, and catechins [ 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ]. Brain targeting is further improved by NP surface modifications, such as chitosan, lactoferrin, transferrin, and PEG coatings, which enhance the transport of NPs from the nose to the brain [ 62 , 165 , 168 , 170 , 171 , 172 ].…”

Targeting the central nervous system: From synthetic nanoparticles to extracellular vesicles—Focus on Alzheimer's and Parkinson's disease

“…These results were confirmed with the in vivo experiment conducted by Ahmad et al, increasing up to two-fold the concentration of L-DOPA compared to the free drug when administered in chitosan modified PLGA NPs. Therefore, concluding that the intranasal administration of L-DOPA-loaded NPs increased the bioavailability of this drug; improving their clinical limitations (Ahmad et al, 2022). Moreover, Ren et al produced L-DOPA/benserazide-loaded PLGA NPs obtaining a sustained release profile after the subcutaneous administration of this nanoformulation.…”

Parkinson's Disease: Technological Approaches for Optimized Therapeutic Efficacy of Levodopa

“…Oтчетено e по-дълго време за достигане на максимална плазмена концентрация (Tmax) при въвеждане на дисперсията, а авторите допускат, че резултатът се дължи на по-големия размер на носителите спрямо свободната лекарствена молекула. Смята се, че повишеното контактно време между хитозановите наночастици и назалната лигавица позволява контролирано освобождаване на допаминовия прекурсор, осигурявайки по-плавно понижаване на плазмените нива (4).…”