Abstract: The blood-brain barrier (BBB) regulates blood and chemical exchange in the central nervous system. It is made up of brain parenchyma capillary endothelial cells. It separates the interstitial cerebrospinal fluid from the circulation and limits brain drug entry. Peptides, antibodies, and even tiny hydrophilic biomolecules cannot flow across the BBB due to their semi-permeability. It protects the brain from poisons, chemicals, and pathogens, and blood cells penetrate brain tissue. BBB-facilitated carrier molecules allow selective permeability of nutrients such as D-glucose, L-lactic acid, L-phenylalanine, L-arginine, and hormones, especially steroid hormones. Brain barriers prevent drug molecules from entering, making medication delivery difficult. Drugs can reach specific brain regions through the nasal cavity, making it a preferred route. The in-situ gels are mucoadhesive, which extends their stay in the nasal cavity, allows them to penetrate deep and makes them a dependable way of transporting numerous medications, including peptides and proteins, straight into the central nervous system. This approach holds great potential for neurological therapy as they deliver drugs directly to the central nervous system, with less interference and better drug release control. The brain affects daily life by processing sensory stimuli, controlling movement and behaviour, and sustaining mental, emotional, and cognitive functioning. Unlike systemic routes, the nasal mucosa is extensively vascularized and directly contacts olfactory sensory neurons. Compared to the systemic circulation, this improves brain bioavailability of medications. Drugs can be delivered to the brain using in-situ gel formulations safely and efficiently, with a greater therapeutic impact than with traditional techniques. 

In-Situ Gels for Brain Delivery: Breaching the Barriers.

Paliperidone, a second-generation antipsychotic approved by USFDA for schizophrenia, exhibits low aqueous solubility and high permeability, classifying it under BCS II. The present study focused on brain delivery of paliperidone through the nasal route in the form of nanoemulsions functionally engineered with chitosan. Mucoadhesive and permeation enhancing properties of cationic chitosan are favored by the presence of hydrophilic groups. These groups allow interactions with anionic nasal mucosa, resulting in bioadhesion via noncovalent bonds. Paliperidone nanoemulsions were optimized using StatEase Design-Expert Software and prepared via spontaneous emulsification and ultrasonication using oleic acid, stearic acid, Tween 80, propylene glycol, Labrasol and chitosan. The resulting nanoemulsions showed a droplet size of 155 ± 5.5 nm, polydispersity index of 0.259 ± 0.1 and zeta potential of +40.5 ± 3.5 mV. Functional engineering of chitosan on the surface of paliperidone nanoemulsion droplets was confirmed qualitatively as well as quantitatively by FTIR, Ninhydrin assay and TEM studies. In vitro release of paliperidone from nanoemulsions and functionally engineered nanoemulsions was found to be 69.55 ± 1.5% and 59.29 ± 0.47%, respectively, at the end of 8 h. Ex vivo studies across goat nasal mucosa demonstrated a higher paliperidone flux of 23.31 ± 0.296 μg/cm2/h from nanoemulsions as compared to 17.87 ± 0.163 μg/cm2/h from functionally engineered nanoemulsions. Studies in RPMI 2650 nasal and Neuro2A brain cell lines indicated that functionally engineered paliperidone nanoemulsions were biocompatible, which was also confirmed from histopathological evaluation. Studies in Wistar rats showed enhanced cataleptic effects with improved memory and anxiolytic effects, demonstrating the effectiveness of this advanced strategy in brain delivery of paliperidone via the nasal route.

Optimization and Evaluation of Functionally Engineered Paliperidone Nanoemulsions for Improved Brain Delivery via Nasal Route

Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, Transcutol HP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173 ± 0.5 nm, 0.413 ± 0.2 and - 22.5 ± 0.1 mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4 ± 0.5 nm, 0.291 ± 0.02 and + 23.6 ± 0.3 mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41 ± 2.1% and 72.02 ± 0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58 ± 0.023 μg/cm2 and 1096.13 ± 0.043 μg/cm2 respectively at the end of 8 h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery.

Systematic Approach in the Development of Chitosan Functionalized Iloperidone Nanoemulsions for Transnasal Delivery, In Vitro and In Vivo Studies

Development and evaluation of nanoparticulate based in-situ gelling system for nasal drug delivery of an anti-epileptic drug

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Development and evaluation of nanoparticulate based in-situ gelling system for nasal drug delivery of an anti-epileptic drug