Chitosan coated niosomes for nose-to-brain delivery of clonazepam: formulation, stability and permeability studies.

Crossing the Blood Brain Barrier constitutes a challenge in drug administration to the brain. In this context, nose-to-brain delivery is explored as an alternative route in the treatment of central nervous system disorders, and nanotechnology constitutes a promising tool for drug delivery to the brain. In this work, we explored niosomes and chitosan-coated niosomes (chitosomes) as possible tools for nose-to-brain delivery of clonazepam. The formulations have been optimised using different chitosan concentrations and different preparation methods as Thin Layer Evaporation-paddle (TLE-P), Evaporation (E), and Solvent Displacement Technique (SDT).

Highlights

• Aim of this work is the obtainment of chitosan-coated niosomes (chitosomes) for nose-to-brain delivery of clonazepam.

• Several techniques have been tested and chitosomes were successfully obtained by evaporation technique.

• Chitosomes showed a good encapsulation efficiency toward drug, particle size below 200 nm and a good PDI.

• Mucoadhesive properties, safety and stability of the formulations were verified.
• Chitosomes release the and improve its permeation across cellular barriers

The most suitable formulations were loaded with clonazepam (CLZ) and a full physicochemical characterization was performed. Chitosomes presented a size of around 200 nm, PDI < 0.3, a positive surface charge, spherical shape and a CLZ encapsulation above 60%. Chitosomes were stable for 12 weeks under storage conditions at 4ºC, in simulated nasal fluid for 24h as well as after a lyophilization-sonication process. A CLZ release of 50% was also achieved after 4 hours in this media. The mucoadhesive properties of chitosomes were also confirmed, with a 1.5-fold reduction of CLZ toxicity after encapsulation and a 10-fold increase of its permeability.

2.1. Materials

Solulan™C24 (SOL) (Poly-24-oxyethylene cholesteryl ether) was a gift by Lubrizol (Cleveland, OH, USA). Cholesterol (CH), Sorbitan Stearate (Span 60, HLB 4.7), low molecular weight chitosan (50 -90 kDa) (CS), Triton X-100 (TX) and Clonazepam (5-(2-chlorophenyl)-7 -nitro-3H-1,4-benzodiazepin-2(1H)-one) (CLZ) and mucin type III were purchased from Sigma-Aldrich (Milan, Italy). N-palmitoyl glucosamine (NPG) was synthesized according to Bragagni et al. 2012 (Bragagni et al., Feb. 2012), and carefully characterized as previously described (Bragagni et al., May 2014). Briefly, glucosamine was added under stirring to triethanolamine and DMSO. The palmitic acid N-hydroxy succinimide was dissolved in CHCl₃ and added to the mixture, under nitrogen atmosphere. The product was precipitated by immersion in an ice bath, filtrated, washed, dried and stored at 4°C protected from the light. For simulated nasal fluid preparation, sodium chloride (NaCl), potassium chloride (KCl) and calcium chloride hydrate (CaCl₂·2H2O) were purchased from Sigma-Aldrich (MO, USA). All other reagents were of analytical grade or higher.

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Giulia Nerli, Sandra Robla, Marta Bartalesi, Cristina Luceri, Mario D’Ambrosio, Noemi Csaba, Francesca Maestrelli, Chitosan coated niosomes for nose-to-brain delivery of clonazepam: formulation, stability and permeability studies., Carbohydrate Polymer Technologies and Applications, 2023, 100332, ISSN 2666-8939,
https://doi.org/10.1016/j.carpta.2023.100332.