Thermosensitive in situ hydrogels of rivastigmine-loaded lipid-based nanosystems for nose-to-brain delivery: characterisation, biocompatibility, and drug deposition studies

Abstract

Acetylcholinesterase inhibitors are the most used drugs to manage Alzheimer's disease, although they show low bioavailability in the brain. In this sense, nasal administration has been considered as a promising route for the direct delivery of these drugs to the brain (nose-to-brain delivery). In this work, in situ thermosensitive nasal gels with nanostructured lipid carriers (NLC) and nanoemulsion loaded with an acetylcholinesterase inhibitor (rivastigmine- RVG) were tested. In situ gels containing optimised rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion were first characterised (size, polydispersity index - PDI, zeta potential - ZP, encapsulation efficiency - EE, loading capacity - LC, pH, osmolarity, organoleptic and morphological analysis and accelerated stability). Afterwards, rheology and texture tests and in vitro studies were conducted to evaluate mucoadhesion, drug release, biocompatibility (with nasal and pulmonary cells, respectively RPMI-2650 and Calu-3) and drug deposition in a nasal cast model. The in situ gels of rivastigmine-loaded NLC and rivastigmine-loaded nanoemulsion had a respective particle/droplet size, PDI, ZP, EE, LC, pH and osmolarity of: 114.00 ± 1.91 nm and 135.80 ± 0.50 nm; 0.45 ± 0.00 and 0.43 ± 0.02; -3.58 ± 1.62 mV and -4.06 ± 1.03 mV; 95.13 ± 0.34% and 89.86 ± 0.19%; 9.30 ± 0.03% and 8.70 ± 0.01%; 6.47 ± 0.01 and 6.451 ± 0.00; 275 ± 0.02 and 280 ± 0.00 mOsm/kg. Organoleptic analysis showed homogeneous appearance, while morphological studies demonstrated that rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion had a spherical shape. Accelerated stability studies predicted good long-term stability. Rheological and texture analysis revealed that both in situ gels showed desirable characteristics for nasal administration. In addition, suitable nasal mucoadhesion and prolonged drug release were observed. Biocompatibility studies showed low and concentration-dependent cytotoxicity in RPMI 2650 and Calu-3 cells. Nasal deposition studies revealed that 4.0% of the drug was deposited in the olfactory region for both rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion alone, while in situ gels with these lipid-based nanosystems showed 8.0% of drug deposition. The results of this study highlight the potential of using thermosensitive in situ hydrogels containing lipid-based nanosystems to improve the nose-to-brain delivery of rivastigmine, providing a promising alternative therapeutic option to advance the management of Alzheimer's disease.