Abstract
Background: Intranasal route offers a direct nose-to-brain delivery via olfactory and trigeminal nerves and minimizes the systemic exposure of the drug. Although reliable and non-invasive, intranasal administration of lipophilic neuroprotective agents for brain targeting is still challenging. Literature focuses on naturally-derived compounds as a promising therapeutics for chronic brain diseases. Naringin, a natural flavonoid obtained from citrus fruits possesses neuroprotective effects. By regulating multiple crucial cellular signaling pathways, naringin acts on several therapeutic targets that make it suitable for the treatment of neurodegenerative diseases like Alzheimer’s disease and making it a suitable candidate for nasal administration. However, the hydrophobicity of naringin is the primary challenge to formulate it in an aqueous system for nasal administration. Method: We designed a lipid-based nanoemulsifying drug delivery system of naringin using Acrysol K140 as an oil, Tween 80 as a surfactant and Transcutol HP as a cosolvent, to improve solubility and harness the benefits of nanosizing like improved cellular penetration. Intranasal instillations of therapeutic agents have limited efficacy due to drug washout and inadequate adherence to the nasal mucosa. Therefore, we reconstituted the naringin self-emulsifying system in a smart, biodegradable, ion-triggered in situ gelling hydrogel and optimized for desirable gel characteristics. The naringin-loaded composition was optimized and characterized for various physicochemical and rheological properties. Results: The formulation showed a mean droplet size 152.03 ± 4.6 nm with a polydispersity index <0.23. Ex vivo transmucosal permeation kinetics of the developed formulation through sheep nasal mucosa showed sustained diffusion and enhanced steady-state flux and permeability coefficient. Scanning and transmission electron microscopy revealed the spherical shape of emulsion droplets and entrapment of droplets in a gel structure. The formulation showed excellent biocompatibility as analyzed from the viability of L929 fibroblast cells and nasal mucosa histopathology after treatment. In vivo biodistribution studies revealed significantly higher drug transport and brain targeting efficiency. Conclusion: In situ gelling system with nanoemulsified naringin demonstrated a safe nasal delivery providing a new dimension to the treatment of chronic neurodegenerative diseases using small hydrophobic phytoconstituents with minimization of dose and related systemic adverse effects.
Highlights
The central nervous system (CNS) is a complex, but a sophisticated system that regulates and coordinates several body activities
The positive outcome of brain targeting through intranasal delivery of phyis the brain AUC fraction contributed by systemic circulation through blood brain is the brain AUC following intravenous barrier following intranasal administration
Naturally-derived medicinal components have the advantages of abundant resources, less side effects and improved efficacy, which can be utilized as potential drugs for the treatment of CNS diseases
Summary
The central nervous system (CNS) is a complex, but a sophisticated system that regulates and coordinates several body activities. Many strategies have been explored for effective drug delivery to the brain by vanquishing the challenges of BBB, both invasively and non-invasively [4]. The intranasal route of administration is amenable to self-administration and offers a non-invasive and virtually painless alternative to oral and parenteral administration for the delivery of drugs to the CNS [8]. Intranasal drug delivery can effectively deliver the drug to CNS by circumventing the BBB. Self-emulsifying can effectively target drugs to CNS because of their particle size, high drug loading capacity, lipophilicity and relatively high physical stability. Intranasal route offers a direct nose-to-brain delivery via olfactory and trigeminal nerves and minimizes the systemic exposure of the drug. Reliable and non-invasive, intranasal administration of lipophilic neuroprotective agents for brain targeting is still challenging
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