J Pharmacol Exp Ther. , 2018., Dec 27. pii: jpet.118.254672. doi: 10.1124/jpet.118.254672.

CNS Delivery and Anti-Inflammatory Effects of Intranasally-Administered Cyclosporine-A in Cationic Nanoemulsion Formulations.

Yadav S Pawar G Kulkarni P et al.

Abstract

The main objective of this study was to develop and evaluate the CNS delivery efficiency, distribution, therapeutic efficacy, and safety of cyclosporine-A (CsA) using cationic oil-in-water nanoemulsion system upon intranasal administration. We have utilized omega-3 fatty acid rich flaxseed oil-based nanoemulsion for intranasal delivery to brain and further used magnetic resonance imaging (MRI) to evaluate and confirm transport of the nanoemulsion in CNS. Furthermore, we have evaluated the anti-inflammatory potential of CsA peptide using the lipopolysaccharide (LPS) model of neuroinflammation in rats. CsA nanoemulsion showed had a good safety profile when tested in vitro in RPMI2650 cells. Upon intranasal administration in rats, nanoemulsion delivery system showed higher uptake in major regions of brain when dosed intranasally based on changes in the MR T1 relaxivity values. Additionally, CsA nanoemulsion showed improved therapeutic efficacy by inhibiting proinflammatory cytokines in the LPS stimulated rat model of neuroinflammation as compared to solution formulation. Preliminary safety evaluations show that the nanoemulsion system was well tolerated and did not cause any acute negative effects in rats. Based on these results, intranasal delivery of CsA and other neuroprotective peptide may provide a clinically-translatable strategy for treating neurological diseases.

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Key points

Various neurological conditions, such as neuroinflammation, pain, psychiatric disorders, stroke, and brain cancers can benefit significantly from disease modifying biological therapies such as peptides and proteins. However, due to their inherent instability, large molecular weight, and permeability restrictions these molecules are unable to cross the blood-brain barrier (BBB) upon systemic administration. These molecules have rapid clearance and short half-life in the systemic circulation.  Cyclosporine-A (CSA), a cyclic decapeptide, a potent immunosuppressive agent that has shown great potential as a neuroprotective agent. Due to its immunosuppressant properties of altering T-lymphocytes (inhibition of interlukin production in T cells) activity, it has been utilized in transplant medicine and has also been used to reduce the incidence of transplant rejection. Beneficial effects of CSA were only observed by chronic administration of the drug at a very high dose of >10mg/kg. The higher dosing strategy leads to systemic levels of CSA that produce limiting negative side effects, such as immune suppression, hepatotoxicity, and nephrotoxicity. There has been an increased interest in developing alternative strategies for delivering CSA specifically to the brain and limiting systemic exposure.

This study was aimed at delivering CSA to the brain using the intranasal route to enhance the therapeutic anti-inflammatory effects with decreased dose and dose related side effects. Intranasal route was utilized for CSA brain delivery as it a non-invasive route of administration and takes advantage of the olfactory epithelium for brain drug delivery without any systemic exposure. An ALA-based nanoemulsion formulation was developed for effective encapsulation of this peptide to overcome absorption limitation within the nasal cavity and for enhancing nose to brain delivery. Nanoemulsions are oil-in-water or water-in-oil formulations which can be prepared with various edible oils and they are versatile in the types of payloads and targeting capabilities that can be made possible. Peptide delivery to brain has been a major challenge due to various barriers. This study utilized the intranasal delivery route to directly deliver peptide to brain overcoming the systemic circulation. Efficient delivery of anti-inflammatory peptide (CSA) using cationic nanoemulsion and significant inhibition of pro-inflammatory cytokines both in vitro and in vivo in the LPS stimulated model of neuroinflammation were shown. Further, nanoemulsion showed enhanced uptake in various regions of brain upon intranasal delivery when compared to solution formulation. Nanoemulsion formulations were found to be safe based on acute safety studies performed in rats. The results indicate that nanoemulsion enhances nose to brain uptake of peptide and further are capable of providing therapeutic effects.