title: Comparative Biodistribution and Pharmacokinetic Analysis of Cyclosporine-A in the Brain upon Intranasal or Intravenous Administration in an Oil-in-Water Nanoemulsion Formulation.
abstract: The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague-Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood-brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts 02115, United States.|‡Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02142, United States.
authors.forename: Sunita
authors.initials: S
authors.lastname: Yadav
authors.affiliation: §IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier University, Montpellier F-34298, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gattacceca
authors.affiliation: ‡Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02142, United States.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Panicucci
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts 02115, United States.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000281:Administration, Intranasal; D061605:Administration, Intravenous; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D016572:Cyclosporine
keywords: brain delivery; cyclosporine-A; intranasal administration; intravenous administration; oil-in-water nanoemulsion; pharmacokinetics