title: Cyclosporine A lipid nanoparticles for oral administration: Pharmacodynamics and safety evaluation.
abstract: The pharmacodynamic effect and the safety of cyclosporine A lipid nanoparticles (CsA LN) for oral administration were investigated using Sandimmune Neoral® as reference. First, the biocompatibility of the unloaded LN on Caco-2 cells was demonstrated. The pharmacodynamic response and blood levels of CsA were studied in Balb/c mice after 5 and 10 days of daily oral administration equivalent to 5 and 15 mg/kg of CsA in different formulations. The in vivo nephrotoxicity after 15 days of treatment at the high dose was also evaluated. The results showed a significant decrease in lymphocyte count (indicator of immunosuppression) for the CsA LN groups which was not observed with Sandimmune Neoral®. CsA blood levels remained constant over the time after treatment with LN, whereas a proportional increase in drug blood concentration was observed with Sandimmune Neoral®. Therefore, CsA LN exhibited a better pharmacological response along with more predictable pharmacokinetic information, diminishing the risk of toxicity. Moreover, a nephroprotective effect against CsA related toxicity was observed in the histopathological evaluation when LN containing Tween® 80 were administered. Therefore, our preliminary findings suggest LN formulations would be a good alternative for CsA oral delivery, enhancing efficacy and reducing the risk of nephrotoxicity.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, E-31008 Pamplona, Spain.
authors.forename: Melissa
authors.initials: M
authors.lastname: Guada
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E-31008 Pamplona, Spain.
authors.forename: Hugo
authors.initials: H
authors.lastname: Lana
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, E-31008 Pamplona, Spain; Drug Development Unit, University of Navarra (DDUNAV), E-31008 Pamplona, Spain.
authors.forename: Ana Gloria
authors.initials: AG
authors.lastname: Gil
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E-31008 Pamplona, Spain.
authors.forename: Maria del Carmen
authors.initials: Mdel C
authors.lastname: Dios-Viéitez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, E-31008 Pamplona, Spain. Electronic address: mjblanco@unav.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D008055:Lipids / Q000008:administration & dosage* / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine
keywords: Biocompatibility; Caco-2 cells; Cyclosporine A; Immunosuppression; Lipid nanoparticles; Nephrotoxicity; Oral route; Pharmacodynamics; Pharmacokinetics; T-lymphocyte