title: Lipid nanoparticles for cyclosporine A administration: development, characterization, and in vitro evaluation of their immunosuppression activity.
abstract: Cyclosporine A (CsA) is an immunosuppressant commonly used in transplantation for prevention of organ rejection as well as in the treatment of several autoimmune disorders. Although commercial formulations are available, they have some stability, bioavailability, and toxicity related problems. Some of these issues are associated with the drug or excipients and others with the dosage forms. With the aim of overcoming these drawbacks, lipid nanoparticles (LN) have been proposed as an alternative, since excipients are biocompatible and also a large amount of surfactants and organic solvents can be avoided. CsA was successfully incorporated into LN using the method of hot homogenization followed by ultrasonication. Three different formulations were optimized for CsA oral administration, using different surfactants: Tween(®) 80, phosphatidylcholine, taurocholate and Pluronic(®) F127 (either alone or mixtures). Freshly prepared Precirol nanoparticles showed mean sizes with a narrow size distribution ranging from 121 to 202 nm, and after freeze-drying were between 163 and 270 nm, depending on the stabilizer used. Surface charge was negative in all LN developed. High CsA entrapment efficiency of approximately 100% was achieved. Transmission electron microscopy was used to study the morphology of the optimized LN. Also, the crystallinity of the nanoparticles was studied by X-ray powder diffraction and differential scanning calorimetry. The presence of the drug in LN surfaces was confirmed by X-ray photoelectron spectroscopy. The CsA LN developed preserved their physicochemical properties for 3 months when stored at 4°C. Moreover, when the stabilizer system was composed of two surfactants, the LN formulations were also stable at room temperature. Finally, the new CsA formulations showed in vitro dose-dependent immuno-suppressive effects caused by the inhibition of IL-2 levels secreted from stimulated Jurkat cells. The findings obtained in this paper suggest that new lipid nanosystems are a good alternative to produce physicochemically stable CsA formulations for oral administration.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona ; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona.
authors.forename: Melissa
authors.initials: M
authors.lastname: Guada
authors.affiliation: Chemical and Environmental Engineering Department and Nanoscience Institute of Aragon, University of Zaragoza, Zaragoza ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Sebastián
authors.affiliation: Chemical and Environmental Engineering Department and Nanoscience Institute of Aragon, University of Zaragoza, Zaragoza ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Irusta
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Feijoó
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona.
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: Dios-Viéitez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona ; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona.
authors.forename: María José
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D005079:Excipients; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008055:Lipids; D013501:Surface-Active Agents; D016572:Cyclosporine
keywords: Jurkat cells; cyclosporine A; immunosuppressive activity; lipid nanoparticles; oral administration; stability