title: A novel cyclosporin a aqueous formulation for dry eye treatment: in vitro and in vivo evaluation.
abstract: OBJECTIVE
  The aim of the present study was the in vitro and in vivo evaluation of a novel aqueous formulation based on polymeric micelles for the topical delivery of cyclosporine A for dry eye treatment.
  
  
  METHODS
  In vitro experiments were carried out on primary rabbit corneal cells, which were characterized by immunocytochemistry using fluorescein-labeled lectin I/isolectin B4 for the endothelial cells and mouse monoclonal antibody to cytokeratin 3+12 for the epithelial ones. Living cells were incubated for 1 hour or 24 hours with a fluorescently labeled micelle formulation and analyzed by fluorescence microscopy. In vivo evaluations were done by Schirmer test, osmolarity measurement, CyA kinetics in tears, and CyA ocular distribution after topical instillation. A 0.05% CyA micelle formulation was compared to a marketed emulsion (Restasis).
  
  
  RESULTS
  The in vitro experiments showed the internalization of micelles in the living cells. The Schirmer test and osmolarity measurements demonstrated that micelles did not alter the ocular surface properties. The evaluation of the tear fluid gave similar CyA kinetics values: AUC = 2339 ± 1032 min*μg/mL and 2321 ± 881.63; Cmax = 478 ± 111 μg/mL and 451 ± 74; half-life = 36 ± 9 min and 28 ± 9 for the micelle formulation and Restasis, respectively. The ocular distribution investigation revealed that the novel formulation delivered 1540 ± 400 ng CyA/g tissue to the cornea.
  
  
  CONCLUSIONS
  The micelle formulation delivered active CyA into the cornea without evident negative influence on the ocular surface properties. This formulation could be applied for immune-related ocular surface diseases.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Tommaso
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Valamanesh
authors.forename: Florence
authors.initials: F
authors.lastname: Miller
authors.forename: Pascal
authors.initials: P
authors.lastname: Furrer
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez-Aller
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.forename: Robert
authors.initials: R
authors.lastname: Gurny
authors.forename: Michael
authors.initials: M
authors.lastname: Möller
mesh_terms: D000287:Administration, Topical; D000818:Animals; D003315:Cornea / Q000378:metabolism*; D016572:Cyclosporine / Q000493:pharmacokinetics*; D005260:Female; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008823:Micelles; D008856:Microscopy, Fluorescence; D009883:Ophthalmic Solutions; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D013666:Tears / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D008823:Micelles; D009883:Ophthalmic Solutions; D016572:Cyclosporine