title: Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits.
abstract: OBJECTIVE
  The aim of this study was to compare the ocular and systemic distribution of cyclosporine A (CsA) in rabbits after the instillation of preservative-free CsA cationic and anionic emulsions.
  
  
  METHODS
  For the single-dose pharmacokinetic (PK) study, rabbits were instilled with 50 μL of the test material. For the multiple-dose PK study, rabbits were instilled twice daily with Restasis or once daily with NOVA22007 for 10 days. At each time point, the cornea, conjunctiva, and whole blood were harvested for CsA quantification. Ocular and systemic distribution were determined after 4 times daily instillations with 50 μL of 3H-CsA cationic and anionic emulsions for 7 days. Restasis was used as a reference in all studies.
  
  
  RESULTS
  Single-dose PK data demonstrated that NOVA22007 0.1% and 0.05% delivered higher CsA concentrations to the cornea than Restasis [concentration maximum (C max): 2692, 1372, and 748 ng/g, respectively] and have a better exposition (area under the curve). Conjunctival Cmax values were 1914, 696, and 849 ng/g and area under the curve values were 3984, 2796, and 2515 ng/g · h, for either dose of the cationic emulsions and Restasis, respectively. The multiple-dose PK and the 3H-CsA distribution data demonstrated that the systemic distribution after repeated instillations was low and comparable for all emulsions.
  
  
  CONCLUSIONS
  These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases.
authors.affiliation: Research and Development Department, Novagli Pharma SAS, Evry Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Daull
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lallemand
authors.forename: Betty
authors.initials: B
authors.lastname: Philips
authors.forename: Grégory
authors.initials: G
authors.lastname: Lambert
authors.forename: Ronald
authors.initials: R
authors.lastname: Buggage
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Garrigue
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003228:Conjunctiva / Q000378:metabolism*; D003315:Cornea / Q000378:metabolism*; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004337:Drug Carriers; D004655:Emulsions / Q000737:chemistry; D005260:Female; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D011310:Preservatives, Pharmaceutical; D011817:Rabbits; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D004655:Emulsions; D007166:Immunosuppressive Agents; D011310:Preservatives, Pharmaceutical; D016572:Cyclosporine