title: In vivo distribution and ex vivo permeation of cyclosporine A prodrug aqueous formulations for ocular application.
abstract: Cyclosporine A is a poorly water-soluble, immunosuppressive drug used to treat a variety of ocular diseases. Its limited solubility makes challenging the development of a cyclosporine A-based eye drop for ocular topical application. Based on the prodrug strategy, the practically insoluble cyclosporine A was converted into a freely soluble prodrug. Such a water-soluble prodrug made it possible to develop water-based concentrated eye drops. The prodrug formulations were tested for their ex vivo permeation and in vivo distribution at three concentrations (equivalent to 0.05%, 0.50% and 2.00% w/v cyclosporine A). The ex vivo permeation experiments were performed on corneal and conjunctival epithelia. The in vivo distribution evaluated the total cyclosporine A present in the ocular structures as well as in serum, spleen and cervical lymphatic ganglions. Each prodrug formulation was compared to conventionally used cyclosporine A eye drops at an equivalent concentration. The experimental results showed that the tested eye drops behaved differently. The prodrug formulation was characterized by the following: i) preferential conjunctival penetration, ii) an interesting capacity to create large tissue deposits and iii) a lower risk of systemic complications and immunosuppression. The prodrug aqueous eye drop was demonstrated to be a patient-friendly option for the treatment of ocular diseases requiring high ocular levels of cyclosporine A, pushing the boundaries of the current therapeutic arsenal.
authors: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
authors: Marta
authors: M
authors: Rodriguez-Aller
authors: Davy
authors: D
authors: Guillarme
authors: Mohamed
authors: M
authors: El Sanharawi
authors: Francine
authors: F
authors: Behar-Cohen
authors: Jean-Luc
authors: JL
authors: Veuthey
authors: Robert
authors: R
authors: Gurny
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005123:Eye / Q000378:metabolism; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D009883:Ophthalmic Solutions; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000378:metabolism; D013552:Swine
chemical_list: D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D011355:Prodrugs; D016572:Cyclosporine