title: Developing an in situ nanosuspension: a novel approach towards the efficient administration of poorly soluble drugs at the anterior eye.
abstract: With about 50-60 million cases in the US alone, dry eye disease represents a severe health care problem. Cyclosporin A (CsA) would be a potent candidate for a causal therapy. However, CsA is not sufficiently water soluble to be administrated via simple eye drops. We developed an in situ nanosuspension (INS) as a novel approach towards the administration of CsA to the cornea. It precipitates upon contact with the tear fluid and creates CsA nanoparticles that enter the cornea and release the drug by dissolution. We selected two liquid poly(ethylene glycols) (PEG) that dissolve CsA and create nanoparticles by precipitation of CsA upon water contact. Aqueous solutions of PEG and Solutol, a non-ionic surfactant, were well tolerated by primary human epithelial cells in vitro. To determine the critical water content needed for a precipitation, the solubility of CsA was investigated in quaternary systems of drug, solvent, surfactant and water. The best INS formulation showed a particle size of 505 ± 5 nm, a polydispersity index (PdI) of 0.23 ± 0.03 and a neutral zeta potential of -0.07 ± 0.05 mV. After single administration to porcine eyes in vitro, 3165 ± 597 ng(CsA)/g(cornea) were detected in corneal tissue, while the levels of Restasis a commercial formulation were, with 545 ± 137 ng(CsA)/g(cornea), significantly lower (P<0.01). These results demonstrate that an INS is a promising, novel approach towards the causal treatment of inflammatory diseases at the anterior eye.
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg, Universitätsstraße 31, 93040 Regensburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Luschmann
authors.forename: Joerg
authors.initials: J
authors.lastname: Tessmar
authors.forename: Simon
authors.initials: S
authors.lastname: Schoeberl
authors.forename: Olaf
authors.initials: O
authors.lastname: Strauss
authors.forename: Carsten
authors.initials: C
authors.lastname: Framme
authors.forename: Karl
authors.initials: K
authors.lastname: Luschmann
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D011232:Chemical Precipitation; D003315:Cornea / Q000378:metabolism*; D016572:Cyclosporine / Q000008:administration & dosage* / Q000737:chemistry; D004847:Epithelial Cells; D006801:Humans; D066298:In Vitro Techniques; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D000069463:Olive Oil; D010938:Plant Oils / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013229:Stearic Acids / Q000737:chemistry; D013535:Suspensions; D013552:Swine; D013666:Tears / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000069463:Olive Oil; D010938:Plant Oils; D012997:Solvents; D013229:Stearic Acids; D013535:Suspensions; D014867:Water; D011092:Polyethylene Glycols; C067028:Solutol HS 15; D016572:Cyclosporine
keywords: Anterior eye; Cyclosporin A; Nanosuspension; Poly(ethylene glycol); Precipitation; Solutol