Oil-in-water emulsions comprising cetalkonium chloride and methods of making and using the same

Abstract

Compositions containing quaternary compounds in which the nitrogen atom is substituted by at least one alkyl group having at least 12 carbon atoms, and the composition includes at least 20% in weight by weight of the total composition, of ammonium halides in which the nitrogen atom is substituted by at least one alkyl group having at least 14 carbon atoms and more than 5%, preferably more than 7% in weight by weight of the total composition, of ammonium halides in which the nitrogen atom is substituted by at least one alkyl group having at least 16 carbon atoms. Also, ophthalmic oil-in-water emulsions containing such compositions, the ophthalmic emulsions being useful for eye care or for the treatment of eye conditions.

1 . An oil-in-water emulsion comprising:
 an oil phase,   0.0005% to 0.1% w/w of an ammonium halide, wherein cetalkonium chloride (CKC) is the sole ammonium halide of the emulsion,   a surfactant, and   water.   
     
     
         2 . The oil-in-water emulsion according to  claim 1 , wherein said oil phase comprises mineral oil, vegetable oil, medium chain triglycerides (MCT), or a mixture thereof. 
     
     
         3 . The oil-in-water emulsion according to  claim 2 , wherein said oil phase comprises mineral oil, castor oil, medium chain triglycerides (MCT), or a mixture thereof. 
     
     
         4 . The oil-in-water emulsion according to  claim 2 , wherein said mineral oil is a mixture of heavy and light mineral oil. 
     
     
         5 . The oil-in-water emulsion according to  claim 2 , wherein said oil phase is medium chain triglycerides (MCT). 
     
     
         6 . The oil-in-water emulsion according to  claim 1 , wherein said surfactant comprises tyloxapol, poloxamer 188, polysorbate 80, tocopherol polyethylene glycol succinate, sorbitan monolaurate, or a mixture thereof. 
     
     
         7 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion comprises at least one buffering agent and/or at least one tonicity agent. 
     
     
         8 . The oil-in-water emulsion according to  claim 7 , wherein the tonicity agent comprises mannitol, glycerol, or a mixture thereof. 
     
     
         9 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion has a positive zeta potential. 
     
     
         10 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion has a droplet size ranging from 100 to 500 nm. 
     
     
         11 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion comprises light and heavy mineral oil, tyloxapol, poloxamer 188, mannitol, and cetalkonium chloride. 
     
     
         12 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion comprises light and heavy mineral oil, tyloxapol, poloxamer 188, glycerol, and cetalkonium chloride. 
     
     
         13 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion comprises medium chain triglycerides (MCT), tyloxapol, poloxamer 188, glycerol, and cetalkonium chloride. 
     
     
         14 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion is hypotonic, relative to normal tears. 
     
     
         15 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion is less toxic than a solution comprising the same amount of cetalkonium chloride (CKC), in weight by weight of the solution. 
     
     
         16 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion comprises an active principle. 
     
     
         17 . The oil-in-water emulsion according to  claim 15 , wherein said active principle is cyclosporine. 
     
     
         18 . The oil-in-water emulsion according to  claim 1 , wherein said oil-in-water emulsion is suitable for ophthalmic use. 
     
     
         19 . A method for treating an eye disease or an eye condition in a subject in need thereof, wherein said method comprises a step of administration to said subject of an oil-in-water emulsion comprising:
 an oil phase,   0.0005% to 0.1% w/w of an ammonium halide, wherein cetalkonium chloride (CKC) is the sole ammonium halide of the emulsion,   a surfactant, and   water.   
     
     
         20 . The method according to  claim 19 , wherein said eye condition is a dry eye condition. 
     
     
         21 . The method according to  claim 20 , wherein said dry eye condition is selected from the group consisting of dry eye accompanying lacrimal fluid reduction, tear deficiency, xerosis of the eye, Sjogren's syndrome, keratoconjunctivitis sicca (KCS), atopic keratoconjunctivitis sicca (AKC), vernal keratoconjunctivitis (VKC), Stevens-Johnson syndrome, pemphigoid of the eye, marginal blepharitis, failure in eyelids closure, or sensory nerve numbness, dry eye accompanying allergic conjunctivitis, dry eye after viral conjunctivitis, dry eye after cornea surgery including laser in situ keratomileusis (LASIK), dry eye after cataract surgery, dry eye associated with contact lens wearing, and dry eye associated with VDT tasks. 
     
     
         22 . The method according to  claim 19 , wherein said oil phase comprises mineral oil, vegetable oil, medium chain triglycerides (MCT), or a mixture thereof. 
     
     
         23 . The method according to  claim 22 , wherein said oil phase comprises mineral oil, castor oil, medium chain triglycerides (MCT), or a mixture thereof. 
     
     
         24 . Process for manufacturing an oil-in-water emulsion comprising:
 an oil phase,   0.0005% to 0.1% w/w of an ammonium halide, wherein cetalkonium chloride (CKC) is the sole ammonium halide of the emulsion,   a surfactant, and   water; and   wherein said method comprises the following steps:   (1) manufacturing a pre-concentrate of said oil-in-water emulsion, said pre-concentrate having a content in oil of at least 4% v/v,
 by emulsifying and/or mixing said oil phase and said surfactant with an aqueous phase, thereby obtaining said pre-concentrate; and then 
   (2) diluting one volume of said pre-concentrate with 2 to 50 volumes of water, thereby obtaining said oil-in-water emulsion.   
     
     
         25 . The process according to  claim 24 , wherein said pre-concentrate has a content in oil of at least 10% v/v, at least 20% v/v, or at least 30% v/v. 
     
     
         26 . The process according to  claim 24 , wherein said oil phase and/or said diluting water comprise(s) said cetalkonium chloride (CKC). 
     
     
         27 . The process according to  claim 24 , wherein said oil phase comprises mineral oil, vegetable oil, medium chain triglycerides (MCT), or a mixture thereof. 
     
     
         28 . The process according to  claim 25 , wherein said oil phase comprises mineral oil, castor oil, medium chain triglycerides (MCT), or a mixture thereof.