Ophthalmic Emulsions Containing Prostaglandins

Abstract

Cationic ophthalmic oil-in-water type emulsions, include colloid particles having an oily core surrounded by an interfacial film. The emulsion includes at least one cationic agent and at least one non ionic surfactant, the oily core including a prostaglandin selected from the group consisting essentially of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandinE 2 , or a mixture thereof, for treating ocular hypertension and/or glaucoma. These emulsions have the property to increase the chemical stability of prostaglandins.

1 . A cationic ophthalmic oil-in-water type emulsion, which comprises colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant selected from the group consisting of poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates and a mixture of two or more thereof, said oily core comprising a drug selected from the group consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandm E 2  or a mixture of two or more thereof said emulsion being free of water-soluble polymer selected from a polyvinyl compound, a water-soluble cellulose compound and a polysaccharide. 
     
     
         2 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , wherein the drug is latanoprost. 
     
     
         3 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , said emulsion being free of water-soluble polymer selected from (1) a polyvinyl compound such as polyvinylalcohol and polyvinylpyrrolidone, (2) a water-soluble cellulose compound such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and/or sodium cellulose and (3) a polysaccharide selected from alginic acid, xanthan gum, carrageenan, and chitosan. 
     
     
         4 . A cationic ophthalmic emulsion according to  claim 1 , comprising at least one further pharmaceutically active substance, either in the oily core or in the aqueous part of the emulsion. 
     
     
         5 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , further comprising an anti-inflammatory compound, preferably a non steroidal anti-inflammatory compound or a omega-3 fatty acid. 
     
     
         6 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , wherein the emulsion further comprise at least one further antiglaucomateous pharmaceutically active substance selected from the group comprising beta-blockers such as levobunolol, befundol, forskolin, metipranolol, cartrolol, timolol; inhibitors of carbonic anhydrase such as bnnzolamide, dorzolamide, acetazolamide, methazolamide, dichlorophenamide; sympathomimetics such as brimomdine, apraclomdine, dipivefrine, epinephrine; parasympathomimetics such as pilocarpine; cholinesterase inhibitors such as physostigmine, echothiophate and/or their derivatives; and/or optically acceptable salts thereof. 
     
     
         7 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , wherein the amount of the drug selected from the group consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandm E 2  or a mixture of two or more thereof in the oily core is 0.001 to 1% w/w, preferably 0.002 to 0.3% w/w and even more preferably 0.004 to 0.15% w/w. 
     
     
         8 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , wherein the concentration of the cationic agent is comprised between 0.001 to 0.1% w/w, preferably between 0.002 to 0.05% w/w and even more preferably between 0.003 to 0.03% w/w. 
     
     
         9 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , wherein the concentration of the oily core is not higher than 7% w/w, preferably between 0.5 to 5% w/w and even more preferably between 1 to 3% w/w. 
     
     
         10 . A cationic ophthalmic emulsion according to  claim 1 , wherein the concentration of the non-ionic agent is less than 1% w/w, comprised preferably from 0.01 to 0.6% w/w. 
     
     
         11 . A cationic ophthalmic oil-in-water emulsion according  claim 1 , wherein the cationic agent is selected in the group consisting of C10-C24 primary alkylamines, tertiary aliphatic amines, quaternary ammonium compounds, cationic lipids, amino alcohols, biguanide salts, cationic compounds and a mixture of two or more thereof. 
     
     
         12 . A cationic ophthalmic oil-in-water emulsion according to  claim 11 , wherein the biguanide salt is selected from the group comprising chlorhexidine and salts thereof, polyaminopropyl biguanide, phenformin, alkylbiguanide or a mixture of two or more thereof. 
     
     
         13 . A cationic ophthalmic oil-in-water emulsion according to  claim 11 , wherein the quaternary ammonium compound is selected from the group comprising benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, rnyristylalkonium halide, stearalkonium halide or a mixture of two or more thereof, halide being preferably chloride or bromide. 
     
     
         14 . A cationic ophthalmic emulsion according to  claim 1 , wherein said cationic agent is selected from the group comprising benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. 
     
     
         15 . A cationic ophthalmic emulsion according to  claim 1 , wherein the cationic agent is selected from at least one quaternary ammonium halide in which the nitrogen atom is substituted by at least one alkyl group having at least 14 carbon atoms. 
     
     
         16 . A cationic ophthalmic emulsion according to  claim 1 , wherein the oil phase has a iodine value of less than 50, preferably equal or less than 15, more preferably equal or less than 5 and even more preferably equal or less than 1. 
     
     
         17 . A cationic ophthalmic emulsion according to  claim 16 , wherein the oil phase comprises one or more components selected from the group consisting of mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil. 
     
     
         18 . A cationic ophthalmic emulsion according to  claim 1 , wherein the oil is MCT. 
     
     
         19 . A cationic ophthalmic emulsion according to  claim 1 , comprising benzalkonium chloride as cationic agent and tyloxapol as non-ionic surfactant. 
     
     
         20 . A cationic ophthalmic emulsion according to  claim 1 , wherein the emulsion contains benzalkonium chloride as cationic agent and a combination of tyloxapol and poloxamer. 
     
     
         21 . A cationic ophthalmic emulsion according to  claim 1 , wherein said colloidal particles have an average particle size of equal or less than 1 μm, advantageously equal or less than 300 nm, more advantageously in the range of 100 to 250 nm. 
     
     
         22 . A cationic ophthalmic oil-in-water type emulsion according to  claim 1 , wherein the emulsion meets zeta potential stability Test A requirements. 
     
     
         23 . An ophthalmic emulsion according to  claim 1 , which meets zeta potential stability Test B requirements. 
     
     
         24 . An ophthalmic emulsion according to  claim 1 , which meets zeta potential stability Test C requirements. 
     
     
         25 . An ophthalmic emulsion according to  claim 1 , which meets zeta potential stability Test D requirements. 
     
     
         26 . (canceled) 
     
     
         27 . Ophthalmic formulation comprising an emulsion according to  claim 1 , optionally in combination with an ophthalmologically acceptable carrier, said formulation being in the form of eye drops, eye ointment, ophthalmic gel. 
     
     
         28 . Delivery device selected from the group comprising lenses, ocular patch, implant, insert, said device containing an emulsion according to  claim 1 . 
     
     
         29 . Method of treating ocular hypertension and/or glaucoma, which comprises administering an effective amount of a cationic ophthalmic oil-in-water emulsion according to  claim 1  to a subject in need thereof.