Esters for Treatment of Ocular Inflammatory Conditions

Abstract

The present invention relates to ophthalmic compositions and methods for the treatment of dry eye and other inflammatory ocular conditions. In particular, the present invention relates to a composition comprising an esterified anti-inflammatory lipid mediator, which is an ester of an anti-inflammatory lipid mediator that is a reaction product of the anti-inflammatory lipid mediator and a monohydric alcohol or an amide wherein the majority of the anti-inflammatory lipid mediator is present in an ester form. In this way, the compositions are substantially free of an acid form of the anti-inflammatory lipid mediators. Anti-inflammatory lipid mediators can be selected from the group consisting of polyunsaturated fatty acids (e.g., omega-three and omega-six fatty acids), resolvins or a metabolically stable analog, protectins or a metabolically stable analog, lipoxins or a metabolically stable analog, prostaglandins or a metabolically stable analog, retinoic acids, endocannabinoids, metabolites thereof, and mixtures thereof. This composition can be topically delivered to the ocular surface via a preparation, solution, gel, ointment, and/or strip and/or a contact lens.

What is claimed is: 
     
         1 . An ophthalmic composition for treatment of ocular conditions, the composition comprising:
 an ester or amide of an anti-inflammatory lipid mediator that is a reaction product of the anti-inflammatory lipid mediator and a monohydric alcohol or an amine; and   an aqueous delivery system;   wherein the majority of the anti-inflammatory lipid mediator is present in an ester form.   
     
     
         2 . The composition of  claim 1 , wherein the ester is present in a therapeutically effective amount. 
     
     
         3 . The composition of  claim 1 , wherein the composition is substantially free of fatty acids. 
     
     
         4 . The composition of  claim 1 , wherein the composition comprises 10% by weight or less of the acid form of the anti-inflammatory lipid mediator. 
     
     
         5 . The composition of  claim 4 , wherein the composition comprises 5% by weight or less of the acid form of the anti-inflammatory lipid mediator. 
     
     
         6 . The composition of  claim 5 , wherein the composition comprises 1% by weight or less of the acid form of the anti-inflammatory lipid mediator. 
     
     
         7 . The composition of  claim 1 , wherein the ester is present in an amount in the range of about 0.01% to 5.0% by weight, based on the total composition. 
     
     
         8 . The composition of  claim 7 , wherein the ester is present in an amount in the range of about 0.025% to 0.5% by weight, based on the total composition. 
     
     
         9 . The composition of  claim 1 , wherein the ester is selected from the group consisting of an esterified polyunsaturated fatty acid, an esterified resolvin or its metabolically stable analog, an esterified protectin or its metabolically stable analog, an esterified lipoxin or its metabolically stable analog, an esterified prostaglandin or its metabolically stable analog, an esterified retinoic acid, metabolites thereof, and mixtures thereof. 
     
     
         10 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator is a prostaglandin selected from the group consisting of prostaglandin E1 (PGE1), prostaglandin E3 (PGE3), or a metabolically stable analog, and combinations thereof. 
     
     
         11 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator is a resolvin selected from the group consisting of resolvin E1 (RvE1), resolvin E2 (RvE2), resolvin D1 (RvD1), resolvin D2 (RvD2), resolvin D3 (RvD3), resolvin D4 (RvD4), or a metabolically stable analog, and combinations thereof. 
     
     
         12 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator is a lipoxin selected from the group consisting of lipoxin A4 (LXA), lipoxin B4 (LXB4), or a metabolically stable analog, and combinations thereof. 
     
     
         13 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator comprises protectin D1 (PD1) or a metabolically stable analog. 
     
     
         14 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator comprises 13-cis-retinoic acid. 
     
     
         15 . The composition of  claim 5 , wherein the anti-inflammatory lipid mediator comprises anandamide. 
     
     
         16 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator comprises at least one omega-three fatty acid selected from the group consisting of: alpha-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docohexaenoic acid (DHA), docosapentaenoic acid (DPA), tetracosapentaenoic acid, and tetracosahexaenoic acid (Nisinic acid), derivatives, metabolites, and mixtures thereof. 
     
     
         17 . The composition of  claim 1 , wherein the ester comprises esterified alpha-linolenic acid. 
     
     
         18 . The composition of  claim 17 , wherein the esterified alpha-linolenic acid is present in an amount in the range of about 0.01% to 5.0% by weight, based on the total composition. 
     
     
         19 . The composition of  claim 17 , wherein the esterified alpha-linolenic acid is alpha-linolenic acid ethyl ester. 
     
     
         20 . The composition of  claim 19 , wherein the composition comprises, by weight of the composition:
 the alpha-linolenic acid ethyl ester in an amount in the range of about 0.025 to 5.0%;   a wetting agent that is methyl gluceth-20 in an amount in the range of about 0.025 to 5.0%;   a surfactant that is polysorbate 80 in an amount in the range of about 0.025 to 5.0%;   an antioxidant that is Vitamin E in an amount in the range of about 0.01 to 0.1%; and   a water-based packing solution that optionally comprises one or more of a salt, a preservative, and a buffer.   
     
     
         21 . The composition of  claim 1 , wherein the aqueous delivery system comprises one or more of the following: a surfactant, an emulsifier, a wetting agent, a chelant, and an antioxidant. 
     
     
         22 . The composition of  claim 1 , wherein the aqueous delivery system comprises one or more ingredients selected from the group consisting of polysorbate 80™, Tyloxapol™, methyl gluceth-20, Vitamin E, diethylenetriaminepentaacetic acid, boric acid, sodium borate, and sodium chloride. 
     
     
         23 . The composition of  claim 1 , wherein the monohydric alcohol has the formula CH 3 —(CH 2 ) z —OH, wherein z is from 0 to 5. 
     
     
         24 . The composition of  claim 1 , wherein the ester has the structure:
   CH 3 —CH 2 —CH═CH—(CH 2 —CH═CH) n —(CH 2 ) x —CO—O—R
   
       or the amide has the structure:
   CH 3 —CH 2 —CH═CH—(CH 2 —CH═CH) n —(CH 2 ) x —CO—NH—R
 
 
       wherein
 n is 2, 3, 4, or 5; 
 x is 2, 3, 4, 5, 6, or 7; 
 R is an ophthalmologically compatible leaving group, including —(CH 2 ) y —CH 3 , where y is 0 or greater. 
 
     
     
         25 . The composition of  claim 24 , wherein y is 1. 
     
     
         26 . The composition of  claim 1 , wherein the anti-inflammatory lipid mediator comprises an omega-three fatty acid, an omega-six fatty acid, or both. 
     
     
         27 . The composition of  claim 26 , wherein
 the omega-three fatty acid is selected from the group consisting of: alpha-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docohexaenoic acid (DHA), docosapentaenoic acid (DPA), tetracosapentaenoic acid, and tetracosahexaenoic acid (Nisinic acid), derivatives, metabolites, and mixtures thereof; and   the omega-six fatty acid is selected from the group consisting of linoleic acid, gamma-linolenic acid (GLA), eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), docosadienoic acid, adrenic acid, docosapentaenoic acid, or combinations thereof.   
     
     
         28 . The composition of  claim 1 , wherein the ester is the reaction product of a fatty acid and an amine to form an amidoester. 
     
     
         29 . A sterile preparation, solution, gel, ointment, emulsion or strip for administration to the eye or a contact lens comprising the composition of  claim 1 . 
     
     
         30 . A method of preparing an ophthalmic composition for treatment of ocular conditions, the method comprising providing the composition of  claim 1  and forming the ophthalmic composition. 
     
     
         31 . A method of preventing inflammatory ocular conditions, dry-eye, or both in an individual in need thereof which comprises delivering a therapeutically effective amount of a composition according to  claim 1  to the individual's ocular surface. 
     
     
         32 . The method of  claim 31  wherein the concentration of the ester in the composition is in the range of 0.025 weight % to 5.0 weight %. 
     
     
         33 . The method of  claim 31  wherein the delivery step comprises administering eye drops comprising the composition of  claim 1 . 
     
     
         34 . The method of  claim 31  wherein the delivery step comprises positioning a contact lens on the ocular surface, wherein the contact lens was soaked or hydrated in the composition. 
     
     
         35 . A method of relieving dry-eye symptoms comprising administering a therapeutically effective amount of the composition of  claim 1  to relieve at least one eye of a patient suffering from said symptoms. 
     
     
         36 . A method of mitigating dry eye symptoms comprising administering a therapeutically effective amount of the composition of  claim 1  to at least one eye of a patient suffering from said symptoms. 
     
     
         37 . A method of treating an eye condition comprising delivering, from an ophthalmic device, a therapeutically effective amount of an ester of an anti-inflammatory lipid mediator that is a reaction product of the anti-inflammatory lipid mediator and a monohydric alcohol to at least one eye suffering in need of therapy for dry eye, meibomian gland dysfunction, blepharitis, atopic keratoconjunctivitis, contact lens-related dry eye, Sjögren's syndrome, uveitis, macular degeneration, and combinations thereof. 
     
     
         38 . The method of  claim 37 , wherein the ophthalmic device is a contact lens. 
     
     
         39 . The method of  claim 37 , wherein the ester is selected from the group consisting of an esterified polyunsaturated fatty acid, an esterified resolvin or its metabolically stable analog, an esterified protectin or its metabolically stable analog, an esterified lipoxin or its metabolically stable analog, an esterified prostaglandin or its metabolically stable analog, an esterified retinoic acid, an endocannabinoid, metabolites thereof, and mixtures thereof. 
     
     
         40 . A method of combating inflammatory ocular conditions, dry-eye, or both in an individual in need thereof which comprises delivering a therapeutically effective amount of a composition according to  claim 1  to the individual's ocular surface.