Ophthalmic formulations of tyrosine kinase inhibitors, methods of use thereof, and preparation methods thereof

Abstract

Ophthalmic formulations containing nintedanib, or a pharmaceutically acceptable salt thereof are provided. The ophthalmic formulations can contain microparticles or nanoparticles of nintedanib. Also provided are methods of using the ophthalmic formulations for treating ocular surface diseases, such as dry eye disease.

What is claimed is: 
     
         1 . An ophthalmic formulation comprising a therapeutically effective amount of Nintedanib, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         2 . The ophthalmic formulation of  claim 1 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of surfactants, preservatives, viscosity regulators, pH-adjusting agents, stabilizers, and osmo-regulators. 
     
     
         3 . The ophthalmic formulation of  claim 2 , wherein the surfactant is selected from the group consisting of Tween 80, Tween 20, Polysorbate, Poloxamer, and Tyloxapol. 
     
     
         4 . The ophthalmic formulation of  claim 3 , wherein the surfactant is Tyloxapol. 
     
     
         5 . The ophthalmic formulation of  claim 2 , wherein the viscosity regulator is selected from the group consisting of Hydroxypropyl Methylcellulose (HPMC), Sodium Carboxymethylcellulose, Carbomer, Polycarbophil, Polyoxyethylene glycol (PEG), and Hyaluronic Acid (HA). 
     
     
         6 . The ophthalmic formulation according to  claim 1 , wherein the ophthalmic formulation comprises micronized particles or nanonized particles comprising Nintedanib, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The ophthalmic formulation according to  claim 1 , wherein the formulation is a solution for topical ocular administration. 
     
     
         8 . The ophthalmic formulation according to  claim 1 , wherein a concentration of Nintedanib, the prodrug thereof, or pharmaceutically acceptable salt thereof is 0.01% to 10% w/v. 
     
     
         9 . An ophthalmic formulation comprising a therapeutically effective amount of nanonized particles comprising a tyrosine kinase inhibitor selected from the group consisting of Axitinib, Nintedanib, Sorafenib, Pazopanib, a prodrug thereof, and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         10 . The ophthalmic formulation of  claim 9 , wherein a concentration of the tyrosine kinase inhibitor is 0.01% to 10% w/v. 
     
     
         11 . The ophthalmic formulation according to  claim 9 , wherein the formulation is a liquid solution for topical ocular administration. 
     
     
         12 . A method of treating an ocular surface disease in a subject in need thereof, the method comprising administering to an eye of the subject the ophthalmic formulation according to  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the ocular surface disease is selected from the group consisting of angiogenesis in the front of the eye; corneal angiogenesis following keratitis, corneal transplantation, or keratoplasty; conjunctival degeneration (pinguecula) with slow proliferation; conjunctival papilloma; corneal angiogenesis due to hypoxia; hyperemia; hyperemia associated with pterygium; hyperthyroidism-induced eye congestion; dry eyes; intraretinal edema; macular edema; macular edema due to retinal vein occlusion; neovascular glaucoma (NVG); ocular cancer; pterygium conjunctivae; recurrent pterygium; Steven Johnson syndrome; stye; and subretinal edema. 
     
     
         14 . The method of  claim 13 , wherein the ocular surface disease is hyperemia associated with pterygium, pterygium conjunctivae, recurrent pterygium or corneal angiogenesis. 
     
     
         15 . A method of preparing the ophthalmic formulation of  claim 1 , comprising optionally forming nanoparticles or microparticles of a tyrosine kinase inhibitor selected from the group consisting of Axitinib, Nintedanib, Sorafenib, Pazopanib, a prodrug thereof, and a pharmaceutically acceptable salt thereof, and combining the tyrosine kinase inhibitor, or microparticles or nanoparticles thereof with at least one pharmaceutically acceptable excipient.