Formulations of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile

Abstract

The present invention provides formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) and methods for treating ocular surface pain by administering such formulations. The present invention also provides methods for treating dry eye disease and ocular hyperemia by administering formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile.

1 .- 94 . (canceled) 
     
     
         95 . A formulation, comprising:
 a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v,   a non-ionic surfactant selected from the group consisting of a polysorbate surfactant, a block copolymer of ethylene oxide, propylene oxide surfactant, poloxamer, tyloxapol, and combinations thereof;   a suspending agent selected from the group consisting of carbomer, hydroxypropyl methyl cellulose (hypromellose), polyethylene glycol, and combinations thereof;   a tonicity agent selected from the group selected from mannitol, glycerin, xylitol, sorbitol and propylene glycol, and combinations thereof;   a buffer;   optionally, a salt;   optionally, a preservative; and   water in quantity sufficient (qs) to 100%.   
     
     
         96 . The formulation according to  claim 95 , wherein the non-ionic surfactant is substantially all tyloxapol, which present in an amount at least about 0.001% w/v, at least about 0.01% w/v, at least about 0.02% w/v, least about 0.03% w/v, or at least about 0.04% w/v, and no more than about 1% w/v, no more than about 0.5% w/v, no more than about 0.3% w/v, or no more than about 0.2% w/v, no more than about 0.1% w/v, or no more than about 0.08% w/v. 
     
     
         97 . The formulation according to  claim 95 , wherein the suspending agent is carbomer, present in the formulation in an amount of at least about 0.05% w/v, at least about 0.1% w/v, or at least about 0.2% w/v, and no greater than about 1.0% w/v, no greater than about 0.6% w/v, or no greater than about 0.5%. 
     
     
         98 . The formulation according to  claim 97 , wherein the suspending agent is substantially all carbomer homopolymer Type B. 
     
     
         99 . The formulation according to  claim 95 , wherein the tonicity agent is mannitol or glycerin, present in the formulation in an amount of from 0.1% w/v to about 5% w/v, or about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 2.5% w/v, about 3.0% w/v, about 3.5% w/v, about 4.0% w/v, about 4.5% w/v, or about 5% w/v. 
     
     
         100 . The formulation according to  claim 95 , wherein the buffer is selected from the group consisting of phosphate, and TRIS (tromethamine). 
     
     
         101 . The formulation according to  claim 95 , comprising sodium chloride as the salt. 
     
     
         102 . The formulation according to  claim 101 , wherein the suspending agent is carbopol (carbomer homopolymer Type B) and amount of sodium chloride is adjusted to an amount to provide a viscosity of the formulation of about 20 cP to about 200 cP, when using spindle CP-42 at 60 rpm at about 25° C. 
     
     
         103 . The formulation according to  claim 95 , wherein the pH of the formulation is about 6.5 to about 7.4 
     
     
         104 . The formulation according to  claim 95 , wherein the formulation exhibits settling of less than about 10%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% after storage at room temperature for six months. 
     
     
         105 . The formulation according to  claim 95 , wherein the amount of compound I in the formulation at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least about 97% or at least about 98% of the initial amount after about 18 months of storage under refrigeration. 
     
     
         106 . A formulation, comprising:
 a suspension of polymorphic form B of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), in an amount of about 0.5% w/v to about 2.5% w/v,   tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v;   carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.4% w/v;   glycerin in an amount of from about 0.5% w/v to about 5% w/v;   a buffer selected from edetate, phosphate, borate, tromethamine, or combinations thereof;   sodium chloride in an amount of from 0.01% w/v to about 1% w/v; and   water qs to 100%;   wherein the formulation has a pH in the range of from about 5.5 to about 8.0.   
     
     
         107 . The formulation according to  claim 106 , comprising:
 compound I in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,   about 0.05% w/v of tyloxapol;   about 0.2% w/v of carbomer homopolymer Type B;   about 2.0% of glycerin;   a tromethamine buffer; and   hydrochloric acid to adjust pH to about 6.4 to about 8.4;   about 0.05% w/v of sodium chloride; and   water qs to 100%;   
       wherein the formulation does not include a preservative. 
     
     
         108 . A method of treating ocular surface pain in a subject in need thereof, comprising ocularly administering to the subject a formulation according to  claim 107 . 
     
     
         109 . The method according to  claim 108 , wherein the subject suffers from one or more of dry eye disease, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, patients recovering from neurotrophic keratitis, or ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery. 
     
     
         110 . A method of treating ocular surface pain in a subject in need thereof, comprising ocularly administering to the subject a formulation according to  claim 95 . 
     
     
         111 . The method according to  claim 110 , wherein the subject suffers from one or more of dry eye disease, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, patients recovering from neurotrophic keratitis, or ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.