Diamine-linked melanocortin receptor-specific cyclic peptides for ocular indications
Receptor-specific cyclic peptides of the formula where Xaa 1 , Xaa 2 , Xaa 3 , x, R 1 , R 2 , R 3 and R 4 are as defined in the specification, compositions and formulations including the peptides of the foregoing formula, and methods of preventing, ameliorating, or treating melanocortin receptor-mediated diseases, indications, conditions, and syndromes utilizing melanocortin receptor-specific cyclic peptides of formula I.
1 . A cyclic peptide having the structure (SEQ ID NO: 51)
or a pharmaceutically acceptable salt thereof.
2 . The pharmaceutically acceptable salt of the cyclic peptide according to claim 1 , which is an acetate salt.
3 . A pharmaceutical composition comprising the cyclic peptide according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4 . The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable carrier is an aqueous solution comprising about 2.79 mg/mL of trisodium citrate dihydrate, about 9 mg/mL of sodium chloride and about 1 mg/mL of polysorbate 80.
5 . The pharmaceutical composition of claim 4 , wherein the cyclic peptide is in a trifluoroacetic acid salt form at a concentration of about 1.0 μg/mL.
6 . The pharmaceutical composition of claim 5 , further comprising about 0.10 mg/mL anhydrous citric acid.
7 . The pharmaceutical composition of claim 4 , wherein the aqueous solution is at about pH 6.5, and the composition further comprises sodium hydroxide or hydrochloric acid as needed to adjust pH.
8 . A method for treating a melanocortin receptor-mediated disease, indication, condition or syndrome in a human or non-human mammal, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 3 .
9 . The method of claim 8 , wherein the melanocortin receptor-mediated disease, indication, condition or syndrome in a human is ocular inflammation.
10 . The method of claim 9 , wherein the pharmaceutical composition is an aqueous pharmaceutical composition suitable for administration to the surface of an eye.
11 . The method of claim 9 , wherein the inflammation is caused by an ocular condition, wherein the ocular condition is dry eye disease, corneal ulcer, corneal erosion, corneal abrasion, corneal degeneration, corneal perforation, corneal scarring, epithelial defect, keratoconjunctivitis, idiopathic uveitis, corneal transplantation, age-related macular degeneration, diabetic eye, blepharitis, glaucoma, ocular hypertension, post-operative eye pain and inflammation, posterior segment neovascularization, proliferative vitreoretinopathy, cytomegalovirus retinitis, endophthalmitis, choroidal neovascular membrane, vascular occlusive disease, allergic eye disease, tumor, retinitis pigmentosa, eye infection, scleritis, ptosis, miosis, eye pain, mydriasis, neuralgia, cicatrizing ocular surface disease, ocular infection, inflammatory ocular disease, ocular surface disease, corneal disease, retinal disease, ocular manifestations of systemic diseases, hereditary eye condition, ocular tumor, increased intraocular pressure, herpetic infection, pterygium, a wound sustained to ocular surface, post-photorefractive keratotomy eye pain and inflammation, thermal or chemical burn to the cornea, scleral wound, keratoconus or conjunctival wound.
12 . The method of claim 11 , wherein the inflammation is caused by dry eye disease or keratoconjunctivitis sicca.
13 . A method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 3 .
14 . A method of treating dry eye disease or keratoconjunctivitis sicca comprising administering no more than about 50 μL of the pharmaceutical composition of claim 5 per eye no more often than about three times per day.
15 . The method of claim 14 , wherein no more than about 150 ng of cyclic peptide or pharmaceutically acceptable salt thereof is administered per eye per day.
16 . A trifluoroacetic acid salt of a cyclic peptide having the structure (SEQ ID NO: 51)
17 . A pharmaceutical composition comprising the trifluoroacetic acid salt according to claim 16 , and a pharmaceutically acceptable carrier.
18 . The pharmaceutical composition of claim 17 , wherein the pharmaceutically acceptable carrier is an aqueous solution comprising about 2.79 mg/mL of trisodium citrate dihydrate, about 9 mg/mL of sodium chloride and about 1 mg/mL of polysorbate 80.
19 . The pharmaceutical composition of claim 18 , wherein the aqueous solution is at about pH 6.5, and the composition further comprises sodium hydroxide or hydrochloric acid as needed to adjust pH.
20 . A method for treating a melanocortin receptor-mediated disease, indication, condition or syndrome in a human or non-human mammal, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 17 , wherein the melanocortin receptor-mediated disease, indication, condition or syndrome in a human is ocular inflammation.
21 . The method of claim 20 , wherein the pharmaceutical composition is an aqueous pharmaceutical composition suitable for administration to the surface of an eye.
22 . The method of claim 20 , wherein the inflammation is caused by an ocular condition, wherein the ocular condition is dry eye disease, corneal ulcer, corneal erosion, corneal abrasion, corneal degeneration, corneal perforation, corneal scarring, epithelial defect, keratoconjunctivitis, idiopathic uveitis, corneal transplantation, age-related macular degeneration, diabetic eye, blepharitis, glaucoma, ocular hypertension, post-operative eye pain and inflammation, posterior segment neovascularization, proliferative vitreoretinopathy, cytomegalovirus retinitis, endophthalmitis, choroidal neovascular membrane, vascular occlusive disease, allergic eye disease, tumor, retinitis pigmentosa, eye infection, scleritis, ptosis, miosis, eye pain, mydriasis, neuralgia, cicatrizing ocular surface disease, ocular infection, inflammatory ocular disease, ocular surface disease, corneal disease, retinal disease, ocular manifestations of systemic diseases, hereditary eye condition, ocular tumor, increased intraocular pressure, herpetic infection, pterygium, a wound sustained to ocular surface, post-photorefractive keratotomy eye pain and inflammation, thermal or chemical burn to the cornea, scleral wound, keratoconus or conjunctival wound.
23 . The method of claim 22 , wherein the inflammation is caused by dry eye disease or keratoconjunctivitis sicca.
24 . A method of treating dry eye disease or keratoconjunctivitis sicca comprising administering no more than about 50 μL of the pharmaceutical composition of claim 19 per eye no more often than about three times per day.
25 . The method of claim 24 , wherein no more than about 150 ng of trifluoroacetic acid salt is administered per eye per day.