WO2017083799A1

WO2017083799A1 - Ophthalmic formulations of squalamine

Info

Publication number: WO2017083799A1
Application number: PCT/US2016/061740
Authority: WO
Inventors: Irach B. Taraporewala; Samuel I. Backenroth
Original assignee: Ohr Pharmaceutical, Inc.
Priority date: 2015-11-13
Filing date: 2016-11-14
Publication date: 2017-05-18
Also published as: TW201720445A; AR106691A1

Abstract

Ophthalmic compositions containing squalamine dilactate were unexpectedly observed to effectively treat ophthalmic conditions. The ophthalmic compositions may also be used in combination with other ophthalmic therapies.

Description

OPHTHALMIC FORMULATIONS OF SQUALAMINE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is technically related to U.S. Published Patent Application No. 20130281420 and U.S. Patent Nos. 5,192,756; 6,962,909; 7,981,876; and 8,716,270, each of which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates to formulations of squalamine dilactate for the treatment of ophthalmic conditions or disorders.

BACKGROUND OF THE INVENTION

[0003] Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss among people in the United States aged 52 or older and is the most common overall cause of blindness in the United States, Canada, Great Britain and Australia. AMD encompasses several types of abnormalities that develop in the macula of affected individuals. Two forms of macular degeneration exist: dry (also known as atrophic) and wet (also known as disciform, exudative, subretinal neovascular or choroidal neovascular). The dry form, which may be a precursor to the wet form, results from an inability of the pigment epithelium of the macula to remove waste materials generated by the retina. The wet form occurs when new blood vessels grow under the retina, particularly the macula.

[0004] Squalamine (IUPAC Name: ([6-[(3S,5R,7R,10S,13R,14S)-3-[3-(4- aminobutylamino)propylamino] -7-hy droxy-10, 13-dimethyl-

2,3,4,5,6,7,8,9,11,12,14,15,16, 17-tetradecahydro-lH-cyclopenta[a]phenanthrene-17-yl]- 2-methylheptan-3-yl] hydrogen sulfate) is an aminosterol exhibiting anti-angiogenic properties that has been utilized as an intravenous infusion for the effective treatment of wet AMD where it functions to prevent the neovascularization and aberrant blood vessel formation in the retina that characterize the progression of the disease (Sills Jr. et al, "Squalamine Inhibits Angiogenesis and Solid Tumor Growth in Vivo Perturbs Embryonic Vasculature", Cancer Research 58: 2784-2792 (1998); Higgins et al , "Squalamine Improves Retinal Neovascularization", Investigative Ophthalmology & Visual Science 41(6): 1507-1512 (2000); PRNEWSWIRE, "Genaera Reports Squalamine Continues to Improve Vision at Four Months Timepoint in Age-Related Macular Degeneration", http : / / www, ev esi ghtnews .com/topic/28. html (Oct. 7, 2003)). Squalamine is the subject of U.S. Patent No. 5,192,756 to Zasloff et al, the disclosure of which is herein incorporated by reference in its entirety. The total chemical synthesis of squalamine is described in U.S. Patent Nos. 6,262,283 and 6,610,866, which are incorporated herein by reference in their entireties.

[0005] It would clearly be desirable from a patient-use and risk standpoint to have a topical formulation available for direct application to the eye as opposed to an intravenous infusion, or especially the current standard of care which requires monthly injections directly into the eye. Topical formulations in the form of, for example, solutions, suspensions, creams or ointments are easily self-administered by patients as compared to more invasive techniques, such as intravitreal injections, which require costly administration under medical supervision and which can result in serious complications such as endophthalmitis and retinal detachment. The general problem with ocular eye drops, however, is that after their administration, typically less than 5% of the drug in the eye drop penetrates the cornea and reaches intraocular tissues. Instead, a major fraction of the administered dose is eliminated due to solution drainage and systemic absorption (Jarvinen K. et al, "Ocular absorption following topical delivery", Adv. Drug Deliv. Rev. 16(1): 3-19 (1995); Conroy C.W., "Sulfonamides do not reach the retina in therapeutic amounts after topical application to the cornea", Ocul. Pharmacol. Ther. 13(5): 465- 472 (1997); and Maurice D.M., "Drug delivery to the posterior segment from drops", Surv. Ophthalmol. 47(suppl. l): S41- S52 (2001)).

[0006] In addition, a previous clinical trial to test the efficacy of squalamine for the treatment of AMD by IV infusion revealed potential problems for long term use. The intravenous dosing regimen in the IV formulation was deemed to be sub-optimal using pharmacokinetic analyses and was not viable on a commercial basis for a variety of reasons. For one, the short plasma half-life of squalamine in human subjects at the 40 mg dose resulted in concentrations in the choroid insufficient to block choroidal

neovascularization (CNV) after 4-6 days. When the dosing was spaced out to monthly "maintenance" infusions, there was potentially only up to a week of inhibition of CNV, followed by three weeks or more of active new angiogenesis. This regimen produced good gains in visual acuity after the first four to five weeks of administration, followed by a decline in the rate of improvement after the fifth week. Intravenous dosing caused local infusion-site reactions (dosing was orders of magnitude higher than dose to be used in the topical formulation). In a "real world" situation, it is unrealistic to expect an elderly patient with wet AMD to be able to visit a clinic on a weekly basis for a prolonged infusion. Most retinal ophthalmic practices are also not set up for such intravenous infusions.

[0007] Compared to the above indicated disadvantages associated with intravenous dosing, the present invention represents the discovery of a safe and non-irritating ocular formulation for topical administration that is able to achieve selected delivery of a therapeutic agent to the back of the eye for treatment of a disorder.

SUMMARY OF THE INVENTION

[0008] One aspect of the present invention is a composition for ophthalmic use comprising at least one of the compositions selected from the group consisting of Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5 and

Formulation 6 as described herein.

[0009] In another aspect of the invention, the composition for ophthalmic use comprises squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0010] In another aspect of the invention, the composition for ophthalmic use comprises squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[001 1] In another aspect of the invention, the composition for ophthalmic use comprises squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0012] In another aspect of the invention, the composition for ophthalmic use comprises squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0013] In another aspect of the invention, the composition for ophthalmic use comprises squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0014] In another aspect of the invention, the composition for ophthalmic use consists of squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0015] In another aspect of the invention, the composition for ophthalmic use consists of squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0016] In another aspect of the invention, the composition for ophthalmic use consists of squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0017] In another aspect of the invention, the composition for ophthalmic use consists of squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0018] In another aspect of the invention, the composition for ophthalmic use consists of squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0019] In an exemplary embodiment of the invention, any of the

compositions/formulations of the invention are suitable for topical administration to the eye.

[0020] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of at least one of the compositions selected from the group consisting of Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0021] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0022] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0023] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0024] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0025] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0026] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0027] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0028] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0029] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0030] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water. [0031] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of at least one of the compositions selected from the group consisting of Formulation 1 , Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0032] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0033] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0034] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0035] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0036] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0037] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0038] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0039] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0040] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0041] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0042] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of at least one of the compositions selected from the group consisting of Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0043] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0044] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0045] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0046] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0047] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0048] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0049] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0050] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0051] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0052] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof comprising administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0053] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of at least one of the compositions selected from the group consisting of Formulation 1 , Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0054] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0055] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0056] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0057] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0058] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition comprising squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0059] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate dibasic heptahydrate; sodium phosphate monobasic dihydrate; glycerol; Povidone K-30; edetate disodium; benzalkonium chloride; and water.

[0060] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium carboxymethylcellulose; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); sodium chloride; benzalkonium chloride; and water.

[0061] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; edetate disodium; glycerol; propylene glycol; hypromellose; sorbic acid; and water.

[0062] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxol 40 hydrogenated castor oil; n-dodecyl- -D-glycoside; benzalkonium chloride; and water.

[0063] Another aspect of the invention is a method of treating and/or preventing an ophthalmic condition in a mammal in need thereof consisting of administering to the eye or eyes of the mammal a therapeutically effective amount of a therapeutic ophthalmic agent in combination with a therapeutically effective amount of a composition consisting of squalamine dilactate; sodium phosphate heptahydrate; sodium phosphate monobasic monohydrate; Povidone K-30; edetate disodium; sodium chloride; benzalkonium chloride; a cyclodextrin (such as 2-hydroxypropyl- -cyclodextrin); and water.

[0064] In an aspect of the invention, the therapeutic ophthalmic agent is administered to the mammal before administration of at least one of the compositions selected from the group consisting of Formulation 1 , Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0065] In an aspect of the invention, the ophthalmic therapeutic agent is administered to the mammal at approximately the same time as administration of at least one of the compositions selected from the group consisting of Formulation 1 , Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0066] In an aspect of the invention, the therapeutic ophthalmic agent is administered to the mammal after administration of at least one of the compositions selected from the group consisting of Formulation 1 , Formulation 2, Formulation 3, Formulation 4, Formulation 5 and Formulation 6 as described herein.

[0067] In an aspect of the invention, the therapeutic ophthalmic agent is administered to the mammal before administration of at least one of the compositions described herein.

[0068] In an aspect of the invention, the therapeutic ophthalmic agent is administered to the mammal at approximately the same time as administration of at least one of the compositions described herein.

[0069] In an aspect of the invention, the therapeutic ophthalmic agent is administered to the mammal after administration of at least one of the compositions described herein.

[0070] In an aspect of the invention, the mammal is a human.

[0071] In an aspect of the invention, the therapeutic ophthalmic agent is any conventional therapeutic ophthalmic agent, such as, but not limited to, one selected from the group consisting of ranibizumab (Lucentis®), bevacizumab (Avastin®), aflibercept (Eylea®), DARPin (Abicipar) and brolucizumab (RTH-258).

[0072] In an aspect of the invention, the ophthalmic condition is selected from the group consisting of wet age-related macular degeneration (wet AMD), dry age-related macular degeneration (dry AMD), diabetic retinopathy, proliferative diabetic retinopathy, ischemic retinopathy (which includes retinal artery occlusion and carotid artery occlusion), cystoid macular edema, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, retinal vascular occlusive disease (which includes central and branch retinal vein occlusions), inflammatory/infectious retinal neovascularization/edema (which includes posterior uveitis, sarcoid, toxoplasmosis, histoplasmosis, Vogt-Koyanagi-Harada Disease, chronic posterior uveitis, punctate and multifocal inner choroidopathy), retinoblastoma, ocular melanoma, ocular tumors, retinal detachment, myopic

neovascularization, angioid streaks, Eales disease, choroidal rupture and any combination thereof.

[0073] In another aspect of the invention, each of the compositions of the invention may further comprise or consist of at least one of a mucoadhesive agent, a penetration enhancer, a viscosity increasing agent, a tonicity modifier, an antimicrobial preservative, a buffering agent, a surfactant, a stabilizing agent, a solubilizing and a resuspension agent if such agent is not already present in the composition, and if such agent is already present in the composition, the composition may comprise or consist of a second such agent. It is recognized that a particular chemical compound present in any of the compositions of the invention may function in more than one capacity - i.e., may function primarily as, for example, a mucoadhesive agent and to a lesser degree as, for example, a stabilizing agent; or primarily as a solubilizing agent but also as a surfactant.

[0074] In an exemplary embodiment, the composition may further comprise at least two or at least three or at least four or at least five of a mucoadhesive agent, a penetration enhancer, a viscosity increasing agent, a tonicity modifier, an antimicrobial preservative, a buffering agent, a surfactant, a stabilizing agent, a solubilizing agent and a resuspension agent. It is recognized that a particular chemical compound may function in multiple capacities in this regard.

[0075] In an exemplary embodiment, the composition is in the form of eye drops.

[0076] An aspect of the invention is a method of delivering one of the described compositions/formulations to the posterior sclera and/or choroid of the eye of a mammal in a therapeutically effective amount.

[0077] In an exemplary embodiment, the compositions/formulations of the invention are present in significantly lower concentrations in the aqueous humor or vitreous humor compared to other locations within the eye after administration of the

compositions/formulations to the eye of a mammal.

[0078] In an exemplary embodiment, the ophthalmic condition is wet AMD.

[0079] In an exemplary embodiment, the squalamine dilactate is present in an amount of 0.01 to 5.0 weight percent. In particular embodiments, the weight percent is 0.05 weight percent or 0.1 weight percent or 0.2 weight percent or 0.3 weight percent. [0080] In an exemplar}¹ embodiment, the salt is present in an amount sufficient to approximate the salt concentration and/or tonicity of the human tear fluid.

[0081] In an exemplary embodiment, the salt is present in an amount ranging from 0.5 to 1.0% weight percent.

[0082] In an exemplary embodiment the preservative is present in an amount sufficient to generate a microbial barrier to maintain or reduce microbial concentrations for a period of from about 12 hours to about 72 hours.

[0083] A particular aspect of the invention is an ophthalmic composition, comprising: 0.05 to 0.25% squalamine dilactate w/v;

0.5 to 1.5% boric acid w/v and 0.05 to 0.30% sodium borate w/v;

0.005 to 0.03% edetate disodium w/v;

0.5 to 3.0 % glycerol w/v;

0.20 to 1.0% propylene glycol w/v;

0.3 to 2.0% hypromellose w/v;

0.005 to 0.3% sorbic acid w/v; and

water.

[0084] Another particular aspect of the invention is an ophthalmic composition, comprising:

0.05 to 0.25% squalamine dilactate w/v;

0.15 to 0.35%) sodium phosphate heptahydrate w/v and 0.03 to 0.12% sodium phosphate monobasic monohydrate w/v;

0.8 to 1.4% Povidone -30 w/v;

0.005 to 0.05% edetate disodium w/v;

0.3 to 1.5% sodium chloride w/v;

0.001 to 0.01 % benzalkonium chloride w/v;

0.5 to 2.0% 2-hydroxypropyl- -cyclodextrin w/v; and

water.

[0085] A particular aspect of the invention is an ophthalmic composition, consisting of: 0.05 to 0.25% squalamine dilactate w/v;

0.5 to 1.5% boric acid w/v and 0.05 to 0.30% sodium borate w/v;

0.005 to 0.03% edetate disodium w/v;

0.5 to 3.0 % glycerol w/v;

0.20 to 1.0% propylene glycol w/v;

0.3 to 2.0% hypromellose w/v;

0.005 to 0.3% sorbic acid w/v; and

water.

[0086] Another particular aspect of the invention is an ophthalmic composition, consisting of:

0.05 to 0.25% squalamine dilactate w/v;

0.15 to 0.35% sodium phosphate heptahydrate w/v and 0.03 to 0.12% sodium phosphate monobasic monohydrate w/v;

0.8 to 1.4% Povidone K-30 w/v;

0.005 to 0.05% edetate disodium w/v;

0.3 to 1.5% sodium chloride w/v;

0.001 to 0.01% benzalkonium chloride w/v;

0.5 to 2.0% 2-hydroxypropyl- -cyclodextrin w/v; and

water.

[0087] In an exemplary embodiment, any of the above compositions is administered topically to the eye of a mammal in need thereof.

[0088] In an exemplary embodiment, the composition is in the form of eye drops.

[0089] In an exemplary embodiment, the mammal suffers from an ophthalmic condition, such as one selected from the group consisting of wet age-related macular degeneration (wet AMD), choroidal neovascularization and dry age-related macular degeneration (dry AMD).

[0090] An aspect of the invention is a method of selectively delivering squalamine or a pharmaceutically acceptable salt thereof to the posterior sclera and choroid of the eye(s) of a mammal in need thereof in an amount therapeutically effective to treat an ophthalmic condition, the method comprising: administering to the eye(s) of the mammal the composition, wherein the ophthalmic condition is selected from the group consisting of wet age-related macular degeneration (wet AMD), choroidal neovascularization and dry age-related macular degeneration (dry AMD).

BRIEF DESCRIPTION OF THE DRAWINGS

[0091] The figures merely illustrate particular embodiments of the invention and are not intended to otherwise limit the scope of the overall invention as described herein.

[0092] Figure 1 illustrates squalamine concentrations in the posterior sclera and choroid for Formulation 6 in a rabbit eye at Day 1, Day 7 and Day 14 with the indicated dosing intervals.

[0093] Figure 2A illustrates the mean change in visual acuity (letters gained) in a patient population through Week 36 using Formulation 5 in combination treatment with Lucentis® (labeled as "Form-5") versus treatment with Lucentis® and a placebo formulation (labeled as "Placebo").

[0094] Figure IB illustrates the percent of patients through Week 36 with a > 3-line gain in visual acuity using Formulation 5 in combination treatment with Lucentis® (labeled as "Form-5") versus treatment with Lucentis® and a placebo formulation (labeled as "Placebo").

[0095] Figure 2C illustrates the percent of patients with a > 4-line gain and a > 5 -line gain in visual acuity using Formulation 5 in combination treatment with Lucentis® (labeled as "Form-5") versus treatment with Lucentis® and a placebo formulation (labeled as "Placebo").

[0096] Figure 3A illustrates the mean change in visual acuity in a patient population through Week 36 using Formulation 5 in combination treatment with Lucentis® (labeled as "Form-5") versus treatment with Lucentis® and a placebo formulation (labeled as "Placebo").

[0097] Figure 3B illustrates the percent of the patients with a > 3-line gain in visual acuity through Week 36 using Formulation 5 in combination treatment with Lucentis® (labeled as "Form-5") versus treatment with Lucentis® and a placebo formulation (labeled as "Placebo"). DETAILED DESCRIPTION OF THE INVENTION

[0098] In view of obtained data, it appears that the topical formulations of the invention target the back of the eye. For a topical formulation to be advantageous in targeting the back of the eye, it should have the properties of being able to reach the posterior sclera of the eye in sufficient concentrations. Ideally, the formulation should have enhanced residence time on the cornea without being flushed away by tears before diffusing to the rear of the eye, such as from the anterior sclera to the posterior sclera. Because a drug molecule may adversely affect the lens of the eye, such as by clouding it, the drug molecule should not pass from the front of the eye into the orb and enter the aqueous humor and vitreous humor within the eyeball to any significant degree. The formulations of the present invention possess the desired and unique characteristics needed to effectively deliver a drug molecule, such as squalamine dilactate, which is applied to the front of the eye to the rear of the eye where the therapeutic concentrations of the drug molecule are required for treatment of the targeted disorder. The inventors unexpectedly found that the sum total of the contribution from each of the individual excipients present in the ophthalmic formulations of the invention, in unison with the inherent

physicochemical properties of the squalamine molecule itself, such as its zwitterionic characteristics, provided the highly desirable selective

bioavailability /biodistribution/tolerability profile achieved in the eye at therapeutic levels. Thus, while the conventional art may separately describe one or more of the excipients of the ophthalmic formulations of the invention as well known, there was no prior appreciation or prediction of the unique properties of the assembly of these particular excipients observed by the inventors of the ophthalmic formulations described herein.

[0099] After administration onto the surface of the eye, the composition enters the conjunctiva and anterior sclera and into the corneal layer. When present, the

mucoadhesive agent appears to increase residence time in the cornea so that the drug may diffuse slowly over time to the posterior sclera, resulting in delivery of sustained concentrations of squalamine or pharmaceutically acceptable salts thereof in the posterior sclera. The mucoadhesive agent accomplishes this objective by retarding the loss of the drug through, for example, drainage from the nasolachrimal duct due to lachrymation and tear turnover. The mucoadhesive agent also typically possesses viscosity enhancing properties that may result in a desirable soothing or lubricating effect. The penetration enhancer agent which is optionally added to the formulation enhances penetration of the formulation into the corneal epithelial layers, further enhancing the residence time of the squalamine or pharmaceutically acceptable salts thereof in the eye. The stabilizing agent may act as an antioxidant or otherwise retard the chemical degradation of the squalamine formulation. The buffering agent buffers the formulation to a comfortable near-neutral pH compatible with ocular administration. The tonicity modifier in the formulation produces the appropriate osmolality of the ophthalmic formulation.

[00100] The resulting formulations are stable, and after sterilization, may be packaged, stored and used directly. In an exemplary embodiment, the formulations are in drop form in the manner typically used to apply eye drops. The normal squeeze-type liquid drop application devices are perfectly suited for use in applying the ophthalmic formulations of the invention. In an exemplary embodiment, the formulations are conveniently administered by dropwise addition of the formulations into the affected eye(s) of the user.

[00101] The formulations of the present invention containing preservatives are especially advantageous for use in multi-dose containers. Multi-dose containers, as used herein, refer to containers which allow two or more separate applications of the ophthalmic formulation present within the container. Such containers are resealable - i.e., the container cap may be removed for a first application, and then the cap may be replaced onto the container, thereby providing a substantially liquid impermeable seal again. In various exemplary embodiments, an antimicrobial preservative is present in an amount sufficient to reduce microbial concentrations for a period of about 12 hours to about 1 month, such as about 12 hours to about 3 weeks, such as about 12 hours to about 2 weeks, such as about 12 hours to about 1 week, such as about 12 hours to about 3 days, such as about 12 hours to about 48 hours, such as about 12 hours to about 24 hours.

[00102] In an exemplary embodiment, those formulations containing no preservative are packaged in a unit dose container - i.e. , where only a single dose can be provided by a given container. Such preservative-free compositions are subject to uncontrolled microbial growth once the consumer initially breaks the container seal. Accordingly, the consumer is instructed to dispose of the container after the first dose. An appropriate unit- dose system such as blow-fill-seal unit dose preservative-free packaging system is typically used for the preservative-free formulations. [00103] Pharmaceutical compositions for the topical ophthalmic administration of the squalamine dilactate of this invention may be formulated in conventional

ophthalmologically compatible vehicles, such as, for example, an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.

[00104] As used herein, the term "ophthalmic condition" or "ophthalmic disorder" includes, but is not limited to, wet age-related macular degeneration (wet AMD), dry age- related macular degeneration (dry AMD), diabetic retinopathy, proliferative diabetic retinopathy, ischemic retinopathy (which includes retinal artery occlusion and carotid artery occlusion), cystoid macular edema, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, retinal vascular occlusive disease (which includes central and branch retinal vein occlusions), inflammatory/infectious retinal neovascularization/edema (which includes posterior uveitis, sarcoid, toxoplasmosis, histoplasmosis, Vogt- Koyanagi-Harada Disease, chronic posterior uveitis, punctate and multifocal inner choroidopathy), retinoblastoma, ocular melanoma, ocular tumors, retinal detachment, myopic neovascularization, angioid streaks, Eales disease, choroidal rupture and any combination thereof.

[00105] As used herein, the term "macular degeneration" is intended to encompass all forms of macular degeneration and includes a gradual loss of central vision usually affecting either or both eyes that occurs especially in the elderly. A slowly progressing form of macular degeneration, usually referred to as the dry form, is marked especially by the accumulation of yellow deposits in the macula lutea and the thinning of the macula lutea. A rapidly progressing form of macular degeneration, usually referred to as the wet form, is marked by scarring produced by bleeding and fluid leakage from new blood vessels formed below the macula lutea. Macular degeneration may exist as either the wet form or the dry form.

[00106] The phrase "pharmaceutically acceptable salt" as used herein, refers to any salt of a chemical compound that is safe for use in mammals. Pharmaceutically acceptable salts include salts of acidic and/or basic groups present in the chemical compound. Exemplary pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, salicylate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, gluconate, formate, benzoate, methanesulfonate, ethanesulfonate, benzensulfonate and p- toluenesulfonate. Pharmaceutically acceptable salts compounds also include quaternary ammonium salts of the formula -NRR'R"⁺Z wherein each of R, R' and R" is

independently, for example, hydrogen, alkyl or alkylaryl, and Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, p-toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate.

[00107] As defined herein, a "therapeutically effective amount" is an amount of an active agent (such as squalamine) which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount that is prophylactically effective. The amount that is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art. The concentration of squalamine dilactate will typically be about 0.01 to about 5.0 weight percent, such as about 0.01 to about 4.0 weight percent, such as about 0.02 to about 3.0 weight percent, such as about 0.03 to about 2.0 weight percent, such as about 0.05 to about 1.0 weight percent.

[00108] In various exemplary embodiments, the squalamine dilactate salt is employed at a concentration of about 0.1 to about 5% w/v, such as about 0.1 to about 4.5% w/v, such as about 0.1 to about 4.0% w/v, such as about 0.1 to about 3.5% w/v, such as about 0.1 to about 3.0% w/v, such as about 0.1 to about 2.5% w/v, such as about 0.1 to about 2.0% w/v, such as about 0.1 to about 1.5% w/v, such as about 0.1 to about 1.0% w/v, such as about 0.1 to about 0.8% w/v, such as about 0.1 to about 0.7% w/v, such as about 0.1 to about 0.6% w/v, such as about 0.1 to about 0.5% w/v, such as about 0.1 to about 0.4% w/v, such as about 0.1 to about 0.3% w/v, such as about 0.1 to about 0.2% w/v.

[00109] Optionally, the formulations of the present invention contain a tonicity modifier.

[00110] In an exemplary embodiment, the tonicity modifier is non-ionic. The tonicity modifier may be selected from, but is not limited to, mannitol, sorbitol, dextrose, sucrose, urea, glycerol, polyethylene glycol and any mixtures thereof. In an exemplary embodiment, the tonicity modifier is present in amount sufficient to generate a tonicity of about 250 to about 350 milliosmoles per kilogram (mOsmol/kg), such as about 265 to about 325 mOsmol/kg, such as about 280 to about 310 mOsmol/kg, such as about 295 to about 315 mOsmol/kg.

[00111] The formulation may also contain, an ionic salt, selected from, but not limited to, alkali metal halides (such as, for example, NaCl, KC1, NaBr, etc.), in an amount ranging from about 0.3% to about 1% weight percent or sufficient to approximate the salt concentration and/or tonicity of the human tear fluid. Selected salts from this group may also be referred to as ionic tonicity modifiers.

[00112] Where a preservative is used in the formulations of the present invention, an antimicrobial is present in an amount sufficient to generate a microbial barrier to maintain or reduce microbial concentrations for a period of about 12 hours to about 1 month, such as about 12 hours to about 3 weeks, such as about 12 hours to about 2 weeks, such as about 12 hours to about 1 week, such as about 12 hours to about 3 days, such as about 12 hours to about 48 hours, such as about 12 hours to about 24 hours. Suitable preservatives include, but are not limited to, benzalkonium chloride, benzyl alcohol, sorbic acid, chlorobutanol, cetrimonium, methylparaben, propylparaben, polyamino propyl biguanide, phenylethyl alcohol, chlorhexidine, chlorhexidine digluconate, chloroquat, stabilized oxychloro complex or any combination thereof.

[00113] Buffering agents that can be used in the formulations of the present invention include, but are not limited to, buffers prepared from sodium, potassium bicarbonate, phosphate, acetate, citrate, borate salts and/or phosphoric acid, acetic acid, citric acid or boric acid. In an exemplary embodiment, the buffer is sodium dihydrogen phosphate or disodium phosphate or boric acid/sodium borate. The buffers of the invention should be present in an amount sufficient to produce and maintain a formulation pH of about 5.0 to about 8.0, such as about 5.5 to about 7.7, such as about 6.0 to about 7.5, such as about 6.3 to about 7.5, such as about 6.7 to 7.5, such as about 6.7 to about 7.1, and including a pH of about 5.7, about 5.9, about 6.1, about 6.3, about 6.5, about 6.7, about 6.9, about 7.1, about 7.3, about 7.5, about 7.7 or about 7.9.

[00114] A surfactant may also be added to the compositions of the present invention. In an exemplary embodiment, the surfactant is present at a concentration range of about 0.001% to about 0.3%, such as about 0.005% to about 0.2%, such as about 0.01% to about 0.1%, such as about 0.05% to about 0.1% to provide enhanced wetting

characteristics to the formulation. The surfactant may include, but is not limited to, poloxamers, polysorbate 80, polysorbate 20, tyloxapol, polyoxethylene, Brij 35, Brij 58, Brij 78, Aptet 100, G 1045, Spans 20, 40 and 85, Tweens 20, 40, 80 or 81, sodium lauroyl sarcosinate, lauroyl-L-glutamic acid triethanolamine, sodium myristyl sarcosinate and sodium lauryl sulfate., poly oxy ethylene sorbitan fatty acid esters, poly oxy ethylene hydrogenated castor oil, polyethylene glycol fatty acid esters (e.g. , polyoxyl stearate), polyoxyethylene polyoxypropylene alkyl ethers, polyoxyalkylene alkyl phenyl ethers, poly glycerol fatty acids esters (e.g., decaglycerol monolaurate), glycerol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene polyoxypropylene glycol (poloxamer), polyoxyl stearate 40, and/or any combination thereof.

[00115] A stabilizer can also be added to the formulations of the present invention.

Suitable stabilizers include, but are not limited to, sodium metabisulfite, sodium bisulfate, acetylcysteine, ascorbic acid, sodium thiosulfate, alpha-tocopherol, carnosine, retinyl palmitate, salts of ethylenediaminetetraacetic acid (EDTA) (such as, for example, the disodium, tetrasodium, calcium or calcium sodium edetate salts), or any combination thereof.

[00116] The mucoadhesive agent, when present in the described formulations, increases corneal contact time, enhances bioavailability and/or produces a lubricating effect, and includes, but is not limited to acrylic acid polymers, methylcellulose, ethylcellulose, Povidone K-30, hydroxypropyl methylcellulose, hydroxyethylcellulose, Carbopol® polymers (such as, for example, Carbopol® 674, 676, 690, 980 NF, EZ-2, EZ-3, EZ-4, Aqua 30 and Novethix™ L-10), hydroxypropyl cellulose, polyvinyl alcohol, gelatin, sodium chondroitin sulfate, or any combination thereof.

[00117] The penetration enhancer optionally present in the described formulations includes, but is not limited to, laurocapram (azone), bile acids and their alkali metal salts, including chenodeoxycholic acid, cholic acid, taurocholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid or ursodeoxycholic acid, glycocholate, n-dodecyl-β-Ο- maltoside, sucrose dodecanoate, octyl maltoside, decyl maltoside, tridecyl maltoside, tetradecyl maltoside, hexamethylene lauramide, hexamethylene octanamide, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide,

methylsulfonylmethane, sodium fusidate, saponins, cyclodextrins (CDs) or any combination thereof. [00118] In addition, a solubilizing or resuspension agent may also be added to the formulations of the present invention. Suitable solubilizing or resuspension agents include, but are not limited to, cyclodextrins (CDs), such as hydroxypropyl γ-cyclodextrin (Cavasol®), sulfobutyl ether 4 β-cyclodextrin (Captisol®), and hydroxypropyl β- cyclodextrin (Kleptose®) (such as 2-hydroxypropyl β-cyclodextrin), Polysorbate 80 (Tween80^®) or hyaluronic acid or hyaluronate salts. The cyclodextrins in particular may also exhibit penetration enhancing properties, although in other instances, cyclodextrins are known to retard the uptake of steroidal compounds (such as hydrocortisone) into ocular tissues. M. Masson et al, Proc. of the 9^th Intl. Symposium on Cyclodextrins, Kluwer Academic Publishers (1999), 363-369; T. Loftsson et al, Acta Ophthalmologica Scandinavica (2003), 144-150; International Journal of Pharmaceutics 156 (1997), 201- 209.

[00119] The dilactate salt of squalamine may exist in an amorphous form or in a

crystalline form. In an exemplary embodiment of the invention, the crystalline form of the dilactate salt exists as a solvate. In another exemplary embodiment, the crystalline form exists as a hydrate, and in a further embodiment the dilactate salt exists as a solvate and a hydrate. The crystalline forms of squalamine dilactate may exist as solvates where solvent molecules are incorporated within the crystal structure. As an example, when the solvent contains ethanol, the crystal may contain ethanol molecules. In another embodiment, the solvate may contain water, and the crystal may be a hydrate containing water in the crystal structure. In another embodiment, the crystal may be both a solvate and a hydrate. A discussion of various crystalline forms of squalamine dilactate may be found in U.S. Patent No. 7,981,876, which is incorporated by reference in its entirety.

[00120] An exemplary listing of typical carriers, stabilizers and adjuvants known to those of skill in the art that may be useful in the ophthalmic compositions described herein may be found in Gennaro (2005) Remington: The Science and Practice of Pharmacy, Mack Publishing, 21^st ed.

[00121] In vivo administration of the compositions of the invention may be effected in one dose, multiple doses, continuously or intermittently throughout the course of treatment. Methods of determining the most effective dosage of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.

[00122] Various particularized and non-limiting formulations described in the examples below. These formulations are merely illustrative of the described invention and are not intended to limit the scope of the described invention.

EXAMPLES

Example 1 - Formulation 1 [00123] Formulation 1 contained the following: 0.05 to 0.25% squalamine dilactate w/v;

0.20 to 0.30% sodium phosphate dibasic heptahydrate w/v and 0.10 to 0.20% sodium phosphate monobasic dihydrate w/v;

0.15 to 0.45% glycerol w/v;

0.5 to 2.5 % Povidone K-30 w/v;

0.005 to 0.05 % edetate disodium w/v;

0.001 to 0.010 % benzalkonium chloride w/v; and

a sufficient quantity of water for injection or purified water USP.

The pH = 6.5 to 7.5 and the osmolality = 260 to 340 mOsm/kg.

[00124] A particular embodiment of Formulation 1 contained 0.2% squalamine dilactate w/v; 027% sodium phosphate dibasic heptahydrate w/v and 0.13% sodium phosphate monobasic dihydrate w/v; 0.3% glycerol w/v; 1.4% Povidone K-30 w/v; 0.01% edetate disodium w/v; 0.005% benzalkonium chloride w/v; and a sufficient quantity of water for injection or purified water USP. The pH = 6.8 and the osmolality = 280 mOsm/kg.

[00125] Preparation of Formulation 1. Approximately 50 mL of purified water was placed in a 250 mL graduated glass beaker with a stir bar. 0.27 g of sodium phosphate heptahydrate was added to the beaker and stirred until it dissolved. 0.13 g of sodium phosphate monobasic monohydrate was added to the beaker and stirred until it dissolved. 0.005 g of benzalkonium chloride was added to the beaker and stirred until it dissolved. 0.01 g of disodium EDTA was added to the beaker and stirred until it dissolved. 0.3 g of glycerol was added to the beaker and stirred until it dissolved. 1.4 g of Povidone K-30 was added to the beaker and stirred until it dissolved. 0.200 g of squalamine dilactate was added to the beaker and stirred until it dissolved. Approximately 40 mL of purified sterile water was added to the beaker and the pH was adjusted to 6.8 using 2 N NaOH and 1 N HC1 (as needed). The volume was made up to 100 mL with a sufficient quantity of water for injection or purified water USP. The solution was sterile filtered through a 0.22 micron filter before use.

Example 2 - Formulation 2

[00126] Formulation 2 contained the following:

0.05 to 0.25% squalamine dilactate w/v;

1.0 to 1.5% boric acid w/v and 0.10 to 0.15% sodium borate w/v;

0.1 to 1.0 % sodium carboxymethylcellulose w/v;

0.2 to 1.5% 2-hydroxypropyl- -cyclodextrin w/v;

0.3 to 1.5% sodium chloride w/v;

0.03 to 0.15 % benzalkonium chloride w/v; and

purified water qs.

The pH = 7.3 and the osmolality = 310 mOsm/kg.

[00127] A particular embodiment of Formulation 2 contained 0.2% squalamine dilactate w/v; 1.18% boric acid w/v; 0.12% sodium borate w/v; 0.4% sodium

carboxymethylcellulose w/v; 0.9% 2-hydroxypropyl- -cyclodextrin w/v; 0.85% sodium chloride w/v; 0.08% benzalkonium chloride w/v; and purified water qs. The pH = 7.3 and the osmolality = 310 mOsm/kg.

[00128] Preparation of Formulation 2. Approximately 50 mL of purified water was placed in a 250 mL graduated glass beaker with a stir bar. 1.18 g of boric acid and 0.12 g of sodium borate were added to the beaker and stirred until they dissolved. 0.85 g of sodium chloride was added to the beaker and stirred until it dissolved. 0.4 g of sodium

carboxymethylcellulose was added to the beaker and stirred until it dissolved. 0.08 g of benzalkonium chloride was added to the beaker and stirred until it dissolved. 0.200 g of squalamine dilactate was added to the beaker and stirred until it dissolved. 0.9 g of hydroxypropyl- -cyclodextrin was added to the beaker and stirred until it dissolved. Approximately 40 mL of purified sterile water was added to the beaker and the pH was adjusted to 7.3 using 2 N NaOH and 1 N HC1 (as needed). The volume was made up to 100 mL and the solution was filtered using a sterile filtration assembly using a 0.22 micron filter.

Example 3 - Formulation 3 [00129] Formulation 3 contained the following: 0.05 to 0.25% squalamine dilactate w/v;

0.5 to 1.5% boric acid w/v and 0.05 to 0.30% sodium borate w/v;

0.005 to 0.03% edetate disodium w/v;

0.5 to 3.0 % glycerol w/v;

0.20 to 1.0% propylene glycol w/v;

0.3 to 2.0% hypromellose w/v;

0.005 to 0.3% sorbic acid w/v; and

a sufficient quantity of water for injection or purified water USP.

The pH = 6.5 to 7.5 and the osmolality = 280 to 340 mOsm/kg.

[00130] A particular embodiment of Formulation 3 contained 0.2% squalamine dilactate w/v; 1.15% boric acid w/v; 0.13% sodium borate w/v; 0.01 % edetate disodium w/v; 1.0% glycerol w/v; 0.45% propylene glycol w/v; 0.7% hypromellose w/v; 0.1 % sorbic acid w/v; and a sufficient quantity of water for injection or purified water USP.

[00131] Preparation of Formulation 3. Approximately 50 mL of purified water was placed in a 250 mL graduated glass beaker with a stir bar. 1.15 g of boric acid and 0.13 g of sodium borate were added to the beaker and stirred until they dissolved. 1.0 g of glycerol was added to the beaker and stirred until it dissolved. 0.45 g of propylene glycol was added to the beaker and stirred until it dissolved. 0.1 g of disodium EDTA was added to the beaker and stirred until it dissolved. 0.700 g of hypromellose was added to the beaker and stirred until it dissolved. 0.200 g of squalamine dilactate was added to the beaker and stirred until it dissolved. 0.1 g of sorbic acid was added to the beaker and stirred until it dissolved. Approximately 40 mL of purified sterile water was added to the beaker and the pH was adjusted to 7.4 using 2 N NaOH and 1 N HCl (as needed). The volume was made up to 100 mL and the solution was filtered using a sterile filtration assembly using a 0.22 micron filter.

Example 4 - Formulation 4 [00132] Formulation 4 contained the following: 0.05 to 0.25% squalamine dilactate w/v;

0.5 to 1.5% boric acid w/v and 0.05 to 0.5% sodium borate w/v;

0.5 to 2.0% NaCl w/v;

2.5 to 4.0% sorbitol w/v;

0.2 to 1.5% propylene glycol w/v;

0.2 to 1.5% polyoxol 40 hydrogenated castor oil w/v;

0.01 to 0.1 % n-dodecyl- -D-glycoside w/v;

0.001 to 0.01% benzalkonium chloride w/v; and

a sufficient quantity of water for injection or purified water USP.

The pH = 6.5 to 7.5 and the osmolality = 250 to 340 mOsm/kg.

[00133] A particular embodiment of Formulation 4 contained 0.2% squalamine dilactate w/v; 1.18% boric acid w/v; 0.12% sodium borate w/v; 0.75% NaCl w/v; 3.5% sorbitol w/v; 0.45% propylene glycol w/v; 0.5% polyoxol 40 hydrogenated castor oil w/v; 0.05% n-dodecyl- -D-glycoside w/v; 0.005% benzalkonium chloride w/v; and a sufficient quantity of water for injection or purified water USP. The pH = 6.9 and the osmolality = 305 mOsm/kg.

[00134] Preparation of Formulation 4. Approximately 50 mL of purified water was placed in a 250 mL graduated glass beaker with a stir bar. 1.18 g of boric acid and 0.12 g of sodium borate were added to the beaker and stirred until they dissolved. 0.5 g of polyoxol 40 hydrogenated castor oil was added to the beaker and stirred until it dissolved. 0.4 g of propylene glycol was added to the beaker and stirred until it dissolved. 0.3 g of sorbitol was added to the beaker and stirred until it dissolved. 0.05 g of n-dodecyl- -D-glycoside was added to the beaker and stirred until it dissolved. 0.200 g of squalamine dilactate was added to the beaker and stirred until it dissolved. 0.005 g of benzalkonium chloride was added to the beaker and stirred until it dissolved. Approximately 40 mL of purified sterile water was added to the beaker and the pH was adjusted to 6.9 using 2 N NaOH and 1 N HCl (as needed). The volume was made up to 100 mL and the solution was filtered using a sterile filtration assembly using a 0.22 micron filter.

Example 5 - Formulation 5

[00135] Formulation 5 contained the following: 0.05 to 0.25% squalamine dilactate w/v;

0.8 to 1.4% Povidone K-30 w/v;

0.005 to 0.05% edetate disodium w/v;

0.3 to 1.5% sodium chloride w/v;

0.001 to 0.01% benzalkonium chloride w/v;

0.5 to 2.0% 2-hydroxypropyl- -cyclodextrin w/v; and

purified water qs.

The pH = 6.5 to 7.5 or 6.7 to 7.1 and the osmolality = 280 to 340 mOsm/kg.

[00136] A particular embodiment of Formulation 5 contained 0.2% squalamine dilactate w/v; 0.27% sodium phosphate heptahydrate w/v; 0.06% sodium phosphate monobasic monohydrate w/v; 1.2% Povidone K-30 w/v; 0.01% edetate disodium w/v; 0.80% sodium chloride w/v; 0.005% benzalkonium chloride w/v; 1.0% 2-hydroxypropyl- -cyclodextrin w/v; and purified water qs. The pH = 6.70 and the osmolality = 315 mOsm/kg.

[00137] Preparation of Formulation 5. Approximately 50 mL of purified water was placed in a 250 mL graduated glass beaker with a stir bar. 0.27 g of sodium phosphate heptahydrate was added to the beaker and stirred until it dissolved. 0.06 g of sodium phosphate monobasic monohydrate was added to the beaker and stirred until it dissolved. 0.005 g of benzalkonium chloride was added to the beaker and stirred until it dissolved. 0.01 g of disodium EDTA was added to the beaker and stirred until it dissolved. 0.8 g of sodium chloride was added to the beaker and stirred until it dissolved. 1.2 g of Povidone K-30 was added to the beaker and stirred until it dissolved. 1.0 g of 2-hydroxypropyl- - cyclodextrin was added to the beaker and stirred until it dissolved. 0.200 g of squalamine dilactate was added to the beaker and stirred until it dissolved. Approximately 40 mL of purified sterile water was added to the beaker and the pH was adjusted to 6.7 using 2 N NaOH and 1 N HC1 (as needed). The volume was made up to 100 mL with sufficient quantity of water for injection or purified water USP. The solution was sterile filtered through 0.22 micron filter before use.

Example 6 - Formulation 6

[00138] Formulation 6 contained the following: 0.2% squalamine dilactate;

0.188% sodium phosphate heptahydrate w/v and 0.1% sodium phosphate monobasic monohydrate w/v;

1.2% Povidone K-30 w/v;

0.01% edetate disodium;

0.005% benzalkonium chloride w/v;

1.0% 2-hydroxypropyl- -cyclodextrin w/v; and

purified water qs.

The pH = 6.70 and the osmolality = 315 mOsm/kg.

[00139] Preparation of Formulation 6. This formulation was prepared in a manner similar to that of Formulation 5.

Example 7 - Pre-clinical Testing of Formulation 6 - Biodistribution Study

[00140] Male Dutch belted rabbits (n=24) were administered Formulation 6 eye drops (40 μί) bilaterally, either QD (every 24 hours) or BID (every 12 hours) for 1, 7, and 14 days (n=4/group/dose). Animals were necropsied and ocular tissues were harvested 24 (±2) or 12(±1) hours post last dosing in the QD or BID groups, respectively. Posterior sclera/choroid, aqueous and vitreous humors, and plasma were assayed for squalamine concentrations using a validated LC-MS/MS method with a lower limit of quantification (LLOQ) of lOng/g of tissue. Values below the LLOQ are reported as below quantifiable limits, or BQL. The ocular toxicity and irritation of the formulation were also evaluated through clinical observations and slit lamp ophthalmoscopy. The result was that the Formulation 6 eye drops, given QD or BID, were well tolerated with no adverse clinical effects. Given QD, the mean concentrations of squalamine in the posterior sclera/choroid were 9.5, 21.9, and 39.8 ng/g in the 1, 7, and 14 day groups, respectively (Figure 1, lower curve). Given BID, the mean concentrations of squalamine in the posterior sclera/choroid were 21.7, 62.6, and 68 ng/g in the 1, 7, and 14 day groups, respectively (Figure 1, upper curve). Values represent levels at one full dosing interval after last administration (QD 24(+2) hours, BID 12(+1) hours). Both QD and BID values demonstrate levels of squalamine in the posterior sclera/choroid well above the threshold level to inhibit tissue angiogenesis (approximately 11 ng/g). In contrast, squalamine concentrations in aqueous and vitreous humors were <LLOQ (10 ng/mL) in all animals and <LLOQ in plasma in 23/24 animals (Table 1). [00141] Table 1

BQL = Below Quantitation Limits (10 ng/g in tissue; 10 ng/mL in plasma)

[00142] The Formulation 6 eye drops proved innocuous and produced no discernible changes in ophthalmological slit lamp ocular examinations.

Example 8 - Clinical Testing of Formulation 5

[00143] The clinical study described below used the following embodiment of

Formulation 5: 0.2% squalamine dilactate w/v; 0.27% sodium phosphate heptahydrate w/v and 0.06% sodium phosphate monobasic monohydrate w/v; 1.2% Povidone K-30 w/v; 0.01% edetate disodium w/v; 0.80% sodium chloride w/v; 0.005% benzalkonium chloride w/v; 1.0% 2-hydroxypropyl- -cyclodextrin w/v; and purified water qs. pH 6.7 to 7.1.

[00144] The study described below represent a nine-month Phase II clinical trial

evaluation of the safety and efficacy of Formulation 5 for the treatment of wet- AMD. The two treatment arms were Formulation 5 drops administered twice daily plus Lucentis® ("Formulation 5" arm or group, labeled as "Form-5" in the figures) versus placebo eye drops administered twice daily plus Lucentis® ("Lucentis® monotherapy" arm or group, labeled as "Placebo" in the figures). All patients in the study received an initial Lucentis® injection. 142 patients were randomized into the study, with 90% of the patients completing the nine month treatment protocol. Formulation 5 was generally well tolerated, with only two treatment related discontinuations in the study.

[00145] Visual acuity outcomes for patients completing a nine-month treatment period (in a modified intent-to-treat or mITT population) were analyzed. In the mITT population with lesions containing classic choroidal neovascularization (CNV) (classic containing lesions) (Formulation 5, n=37; Lucentis® monotherapy, n=28), mean gains in visual acuity at month nine were +11 letters for the OHR-102 combination arm and +5 letters with Lucentis® monotherapy, a clinically meaningful benefit of 6 letters (Figure 2A). In addition, 44% of the patients receiving Formulation 5 combination therapy achieved a >3 line vision gain at nine months, as compared to 28% in the Lucentis® monotherapy group (Figure 2B). This positive effect on visual acuity in classic containing lesions was observed early in the course of treatment and continued to increase through the end of the study. The classic-containing CNV population represents approximately two thirds of the total wet- AMD patient population.

[00146] The mITT data in classic-containing lesions also showed a more pronounced separation between the Formulation 5 and Lucentis® monotherapy groups for those patients who achieved >4 and >5 line vision gains. Of the patients receiving Formulation 5, 22% achieved a >4 line gain and 17% achieved >5 line gains at nine months, as compared to 7% with a >4 line gain and 7% with a >5 line gain for those who received Lucentis® monotherapy (Figure 2C).

[00147] Data for patients with classic-containing lesions in the intent-to-treat (ITT-LOCF) population (Formulation 5, n=38; Lucentis® monotherapy, n=32) was analyzed. In this group, the mean gains in visual acuity were +10.5 letters for the Formulation 5 combination arm and +5.4 letters with Lucentis® monotherapy, a clinically meaningful benefit of +5.1 letters (Figure 3A). In addition, 31% of the patients receiving Formulation 5 achieved a >3 line gain at nine months, as compared to 25% in the Lucentis® monotherapy group (Figure 3B).

[00148] All patents/publications cited herein are incorporated by reference in their entireties.

Claims

WHAT IS CLAIMED IS:

An ophthalmic composition, comprising:

0.05 to 0.25% squalamine dilactate w/v;

0.5 to 1.5% boric acid w/v and 0.05 to 0.30% sodium borate

0.005 to 0.03% edetate disodium w/v;

0.5 to 3.0 % glycerol w/v;

0.20 to 1.0% propylene glycol w/v;

0.3 to 2.0% hypromellose w/v;

0.005 to 0.3% sorbic acid w/v; and

water.

2. An ophthalmic composition, comprising:

0.05 to 0.25% squalamine dilactate w/v;

0.8 to 1.4% Povidone K-30 w/v;

0.005 to 0.05% edetate disodium w/v;

0.3 to 1.5% sodium chloride w/v;

0.001 to 0.01% benzalkonium chloride w/v;

0.5 to 2.0% 2-hydroxypropyl^-cyclodextrin w/v; and

water.

3. An ophthalmic composition, consisting of: 0.05 to 0.25% squalamine dilactate w/v;

0.5 to 1.5% boric acid w/v and 0.05 to 0.30% sodium borate w/v;

0.005 to 0.03% edetate disodium w/v;

0.5 to 3.0 % glycerol w/v;

0.20 to 1.0% propylene glycol w/v;

0.3 to 2.0% hypromellose w/v;

0.005 to 0.3% sorbic acid w/v; and

water.

4. An ophthalmic composition, consisting of:

0.05 to 0.25% squalamine dilactate w/v;

0.8 to 1.4% Povidone K-30 w/v;

0.005 to 0.05% edetate disodium w/v;

0.3 to 1.5% sodium chloride w/v;

0.001 to 0.01% benzalkonium chloride w/v;

0.5 to 2.0% 2-hydroxypropyl- -cyclodextrin w/v; and

water.

5. The composition according to claim 1, wherein the composition is suitable for topical administration to the eye of a mammal in need thereof.

6. The composition according to claim 2, wherein the composition is suitable for topical administration to the eye of a mammal in need thereof.

7. The composition according to claim 3, wherein the composition is suitable for topical administration to the eye of a mammal in need thereof.

8. The composition according to claim 4, wherein the composition is suitable for topical administration to the eye of a mammal in need thereof.

9. The composition according to any one of claims 1 to 4, wherein the composition is in the form of eye drops.

10. The composition according to any one of claims 5 to 8, wherein the composition is selectively present after administration in the posterior sclera and choroid of the eye of the mammal.

1 1. The composition according to any one of claims 5 to 8, wherein the mammal suffers from an ophthalmic condition.

12. The composition according to claim 1 1, where the ophthalmic condition is selected from the group consisting of wet age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, proliferative diabetic retinopathy, ischemic retinopathy, cystoid macular edema, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, retinal vascular occlusive disease, inflammatory/infectious retinal neovascularization/edema, retinoblastoma, ocular melanoma, ocular tumors, retinal detachment, myopic neovascularization, angioid streaks, Eales disease, choroidal rupture and any combination thereof.

13. The composition according to claim 1 1, wherein the ophthalmic condition is wet AMD.

14. The composition according to any one of claims 5 to 8, wherein the mammal is a human.

15. A method of selectively delivering squalamine or a pharmaceutically acceptable salt thereof to the posterior sclera and choroid of the eye(s) of a mammal in need thereof in an amount therapeutically effective to treat an ophthalmic condition, the method comprising:

administering to the eye(s) of the mammal the composition of any one of claims 1 to 4.

16. The method according to claim 15, wherein the ophthalmic condition is selected from the group consisting of wet age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, proliferative diabetic retinopathy, ischemic retinopathy, cystoid macular edema, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, retinal vascular occlusive disease, inflammatory/infectious retinal neovascularization/edema, retinoblastoma, ocular melanoma, ocular tumors, retinal detachment, myopic neovascularization, angioid streaks, Eales disease, choroidal rupture and any combination thereof.

17. The method according to claim 15, wherein the ophthalmic condition is wet age- related macular degeneration (wet AMD).

18. The method according to claim 15, wherein the composition is administered to the eye(s) topically.

19. The method according to claim 15, wherein the mammal is a human.