# US 10,307,404 B1 · Ocular formulations for drug-delivery to the posterior segment of the eye

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- Number: US 10,307,404 B1
- Document ID: US10307404B1
- Status: Granted
- Kind: B1
- Application number: 16/042,003
- Filed: 2018-07-23
- Published: 2019-06-20
- Granted: 2019-06-04
- Earliest claimed: 2013-03-14
- Assignees: PanOptica, Inc.
- Applicants: PanOptica, Inc.
- Inventors: David P. Bingaman; Paul G. Chaney; Martin B. Wax
- Web page: https://patentgrep.com/patent/US10307404B1

## CPC

- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/186: {Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide}
- A61K 47/40: Cyclodextrins; Derivatives thereof
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to topical formulations comprising a compound of the following formula: for treating ocular neovascularization. The Compound-I is present in a solution or a suspension in about 0.005% to about 5.0% w/v, such that the solution or suspension delivers the compound at the posterior segment of the eye for inhibiting VEGF in the retina and/or the choroid.

## Claims

### Claim 1

A topical, ocular suspension formulation, comprising:
a. solid particles of an active agent of Formula II:
or a pharmaceutically acceptable salt thereof, and
b. pharmaceutically acceptable excipients;
wherein the active agent or the pharmaceutically acceptable salt is present in about 0.005% to about 5.0% w/v.

### Claim 2 (depends on 1)

The formulation of claim 1, further comprising a solubilizing agent.

### Claim 3 (depends on 2)

The formulation of claim 2, wherein the solubilizing agent is cyclodextrin selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, trimethyl-γ-cyclodextrin, and combinations thereof.

### Claim 4 (depends on 1)

The formulation of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt provided by the formula:

### Claim 5 (depends on 3)

The formulation of claim 3, wherein the solubilizing agent is 2-hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutyl ether.

### Claim 6 (depends on 1)

The formulation of claim 1, comprising about 0.005%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, or about 5.0% w/v of the active agent or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The formulation of claim 1, further comprising one or more of benzalkonium chloride (BAK), sodium chloride, and a pH adjusting agent.

### Claim 8 (depends on 1)

The formulation of claim 1, comprising about 0.005%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, or about 5.0% w/v of the active agent or a pharmaceutically acceptable salt thereof, and about 0.3%-about 1% w/v tromethamine.

### Claim 9 (depends on 1)

The formulation of claim 1, comprising about 0.005%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, or about 5.0% w/v of the active agent or a pharmaceutically acceptable salt thereof, about 0.3%-about 1% w/v tromethamine, and about 0.005% w/v benzalkonium chloride (BAK).

### Claim 10 (depends on 1)

The formulation of claim 1, having a pH value of about 4.5 to about 7.5 at or under about 40° C.

### Claim 11 (depends on 1)

The formulation of claim 1, having a pH value of about 6.0 at or under about 40° C.

### Claim 12 (depends on 1)

The formulation of claim 1, having a pH value of about 5.0 to about 7.0 at or under about 40° C.

### Claim 13 (depends on 1)

The formulation of claim 1, wherein the formulation is suitable for accessing posterior segment of the eye and/or for treating and/or ameliorating ocular neovascularization.

### Claim 14 (depends on 1)

A method for treating and/or ameliorating a posterior segment disease of the eye, comprising administering to a subject in need thereof the formulation of claim 1, wherein the disease is selected from the group consisting of: diabetic retinopathy, age-related macular degeneration (AMD), pathologic choroidal neovascularization (CNV), pathologic retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, Coat's disease, sickle cell retinopathy, and neovascular glaucoma.

### Claim 15 (depends on 14)

The method of claim 14, wherein the diabetic retinopathy is background diabetic retinopathy, proliferative diabetic retinopathy,
or diabetic macular edema.

### Claim 16 (depends on 14)

The method of claim 14, wherein the AMD is neovascular AMD, dry AMD, or Geographic Atrophy.

### Claim 17 (depends on 16)

The method of claim 16, wherein the neovascular AMD is wet or exudative AMD.

### Claim 18 (depends on 14)

The method of claim 14, wherein the CNV is related to high myopia, trauma, sickle cell disease, ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, drusen of the optic nerve, or retinal dystrophies.

### Claim 19 (depends on 14)

The method of claim 14, wherein the pathologic retinal neovascularization is related to sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteriolitis, birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis.

### Claim 20 (depends on 14)

The method of claim 14, wherein retinal vein occlusion is central or branch occlusion.

### Claim 21 (depends on 1)

The formulation of claim 1, wherein the pharmaceutically acceptable excipient is selected from hydroxy propyl methyl cellulose (HPMC) and carboxylmethyl cellulose and salts thereof.

### Claim 22 (depends on 1)

The formulation of claim 1, further comprising a nonionic liquid polymer of the alkyl aryl polyether alcohol type.

### Claim 23 (depends on 22)

The formulation of claim 22, wherein the nonionic liquid polymer of the alkyl aryl polyether alcohol type is tyloxapol.

### Claim 24 (depends on 1)

The formulation of claim 1, further comprising a hydrophilic non-ionic surfactant.

### Claim 25 (depends on 24)

The formulation of claim 24, wherein the hydrophilic non-ionic surfactant is poloxamer.

### Claim 26 (depends on 25)

The formulation of claim 25, wherein the poloxamer is poloxamer 407.

### Claim 27

A topical, ocular, suspension formulation, comprising:
solid particles of an active agent of Formula II:
or a pharmaceutically acceptable salt thereof,
pharmaceutically acceptable excipients selected from hydroxy propyl methyl cellulose (HPMC) and carboxylmethyl cellulose and salts thereof, and
a nonionic liquid polymer of the alkyl aryl polyether alcohol type,
wherein the active agent or the pharmaceutically acceptable salt is present in about 0.005% to about 5.0% w/v.

### Claim 28 (depends on 27)

The formulation of claim 27, wherein the active agent is present in about 0.1% to about 2.0% w/v.

### Claim 29 (depends on 27)

The formulation of claim 27, wherein the pharmaceutically acceptable salt is a hydrochloride salt of the formula:

### Claim 30 (depends on 27)

The formulation of claim 27, wherein the nonionic liquid polymer of the alkyl aryl polyether alcohol type is tyloxapol.

### Claim 31 (depends on 27)

The formulation of claim 27, further comprising a hydrophilic non-ionic surfactant.

### Claim 32 (depends on 31)

The formulation of claim 31, wherein the hydrophilic non-ionic surfactant is poloxamer.

### Claim 33 (depends on 32)

The formulation of claim 32, wherein the poloxamer is poloxamer 407.

### Claim 34

A topical, ocular, suspension formulation, comprising:
solid particles of an active agent of Formula II:
or a pharmaceutically acceptable salt thereof,
pharmaceutically acceptable excipients selected from hydroxy propyl methyl cellulose (HPMC) and carboxylmethyl cellulose and salts thereof, and
about 0.3%-1% w/v tromethamine,
about 2% glycerin,
tyloxapol, and
poloxamer,
wherein the active agent or the pharmaceutically acceptable salt is present in about 0.005% to about 5.0% w/v.

### Claim 35 (depends on 34)

The formulation of claim 34, wherein the active agent is present in about 0.1% to about 2.0% w/v.

### Claim 36 (depends on 34)

The formulation of claim 34, wherein the pharmaceutically acceptable salt is a hydrochloride salt of the formula:

### Claim 37 (depends on 34)

The formulation of claim 34, wherein the poloxamer is poloxamer 407.