# US 12,766,096 B2 · High concentration pharmaceutical compositions of roflumilast for ophthalmic delivery

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- Number: US 12,766,096 B2
- Document ID: US12766096B2
- Status: Granted
- Kind: B2
- Application number: 18/368,832
- Filed: 2023-09-15
- Published: 2024-04-11
- Granted: 2026-10-20
- Earliest claimed: 2022-09-16
- Assignees: Iolyx Therapeutics, Inc.
- Applicants: lolyx Therapeutics, Inc.
- Inventors: Richard Graham; Elizabeth W. Jeffords; Hovhannes J. Gukasyan; Shannon Dahl
- Web page: https://patentgrep.com/patent/US12766096B2

## CPC

- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/38: Cellulose; Derivatives thereof
- 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)

## Abstract

The present invention relates to high concentration ophthalmic pharmaceutical formulations of the phosphodiesterase-4 inhibitor, roflumilast, which are suitable for intravitreal or other ocular administration to injection sites internal or external to the eye and orbit. The compositions can comprise about 2% to about 5% w/v of roflumilast, a viscosity agent, a tonicity agent, a buffer agent, a surfactant, and water. The pharmaceutical compositions are stable with little to no impurities and can be injected from a 27 Gauge or 30 Gauge syringe with minimal force, resulting in therapeutic levels of pharmaceutical in relevant tissues for the ocular surface, anterior compartment, vitreous/posterior compartments, and tissues or chambers surrounding the eye.

## Claims

### Claim 1

A high concentration ophthalmic pharmaceutical composition comprising:
about 2% to about 5% w/v of roflumilast;
a viscosity agent selected from the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone, or sodium carboxymethyl cellulose;
a tonicity agent comprising sodium chloride;
a surfactant;
a buffer; and
water,
wherein the ophthalmic pharmaceutical composition is suitable for intravitreal administration into the eye.

### Claim 2 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the viscosity agent is sodium carboxymethyl cellulose.

### Claim 3 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the buffer is sodium acetate and sodium citrate.

### Claim 4 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the surfactant is a polysorbate.

### Claim 5 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the pH of the composition is between 5.5 and 7.5.

### Claim 6 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical formulation does not include any preservatives or anti-microbial agents.

### Claim 7 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a particle size distribution characterized by a d90 value of less than or equal to about 15 μm.

### Claim 8 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the pharmaceutical composition is capable of being injected from a 30G syringe needle with a force of less than about 3.50 N from a 30G needle.

### Claim 9 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the pharmaceutical composition is capable of being injected from a 27G syringe needle with a force of less than about 3.00 N.

### Claim 10 (depends on 1)

The ophthalmic pharmaceutical composition of claim 1, wherein the pharmaceutical composition has been subjected to terminal sterilization by gamma irradiation or dry heat sterilization to achieve less than about 0.2% impurities.

### Claim 11

A high concentration ophthalmic pharmaceutical composition comprising:
about 2% to about 5% w/v of roflumilast;
about 0.2% to about 0.8% w/v of sodium carboxymethyl cellulose;
about 0.2% to about 0.8% w/v of sodium chloride;
about 0.02% to about 0.25% w/v of polysorbate 20;
about 0.005% to about 0.20% w/v of potassium chloride;
about 0.005% to about 0.20% w/v of calcium chloride;
about 0.005% to about 0.20% w/v of magnesium chloride;
about 0.005% to about 0.20% w/v of sodium acetate;
about 0.005% to about 0.20% w/v of sodium citrate; and
water,
wherein the pH of the composition is between 5.5 and 7.5, and
wherein the ophthalmic pharmaceutical composition is suitable for intravitreal administration into the eye.

### Claim 12 (depends on 11)

The ophthalmic pharmaceutical composition of claim 11, wherein the pharmaceutical composition has a particle size distribution characterized by a d90 value of less than or equal to about 15 μm.

### Claim 13 (depends on 11)

The ophthalmic pharmaceutical composition of claim 11, wherein the pharmaceutical composition is capable of being injected from a 30G syringe needle with a force of less than about 3.50 N from a 30G needle.

### Claim 14 (depends on 11)

The ophthalmic pharmaceutical composition of claim 11, wherein the pharmaceutical composition is capable of being injected from a 27G syringe needle with a force of less than about 3.00 N.

### Claim 15 (depends on 11)

The ophthalmic pharmaceutical composition of claim 11, wherein the pharmaceutical composition has been subjected to terminal sterilization by gamma irradiation or dry heat sterilization to achieve less than about 0.2% impurities.

### Claim 16

A method for treating an eye disorder in a patient comprising:
injecting a high concentration ophthalmic pharmaceutical composition of roflumilast into the eye of the patient,
wherein the pharmaceutical composition comprises about 2% to about 5% w/v of roflumilast; a viscosity agent; a tonicity agent; a buffer agent; a surfactant; and water;
wherein the ophthalmic pharmaceutical composition is suitable for intravitreal administration.

### Claim 17 (depends on 16)

The method of claim 16, wherein the eye disorder is selected from the group consisting of anterior, posterior, pan or intermediate uveitis, uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behcets disease, ankylosing spondylitis, Vogt-Koyanagi-Harada disease (VKH), or autoimmune disease, ocular graft vs host disease, Stevens-Johnson syndrome/toxic epidermal necrolysis, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, age-related macular degeneration (AMD) including dry, geographic atrophy, or exudative AMD, choroidal neovascularization, retinal vasculitis (drug related/iatrogenic, non-infectious/sterile, or idiopathic), choroidal thickening associated with thyroid eye disease, Coats' disease, central serous retinopathy or chorioretinopathy, sterile or infectious endopthalmitis, retinitis, choroiditis, anterior or posterior sclertis/episcleritis, endothelial keratitis (bacterial, viral, fungal, or non-infectious in nature), and other inflammatory diseases of the anterior and posterior tissues of the eye or ocular complications of other inflammatory or autoimmune diseases, inflammation associated with inherited retinal diseases, retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Leber hereditary optic neuropathy, Usher syndrome, X-linked retinoschisis, choroidemia, zonal occult outer retinopathy, myopia, vitreomacular adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal rupture, choroidal folds, proliferative vitreoretinopathy, idiopathic ischemia, achromatopsia, retinopathy of prematurity, gyrate atrophy, central areolar choroidal dystrophy, punctate inner choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroidopathy, birdshot retinochoroidopathy, multiple evanescent white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma, iatrogenic posterior and vitreous chamber inflammation.

### Claim 18 (depends on 16)

The method of claim 16, wherein the pharmaceutical composition results in a well tolerated delivery and use.

### Claim 19 (depends on 17)

The method of claim 17, wherein the pharmaceutical composition delivers a therapeutic level of roflumilast to one or more of the cornea, limbus, conjunctiva, eyelids, lacrimal and Meibomian glands, lens, pupil, iris, anterior sclera, ciliary body, lacrimal glands, aqueous humor, the internal or endothelial or inner layer of the cornea, lacrimal glands, lymph nodes, posterior sclera, retina, choroid, macula, fovea, optic disc, optic nerve, vitreous humor, hyaloid canal, or extraorbital or periorbital tissues and muscle/connective tissues.