# US 2024/0197740 A1 · Methotrexate treatment methods

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- Number: US 2024/0197740 A1
- Document ID: US20240197740A1
- Status: Published application
- Kind: A1
- Application number: 18/391,167
- Filed: 2023-12-20
- Published: 2024-06-20
- Earliest claimed: 2022-12-14
- Assignees: Aldeyra Therapeutics, Inc.
- Applicants: Aldeyra Therapeutics, Inc.
- Inventors: Stephen Gitu MACHATHA; Dean Eliott; Tomasz Stryjewski
- Web page: https://patentgrep.com/patent/US20240197740A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- 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 9/0048: {Eye, e.g. artificial tears}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- 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
- A61P 27/02: Ophthalmic agents
- 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 disclosure provides compositions of methotrexate for ocular administration, including intravitreal administration, and use of the formulations for treating proliferative vitreoretinopathy (PVR), uveitis, macular edema, and uveitic macular edema.

## Claims

### Claim 1

A method of treating proliferative vitreoretinopathy (PVR), comprising administering intravitreally to a subject in need thereof a composition comprising methotrexate at a concentration of about 5 mg/mL to about 12 mg/mL; sucrose at a concentration of about 7% w/v to about 12% w/v; and a phosphate buffer; wherein the volume of composition administered is about 20 μL to about 300 μL, and the incidence of secondary punctate keratitis in the subject is reduced.

### Claim 2 (depends on 1)

The method of claim 1, wherein the incidence of secondary punctate keratitis in the subject is reduced by about 10% to 50% compared to a similar subject administered a non-GMP composition of methotrexate or a composition comprising methotrexate in a volume greater than 300 μL.

### Claim 3 (depends on 1)

The method of claim 1, wherein the incidence of secondary punctate keratitis in the subject is reduced by about 20% to 40% compared to a similar subject administered a non-GMP composition of methotrexate or a composition comprising methotrexate in a volume greater than 300 μL.

### Claim 4 (depends on 1)

The method of claim 1, wherein the incidence of secondary punctate keratitis in the subject is reduced by about 40% compared to a similar subject administered a non-GMP composition of methotrexate or a composition comprising methotrexate in a volume greater than 300 μL, wherein the method produces a statistically significant (p<0.05) reduction in incidence of punctate keratitis across a representative group of subjects.

### Claim 5

(canceled)

### Claim 6 (depends on 5)

The method of claim 5, wherein the volume of composition administered is about 20 μL to about 80 μL.

### Claim 7 (depends on 5)

The method of claim 5, wherein the volume of composition administered is about 50 μL±10 μL.

### Claim 8 (depends on 1)

The method of claim 1, wherein the method provides an improved incidence of intraocular pressure (IOP) elevation (hypotony) compared to a similar subject administered a non-GMP composition of methotrexate or a composition comprising methotrexate in a volume greater than 300 μL.

### Claim 9 (depends on 1)

The method of claim 1, wherein the method provides a reduced incidence of retinal re-detachments due to PVR requiring re-operation within 6 months vs. routine surgical care.

### Claim 10 (depends on 1)

The method of claim 1, wherein the composition has a transit rate of less than 10 min in 1 mL of silicone oil (SiO) having a viscosity of at least 1000 centistoke and depth of 1 cm.

### Claim 11 (depends on 10)

The method of claim 10, wherein the transit rate is less than 8 min.

### Claim 12 (depends on 11)

The method of claim 11, wherein the SiO is polydimethyl siloxane 5000 centistoke oil or polydimethyl siloxane 1000 centistoke oil.

### Claim 13 (depends on 1)

The method of claim 1, wherein the methotrexate is at a concentration of about 7 mg/mL to about 9 mg/mL.

### Claim 14 (depends on 1)

The method of claim 1, wherein the composition has a density of about 1.0 to about 1.20 g/cm3 at 20° C.

### Claim 15 (depends on 13)

The method of claim 13, wherein the sucrose is at a concentration of about 7.0% w/v to about 8% w/v.

### Claim 16 (depends on 15)

The method of claim 15, wherein the phosphate buffer is sodium phosphate dibasic and the composition has a pH of about 6 to about 8.

### Claim 17 (depends on 1)

The method of claim 1, wherein the subject has a prior history of one or more of: chronic ocular inflammation, infectious retinitis, multiple retinal detachments, large retinal breaks or giant retinal tears, multiple retinal breaks, ocular trauma, retinal detachment associated with vitreous hemorrhage, and choroidal detachment; and combinations thereof.

### Claim 18 (depends on 15)

The method of claim 15, wherein each dose of methotrexate is independently about 200 μg to about 600 μg, or about 300 μg to about 500 μg.

### Claim at position 19

-21. (canceled)

### Claim 22 (depends on 21)

The method of claim 21, wherein the composition is administered before, during, or within 24 hrs of retinal detachment surgery, followed by administration about once a week for about 6-12 weeks.

### Claim 23 (depends on 22, 23)

The method of claim 22, wherein, after the administration about once a week, the composition is then administered about once every 2 weeks for up to 24 weeks. 24 (Original) The method of claim 23, wherein the administration about once every 2 weeks continues for about 8 weeks (about 4 administrations over about 8 weeks).

### Claim 25

A method of treating proliferative vitreoretinopathy (PVR) comprising administering to a subject in need thereof a composition comprising methotrexate at a concentration of about 8 mg/mL; sucrose at a concentration of about 7.5% w/v, and a phosphate buffer at a pH of about 7.9 to about 9.0; wherein the volume of composition administered is 50 μL±10 μL; and the incidence of secondary punctate keratitis in the subject is substantially reduced.

### Claim at position 23

-30. (canceled)