# US 12,005,060 B2 · Ophthalmic formulations of methotrexate

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- Number: US 12,005,060 B2
- Document ID: US12005060B2
- Status: Granted
- Kind: B2
- Application number: 17/932,426
- Filed: 2022-09-15
- Published: 2023-01-19
- Granted: 2024-06-11
- Earliest claimed: 2019-09-13
- Assignees: Aldeyra Therapeutics, Inc.
- Applicants: Aldeyra Therapeutics, Inc.
- Inventors: Dean Eliott; Stephen Gitu Machatha; Pramod Sarpotdar; Tomasz Stryjewski
- Web page: https://patentgrep.com/patent/US12005060B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 47/02: Inorganic compounds
- 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
- 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 disclosure provides formulations of methotrexate for ocular administration, including intravitreal administration, and use of the formulations for treating proliferative vitreoretinopathy (PVR), intraocular lymphoma (e.g., PVRL), and intraocular inflammation.

## Claims

### Claim 1

A composition suitable for intravitreal administration, comprising:
methotrexate, a density enhancing agent, and a phosphate buffer, 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; the methotrexate is at a concentration of about 7 mg/mL to about 9 mg/mL, the density enhancing agent comprises sucrose at a concentration of about 7.0% w/v to about 8.0% w/v; the phosphate buffer is sodium phosphate dibasic dihydrate at a concentration of about 0.113 mg/mL to 0.142 mg/mL, and the composition is in a pre-filled syringe and has an administration volume of about 40 μL, about 45 μL, about 50 μL, or about 60 μL.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the transit rate is less than 8 min.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the SiO is polydimethyl siloxane 5000 centistoke oil or polydimethyl siloxane 1000 centistoke oil.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The composition of claim 1, wherein the composition has a pH of about 5.5 to about 8.5.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the composition has an osmolarity of 250 mOsm/L to 350 mOsm/L.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the composition is in a pre-filled syringe and has an administration volume of about 50 μL.

### Claim 8 (depends on 1)

A method of treating proliferative vitreoretinopathy (PVR), comprising administering to a subject in need thereof the composition of claim 1; wherein a volume of the composition of about 40 μL, about 45 μL, about 50 μL, or about 60 μL is administered to the subject.

### Claim 9 (depends on 8)

The method of claim 8, wherein the methotrexate is at a concentration of about 8 mg/mL; the sucrose is at a concentration of about 7.5% w/v; and the volume of composition administered is about 50 μL.

### Claim 10 (depends on 9)

The method of claim 9, wherein the composition has a pH of 7.4±0.2.

### Claim 11 (depends on 8)

The method of claim 8, wherein the composition is administered intravitreally once every 4 weeks, once every two weeks, once a week, two times a week, three times a week, or four times a week.

### Claim 12 (depends on 8)

The method of claim 8, wherein the treatment includes an induction phase, and optionally a consolidation phase, and/or optionally a maintenance phase.

### Claim 13 (depends on 12)

The method of claim 12, wherein the induction phase comprises administration of the composition two times a week, or up to four times a week.

### Claim 14 (depends on 12)

The method of claim 12, wherein the consolidation phase, when present, comprises administration once a week or once every two weeks.

### Claim 15 (depends on 12)

The method of claim 12, wherein the maintenance phase, when present, comprises administration once every two weeks or once every month.

### Claim 16 (depends on 8)

The method of claim 8, 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.