# US 12,005,097 B2 · Aflibercept formulations and uses thereof

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- Number: US 12,005,097 B2
- Document ID: US12005097B2
- Status: Granted
- Kind: B2
- Application number: 17/492,649
- Filed: 2021-10-03
- Published: 2022-01-20
- Granted: 2024-06-11
- Earliest claimed: 2016-11-21
- Assignees: Just-Evotec Biologics, Inc.
- Applicants: Just-Evotec Biologics, Inc.
- Inventors: Bruce A. Kerwin; Julee A. Floyd; Alison J. Gillespie; Christine C Siska
- Web page: https://patentgrep.com/patent/US12005097B2

## CPC

- A61K 38/179: {for growth factors; for growth regulators}
- 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 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- 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 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- 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

Ophthalmic formulations comprising aflibercept are disclosed that are suitable for a method of treatment of an eye disorder or disease by intravitreal or topical administration.

## Claims

### Claim 1

An ophthalmic formulation, comprising:
(a) aflibercept in a concentration of 5-100 mg/mL;
(b) a histidine buffer, wherein the histidine buffer concentration is 5-50 mM;
(c) a non-ionic surfactant selected from the group consisting of a polysorbate, a polyethylene glycol dodecyl ether, a poloxamer, 4-(1,1,3,3-Tetramethylbutyl)phenyl-polyethylene glycol, an alkylsaccharide and an alkylglycoside, at a concentration of 0.001% (w/v) to 5% (w/v);
(d) a tonicifying agent comprising a polyol or an amino acid selected from proline, arginine, aspartate, glutamate, glycine, histidine, isoleucine, and lysine, at a concentration of 2-4% (w/v), wherein the formulation has a final osmolality of 300±50 mOsm/kg;
(e) an additional amino acid stabilizing agent selected from the group consisting of proline, arginine, methionine, lysine and mixtures thereof; and
wherein the pH of the formulation is about pH 5.0 to about pH 6.5.

### Claim 2 (depends on 1)

The ophthalmic formulation of claim 1, wherein the histidine buffer concentration is 5-20 mM.

### Claim 3 (depends on 1)

The ophthalmic formulation of claim 1, wherein the non-ionic surfactant is a polysorbate or Poloxamer 188.

### Claim 4 (depends on 1)

The ophthalmic formulation of claim 1, wherein the tonicifying agent is a polyol selected from sucrose, trehalose, sorbitol, mannitol, and glycerol.

### Claim 5 (depends on 1)

The ophthalmic formulation of claim 1, wherein the tonicifying agent is sucrose.

### Claim 6 (depends on 1)

The ophthalmic formulation of claim 1, wherein the tonicifying agent is trehalose.

### Claim 7 (depends on 1)

The ophthalmic formulation of claim 1, wherein the tonicifying agent is an amino acid selected from proline, arginine, aspartate, glutamate, histidine, isoleucine, and lysine.

### Claim 8 (depends on 1)

The ophthalmic formulation of claim 1, wherein the tonicifying agent is proline.

### Claim 9 (depends on 1)

The ophthalmic formulation of claim 1, wherein the tonicifying agent is arginine.

### Claim 10 (depends on 1)

The ophthalmic formulation of claim 1, wherein:
(i) the non-ionic surfactant is polysorbate or poloxamer;
(ii) the tonicifying agent is sucrose or trehalose;
(iii) the additional amino acid stabilizing agent is proline, arginine, or lysine; and
the pH of the formulation is about pH 5.5 to about pH 6.5.

### Claim 11 (depends on 10)

The ophthalmic formulation of claim 10, wherein the non-ionic surfactant is a poloxamer.

### Claim 12 (depends on 1)

The ophthalmic formulation of claim 1, wherein the aflibercept concentration is 20-80 mg/mL.

### Claim 13 (depends on 1)

The ophthalmic formulation of claim 1, wherein the aflibercept concentration is at about 30 mg/mL to about 50 mg/mL.

### Claim 14 (depends on 1)

A method of treating an eye disorder or disease, comprising administering a therapeutically effective amount of the ophthalmic formulation of claim 1 by intravitreal injection to a patient in need of treatment, wherein the eye disorder or disease is selected from the group consisting of macular edema following Retinal Vein Occlusion (RVO), Central Retinal Vein Occlusion (CRVO), Branch Retinal Vein Occlusion (BRVO), Neovascular (Wet) Age-Related Macular Degeneration (AMD), Impaired vision due to Myopic Choroidal Neovascularisation, Diabetic Macular Edema (DME), Diabetic Retinopathy (DR) in patients with DME, and neovascular Age-Related Macular Degeneration (AMD).

### Claim 15 (depends on 14)

The method of claim 14, wherein the eye disorder or disease is macular edema following Retinal Vein Occlusion (RVO).

### Claim 16 (depends on 14)

The method of claim 14, wherein the eye disorder or disease is Central Retinal Vein Occlusion (CRVO).

### Claim 17 (depends on 14)

The method of claim 14, wherein the eye disorder or disease is Branch Retinal Vein Occlusion (BRVO).

### Claim 18 (depends on 14)

The method of claim 14, wherein the eye disorder or disease is neovascular Age-Related Macular Degeneration (AMD) or Neovascular (Wet) Age-Related Macular Degeneration (AMD).