# US 12,178,874 B2 · Aflibercept formulations containing a lysine salt as tonicifying agent and uses thereof

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- Number: US 12,178,874 B2
- Document ID: US12178874B2
- Status: Granted
- Kind: B2
- Application number: 16/763,193
- Filed: 2018-11-18
- Published: 2021-06-10
- Granted: 2024-12-31
- Earliest claimed: 2017-11-20
- Assignees: Just-Evotec Biologics, Inc.
- Applicants: Just-Evotec Biologics, Inc.
- Inventors: Alison J. Gillespie; Julee A. Floyd; Bruce A. Kerwin; Christine C. Siska
- Web page: https://patentgrep.com/patent/US12178874B2

## CPC

- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 38/1866: {Vascular endothelial growth factor [VEGF]}
- 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 47/22: 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 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

Ophthalmic formulations comprising aflibercept and a lysine salt tonicifying agent 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 phosphate or acetate buffer at 5-50 mM concentration;
(c) a non-ionic surfactant; and
(d) a lysine salt as a tonicifying agent, in the range of 2-3% (w/v), wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg;
wherein the pH of the ophthalmic formulation is about pH 5.0 to about pH 6.5.

### Claim 2 (depends on 1)

The ophthalmic formulation of claim 1, wherein the buffer is a phosphate buffer.

### Claim 3 (depends on 1)

The ophthalmic formulation of claim 1, wherein the buffer is an acetate buffer.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The ophthalmic formulation of claim 1, wherein the non- ionic surfactant is 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.

### Claim 6 (depends on 1)

The ophthalmic formulation of claim 1, further comprising an additional amino acid stabilizing agent.

### Claim 7 (depends on 6)

The ophthalmic formulation of claim 6, wherein the additional amino acid stabilizing agent is selected from the group consisting of proline, arginine, glycine, lysine, and methionine.

### Claim 8 (depends on 1)

The ophthalmic formulation of claim 1, wherein:
(a) the aflibercept concentration is 20-80 mg/mL;
(b) the phosphate buffer concentration is about 10 mM,
(c) the non-ionic surfactant is a polysorbate or a poloxamer,
(d) the lysine salt as the tonicifying agent is at a concentration of about 2-3% (w/v);
and the pH of the ophthalmic formulation is about pH 6.0 to about pH 6.5.

### Claim 9 (depends on 8)

The ophthalmic formulation of claim 8, wherein the non-ionic surfactant is Poloxamer 188.

### Claim 10 (depends on 1)

The ophthalmic formulation of claim 1, wherein:
(a) the aflibercept concentration is 20-80 mg/mL;
(b) the acetate buffer concentration is about 10 mM,
(c) the non-ionic surfactant is a polysorbate or a poloxamer,
(d) the lysine salt as the tonicifying agent is at a concentration of about 2-3% (w/v);
and the pH of the ophthalmic formulation is about pH 5.0 to about pH 5.5.

### Claim 11 (depends on 10)

The ophthalmic formulation of claim 10, wherein the non-ionic surfactant is Poloxamer 188.

### Claim 12 (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 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) Aged-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 13 (depends on 12)

The method of claim 12, wherein administering the ophthalmic formulation is by intravitreal injection.

### Claim 14

An ophthalmic formulation, comprising:
(a) aflibercept in a concentration of 20-80 mg/ml;
(b) a phosphate or acetate buffer at 5-50 mM concentration;
(c) a non-ionic surfactant selected from the group consisting of a polysorbate and a poloxamer; and
(d) a lysine salt as a tonicifying agent, at a concentration of about 2-3% (w/v), wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg;
wherein the pH of the ophthalmic formulation is about pH 5.0 to about pH 6.5.

### Claim 15 (depends on 14)

The ophthalmic formulation of claim 14, wherein the non- ionic surfactant is 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.

### Claim 16 (depends on 14)

The ophthalmic formulation of claim 14, wherein the non-ionic surfactant is Poloxamer 188.

### Claim 17 (depends on 14)

The ophthalmic formulation of claim 14, wherein the buffer concentration is 5-20 mM.

### Claim 18 (depends on 14)

The ophthalmic formulation of claim 14, wherein the phosphate buffer concentration is about 10 mM.

### Claim 19 (depends on 14)

The ophthalmic formulation of claim 14, wherein the lysine salt is selected from the group consisting of (2S)-2,6-diaminohexanoic acid; (2R)-2,6-diaminohexanoic acid; L-Lysine hydrate; (S)-2,6-Diaminocaproic acid hydrate; (2S)-2,6-bis (azanyl) hexanoic acid hydrate; L-Lysine acetate; L-Lysine monoacetate; 2,6-diaminohexanoic acid; dl-lysine acetate; L-Lysine hydrochloride; L-Lysine monohydrochloride; (S)-2,6-Diaminohexanoic acid hydrochloride; D-Lysine hydrochloride; D-Lysine monohydrochloride; (D)-2,6-Diaminohexanoic acid hydrochloride; L-Lysine dihydrochloride; 2,6-diaminohexanoic acid dihydrochloride; L-Lysine Lactate; L-Lysine mono-(2-hydroxypropanoate); L-Lysine mono (+/−)-2-hydroxypropanoate); L-Lysine Succinate; (S)-2,6-Diaminohexanoic acid(S)-2-aminopentanedioic acid; and L-Lysine L-Glutamate.

### Claim 20 (depends on 14)

The ophthalmic formulation of claim 14, wherein the lysine salt is L-Lysine monohydrochloride.

### Claim 21 (depends on 14)

The ophthalmic formulation of claim 14, wherein the buffer is a phosphate buffer, and the pH is about 6.0 to about 6.5.

### Claim 22 (depends on 14)

The ophthalmic formulation of claim 14, wherein the buffer is an acetate buffer, and the pH is about 5.0 to about 5.5.

### Claim 23 (depends on 14)

The ophthalmic formulation of claim 14, wherein the polysorbate concentration is 0.03% (w/v) or the poloxamer concentration is about 0.1% (w/v) to about 1% (w/v).

### Claim 24 (depends on 1)

The ophthalmic formulation of claim 1, wherein the non-ionic surfactant is a polysorbate at about 0.001 (w/v) to about 0.1% (w/v) concentration or a poloxamer at about 0.01% (w/v) to about 1% (w/v) concentration.

### Claim 25 (depends on 8)

The ophthalmic formulation of claim 8, wherein the non-ionic surfactant is a polysorbate at about 0.001 (w/v) to about 0.1% (w/v) concentration or a poloxamer at about 0.01% (w/v) to about 1% (w/v) concentration.

### Claim 26 (depends on 10)

The ophthalmic formulation of claim 10, wherein the non-ionic surfactant is a polysorbate at about 0.001 (w/v) to about 0.1% (w/v) concentration or a poloxamer at about 0.01% (w/v) to about 1% (w/v) concentration.

### Claim 27

An ophthalmic formulation, comprising:
(a) aflibercept in a concentration of 5-100 mg/mL;
(b) a phosphate buffer at 5-50 mM concentration;
(c) a non-ionic surfactant selected from the group consisting of a polysorbate at about 0.001% (w/v) to about 0.1% (w/v) concentration and a poloxamer at about 0.01% (w/v) to about 1% (w/v) concentration; and
(d) a lysine salt as a tonicifying agent, at a concentration of about 2-3% (w/v), wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg;
wherein the pH of the ophthalmic formulation is about pH 6.0 to about pH 6.5.

### Claim 28 (depends on 27)

The ophthalmic formulation of claim 27, wherein the lysine salt is selected from the group consisting of (2S)-2,6-diaminohexanoic acid; (2R)-2,6-diaminohexanoic acid; L-Lysine hydrate; (S)-2,6-Diaminocaproic acid hydrate; (2S)-2,6-bis (azanyl) hexanoic acid hydrate; L-Lysine acetate; L-Lysine monoacetate; 2,6-diaminohexanoic acid; dl-lysine acetate; L-Lysine hydrochloride; L-Lysine monohydrochloride; (S)-2,6-Diaminohexanoic acid hydrochloride; D-Lysine hydrochloride; D-Lysine monohydrochloride; (D)-2,6-Diaminohexanoic acid hydrochloride; L-Lysine dihydrochloride; 2,6-diaminohexanoic acid dihydrochloride; L-Lysine Lactate; L-Lysine mono-(2-hydroxypropanoate); L-Lysine mono (+/−)-2-hydroxypropanoate); L-Lysine Succinate; (S)-2,6-Diaminohexanoic acid(S)-2-aminopentanedioic acid; and L-Lysine L-Glutamate.

### Claim 29 (depends on 27)

The ophthalmic formulation of claim 27, wherein the lysine salt is L-Lysine monohydrochloride.

### Claim 30

An ophthalmic formulation, comprising:
(a) aflibercept in a concentration of 5-100 mg/mL;
(b) an acetate buffer at 5-50 mM concentration;
(c) a non-ionic surfactant selected from the group consisting of a polysorbate at about 0.001% (w/v) to about 0.1% (w/v) concentration and a poloxamer at about 0.01% (w/v) to about 1% (w/v) concentration; and
(d) a lysine salt as a tonicifying agent, at a concentration of about 2-3% (w/v), wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg;
wherein the pH of the ophthalmic formulation is about pH 5.0 to about pH 5.5.

### Claim 31 (depends on 30)

The ophthalmic formulation of claim 30, wherein the lysine salt is selected from the group consisting of (2S)-2,6-diaminohexanoic acid; (2R)-2,6-diaminohexanoic acid; L-Lysine hydrate; (S)-2,6-Diaminocaproic acid hydrate; (2S)-2,6-bis (azanyl) hexanoic acid hydrate; L-Lysine acetate; L-Lysine monoacetate; 2,6-diaminohexanoic acid; dl-lysine acetate; L-Lysine hydrochloride; L-Lysine monohydrochloride; (S)-2,6-Diaminohexanoic acid hydrochloride; D-Lysine hydrochloride; D-Lysine monohydrochloride; (D)-2,6-Diaminohexanoic acid hydrochloride; L-Lysine dihydrochloride; 2,6-diaminohexanoic acid dihydrochloride; L-Lysine Lactate; L-Lysine mono-(2-hydroxypropanoate); L-Lysine mono (+/−)-2-hydroxypropanoate); L-Lysine Succinate; (S)-2,6-Diaminohexanoic acid(S)-2-aminopentanedioic acid; and L- Lysine L-Glutamate.

### Claim 32 (depends on 30)

The ophthalmic formulation of claim 30, wherein the lysine salt is L-Lysine monohydrochloride.

### Claim 33 (depends on 27)

A method of treating an eye disorder or disease, comprising administering a therapeutically effective amount of the ophthalmic formulation of claim 27 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); and
wherein administering the ophthalmic formulation is by intravitreal injection.

### Claim 34 (depends on 30)

A method of treating an eye disorder or disease, comprising administering a therapeutically effective amount of the ophthalmic formulation of claim 30 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); and
wherein administering the ophthalmic formulation is by intravitreal injection.