# US 10,765,677 B2 · Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof

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- Number: US 10,765,677 B2
- Document ID: US10765677B2
- Status: Granted
- Kind: B2
- Application number: 16/434,966
- Filed: 2019-06-07
- Published: 2019-12-05
- Granted: 2020-09-08
- Earliest claimed: 2014-08-08
- Assignees: ForSight Vision4, Inc.
- Applicants: ForSight Vision4, Inc.
- Inventors: Judit Horvath; Irina Astafieva; Signe Erickson; Kathleen Cogan Farinas
- Web page: https://patentgrep.com/patent/US10765677B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61K 47/40: Cyclodextrins; Derivatives thereof
- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61M 5/14: Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- 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
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}

## Abstract

The present disclosure relates to stable formulations of receptor tyrosine kinase inhibitors (TKI), e.g., pazopanib; methods of preparation thereof; and use of the disclosed formulations in sustained delivery of the active agent to a target site. The disclosure further relates to methods of converting one polymorphic Form of a TKI to another polymorphic Form and/or an amorphous form.

## Claims

### Claim 1

A method of treating an ophthalmic disease or disorder in a subject in need thereof, the method comprising administering to an eye of the subject an effective amount of a pharmaceutical solution comprising:
(i) β-cyclodextrin sulfobutyl ether, hydroxypropyl β-cyclodextrin, or a combination thereof;
(ii) about 0.2% to about 1.0% of polyvinylpyrrolidone; and
(iii) about 30 mg/mL to about 60 mg/mL of an ophthalmic therapeutic agent or a pharmaceutically acceptable salt thereof having a solubility of less than 1 mg/mL in water.

### Claim 2 (depends on 1)

The method of claim 1, wherein the ophthalmic disease or disorder is a retinopathy or a neovascularization.

### Claim 3 (depends on 2)

The method of claim 2, wherein the neovascularization is choroidal neovascularization, surgery-induced neovascularization, retinal neovascularization, or neovascular glaucoma; and wherein the retinopathy is neo-proliferative retinopathy, sickle cell retinopathy, diabetic retinopathy, or retinopathy of prematurity.

### Claim 4 (depends on 1)

The method of claim 1, wherein the ophthalmic disease or disorder is diabetic macular edema, age-related macular degeneration, retinal edema, ocular ischemia, retinal vein occlusion, ocular trauma, surgery-induced edema, cystoid macular edema, uveitis, or Coat's disease.

### Claim 5 (depends on 1)

The method of claim 1, wherein the weight ratio of (i) to (iii) in the pharmaceutical solution is from about 2:1 to about 8:1.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pharmaceutical solution comprises from about 30 mg/mL to about 40 mg/mL of the ophthalmic therapeutic agent.

### Claim 7 (depends on 1)

The method of claim 1, wherein the pharmaceutical solution comprises from about 40 mg/mL to about 60 mg/mL of the ophthalmic therapeutic agent.

### Claim 8

A method of treating an ophthalmic disease or disorder in a subject in need thereof, the method comprising administering to an eye of the subject an effective amount of a pharmaceutical solution comprising:
(i) hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, trimethyl-γ-cyclodextrin, or a combination of two or more thereof,
(ii) about 0.1% to about 5.0% of trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, glycerin, propylene glycol, triacetin, N,N-dimethylacetamide, polyvinylpyrrolidone, pyrrolidone, or a combination of two or more thereof; and
(iii) about 30 mg/mL to about 70 mg/mL of an ophthalmic therapeutic agent or a pharmaceutically acceptable salt thereof having a solubility of less than 1 mg/mL in water.

### Claim 9 (depends on 8)

The method of claim 8, wherein the ophthalmic disease or disorder is a retinopathy or a neovascularization.

### Claim 10 (depends on 9)

The method of claim 9, wherein the neovascularization is choroidal neovascularization, surgery-induced neovascularization, retinal neovascularization, or neovascular glaucoma; and wherein the retinopathy is neo-proliferative retinopathy, sickle cell retinopathy, diabetic retinopathy, or retinopathy of prematurity.

### Claim 11 (depends on 8)

The method of claim 8, wherein the ophthalmic disease or disorder is diabetic macular edema, age-related macular degeneration, retinal edema, ocular ischemia, retinal vein occlusion, ocular trauma, surgery-induced edema, cystoid macular edema, uveitis, or Coat's disease.

### Claim 12 (depends on 8)

The method of claim 8, wherein the pharmaceutical solution comprises from about 40 mg/mL to about 60 mg/mL of the ophthalmic therapeutic agent.

### Claim 13 (depends on 8)

The method of claim 8, wherein the weight ratio of (i) to (iii) in the pharmaceutical solution is from about 2:1 to about 9:1.

### Claim 14

A method of treating an ophthalmic disease or disorder in a subject in need thereof, the method comprising administering to an eye of the subject an effective amount of a pharmaceutical solution comprising: (i) a cyclodextrin, and (ii) about 30 mg/mL to about 90 mg/mL of an ophthalmic therapeutic agent or a pharmaceutically acceptable salt thereof having a solubility of less than 1 mg/mL in water.

### Claim 15 (depends on 14)

The method of claim 14, wherein the ophthalmic disease or disorder is a retinopathy or a neovascularization.

### Claim 16 (depends on 15)

The method of claim 15, wherein the neovascularization is choroidal neovascularization, surgery-induced neovascularization, retinal neovascularization, or neovascular glaucoma; and wherein the retinopathy is neo-proliferative retinopathy, sickle cell retinopathy, diabetic retinopathy, or retinopathy of prematurity.

### Claim 17 (depends on 14)

The method of claim 14, wherein the ophthalmic disease or disorder is diabetic macular edema, age-related macular degeneration, retinal edema, ocular ischemia, retinal vein occlusion, ocular trauma, surgery-induced edema, cystoid macular edema, uveitis, or Coat's disease.

### Claim 18 (depends on 14)

The method of claim 14, wherein the pharmaceutical solution comprises from about 30 mg/mL to about 70 mg/mL of the ophthalmic therapeutic agent.

### Claim 19 (depends on 14)

The method of claim 14, wherein the cyclodextrin in the pharmaceutical solution is hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, trimethyl-γ-cyclodextrin, or a combination of two or more thereof.

### Claim 20 (depends on 14)

The method of claim 14, wherein the pharmaceutical solution further comprises trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, glycerin, propylene glycol, triacetin, N,N-dimethylacetamide, polyvinylpyrrolidone, pyrrolidone, or a combination of two or more thereof.