# US 2024/0197818 A1 · Topical cyclosporine-containing formulations and uses thereof

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- Number: US 2024/0197818 A1
- Document ID: US20240197818A1
- Status: Published application
- Kind: A1
- Application number: 18/590,539
- Filed: 2024-02-28
- Published: 2024-06-20
- Earliest claimed: 2016-02-29
- Assignees: Sun Pharmaceutical Industries Limited
- Applicants: Sun Pharmaceutical Industries Limited
- Inventors: Sidney L. WEISS; Ashim K. MITRA; Eugene J. MCNALLY
- Web page: https://patentgrep.com/patent/US20240197818A1

## CPC

- A61K 38/13: Cyclosporins
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 31/202: having three or more double bonds, e.g. linolenic (eicosanoids, e.g. leukotrienes A61K31/557)
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- 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

Provided herein are formulations for topical ophthalmic formulations containing 0.087-0.093 wt % of cyclosporine, and methods of making and using such formulations. In some aspects and embodiments the formulations may include a polyoxyl lipid or fatty acid, and/or a polyalkoxylated alcohol and may include nanomicelles. Also included herein are methods of treating or preventing diseases or conditions, such as ocular diseases or conditions.

## Claims

### Claim 1

An ophthalmic topical formulation comprising cyclosporine and one or more additional formulation ingredients, wherein cyclosporine is present in an amount of about 0.087-0.093% of the formulation.

### Claim 2 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said formulation is stable at temperatures above 40 degrees C.

### Claim 3 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said formulation is substantially free of organic solvent.

### Claim 4 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said formulation is free of preservatives.

### Claim 5 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said formulation is a clear aqueous solution.

### Claim 6 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said formulation is a mixed nanomicellar solution.

### Claim 7 (depends on 6)

The ophthalmic topical formulation according to claim 6, wherein said cyclosporine is encapsulated in the core of mixed nanomicelles.

### Claim 8 (depends on 7)

The ophthalmic topical formulation according to claim 7, wherein said nanomicelles have a particle size of about 5-100 nm.

### Claim 9 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said additional formulation ingredients are selected from the group consisting of a polyoxyl lipid or a fatty acid and polyalkoxylated alcohol.

### Claim 10 (depends on 9)

The ophthalmic topical formulation according to claim 9, wherein said polyoxyl lipid is a polyoxyl castor oil.

### Claim 11 (depends on 10)

The ophthalmic topical formulation according to claim 10, wherein said polyoxyl lipid is selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100.

### Claim 12 (depends on 9)

The ophthalmic topical formulation according to claim 9, wherein said polyoxyl lipid or fatty acid is present in an amount of about 0.1-5 wt % of the formulation.

### Claim 13 (depends on 9)

The ophthalmic topical formulation according to claim 9, wherein said polyalkoxylated alcohol is octoxynol 40.

### Claim 14 (depends on 9)

The ophthalmic topical formulation according to claim 9, wherein said polyalkoxylated alcohol is present in an amount of about 0.002-4 wt % of the formulation.

### Claim 15 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said one or more additional formulation ingredients are further selected from the group consisting of additives, adjuvants, buffers, tonicity agents, bioadhesive polymers and preservatives.

### Claim 16 (depends on 15)

The ophthalmic topical formulation according to claim 15, wherein said buffer is selected from the group consisting of phosphate, borate, acetate, citrate, carbonate and borate-polyol complexes.

### Claim 17 (depends on 15)

The ophthalmic topical formulation according to claim 15, wherein said tonicity agent is selected from the group consisting of mannitol, sodium chloride, sodium nitrate, sodium sulfate, dextrose, xylitol or combinations thereof.

### Claim 18 (depends on 15)

The ophthalmic topical formulation according to claim 15, wherein said bioadhesive polymer is selected from the group consisting of carbopol, carbophils, cellulose derivatives, gums such as xanthum, karaya, guar, tragacanth, agarose and other polymers such as povidone, polyethylene glycol, poloxamers, hyaluronic acid or combinations thereof.

### Claim 19 (depends on 18)

The ophthalmic topical formulation according to claim 18, wherein said bioadhesive polymer is povidone.

### Claim 20

An ophthalmic topical formulation comprising: 0.087-0.093 wt % cyclosporine, about 0.1-6 wt % hydrogenated 40 polyoxyl castor oil, and about 0.002-4 wt % octoxynol-40.

### Claim 21

An ophthalmic topical formulation comprising: 0.087-0.093 wt % cyclosporine, about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and about 0.05 wt % octoxynol-40.

### Claim 22 (depends on 1)

The ophthalmic topical formulation according to claim 1, wherein said formulation comprises further active ingredients.

### Claim 23 (depends on 22)

The ophthalmic topical formulation according to claim 22, wherein further active ingredients are selected from the group consisting of resolvin, resolvin-like compounds, steroids, antibiotics, antivirals, hormones, cytokines, toxins, vitamins or combinations thereof.

### Claim 24

An ophthalmic topical formulation comprising:
0.087-0.093 wt % cyclosporine,
about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and
about 0.05 wt % octoxynol-40, and optionally
about 0.20-0.405 wt % sodium phosphate monobasic,
about 0.23-0.465 wt % sodium phosphate dibasic,
about 0.05 wt % sodium chloride,
about 0.3 wt % povidone,
sodium hydroxide/hydrochloric acid, and
water for injection.

### Claim 25

An ophthalmic topical formulation comprising 0.087-0.093 wt % cyclosporine, wherein the said formulation demonstrates a clinically significant improvement as compared to the vehicle in tear production with >10 mm increase in Schimer test score from baseline.

### Claim 26 (depends on 25)

The ophthalmic topical formulation according to claim 25, wherein the composition has early onset as compared to other formulations of cyclosporine A.

### Claim 27

A process of preparing the ophthalmic topical formulation of cyclosporine, said method comprising the steps of:
(1) melting the required amount of polyoxyl lipid,
(2) slowly adding cyclosporine to step (1) and substantially homogenizing the mixture,
(3) adding polyalkoxylated alcohol to step (2) and continue stirring until a uniform homogeneous solution is obtained,
(4) adding buffer system and tonicity agent to the solution obtained from step (3) and continue stirring to achieve a good dissolution,
(5) adding required amount of bioadhesive polymer to the solution of above step,
(6) adjusting the pH of the solution if required, and making up the final volume with water for injection; and
(7) aseptically filtering and filling the solution into unit dose vials.

### Claim 28

A process of preparing the ophthalmic topical formulation of cyclosporine, said method comprising the steps of:
(1) melting the required amount of hydrogenated 40 polyoxyl castor oil,
(2) slowly adding cyclosporine to step (1) and substantially homogenizing the mixture,
(3) adding octoxynol-40 alcohol to step (2) and continue stirring until a uniform homogeneous solution is obtained,
(4) adding phosphate buffer and sodium chloride to the solution obtained from step (3) and continue stirring to achieve a good dissolution,
(5) adding required amount of povidone to the solution of above step,
(6) adjusting the pH of the solution if required, and making up the final volume with water for injection; and
(7) aseptically filtering and filling the solution into unit dose vials.

### Claim 29

A process of preparing the ophthalmic topical formulation of cyclosporine, said method comprising the steps of:
(1) dissolving the required amounts of cyclosporine, polyalkoxylated alcohol and polyoxyl lipid in a suitable solvent,
(2) charging the solution obtained from step (1) to a suitable sized round bottom flask,
(3) removing the solvent by rotary evaporation until a thin film is obtained,
(4) adding and mixing required amount of water for injection to the flask containing film of step (3);
(5) adding buffer system and tonicity agent to the solution of step (4);
(6) adding required amount of bioadhesive polymer to the solution of above step,
(7) adjusting the pH of the solution if required, and making up the final volume with water for injection; and
(8) aseptically filtering and filling the solution into unit dose vials.

### Claim 30

A process of preparing the ophthalmic topical formulation of cyclosporine, said method comprising the steps of:
(1) dissolving the required amounts of cyclosporine, octoxynol-40 and hydrogenated 40 polyoxyl castor oil in a suitable solvent,
(2) charging the solution obtained from step (1) to a suitable sized round bottom flask,
(3) removing the solvent by rotary evaporation until a thin film is obtained,
(4) adding and mixing required amount of water for injection to the flask containing film of step (3);
(5) adding phosphate buffer and sodium chloride to the solution of step (4);
(6) adding required amount of povidone to the solution of above step,
(7) adjusting the pH of the solution if required, and making up the final volume with water for injection; and
(8) aseptically filtering and filling the solution into unit dose vials.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

A method of treating or preventing ocular diseases or disorders, said method comprising topically administering an ophthalmic formulation according to any of claims 1-30 to a subject in need thereof.