# US 11,304,901 B2 · Liposome formulation of fluticasone furoate and method of preparation

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- Number: US 11,304,901 B2
- Document ID: US11304901B2
- Status: Granted
- Kind: B2
- Application number: 17/001,889
- Filed: 2020-08-25
- Published: 2021-03-04
- Granted: 2022-04-19
- Earliest claimed: 2019-08-28
- Assignees: Anovent Pharmaceutical (U.S.), LLC
- Applicants: Anovent Pharmaceutical (U.S.), LLC
- Inventors: Cai Gu Huang; Hailong Zhang; Abid Hussain
- Web page: https://patentgrep.com/patent/US11304901B2

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K 9/1277: Preparation processes; Proliposomes
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 47/02: Inorganic compounds
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- B01F 21/02: {Methods}
- 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)
- B01F: MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING (mixing paints B44D3/06)

## Abstract

The present invention is directed to a liposomal formulation having a lipid ingredient encapsulating fluticasone furoate, and a method for preparing the liposomal formulation. The liposome formulation comprises a lipid and a sterol. The method of preparing the liposomes comprises the steps of (1) mixing fluticasone furoate with lipid ingredients comprising a lipid and a sterol, (2) injecting the mixture into normal saline solution, and (3) ultrafiltering and concentrating the resulting solution. This preparation method can produce a liposome formulation having desirable properties and compositions, for example, the ratio of the lipid ingredient, the drug to lipid ratio, and the pH value, which is suitable for nebulization inhalation.

## Claims

### Claim 1

A formulation comprising a suspension of a plurality of liposomes in a solvent, wherein the liposomes comprise a lipid ingredient that encapsulates fluticasone furoate, wherein the lipid ingredient comprises DPPC and cholesterol in a DPPC:cholesterol molar ratio of about 0.8:1 to about 1.2:1, the weight ratio of fluticasone furoate to lipid ingredient is about 1:30, the concentration of fluticasone furoate is about 1 mg/100 mL, and the solvent is normal saline.

### Claim 2 (depends on 1)

The formulation according to claim 1, wherein the liposomes have an average size of about 130 nm.

### Claim 3 (depends on 1)

The formulation according to claim 1, having a pH ranging from about 4.0 to about 7.0.

### Claim 4 (depends on 1)

The formulation according to claim 1, wherein the composition has a pH of about 5.7.

### Claim 5 (depends on 1)

The formulation according to claim 1, wherein the composition has an encapsulation efficiency of at least 90%.

### Claim 6 (depends on 1)

The formulation according to claim 1, wherein the formulation when nebulized forms droplets with a D50 value ranging from about 3.9 μm to about 4.8 μm.

### Claim 7 (depends on 1)

The formulation according to claim 1, wherein the formulation when nebulized forms droplets with a D90 value ranging from about 7.3 μm to about 11.2 μm.

### Claim 8 (depends on 1)

The formulation according to claim 1, further comprising an antioxidant selected from the group consisting of a water-soluble antioxidant and an oil-soluble antioxidant.

### Claim 9 (depends on 8)

The formulation according to claim 8, wherein the oil-soluble antioxidant is selected from the group consisting of alpha-tocopherol, alpha-tocopherol succinate, alpha-tocopherol acetate and mixtures thereof, and the water-soluble antioxidant is selected from the group consisting of ascorbic acid, sodium bisulfate, sodium sulfite, sodium pyrosulfite, L-cysteine, and mixtures thereof.

### Claim 10 (depends on 1)

A method of preparing the formulation of claim 1 comprising:
(1) dissolving fluticasone furoate, DPPC, and cholesterol in ethanol, wherein the fluticasone furoate is present in an amount of about 1 mg/30 mL of ethanol, the DPPC is present in an amount of about 19.6 mg/30 mL of ethanol, and the cholesterol is present in about 10.4 mg/30 mL of ethanol, to provide a first mixture;
(2) injecting the first mixture into a normal saline solution with stirring, wherein the ratio of the first mixture to the saline solution is about 30:50 (v/v) to form a second mixture comprising liposome vesicles;
(3) adding normal saline to the second mixture comprising liposome vesicles in an amount sufficient to provide a volume of about 100 mL for each 30 mL of ethanol to provide a third mixture; and
(4) ultrafiltering and concentrating the third mixture to a volume of 10 mL per each 100 mL of the third mixture to provide the formulation.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the formulation has a pH ranging from about 4.0 to about 7.0.

### Claim 12 (depends on 10)

The method of claim 10, wherein the first mixture is heated to a temperature ranging from about 40° C. to about 80° C.

### Claim 13 (depends on 11)

The method of claim 11, wherein the first mixture is heated to a temperature of about 50° C.

### Claim 14 (depends on 10)

The method of claim 10, wherein the ultrafiltering uses a hollow fiber membrane.