# US 12,005,140 B2 · Pharmaceutical formulation

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- Number: US 12,005,140 B2
- Document ID: US12005140B2
- Status: Granted
- Kind: B2
- Application number: 17/054,945
- Filed: 2019-05-23
- Published: 2021-12-02
- Granted: 2024-06-11
- Earliest claimed: 2018-05-23
- Assignees: Klaria Pharma Holding AB
- Applicants: Klaria Pharma Holding AB
- Inventors: Scott Boyer; Shengzhen Cai; Fredrik Hübinette; Leif Ingemarsson
- Web page: https://patentgrep.com/patent/US12005140B2

## CPC

- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/7007: {Drug-containing films, membranes or sheets (A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence)}
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 47/02: Inorganic compounds
- 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 47/22: 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 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61P 37/00: Drugs for immunological or allergic disorders
- 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

The present invention relates to a film comprising an alginate salt of a monovalent cation or a mixture of alginate salts containing at least one alginate salt of a monovalent cation, and a compound of Formula (I), such as adrenaline, or a pharmaceutically acceptable salt thereof. The present invention further relates to methods for manufacturing such a film, and the use of such a film in the treatment of a human patient, in particular the use of such a film in the treatment of a condition selected from anaphylaxis, superficial bleeding and cardiac arrest.

## Claims

### Claim 1

A film suitable for administration to an oral cavity comprising:
(i) an alginate salt of a monovalent cation or a mixture of alginate salts containing at least one alginate salt of a monovalent cation, wherein said alginate salt is a sodium alginate or a potassium alginate;
(ii) an active pharmaceutical ingredient (API) which is adrenaline or a pharmaceutically acceptable salt thereof;
(iii) an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, and combinations thereof; and
(iv) at least one plasticizer which is selected from sorbitol, glycerol, or both sorbitol and glycerol,
further wherein the alginate salt of a monovalent cation (a) comprises from 25 to 35% by weight of β-D-mannuronate and from 65 to 75% by weight of α-L-guluronate, and (b) has a weight average molecular weight of from 30,000 g/mol to 90,000 g/mol,
wherein the film is stable for 83 days at room temperature.

### Claim 2 (depends on 1)

The film according to claim 1, wherein the API is (−)-adrenaline or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The film according to claim 1, wherein the API is the tartrate salt of adrenaline.

### Claim 4 (depends on 1)

The film according to claim 1, wherein the alginate salt of a monovalent cation is a sodium alginate.

### Claim 5 (depends on 1)

The film according to claim 1, wherein the film comprises from 25% to 99% by weight of the alginate salt of a monovalent cation or the mixture of alginate salts containing at least one alginate salt of a monovalent cation, from 0% to 20% by weight of water, and from 0.001% to 75% by weight of the API.

### Claim 6 (depends on 1)

The film according to claim 1, wherein the film comprises from 29% to 93% by weight of the alginate salt of a monovalent cation or the mixture of alginate salts containing at least one alginate salt of a monovalent cation, from 5% to 15% by weight of water, and from 0.15% to 50% by weight of the API.

### Claim 7 (depends on 1)

The film according to claim 1, wherein the film comprises from 0.01 to 10% by weight of the antioxidant.

### Claim 8 (depends on 1)

The film according to claim 1, wherein the film comprises sodium metabisulfite or sodium bisulfite and at least one further antioxidant.

### Claim 9 (depends on 1)

The film according to claim 1, wherein the ratio of total antioxidants present in the film to total API present in the film, by weight, is from 0.01:1 to 10:1.

### Claim 10 (depends on 8)

The film according to claim 8, wherein the film comprises (i) ascorbic acid and (ii) sodium bisulfite or sodium metabisulfite.

### Claim 11 (depends on 1)

The film according to claim 1, wherein the film further comprises a basifying agent.

### Claim 12 (depends on 1)

The film according to claim 1, wherein the film comprises up to 40% by weight of sorbitol, and up to 40% by weight of glycerol.

### Claim 13 (depends on 1)

A method of treating anaphylaxis, superficial bleeding, or cardiac arrest in a human patient, wherein said method comprises administration of at least one film according to claim 1 to said human patient.

### Claim 14 (depends on 13)

The method of claim 13, wherein the film is administered to the oral cavity of the human patient.

### Claim 15 (depends on 1)

A method of manufacturing a film according to claim 1, said method comprising:
(a) either:
(i) mixing the API in water, or in a solution comprising water and at least one antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, and combinations thereof;
(ii) mixing one or more excipients into the solution obtained; and
(iii) adding the alginate salt of monovalent cation to result in the formation of a cast;
or alternatively:
(iv) mixing one or more excipients in water;
(v) separately, dissolving the API in water, or an aqueous solution containing at least one antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, and combinations thereof;
(vi) mixing the solution obtained in (iv) with the alginate salt of monovalent cation; and
adding the solution obtained in (v) to the solution obtained in (vi) to result in the formation of a cast;
(b) leaving the cast to de-aerate;
(c) pouring the cast onto a surface and spreading the cast out to the desired thickness; and
(d) drying the cast layer until the residual water content of the film is from 0 to 20% by weight and a solid film is formed.

### Claim 16 (depends on 15)

The method of claim 15, wherein after the cast is poured onto a surface, it is first spread out to a thickness of about 2 mm by means of an applicator with a slit height of about 2 mm, and is then subsequently spread out to a thickness of about 1 mm by means of an applicator with a slit height of about 1 mm.

### Claim 17 (depends on 8)

The film according to claim 8, wherein the film comprises citric acid and sodium metabisulfite.

### Claim 18 (depends on 1)

The film according to claim 1, wherein the film comprises both sorbitol and glycerol.

### Claim 19 (depends on 1)

The film according to claim 1, wherein the film comprises sorbitol, glycerol, sodium metabisulfite and citric acid.

### Claim 20 (depends on 6)

The film according to claim 6, wherein the film comprises from 0.01% to 10% by weight of each antioxidant present and from 3% to 25% by weight of each plasticizer present.

### Claim 21 (depends on 13)

The method of claim 13, wherein the method is a method of treating anaphylaxis.

### Claim 22 (depends on 1)

The film of claim 1, wherein the ratio of total antioxidants present in the film to total API present in the film, by weight, is from 0.25:1 to 10:1.

### Claim 23 (depends on 1)

The film of claim 1, wherein the film comprises sodium metabisulfite or sodium bisulfite, and wherein said sodium metabisulfite or said sodium bisulfite is in a molar amount of from 0.001 to 1.0 per mole of the API present in the film.

### Claim 24 (depends on 3)

The film according to claim 3, wherein the API is the tartrate salt of (−)-adrenaline.

### Claim 25 (depends on 9)

The film according to claim 9, wherein the ratio of total antioxidants present in the film to total API present in the film, by weight, is from 0.5:1 to 10:1.

### Claim 26 (depends on 11)

The film according to claim 11, wherein the basifying agent is aqueous sodium hydroxide.