# US 2021/0275500 A1 · Liquid bendamustine pharmaceutical compositions

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2021/0275500 A1
- Document ID: US20210275500A1
- Status: Published application
- Kind: A1
- Application number: 17/268,780
- Filed: 2019-08-14
- Published: 2021-09-09
- Earliest claimed: 2018-08-17
- Assignees: Hospira Australia Pty Ltd.
- Applicants: Hospira Australia Pty Ltd
- Inventors: Andrew Malcolm Knill; Noel Norris
- Web page: https://patentgrep.com/patent/US20210275500A1

## CPC

- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- 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)

## Abstract

Concentrated liquid pharmaceutical compositions comprising a) a pharmaceutically effective amount of bendamustine or a pharmaceutically acceptable salt thereof, b) a non-aqueous solvent, and c) at least about 2% water, suitable, after dilution, for administration to a mammal by injection are provided. The concentrated liquid pharmaceutical compositions can comprise a non-aqueous solvent comprising at least one organic polymeric compound solvent and at least one organic small molecule solvent. Methods of treating a cancer in a mammal in need of such treatment comprising administering to the mammal an effective amount of a concentrated liquid bendamustine pharmaceutical composition of the invention are also provided.

## Claims

### Claim 1

A concentrated liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of bendamustine or a pharmaceutically acceptable salt thereof, b) a non-aqueous solvent, and c) at least about 2% water v/v of the composition, wherein the pharmaceutical composition is, after dilution, suitable for administration to a mammal by injection.

### Claim 2

A concentrated liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of bendamustine or a pharmaceutically acceptable salt thereof, b) a non-aqueous solvent, and c) from about 2% to about 30% water v/v of the composition, wherein the pharmaceutical composition is, after dilution, suitable for administration to a mammal.

### Claim 3 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or 2, wherein the non-aqueous solvent comprises one or more organic compounds selected from organic polymeric compound solvents and organic small molecule solvents.

### Claim 4 (depends on 3)

A pharmaceutical composition according to claim 3 wherein the non-aqueous solvent comprises one or more organic compounds selected from organic polymeric compound solvents comprising hydroxy moieties and organic small molecule solvents.

### Claim 5 (depends on 3)

A pharmaceutical composition according to claim 3, wherein the non-aqueous solvent comprises one or more organic compounds selected from polysorbates, polyethylene glycols, polyalkoxylated castor oils, N,N-dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, and organic small molecule alcohols.

### Claim 6 (depends on 3)

A pharmaceutical composition according to claim 3, wherein the non-aqueous solvent comprises one or more organic compounds selected from polysorbates, polyethylene glycols, polyalkoxylated castor oils, N,N-dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, ethanol, isopropyl alcohol, benzyl alcohol, and propylene glycol.

### Claim 7 (depends on 3)

A pharmaceutical composition according to claim 3, wherein the non-aqueous solvent comprises at least one organic polymeric compound solvent and at least one organic small molecule solvent.

### Claim 8 (depends on 7)

A pharmaceutical composition according to claim 7, wherein the non-aqueous solvent comprises a polyethylene glycol.

### Claim 9 (depends on 8)

A pharmaceutical composition according to claim 8, wherein the organic small molecule solvent is selected from N,N-dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, ethanol, isopropyl alcohol, benzyl alcohol, and propylene glycol.

### Claim 10 (depends on 9)

A pharmaceutical composition according to claim 9, wherein the organic small molecule solvent is ethanol.

### Claim 11 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, wherein the composition remains in a liquid state at about 2° C.

### Claim 12 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, wherein the amount of the non-aqueous solvent in the composition is from about 70% to about 98% v/v.

### Claim 13 (depends on 3)

A pharmaceutical composition according to claim 3, wherein the non-aqueous solvent comprises at least two different organic compound solvents, wherein (i) one of the organic compound solvents is a polyethylene glycol or a mixture of polyethylene glycols, (ii) at least one of the organic compound solvents is an organic small molecule solvent, and (iii) wherein the total amount of the organic compounds solvents in the composition is from about 70% to about 98% v/v.

### Claim 14 (depends on 3)

A pharmaceutical composition according to claim 3, wherein the non-aqueous solvent comprises (i) one or more organic polymeric compound solvents in a total amount of from about 60% to about 96% v/v in the composition, and (ii) one or more organic small molecule solvents in a total amount of from about 2% to about 10% v/v in the composition, wherein the total amount of organic compound solvents in the composition is from about 70% v/v to a maximum of about 98% v/v of the composition.

### Claim 15 (depends on 14)

A pharmaceutical composition according to claim 14, comprising from about 2.4% to about 4% v/v water and a total of about 96% to about 97.6% v/v organic compound solvents.

### Claim 16 (depends on 15)

A pharmaceutical composition according to claim 15, comprising from about 3% to about 3.5% v/v water and a total of about 96.5% to about 97% v/v organic compound solvents.

### Claim 17 (depends on 14)

A pharmaceutical composition according to claim 14, wherein the non-aqueous solvent comprises (i) a polyethylene glycol or mixture of polyethylene glycols present in an amount of from about 60% to about 96% v/v in the composition, and (ii) one or more organic small molecule solvents in an amount of from about 2% to about 10% v/v in the composition, wherein the total amount of organic compound solvents in the composition is from about 70% v/v to a maximum of about 98% v/v of the composition.

### Claim 18 (depends on 17)

A pharmaceutical composition according to claim 17, wherein the amount of water in the composition is from about 2% v/v to about 30% v/v of the composition.

### Claim 19 (depends on 14)

A pharmaceutical composition according to claim 14, wherein the organic small molecule solvent is ethanol.

### Claim 20 (depends on 1)

A pharmaceutical composition according to claim 1, wherein the amount of water in the composition is from about 2% to about 30%, about 2.4% to about 30%, about 2.8% to about 30%, about 3% to about 30%, about 3.5% to about 30%, about 4% to about 30%, about 2% to about 25%, about 2.4% to about 25%, about 2.8% to about 25%, about 3% to about 25%, about 3.5% to about 25%, about 4% to about 25%, about 2% to about 20%, about 2.4% to about 20%, about 2.8% to about 20%, about 3% to about 20%, about 3.5% to about 20%, about 4% to about 20%, about 2% to about 15%, about 2.4% to about 15%, about 2.8% to about 15%, about 3% to about 15%, about 3.5% to about 15%, about 4% to about 15%, about 2% to about 10%, about 2.4% to about 10%, about 2.8% to about 10%, about 3% to about 10%, about 3.5% to about 10%, about 4% to about 10%, about 2% to about 5%, about 2.4% to about 5%, about 2.8% to about 5%, about 3% to about 5%, about 3.5% to about 5%, about 4% to about 5%, about 2% to about 4%, about 2.4% to about 4%, about 2.8% to about 4%, about 3% to about 4%, about 2% to about 3.5%, about 2.4% to about 3.5%, about 2.8% to about 3.5%, or about 3% to about 3.5% v/v.

### Claim 21 (depends on 2)

A pharmaceutical composition according to claim 2, wherein the amount of water in the composition is from about 2.4% to about 30%, about 2.8% to about 30%, about 3% to about 30%, about 3.5% to about 30%, about 4% to about 30%, about 2% to about 25%, about 2.4% to about 25%, about 2.8% to about 25%, about 3% to about 25%, about 3.5% to about 25%, about 4% to about 25%, about 2% to about 20%, about 2.4% to about 20%, about 2.8% to about 20%, about 3% to about 20%, about 3.5% to about 20%, about 4% to about 20%, about 2% to about 15%, about 2.4% to about 15%, about 2.8% to about 15%, about 3% to about 15%, about 3.5% to about 15%, about 4% to about 15%, about 2% to about 10%, about 2.4% to about 10%, about 2.8% to about 10%, about 3% to about 10%, about 3.5% to about 10%, about 4% to about 10%, about 2% to about 5%, about 2.4% to about 5%, about 2.8% to about 5%, about 3% to about 5%, about 3.5% to about 5%, about 4% to about 5%, about 2% to about 4%, about 2.4% to about 4%, about 2.8% to about 4%, about 3% to about 4%, about 2% to about 3.5%, about 2.4% to about 3.5%, about 2.8% to about 3.5%, or about 3% to about 3.5% v/v.

### Claim 22 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, wherein the bendamustine or pharmaceutically acceptable salt thereof is bendamustine hydrochloride.

### Claim 23 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, wherein the composition comprises a concentrated pharmaceutically effective amount of bendamustine or a pharmaceutically acceptable salt thereof and is ready-to-dilute with a diluent suitable for injection before administration.

### Claim 24 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, wherein the bendamustine or pharmaceutically acceptable salt thereof is bendamustine hydrochloride and wherein the composition comprises from about 35 to about 40 mg/mL bendamustine hydrochloride.

### Claim 25 (depends on 24)

A pharmaceutical composition according to claim 24, comprising about 25 mg/mL bendamustine hydrochloride.

### Claim 26 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, further comprising an antioxidant.

### Claim 27 (depends on 26)

A pharmaceutical composition according to claim 26, wherein the antioxidant is selected from monothioglycerol, L-cysteine, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, glutathione, gentisic acid, lipoic acid, ascorbityl palmitate, propyl gallate, nordihydroguaiaretic acid, or a combination thereof.

### Claim 28 (depends on 27)

A pharmaceutical composition according to claim 27, wherein the antioxidant is butylated hydroxyanisole.

### Claim 29 (depends on 1, 2)

A pharmaceutical composition according to claim 1 or claim 2, having a pH of from about 3.3 to about 3.7 when the composition is tested in a water solution at about 12.4% v/v.

### Claim 30 (depends on 29)

A pharmaceutical composition according to claim 29, comprising a strong base, for example NaOH, in an amount sufficient to obtain the pH.

### Claim 31 (depends on 1, 2)

A sealed container containing a pharmaceutical composition according to claim 1 or claim 2.

### Claim 32 (depends on 2)

A pharmaceutical composition according to claim 2 wherein the bendamustine or pharmaceutically acceptable salt thereof is bendamustine hydrochloride and wherein each mL of the composition contains 25 mg said bendamustine hydrochloride, 23.7 mg absolute ethanol, 30 mg water for injection, and polyethylene glycol quantity sufficient.

### Claim 33 (depends on 32)

A pharmaceutical composition according to claim 32, wherein the polyethylene glycol is polyethylene glycol 400.

### Claim 34 (depends on 32)

A pharmaceutical composition according to claim 32, further comprising an antioxidant.

### Claim 35 (depends on 34)

A pharmaceutical composition according to claim 34, wherein the antioxidant is butylated hydroxyanisole and wherein each mL of the composition contains 1 mg said butylated hydroxyanisole.

### Claim 36 (depends on 35)

A pharmaceutical composition according to claim 35, wherein the polyethylene glycol is polyethylene glycol 400.

### Claim 37 (depends on 31)

A sealed container according to claim 31, wherein the bendamustine or pharmaceutically acceptable bendamustine salt in the pharmaceutical composition contained therein is bendamustine HCl in an amount of from about 5 mg to about 500 mg, from about 10 mg to about 350 mg, or from about 20 mg to about 300 mg.

### Claim 38 (depends on 37)

A sealed container according to claim 37, wherein the pharmaceutical composition contained therein contains 25 mg, 100 mg or 200 mg bendamustine HCl.

### Claim 39 (depends on 36)

A sealed container containing from about 0.5 mL to about 50 mL of a pharmaceutical composition according to claim 36.

### Claim 40 (depends on 39)

A sealed container according to claim 39 containing 1 mL, 4 mL, or 8 mL of said pharmaceutical composition.

### Claim 41 (depends on 1, 2)

A method of treating a cancer in a mammal, comprising i) diluting a pharmaceutically effective amount of a concentrated liquid pharmaceutical composition according to claim 1 or claim 2 with a pharmaceutically acceptable diluent to obtain a diluted pharmaceutical composition, and ii) administering the diluted pharmaceutical composition of (i) by injection to a mammal in need thereof.

### Claim 42 (depends on 41)

A method according to claim 41, wherein the cancer is a leukemia or a lymphoma.

### Claim 43 (depends on 42)

A method according to claim 42, wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin lymphoma.

### Claim 44

A method for preparing a concentrated liquid pharmaceutical composition, which method comprises combining:
a. bendamustine or a pharmaceutically acceptable salt thereof,
b. one or more organic compounds selected from organic polymeric compound solvents and organic small molecule solvents,
c. at least about 2% water v/v (water/pharmaceutical composition), and
d. optionally, one or more antioxidants.

### Claim 45 (depends on 44)

A method according to claim 44, wherein after combining (a)-(c), and optionally (d):
i) the pH of an aqueous solution containing about 12.4% volume of said pharmaceutical composition is measured;
ii) if the pH of (i) is not from about 3.4 to about 3.6, a pH adjuster is added to the concentrated liquid pharmaceutical composition; and
iii) steps (i) and (ii) are repeated, if necessary, until the pH of an aqueous solution containing about 12.4% of the pharmaceutical composition v/v is from about 3.4 to about 3.6.

### Claim 46

A method for preparing a concentrated liquid bendamustine pharmaceutical composition, which method comprises 1) combining:
a) bendamustine or a pharmaceutically acceptable salt thereof;
b) optionally, one or more antioxidants;
c) water;
d) one or more organic small molecule solvents; and
e) one or more organic polymeric compound solvents;
2) agitating the combination resulting from (1) until the bendamustine or pharmaceutically acceptable salt thereof and the antioxidant or antioxidants, if present, are dissolved; and
3) adding a further amount of the organic polymeric compound solvent or organic polymeric compound solvents of 1(d) to obtain a liquid bendamustine pharmaceutical composition comprising at least about 2% water v/v (water/pharmaceutical composition).

### Claim 47 (depends on 46)

A method according to claim 46, further comprising, after step (3),
(i) measuring the pH of an aqueous solution containing about 12.4% volume of the pharmaceutical composition;
(ii) if the pH of (i) is not between from about 3.4 to about 3.6, adding a pH adjuster to the concentrated liquid pharmaceutical composition; and
(iii) repeating (i) and (ii), if necessary, until the pH of an aqueous solution containing about 12.4% of the composition v/v is from about 3.4 to about 3.6.

### Claim 48

A concentrated liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of bendamustine or a pharmaceutically acceptable salt thereof, b) from about 82% to about 98% of a non-aqueous solvent v/v of the composition, and c) from about 2% to about 18% water v/v of the composition, wherein the pharmaceutical composition is, after dilution, suitable for administration to a mammal.

### Claim 49 (depends on 48)

A pharmaceutical composition according to claim 48, wherein the non-aqueous solvent comprises a polyethylene glycol or mixture of polyethylene glycols present in an amount of from about 80% to about 96% v/v in the composition and one or more organic small molecule solvents in an amount of from about 2% to about 10% v/v in the composition.

### Claim 50 (depends on 49)

A pharmaceutical composition according to claim 49, wherein the organic small molecule solvent is ethanol.