# US 10,117,888 B2 · Formulation comprising a gemcitabine-prodrug

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- Number: US 10,117,888 B2
- Document ID: US10117888B2
- Status: Granted
- Kind: B2
- Application number: 15/308,475
- Filed: 2015-06-25
- Published: 2017-04-06
- Granted: 2018-11-06
- Earliest claimed: 2014-06-25
- Assignees: NuCana plc
- Applicants: NuCana plc
- Inventors: Hugh Griffith; Gordon Kennovin
- Web page: https://patentgrep.com/patent/US10117888B2

## CPC

- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- 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 47/16: containing nitrogen, {e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates}
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- 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 47/44: 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)
- A61K 47/548: {Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544)}
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

This invention relates to pharmaceutical formulations of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate, a monophosphate derivative of the well-known oncology drug gemcitabine. In particular, the invention relates to formulations which comprise a polar aprotic solvent, preferably dimethyl acetamide (DMA). Formulations comprising these solvent provide therapeutically effective treatments of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. The invention also relates to methods of using said formulations and kits comprising said formulations.

## Claims

### Claim 1

A pharmaceutical formulation comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate;
dimethyl acetamide (DMA); and
optionally one or more pharmaceutically acceptable excipients.

### Claim 2 (depends on 1)

The formulation according to claim 1, further comprising an aqueous vehicle.

### Claim 3 (depends on 2)

The formulation according to claim 2, wherein the aqueous vehicle is saline.

### Claim 4 (depends on 2)

The formulation according to claim 2, wherein the aqueous vehicle is water for injection (WFI).

### Claim 5 (depends on 1)

The formulation according to claim 1, further comprising at least one solubilizer.

### Claim 6 (depends on 5)

The formulation according to claim 5, wherein the formulation comprises two or more solubilizers.

### Claim 7 (depends on 5)

The formulation according to claim 5, wherein each solubilizer is a polyethoxylated fatty acid or a mixture thereof.

### Claim 8 (depends on 1)

The formulation according to claim 1, wherein the formulation comprises:
from 30% to 95% by volume DMA;
from 5% to 50% by volume aqueous vehicle; and
from 100 mg to 300 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate.

### Claim 9 (depends on 1)

The formulation according to claim 1, wherein the formulation comprises:
from 20% to 80% by volume DMA;
from 30% to 80% by volume solubilizer or solubilizers; and
from 50 mg to 150 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate.

### Claim 10 (depends on 9)

The formulation according to claim 9, wherein the formulation comprises:
from 20% to 80% by volume DMA;
from 20% to 60% by volume a first solubilizer;
from 10% to 40% by volume a second solubilizer; and
from 50 mg to 150 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate.

### Claim 11 (depends on 10)

The formulation of claim 10, further comprising from 3% to 15% by volume aqueous vehicle.

### Claim 12 (depends on 1)

The formulation according to claim 1, wherein the formulation comprises:
from 0.5% to 7.5% by volume DMA;
from 0.5% to 7.5% by volume solubilizer or solubilizers;
from 85% to 99% by volume aqueous vehicle and
from 2.0 mg to 12.0 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]phosphate.

### Claim 13 (depends on 1)

The formulation according to claim 1 wherein the formulation is for intravenous administration.

### Claim 14 (depends on 1)

The formulation according to claim 1 wherein dilution with an aqueous vehicle forms a formulation for intravenous administration.

### Claim 15 (depends on 1)

The formulation according to claim 1, wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.

### Claim 16 (depends on 1)

The formulation according to claim 1, wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in substantially diastereomerically pure form.

### Claim 17

A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate; and
dimethyl acetamide (DMA).

### Claim 18 (depends on 17)

The method according to claim 17, further comprising the steps of:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and DMA with an aqueous vehicle to provide a formulation for infusion or injection; and
administering the formulation for infusion or injection to the subject by infusion or injection.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the administration step is carried out up to 48 hours after the dilution step.

### Claim 20 (depends on 17)

The method according to claim 17, wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.

### Claim 21 (depends on 17)

The method according to claim 17, wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in substantially diastereomerically pure form.

### Claim 22 (depends on 17)

The method according to claim 17, further comprising the steps of:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and DMA with a diluent solution to provide an intermediate formulation, said first diluent solution comprising at least one solubilizer;
diluting the intermediate formulation with an aqueous vehicle to provide a formulation for infusion or injection; and
administering the formulation for infusion or injection to the subject by infusion or injection.

### Claim 23 (depends on 22)

The method according to claim 22, wherein at least one solubilizer is a polyethoxylated fatty acid or a mixture thereof.

### Claim 24

A method of preparing a pharmaceutical formulation of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate for infusion or injection, comprising:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and dimethyl acetamide (DMA) with an aqueous vehicle to provide the formulation for infusion or injection.

### Claim 25 (depends on 24)

The method according to claim 24, the method further comprising the steps of:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and DMA with a diluent solution to provide an intermediate formulation, said first diluent solution comprising at least one solubilizer;
diluting the intermediate formulation with an aqueous vehicle to provide the formulation for infusion or injection.

### Claim 26 (depends on 25)

The method according to claim 25, wherein at least one solubilizer is a polyethoxylated fatty acid or a mixture thereof.

### Claim 27

A kit comprising:
a first formulation comprising:
from 30% to 95% by volume dimethyl acetamide (DMA);
from 5% to 50% by volume aqueous vehicle; and
from 100 mg to 400 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate; and
a second formulation comprising:
from 10% to 40% by volume DMA;
from 20% to 60% by volume a first solubilizer; and
from 30% to 80% by volume a second solubilizer.

### Claim 28 (depends on 27)

The kit according to claim 27, wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.

### Claim 29 (depends on 27)

The kit according to claim 27, wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in substantially diastereomerically pure form.