# US 2019/0167665 A1 · Morphine formulations

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- Number: US 2019/0167665 A1
- Document ID: US20190167665A1
- Status: Published application
- Kind: A1
- Application number: 16/272,108
- Filed: 2019-02-11
- Published: 2019-06-06
- Earliest claimed: 2013-03-14
- Assignees: Fresenius Kabi Deutschland GmbH
- Applicants: Fresenius Kabi Deutschland GmbH
- Inventors: Alain CUINE; Didier HOARAU; Pauline ROMAIN
- Web page: https://patentgrep.com/patent/US20190167665A1

## CPC

- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- 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 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- 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, generally, are pharmaceutical formulations, e.g., injectable pharmaceutical formulations with improved stability, comprising morphine sulfate or a hydrate thereof, and methods of producing and using the same. Also provided herein are kits comprising the formulations, e.g., injectable morphine formulations.

## Claims

### Claim at position 1

1-49. (canceled)

### Claim 50

A pharmaceutical formulation comprising:
(a) morphine, or a salt thereof, or a hydrate thereof;
(b) an isotonic agent;
(c) a buffering agent with anti-oxidative properties;
(d) a chelating agent;
(e) a complement to a chelating agent; and
(f) water,
wherein the formulation has a pH of from about 2.5 to about 6.5.

### Claim 51 (depends on 50)

The formulation of claim 50, wherein, the morphine, or a salt thereof, or a hydrate thereof, is selected from anhydrous morphine, morphine hydrochloride, morphine sulfate, morphine tartrate, morphine citrate, morphine acetate, morphine methobromide, morphine hydrobromide, morphine hydroiodide, morphine lactate and morphine bitartrate.

### Claim 52 (depends on 50)

The formulation of claim 50, wherein the morphine, or a salt thereof, or a hydrate thereof, is selected from morphine sulfate pentahydrate or morphine hydrochloride.

### Claim 53 (depends on 50)

The formulation of claim 50, wherein the isotonic agent is selected from sodium chloride, calcium chloride, potassium chloride, sodium bicarbonate, sodium lactate, Ringer's solution, dextrose, lactose, mannitol, glucose, glycerine, dextran, Normosol R, saline, Hartmann's solution, and mixtures and combinations thereof.

### Claim 54 (depends on 50)

The formulation of claim 50, wherein the buffering agent is a di-carboxylic or tri-carboxylic acid.

### Claim 55 (depends on 50)

The formulation of claim 50, wherein the buffering agent is citric acid, iso citric acid, aconitic acid, trimesic acid, propane-1,2,3-tricarboxylic acid, fumaric acid, oxalic acid, maleic acid, malonic acid, glutaric acid, succinic acid or tartaric acid, or hydrates thereof.

### Claim 56 (depends on 50)

The formulation of claim 50, wherein the buffering agent comprises a conjugate base.

### Claim 57 (depends on 50)

The formulation of claim 50, wherein the pH is from about 4.5 to about 5.5.

### Claim 58 (depends on 50)

The formulation of claim 50, wherein the pH is about 5.

### Claim 59 (depends on 50)

The formulation of claim 50, wherein the buffering agent is in an amount which provides a molar ratio of morphine to the buffering agent from about 0.4 to about 1.3.

### Claim 60 (depends on 50)

The formulation of claim 50, wherein the buffering agent comprises citric acid and sodium citrate.

### Claim 61 (depends on 50)

The formulation of claim 50, wherein the chelating agent is selected from edetic acid, ethylene glycol tetraacetic acid, ethylenediamine, diethylene triamine pentaacetic acid, N (hydroxyethyl) ethylenediaminetriacetic acid, aminotriacetic acid, 2,3-dimercapto-1-propanesulfonic acid, dimercaptosuccinic acid, dimercaprol, 1,2-bis(o-aminophenoxy)ethane N,N,N′,N′-tetraacetic acid, salts and hydrates thereof.

### Claim 62 (depends on 50)

The formulation of claim 50, wherein the complement to chelating agent is a calcium salt.

### Claim 63 (depends on 50)

The formulation of claim 50, wherein, the formulation provides a unit dose of morphine, or a salt thereof, or a hydrate thereof, in a concentration from about 2 mg/mL to about 15 mg/mL.

### Claim 64 (depends on 50)

The formulation of claim 50, wherein the formulation comprises no more than about 1.5% total impurities following storage at 25° C. and 60% Relative Humidity for at least 12 months.

### Claim 65 (depends on 50)

The formulation of claim 50, wherein the formulation comprises no more than about 0.2% pseudomorphine following storage at 25° C. and 60% Relative Humidity for at least 12 months.

### Claim 66 (depends on 50)

The formulation of claim 50, wherein the formulation is stored in a glass or plastic container.

### Claim 67 (depends on 50)

The formulation of claim 50, for injectable administration.

### Claim 68

A pharmaceutical formulation comprising:
(a) morphine, or a salt thereof, or a hydrate thereof;
(b) an isotonic agent;
(c) a buffering agent with anti-oxidative properties;
(d) a chelating agent;
(e) a complement to a chelating agent; and
(f) water,
wherein the formulation comprises no more than about 1.5% total impurities following storage at 25° C. and 60% Relative Humidity for at least 12 months.

### Claim 69

A pharmaceutical formulation comprising:
(a) morphine, or a salt thereof, or a hydrate thereof;
(b) an isotonic agent;
(c) a buffering agent with anti-oxidative properties;
(d) a chelating agent;
(e) a complement to a chelating agent; and
water,
wherein the formulation comprises no more than about 0.2% pseudomorphine following storage at 25° C. and 60% Relative Humidity for at least 12 months.