# US 6,284,792 B1 · Formulation of valnemulin

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- Number: US 6,284,792 B1
- Document ID: US6284792B1
- Status: Granted
- Kind: B1
- Application number: 09/733,477
- Filed: 2000-12-08
- Published: 2001-09-13
- Granted: 2001-09-04
- Earliest claimed: 1999-12-09
- Assignees: Novartis AG
- Inventors: Kurt Koller; Franz Schwarz
- Web page: https://patentgrep.com/patent/US6284792B1

## CPC

- 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 31/221: with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- 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 preparation of an improved galenic delivery form of valnemulin, which is notable for its good tolerance and stability in storage, is described. The new delivery form in question is a non-aqueous or oily injection formulation, which is obtainable by means of in-situ preparation and subsequent stabilisation of the free, relatively unstable base of the active ingredient. A further aspect of the present invention concerns the usage of such an injection formulation in a method of treating infectious diseases in productive livestock or domestic animals.

## Claims

### Claim 1

A method of producing a non-aqueous composition comprising a free valnemulin base; wherein the free valnemulin base is produced in situ by contacting a salt of valnemulin with a physiologically acceptable non-aqueous solvent or solvent mixture (i) and is stabilized by adding a further solvent (ii).

### Claim 2 (depends on 1)

The method according to claim 1 further comprising contacting the free valnemulin base with a stabilizing agent for protecting the free valnemulin base from oxidation.

### Claim 3

A method of producing a non-aqueous composition comprising a free valnemulin base; wherein the free valnemulin base is produced in situ by contacting a salt of valnemulin with a physiologically acceptable non-aqueous solvent or solvent mixture (i) and optionally stabilizing the composition by adding a further solvent (ii).

### Claim 4 (depends on 3)

The method according to claim 3 in which 0.5 to 30% by weight of the salt of valnemulin is reacted with the physiologically acceptable non-aqueous solvent or solvent mixture (i) to yield the composition in situ in the presence of heat and an alkaline compound.

### Claim 5 (depends on 3)

The method according to claim 3 in which the non-aqueous solvent or solvent mixture (i) is selected from one or more solvents of isopropyl myristate, semi-synthetic and synthetic esters cf glycerol, ethylene or propylene glycol with short-chained to medium-chained mono- or dicarboxylic acids, and medium-chained to long-chained carboxylic acids with monovalent alcohols.

### Claim 6 (depends on 4)

The method according to claim 4 in which the salt of valnemulin is suspended in a physiologically acceptable non-aqueous solvent or solvent mixture (i) in a concentration range of 50 to 99% by weight, and the free base of valnemulin is produced in situ in the presence of an alkaline compound, heat and stirring.

### Claim 7 (depends on 1)

The method according to claim 1 wherein the stabilizing solvent (ii) comprises an ester of medium-chained to long-chained carboxylic acids with monovalent alcohols, 1,2-O-isopropylidene glycerol, glycerol, ethanol, N,N-dimethylacetamide, benzyl benzoate or tetraethylene glycol, or mixture thereof.

### Claim 8 (depends on 1)

The method according to claim 1 wherein solvents (i) and (ii) are present in the composition in a ratio of about 70:15.

### Claim 9

The method of producing a non-aqueous composition comprising suspending a salt of valnemulin in a physiologically acceptable non-aqueous solvent or solvent mixture (i), adding an alkaline compound to the suspension while stirring and heating in a temperature range of about 50° C. to about 80° C. in order to effect in situ release of the valnemulin base in solvent (i), separating the aqueous phase and the non-aqueous phase at a temperature of about 50 to about 80°C.; washing the valnemulin free base-containing non-aqueous phase with water at room temperature to yield a fresh phase separation at a temperature of about 50 to 80° C.; drying the non-aqueous phase and removing volatile components, and mixing the dried non-aqueous phase with a stabilizing solvent or solvent mixture (ii).

### Claim 10 (depends on 1)

A composition comprising free valnemulin base obtainable by the method according to claim 1.

### Claim 11 (depends on 10)

A composition according to claim 10 in a form suitable for administration to a mammal by injection.
12., The composition according to claim 10 in an amount effective to treat infectious diseases of productive livestock or domestic animals.