# US 8,541,399 B2 · Solvent-based sterilisation of pharmaceuticals

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- Number: US 8,541,399 B2
- Document ID: US8541399B2
- Status: Granted
- Kind: B2
- Application number: 10/505,137
- Filed: 2003-02-19
- Published: 2005-10-06
- Granted: 2013-09-24
- Earliest claimed: 2002-02-19
- Assignees: Resolution Chemicals Limited
- Applicants: Parveen Bhatarah; Kenneth Alan Greenwood
- Inventors: Parveen Bhatarah; Kenneth Alan Greenwood
- Web page: https://patentgrep.com/patent/US8541399B2

## CPC

- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61L 2/02: using physical processes
- A61L 2/022: Filtration
- A61L 2/18: Liquid substances
- A61P 11/06: Antiasthmatics
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61L 2103/05: Living organisms or biological materials
- Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.]
- 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)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

A sterile composition of a pharmaceutical compound is prepared by combining solvent with a non-sterile pharmaceutical compound to form a solution and filtering to yield a sterile pharmaceutical compound, optionally removing all or part of the solvent, and under sterile conditions combining the compound with a pharmaceutically acceptable carrier.

## Claims

### Claim 1

A method for preparing a sterile pharmaceutical composition of a steroid comprising:
(i) dissolving a non-sterile steroid in a non-aqueous solvent to yield a solution of the steroid,
(ii) filtering the solution of (i) to yield a sterile solution,
(iii) combining the sterile solution of (ii) with sterile water to form a sterile aqueous suspension,
(iv) treating the sterile aqueous suspension of (iii) to obtain a sterile aqueous suspension with a particle size distribution having a mass median diameter less than 10 μm,
(v) under sterile conditions combining the sterile aqueous suspension of (iv) with a pharmaceutically acceptable carrier to yield a sterile pharmaceutical composition comprising a sterile aqueous suspension of the steroid having a mass median diameter less than 10 μm, and
(vi) storing the sterile pharmaceutical composition of (v) in sterile containers.

### Claim 2 (depends on 1)

The method of claim 1, wherein the non-sterile steroid is a powder.

### Claim 3 (depends on 2)

The method of claim 2, wherein the powder is a micronized powder.

### Claim 4 (depends on 1)

The method of claim 1, wherein the steroid is budesonide.

### Claim 5 (depends on 1)

The method of claim 1, wherein the solvent comprises an alcohol.

### Claim 6 (depends on 1)

The method of claim 1, wherein the solvent comprises a Class 3 solvent.

### Claim 7 (depends on 1)

The method of claim 1, wherein the solvent comprises a Class 2 solvent.

### Claim 8 (depends on 1)

The method of claim 1, comprising combining solvent with the steroid at a temperature from 20° C. below the boiling point of the solvent up to its boiling point.

### Claim 9 (depends on 1)

The method of claim 1, wherein the solvent is at reflux.

### Claim 10 (depends on 1)

The method of claim 1, comprising filtering the solution through a filter having a pore size of 0.2 μm or less.

### Claim 11 (depends on 1)

The method of claim 1, wherein the sterile water contains a surfactant.

### Claim 12 (depends on 1)

The method of claim 1, comprising treating the suspension to obtain a particle size distribution having a mass median diameter in the range 1-5 μm.

### Claim 13 (depends on 12)

The method of claim 12, comprising treating the suspension to obtain a particle size distribution having a mass median diameter in the range 2-3 μm.

### Claim 14 (depends on 1)

The method of claim 1, comprising storing the sterile composition in sterile ampoules.

### Claim 15

A method for preparing a sterile suspension of budesonide, comprising:
(i) dissolving non-sterile budesonide in a non-aqueous solvent to yield a budesonide solution,
(ii) filtering the solution of (i) to yield a sterile solution,
(iii) combining the sterile solution of (ii) with sterile water to form a sterile aqueous suspension of budesonide,
(iv) treating the sterile aqueous suspension of (iii) to obtain a sterile aqueous suspension with a particle size distribution having a mass median diameter less than 10 μm,
(v) under sterile conditions combining the sterile aqueous suspension of (iv) with a pharmaceutically acceptable carrier to yield a sterile pharmaceutical composition comprising the sterile aqueous suspension of budesonide having a mass median diameter less than 10 μm, and
(vi) storing the sterile pharmaceutical composition of (v) in sterile containers.

### Claim 16 (depends on 15)

The method of claim 15, wherein the solvent comprises an alcohol.

### Claim 17 (depends on 15)

The method of claim 15, comprising filtering the solution through a filter having a pore size of 0.2 μm or less.

### Claim 18 (depends on 17)

The method of claim 17, comprising treating the suspension to obtain a particle size distribution having a mass median diameter in the range 1-5 μm.

### Claim 19 (depends on 17)

The method of claim 17, comprising treating the suspension to obtain a particle size distribution having a mass median diameter in the range 2-3 μm.

### Claim 20

A method for preparing a sterile pharmaceutical composition of a steroid comprising:
(i) dissolving a non-sterile steroid in a non-aqueous solvent to yield a solution of the steroid,
(ii) filtering the solution of (i) to yield a sterile solution,
(iii) combining the sterile solution of (ii) with sterile water to form a sterile aqueous suspension,
(iv) removing all or part of the non-aqueous solvent from the sterile aqueous suspension of (iii) to yield a sterile aqueous suspension having reduced non-aqueous solvent content,
(v) treating the sterile aqueous suspension having reduced non-aqueous solvent content of (iv) to obtain a sterile aqueous suspension with a particle size distribution having a mass median diameter less than 10 μm,
(vi) under sterile conditions combining the sterile aqueous suspension of (v) with a pharmaceutically acceptable carrier to yield a sterile pharmaceutical composition comprising a sterile aqueous suspension of the steroid having a mass median diameter less than 10 μm, and
(vii) storing the sterile pharmaceutical composition of (vi) in sterile containers.

### Claim 21

A method for preparing a sterile pharmaceutical composition of budesonide comprising:
(i) dissolving a non-sterile budesonide in a non-aqueous solvent to yield a budesonide solution,
(ii) filtering the solution of (i) to yield a sterile solution,
(iii) combining the sterile solution of (ii) with sterile water to form a sterile aqueous suspension of budesonide,
(iv) removing all or part of the non-aqueous solvent from the sterile aqueous suspension of (iii) to yield a sterile aqueous suspension having reduced non-aqueous solvent content,
(v) treating the sterile aqueous suspension having reduced non-aqueous solvent content of (iv) to obtain a sterile aqueous suspension with a particle size distribution having a mass median diameter less than 10 μm,
(vi) under sterile conditions combining the sterile aqueous suspension of (v) with a pharmaceutically acceptable carrier to yield a sterile pharmaceutical composition comprising a sterile aqueous suspension of budesonide having a mass median diameter less than 10 μm, and
(vii) storing the sterile pharmaceutical composition of (vi) in sterile containers.

### Claim 22 (depends on 15)

The method of claim 15, comprising storing the sterile composition in sterile ampoules.

### Claim 23 (depends on 20)

The method of claim 20, comprising storing the sterile composition in sterile ampoules.

### Claim 24 (depends on 21)

The method of claim 21, comprising storing the sterile composition in sterile ampoules.

### Claim 25 (depends on 20)

The method of claim 20, comprising removing solvent under reduced pressure.

### Claim 26 (depends on 20)

The method of claim 20, comprising removing solvent at atmospheric pressure.