NZ528792A - Carprofen composition - Google Patents

Abstract

A stable solvent-based composition comprising: a) a therapeutically effective amount of carprofen; b) one or more polyols in an amount of from 20 to 998g/L; c) one or more stabilizing agents in an amount of from 0.1 to 50g/L; and d) one or more co-solvents in an amount of from 0 to 500g/L.

Description

New Zealand Paient Spedficaiion for Paient Number 528792 5287 92 1 PATENTS FORM NO 5 NEW ZEALAND Patents Act 1953 JUROX PTY LTD COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Stable carprofen composition We, Jurox Pty Ltd of 85 Gardiners Road, Rutherford, New South Wales, 2320, Australia hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is performed, to be particularly described in and by the following statement: 2 STABLE CARPROFEN COMPOSITION Technical Field This invention relates to non-steroidal anti-inflammatory drug (NSAID) compositions and in particular to such compositions where the NSAID is presented in 5 the form of a solution for use in warm blooded animals, such as dogs.

Background Art There are a number of NSAID's that are known to be useful for the treatment of inflammation and pain in animals such as dogs. These NSAID's are typically used in treating postoperative pain associated with soft tissue and orthopaedic surgeries as well 10 as for the relief of pain and inflammation associated with osteoarthritis.

One such useful NSAID is carprofen. This drug is a member of the class of drugs that includes indomethacin, naproxen and ketoprofen. Chemically, carprofen is 6-chloro-a-methyl-9H-carbazole-2-acetic acid.

Whilst carprofen has been found to be a very effective therapeutically, in order 15 to maintain an acceptable stability profile, it must be formulated in dosage forms such as tablets where solvents are largely excluded. For administration to humans, such dosage forms do not present a barrier to use. However, for administration to non-human animals, solid dosage forms are not well tolerated and are generally difficult to administer.

It would therefore be desirable if carprofen could be presented in a non- solid dosage form thereby allowing the substance to be more easily administered.

The present inventors have recognised this limitation on the use of carprofen and accordingly have sought to provide compositions that are stable and solvent-based for ease of administration to warm-blooded animals, especially dogs.

In the disclosure that follows, any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it 30 existed in Australia before the priority date of each claim of this application.

Moreover, throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. 3 Disclosure of Invention The present inventors have achieved stable solvent-based compositions of carprofen through the finding that certain solvent combinations with carprofen result in 5 formulations that are stable and are suitable for oral administration to animals.

Accordingly, in a first aspect, the present invention is directed to a stable solvent-based composition comprising: a therapeutically effective amount of carprofen; one or more polyols; one or more stabilising agents; and optionally, one or more co-solvents.

In a second aspect, the present invention is further directed to a method of treating pain and/or inflammation in a warm-blooded non-human animal, the method comprising administering to the animal a therapeutically effective amount of carprofen 15 which is solubilised in a composition which comprises: one or more polyols; one or more stabilising agents; and optionally, one or more co-solvents.

In a third aspect, the present invention is still further directed to the use of a 20 composition which comprises: one or more polyols; one or more stabilising agents; and optionally, one or more co-solvents, to stabilise carprofen and to facilitate the oral administration of a therapeutically 25 effective amount of carprofen to a warm-blooded non-human animal.

Carprofen is included in the composition in an amount of 1 to 500g/L, preferably 20 to 50g/L. At these concentrations, an appropriately therapeutically effective amount of the composition may be administered to an animal.

One or more polyols are included in the composition and these may be selected 30 from the group consisting of propylene glycol, glycerol, sorbitol, solid polyethylene glycols, liquid polyethylene glycols and mixtures of the foregoing. Broadly the polyols may be incorporated in an amount of from 20 to 998g/L. Preferably they are used in an amount of from 700 to 998g/L. In the case of sorbitol, it is usual to provide the sorbitol as a 70% w/v aqueous solution. In addition, in order for the polyethylene 35 glycols to be liquid, there molecular weight will generally be in the range of about 300- 4 600. However, potentially solid polyethylene glycols could be used in combination with one or more suitable co-solvents.

Amongst the stabilising agents that may be used are antioxidants. These include a tocopherol and salts thereof, ascorbic acid and salts thereof, methoxyphenol and 5 derivatives thereof, trihydroxybenzoate and derivatives thereof, hydroquinone and derivatives thereof, methyl phenol and derivatives thereof and sodium metabisulfite. Generally these stabilising agents are regarded as antioxidants. In addition, benzyl alcohol may be used as a stabilising agent. Such stabilising agents may be used singly or in combination in a total amount of 0.1 to 50 g/L, preferably 10 to 20g/L.

Optionally, one or more co-solvents may be included in the compositions of the invention. One co-solvent that may be used is ethanol. If a co-solvent is used, the amount is typically up to 500g/L, preferably 10 to 300g/L.

Although the compositions of the invention are solutions of carprofen, it will be readily appreciated that the viscosity of such solutions may be modified to produce compositions that are enhanced so as to be, for example, more paste like or in the form of a gel.

To produce the compositions of the invention, the carprofen may be dissolved in polyol along with the stabilising agent. If a co-solvent is used, it may be added following the dissolution of the carprofen and stabilising agent.

The compositions according to the present invention are for oral administration to warm-blooded animals, particularly dogs. For successful administration, these compositions must be palatable to the animal to be treated.

Modes for Carrying out the Invention In order to better understand the nature of this invention, a number of examples will now be described.

Example 1 Ingredient Amount Carprofen 25g Butylated hydroxytoluene lg Ethanol lOOmL Polyethylene glycol 400 qs 500mL Example 2 Ingredient Amount Carprofen 10g Butylated hydroxyanisole 2g Sorbitol 70% aqueous solution qs 500mL Example 3 Ingredient Amount Carprofen 10g Butylated hydroxytoluene lg Sorbitol 70% aqueous solution lOOmL Propylene glycol qs 500mL Example 4 Ingredient Amount Carprofen 25g Butylated hydroxyanisole 2g Polyethylene glycol 400 400mL Ascorbic acid 5g Ethanol qs 500mL Example 5 Ingredient Amount g.

Carprofen 20g Propylene glycol qs to 1L Benzyl alcohol 10g 6 Example 6 Ingredient Amount Carprofen 50g Butylated hydroxytoluene 5g Ethylene glycol qs to 1L In Examples 1-6, each composition was prepared by dissolving the carprofen in the polyol. The stabilising agent was then dissolved and if appropriate, co-solvent was added to complete the formulations. The availability of all of the ingredients used is set out in Table 1.

Table 1 - Ingredient Availability Ingredient Available from Carprofen Pacific Resources International Pty Ltd Butylated hydroxyanisole Bronson & Jacobs Polyethylene glycol 400 Bronson & Jacobs Ascorbic acid Bronson & Jacobs Ethanol CSR Butylated hydroxytoluene Bronson & Jacobs Sorbitol Bronson & Jacobs Propylene glycol Bronson & Jacobs Benzyl alcohol Bronson & Jacobs Ethylene glycol Bronson & Jacobs

Claims (23)

7 The stability of Examples 3 and 6 was evaluated by storing samples for various times at 30 and 40°C. The results of these stability trials are set out in Tables 2 and 3 from which it can be seen that the samples were stable for the time tested. By comparison, an example tested that did not incorporate a stabilising agent, had 5 degraded to an unacceptable level of carprofen after 1-3 months storage at 30°C. Table 2 - Stability Evaluation of Example 3 Storage Time (months) Carprofen (g/L) Temperature 30°C Carprofen (g/L) Temperature 40°C Initial 19.8 19.8 3 19.9 20.2 6 20.1 19.9 9 19.7 20.3 Table 3 - Stability Evaluation of Example 6 Storage Time (months) Carprofen (g/L) Temperature Carprofen (g/L) Temperature 40°C Initial 21.0 21.0 3 21.0 21.0 6 20.6 20.6 12 20.0 19.8 It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. 8 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A stable solvent-based composition comprising: a therapeutically effective amount of carprofen; one or more polyols in an amount of from 20 to 998g/L; one or more stabilising agents in an amount of from 0.1 to 50g/L; and one or more co-solvents in an amount of from 0 to 500g/L.

2. The carprofen composition according to claim 1 wherein the one or more polyols are selected from the group consisting of propylene glycol, glycerol, sorbitol, solid polyethylene glycols and liquid polyethylene glycols and mixtures of the foregoing; the one or more stabilising agents are selected from the group consisting of a tocopherol and salts thereof, ascorbic acid and salts thereof, methoxyphenol and derivatives thereof, trihydroxybenzoate and derivatives thereof, hydroquinone and derivatives thereof, methyl phenol and derivatives thereof, sodium metabisulfite and benzyl alcohol.

3. The carprofen composition according to claim 1 or claim 2 wherein the carprofen is in an amount of from 1 to 500g/L.

4. The carprofen composition according to claim 3 wherein the carprofen is in an amount of from 20 to 50g/L.

5. The carprofen composition according to any one of claims 1 to 4 wherein the one or more polyols are in an amount of from 700 to 998g/L

6. The carprofen composition according claim 5 wherein the one or more stabilising agents are in an amount of from 10 to 20g/L.

7. The carprofen composition according claim 5 or claim 6 wherein the one or more co-solvents are in an amount of from 10 to 300g/L.

8. Use of a composition which comprises: one or more polyols; one or more stabilising agents; and optionally, 9 one or more co-solvents, to stabilise carprofen and to facilitate the oral administration of a therapeutically effective amount of carprofen to a warm-blooded non-human animal.

9. The use according to claim 8 wherein the one or more polyols are selected from the group consisting of propylene glycol, glycerol, sorbitol, solid polyethylene glycols and liquid polyethylene glycols and mixtures of the foregoing; the one or more stabilising agents are selected from the group consisting of a tocopherol and salts thereof, ascorbic acid and salts thereof, methoxyphenol and derivatives thereof, trihydroxybenzoate and derivatives thereof, hydroquinone and derivatives thereof, methyl phenol and derivatives thereof, sodium metabisulfite and benzyl alcohol.

10. The use according to claim 8 or claim 9 wherein the carprofen is in an amount of from 1 to 500g/L.

11. The use according to claim 10 wherein the carprofen is in an amount of from 20 to 50g/L.

12. The use according to any one of claims 8 to 11 wherein the one or more polyols are in an amount of from 700 to 998g/L

13. The use according claim 12 wherein the one or more stabilising agents are in an amount of from 10 to 20g/L.

14. The use according claim 12 or claim 13 wherein the one or more co-solvents are in an amount of from 10 to 300g/L.

15. A method of treating pain and/or inflammation in a warm-blooded non-human animal, the method comprising administering to the animal a therapeutically effective amount of carprofen which is solubilised in a composition which comprises: one or more polyols; one or more stabilising agents; and optionally, one or more co-solvents. 10

16. The method of claim 15 wherein the composition is administered orally.

17. The method according to claim 16 wherein the one or more polyols are selected from the group consisting of propylene glycol, glycerol, sorbitol, solid polyethylene glycols and liquid polyethylene glycols and mixtures of the foregoing; the one or more stabilising agents are selected from the group consisting of a tocopherol and salts thereof, ascorbic acid and salts thereof, methoxyphenol and derivatives thereof, trihydroxybenzoate and derivatives thereof, hydroquinone and derivatives thereof, methyl phenol and derivatives thereof, sodium metabisulfite and benzyl alcohol.

18. The method according to any one of claims 15 to 17 wherein the carprofen is in an amount of from 1 to 500g/L.

19. The method according to claim 18 wherein the carprofen is in an amount of from 20 to 50g/L.

20. The method according to any one of claims 15 to 19 wherein the one or more polyols are in an amount of from 700 to 998g/L.

21. The method according claim 20 wherein the one or more stabilising agents are in an amount of from 10 to 20g/L.

22. The method according claim 20 or claim 21 wherein the one or more co-solvents are in an amount of from 10 to 300g/L.

23. A stable solvent-based composition as hereinbefore described with reference to any one of Examples 1 to 6. Dated this 3rd day of October 2003 Jurox Pty Ltd Patent Attorneys for the Applicant: F B RICE & CO