WO2007069033A2

WO2007069033A2 - Pharmaceutical compositions comprising dexibuprofen, an opiate analgesic and paracetamol

Info

Publication number: WO2007069033A2
Application number: PCT/IB2006/003567
Authority: WO
Inventors: Bradley Ryan Parsons
Original assignee: Adcock Ingram Limited
Priority date: 2005-12-12
Filing date: 2006-12-12
Publication date: 2007-06-21
Also published as: WO2007069033A3; ZA200803566B

Abstract

A pharmaceutical composition including a combination of a sub-therapeutic amount of the S isomer of ibuprofen, also referred to as dexibuprofen, or a pharmaceutically acceptable salt or derivative thereof, an opiate or a pharmaceutically acceptable salt or derivative thereof, and a centrally-acting cyclo-oxygenase inhibitor, as active ingredients, and a pharmaceutically acceptable carrier. A typical combination includes paracetamol, dexibuprofen and codeine, with the dexibuprofen being provided in an amount to give a daily dose of 100 mg or less. A method of treatment using a combination of a sub-therapeutic amount of dexibuprofen, an opiate and a centrally-acting cyclo-oxygenase inhibitor is also described.

Description

PHARMACEUTICAL COMPOSITIONS

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions and their use in the symptomatic relief and treatment of pain, during algesic and/or hyperalgesic states, with or without fever.

A hyperalgesic state can be defined as the state of exaggerated response to painful stimuli. It is a behavioral state in which the threshold to potentially painful events is reduced, and reactions to supra-threshold painful events are exaggerated. Algesia describes a normal physiological response to pain.

Pain of any aetiology can be a debilitating problem. Numerous theories have been proposed on the cause and treatment of this pathological condition. A vast number of receptors, biochemical transmitters and physiological processes are involved in the sensation and response to painful stimuli. Most pharmacological modalities target one specific site to reduce painful symptoms, which frequently does not provide adequate pain relief.

It is therefore a challenge for pharmaceutical scientists to provide a product that can provide effective pain relief while maintaining its quality over a period of time.

SUMMARY OF THE INVENTION

According to one aspect of the invention, there is provided a pharmaceutical composition including a combination of a sub-therapeutic amount of the S isomer of ibuprofen, also referred to as dexibuprofen, or a pharmaceutically acceptable salt or derivative thereof and an opiate or a pharmaceutically acceptable salt or derivative thereof, as active ingredients, and a pharmaceutically acceptable carrier.

The opiate may be selected from the group consisting of codeine, morphine, tramadol, fentanyl and pharmaceutically acceptable salts or derivatives thereof.

The pharmaceutical composition may further include a centrally-acting cyclo- oxygenase inhibitor, such as paracetamol or its pharmaceutically acceptable salts and derivatives.

One preferred composition of the invention comprises a combination of dexibuprofen and codeine, and in particular consists essentially of dexibuprofen and codeine.

A further preferred composition of the invention comprises a combination of dexibuprofen and tramadol.

A yet further preferred composition of the invention comprises a combination of dexibuprofen, codeine or tramadol, and paracetamol.

The ratio of dexibuprofen to codeine may range from about 1 :1 to about 1 :140

The dexibuprofen may be provided in an amount to give a dose of 100 mg or less, such as from about 50 mg to about 100 mg, or from about 70 mg to about 80 mg. Typical amounts are 100 mg, 80 mg, 75 mg, 70 mg or 50 mg.

The codeine may be provided in an amount to give a daily dose of from about 5 mg to about 360 mg, such as 10 mg. The tramadol may be provided in an amount to give a daily dose of from about 15 mg to about 500 mg.

The paracetamol may be provided in an amount to give a daily dose of from about 60 mg to about 4000 mg, such as 250 mg.

The invention extends to the use of a combination as defined above in a method of providing symptomatic relief or treatment of pain, in an algesic and/or hyperalgesic state, with or without fever, in particular that associated with inflammation such as that associated with trauma, osteoarthritis, rheumatoid arthritis, non-inflammatory myalgia or dysmenorrhoea.

The invention also extends to the use of a combination as defined above in the manufacture of a medicament for use in the symptomatic relief or treatment of pain, in an algesic and/or hyperalgesic state, with or without fever.

The invention also extends to a method of treating or preventing pain, in an algesic and/or hyperalgesic state, with or without fever, comprising administering to a patient in need thereof a combination as defined above.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a pharmaceutical composition including a combination of the S isomer of ibuprofen, also referred to as dexibuprofen, or a pharmaceutically acceptable salt or derivative thereof and an opiate or a pharmaceutically acceptable salt or derivative thereof, as active ingredients, and a pharmaceutically acceptable carrier.

Stereochemistry is a field of pharmaceutical interest which encompasses the investigation and quantification of molecules that are mirror images of one another. These chemical moieties have the same molecular mass and formulae, but due to the existence of chiral groups in their structures have the ability to rotate plane polarized light in opposite directions. Molecules that rotate light to the left are termed laevorotatory and those that rotate light to the right are said to be dextrorotatory. The mirror image molecules are termed enantiomers. When equal amounts of enantiomeric molecules are present together in a mixture, the mixture is said to be a 'racemic mixture'. The use of the symbols (R) and (S) are common-place to denote the different enantiomers. In the case of ibuprofen, the dextro-ibuprofen component is also referred to as dexibuprofen or the S (+) -enantiomer.

Recent developments in chiral chemistry have made it possible for pharmaceutical scientists to separate racemic mixtures of molecules and investigate the properties of each of the enantiomers from a clinical perspective. The findings in some cases have been quite profound. Often one of the two enantiomers appears to be responsible for the clinical efficacy of a drug while the remaining enantiomers is either inert or could be responsible for a number of side effects which are attributed to the drug in question. Two molecules which have successfully been refined through the evaluation of enantiomers are omeprazole (a widely-prescribed gastric ulcer medication) and citalopram (a leading antidepressant molecule). In each case the esomeprazole and escitalopram molecules have been successfully commercialized based on improved safety and efficacy profiles.

Ibuprofen, or 2-(4-isobuty!phenyl) propionic acid, is a widely used non-steroidal antiinflammatory drug which belongs to the propionic acid class of drugs. It is commonly available as a racemic mixture and has a long history of safety and efficacy in the treatment of pain and fever, with or without inflammation. Data suggests that the R (-) - enantiomer is inactive when administered to humans, prompting several clinical trials that investigated the therapeutic use of dexibuprofen. Efficacy was proven in a number of conditions, including rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and dysmenorrhoea. Further to this, tolerability was good when compared to other nonsteroidal anti-inflammatory drugs.

Pain management frequently requires a multi-tiered pharmacological approach due to its complex pathophysiology. The combination of paracetamol, ibuprofen (racemic) and codeine has been a hugely successful innovation in reducing pain and inflammation in human subject. At high doses, however, patients may experience untoward adverse side effects such as gastric irritation, which can be attributed to the ibuprofen component of the combination. The current invention proposes that the racemic ibuprofen be replaced by the dexibuprofen enantiomer to provide a product with high efficacy and safety profiles. It is further envisage that higher therapeutic doses of the combination could be used without compromising patient safety.

The pharmaceutical compositions of the invention are suitable for the symptomatic relief or treatment of pain, algesic and/or hyperalgesic, with or without fever, in particular but not limited to that associated with inflammatory processes, such as trauma, osteoarthritis, rheumatoid arthritis, non-inflammatory myalgia and dysmenorrhoea.

The first ingredient is dexibiprofen. This agent has anti-inflammatory and analgesic properties. As indicated above, it has been shown to provide an enhanced safety profile over racemic ibuprofen with equivalent efficacy. The dexibuprofen is typically administered in a sub-therapeutic amount, such as a daily dose of about 50 to 100 mg (the upper limit of a daily dose of 100 mg per day of dexibuprofen is half the dose of the racemic ibuprofen used in known compositions containing ibuprofen). This may be administered from 1 to 8 times per day (i.e. a daily dose of dexibuprofen of from 50 mg to 1000 mg).

The second ingredient is an opiate such as codeine, morphine, tramadol or fentanyl, for example. These compounds bind with specific receptors at many sites within the central nervous system to alter processes affecting both the perception of pain and the emotional response to pain.

The preferred opiates are codeine phosphate or tramadol, a derivative of codeine. The dose of codeine phosphate is from about 5 mg to about 360 mg, whilst the dose of tramadol is in the range of from about 15 mg to about 500 mg.

The above ingredients provide the preferred combination for the pharmaceutical compositions of the invention. Where appropriate, a centrally-acting cyclo-oxygenase inhibitor may be added to these compositions.

The preferred centrally-acting cyclo-oxygenase inhibitor is the analgesic paracetamol (acetaminophen) or a pharmaceutically acceptable salt or derivative thereof. It has analgesic and antipyretic properties but limited or no anti-inflammatory action.

The dose of the paracetamol active ingredient is typically in the range of from about 60 mg (pediatric) to about 4000 mg (adults).

The pharmaceutical compositions of the invention include a pharmaceutically acceptable carrier and may include other necessary non-active excipients, such as sorbitol, sucrose, saccharin, starch, lactose, guar gum, xanthan gum, magnesium stearate, bees wax, talc, methylcellulose, dextrin, povidone, polyvinylpyrrolidone and so forth. The pharmaceutical compositions may be provided in any appropriate dosage form, such as tablets, capsules, granules, suspensions, solutions or other liquid forms and so forth, and are intended for oral, rectal, transdermal, intramuscular or intravenous administration. The dosage form will typically be administered to a patient from 1 to 4 times per day. The product may be administered as an infusion, continuous or otherwise.

The invention will now be described, by way of example only, with reference to the following non-limiting examples.

The challenge is to formulate a therapeutically rational dosage form based on the marked differences in the pharmacokinetics and dosage quantities of the active agents in question. Furthermore, the inclusion of three active pharmaceutical ingredients with vastly different physiochemical properties into one convenient dosage form provides a unique challenge in that the formulation must be stable to environmental challenges over the duration of the product's shelf-life. Strict regulatory guidelines define the experimental methodology to be used to determine whether a product formulation is acceptable for use in patients. A product's integrity must be maintained under numerous temperature and humidity conditions. Ingredients may not degrade, and in the event that degradation does occur, strict conditions are set out as to the degree of degradation that is allowed. This is particularly relevant to this invention, and the potential breakdown components of paracetamol, para-amino phenol and codeine, codeine-N-oxide, are potentially toxic. The formulation therefore needs to be robust enough to ensure product quality is not compromised during manufacture or while on the market once commercialized.

Tablets and capsules are the most widely used dosage forms. For pediatric use, syrups and suspensions are popular. Due to the relatively poor solubility of ibuprofen in water, a suspension format is proposed. Table 1 reflects some potential formulation options which may result in a pharmaceutically stable product.

Table 1:

Method of manufacture and product test methodology

Capsule dosage form of manufacture

The composition of the invention can be manufactured using conventional pharmaceutical manufacturing methods, one of which is detailed below:

Paracetamol DC 500/600 is mixed with dexibuprofen and codeine phosphate to yield the bulk for encapsulation. It should be noted that 300 mg paracetamol DC 500/600 is equivalent to 250 mg paracetamol. Dexibuprofen, codeine phosphate and paracetamol DC 500/600 are screened through a 20 mesh (820 micron) sieve. The bulk is then blended for 10 minutes, and encapsulated using a Zanasi Matic 90 machine.

Tablet dosage form method of manufacture

Paracetamol dense powder (25kg), dexibuprofen (10kg), starch 1500 (4,62kg), Explotab (90Og) and Avicel pH 101 (3kg) are placed in a Diosna, which is run on a slow mixer setting for approximately 2 minutes.

Polyvinylpyrrolidone (PVP) K25 (2,4kg) should be dissolved in 13 litres of purified water and stirred until a clear yellowing solution is obtained.

In the Diosna, the above-mentioned bulk should be granulated with the PVP solution on a fast mixer setting for approximately 10 minutes until white-coloured easy flowing granules are obtained.

The granulate should then be emptied into an Aeromatic Fluid Bed Drier bowl and dried at 60 degrees Celsius until a moisture content of about 2,0-4,0% is attained.

The dried granules should then be passed through a 12 mesh vibrating sieve. The coarse granules should be passed through a 14 mesh Mill set at a slow hammer speed.

Codeine phosphate (1kg), AC-DI-SoI (1,96kg) and Avicel pH 101 (4,62kg) should be added to a Bulsbin or Hoop Blender and blended for 10 minutes. Magnesium Stearate (25Og) should also be added to the mixture and blended for a further 5 minutes.

Granules should have an angle of repose in the region of about 29.8 degrees and a flow rate of about 8 seconds.

The granules should be compresses on a Manesty BB3B compression machine to a hardness of about 70 Newtons. Disintegration time should be limited to not more than 20 minutes. A yield of approximately 50,000 tablets should be obtained.

In the event that a coating for the product is required, the following steps can be followed:

30Og of acacia powder should be dissolved in 870 ml of purified water using an industrial mixer. The temperature of the solution should be in the range of about 70 - 80 degrees Celsius. Mixing should continue for at least 25 minutes, after which 500 g of refined sugar can be added with continual stirring. The solution should be strained through a nylon straining bag. This should yield an effective sub-coat solution.

Build-up syrup should be prepared by adding acacia powder to heated purified water. Refined sugar can then be added and mixed for about an hour. Two kg of talc can then be added with further mixing.

Smoothing syrup can be made from 2 litres of water and 5 kg of sugar. A colourant such as Opalux Green can then be added to the solution while continuous mixing takes place.

The tablet cores should be placed in the coating pan and rolled until the cores are rolling freely. The sub-coat is applied whilst in dampings of approximately 400 ml, each spaced about a minute apart. Four applications should be sufficient. Whilst the tablets are rolling, sufficient talc should be applied slowly until no powder adheres to the cores. They should then be dried with hot air for about 10 minutes and the dust can be removed with a dust extractor. The build-up syrup can then be applied in volumes of about 400 ml. This can be applied until a mass of 80 g is achieved per 100 tablets. Smoothing syrup can then be applied in the same volume until a mass of 91 g is achieved per 100 tablets.

The coated tablets should be transferred to a Pellegrini polishing pan. Carnauba wax (2,5Og), Beswax-White (5g) and isopropyl alcohol (10g) should be melted and the warm solution should be applied slowly over the mass of tablets. All tablets should then be rolled in the pan until a shiny texture has been obtained.

Analytical development

The assays of the active pharmaceutical ingredients (API's) were performed by spectrophotometry after separation by high performance liquid chromatography (HPLC). HPLC is the applicant's analytical method of choice for the majority of drug stability protocols, as it is a selective technique, allowing the separation and measurement of the active pharmaceutical ingredients (API's) and their degradation products. The analytical test method was developed to be simple, precise and accurate.

The method has been developed by the applicant, consulting United States Pharmacopoeia (USP 27) 2004 "Acetaminophen and Codeine Phosphate Capsules" and "Ibuprofen Tablets" monographs. The chromatographic equipment utilized during the analytical development consisted of a Waters 2695 Alliance Separations module. A Waters 996 photo-diode array system provided the detector. The equipment interfaces Empower Pro software for interpretation of analytical data. A Discovery HS F5 (4,6 x 150) mm (Supelco) column was used. A wavelength of 275 nm was used for 4-aminophenol and paracetamol, 214 for codeine phosphate, 230 nm for ibuprofen and 260 nm for 4-isobutylacetophenone.

Elution of the active pharmaceutical ingredients and their degradation products was satisfactorily performed using isocratic analysis. The mobile phase consisted of 0,01 M ammonium acetate in 0,1 % formic acid (buffer solution). The ammonium acetate serves as the ion-pairing reagent.

Elution of paracetamol and its degradation product, 4-aminophenol was achieved with a ratio of 10 % acetonitrile and 90 % buffer solution, and that of codeine phosphate, dexibuprofen and its degradation product, 4-isobutylacetophenone with a ratio of 50 % acetonitrile and 50 % buffer solution.

The degradation products of paracetamol, 4-aminophenol and dexibuprofen, 4- isobutylacetophenone were measured and calculated with reference to the paracetamol and ibuprofen content in the formulation. The degradation limit was set at "not more than 0,1 % m/m of the API content" and was monitored over the full length of the stability testing program of the product.

The assay method to determine the content of the active pharmaceutical ingredients has been validated. It has been shown that the HPLC methods for the active pharmaceutical ingredients in the capsule have the following characteristics:

a) Linear results corresponding to 50 % to 150 % of the API in the capsules as tabulated in Table 2.

Table 2:

b) Specific, accurate and precise results for paracetamol, codeine phosphate and dexibuprofen in the range 90 % to 110 % of the concentration of active pharmaceutical ingredients in the product; and

c) Stable test solution up to 24 hours.

Limit tests were performed to determine the content of degradation products. The suitability of this test was established by meeting the requirements of the Specificity and Limit of Detection as per the USP 27<1225>, Validation of Compendial Methods pages 2622 to 2625.

The method outlined is simple and combines both specificity and sensitivity for the simultaneous estimation of the active pharmaceutical ingredients and their degradation products. The stability-indicating nature of the method offers a rapid and efficient method of stability control of the active pharmaceutical ingredients in the capsule preparation, as well as in assessing the degradation products of the active pharmaceutical ingredients

Test parameters and results

Once stored at the required ICH (International Conference on Harmonization) conditions, the following parameters were tested, initially and during the stability studies of the product:

Description;

Capsule contents;

Odour of contents;

Disintegration;

Average fill mass;

Uniformity of fill mass;

Loss on drying;

Paracetamol assay;

Codeine phosphate assay;

Dexibuprofen assay;

Content Uniformity of codeine phosphate;

Degradation products:

- 4-aminophenol, - 4-isobutylacetophenone; Paracetamol dissolution; Codeine phosphate dissolution; Dexibuprofen dissolution.

In addition to the parameters mentioned above, identification of active pharmaceutical ingredients were performed for lot release. No significant changes regarding the most critical tests were observed during the stability study. Based on these results, the proposed lot release tests are adequate for assessing the reproducibility and quality of this product.

Tablet dosage form method of manufacture

In vitro dissolution:

The choice of dissolution criteria at the time of submission of the MRF 1 was based on the USP 27, pages 33 to 34, "Acetaminophen and Codeine Phosphate Capsules" monograph and USP 27, pages 955 to 956, lbuprofen Tablets" monograph. The determination of the in vitro dissolution assay of the active pharmaceutical ingredients has been validated.

Table 3: Dissolution Criteria

While the invention has been described in detail with respect to specific embodiments thereof, it will be appreciated by those skilled in the art that various alterations, modifications and other changes may be made to the invention without departing from the spirit and scope of the present invention. It is therefore intended that the invention covers or encompasses all such modifications, alterations and/or changes.

Claims

CLAIMS:

1. A pharmaceutical composition comprising a combination of dexibuprofen or a pharmaceutically acceptable salt or derivative thereof in a sub-therapeutic amount, an opiate or a pharmaceutically acceptable salt or derivative thereof, and a centrally-acting cyclo-oxygenase inhibitor or a pharmaceutically acceptable salt or derivative thereof, as active ingredients, and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 50 mg to 100 mg.

3. A pharmaceutical composition according to claim 1, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 70 mg to 80 mg.

4. A pharmaceutical composition according to claim 1, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of 100 mg.

5. A pharmaceutical composition according to claim 1, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of 75 mg.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the opiate salt or derivative thereof, is selected from the group consisting of codeine, morphine, tramadol, fentanyl and pharmaceutically acceptable salts or derivatives thereof.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the centrally-acting cyclo-oxygenase inhibitor is paracetamol.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the dexibuprofen, opiate and centrally-acting cyclo-oxygenase inhibitor are provided in amounts such that the combination is therapeutically effective in treating pain, in an algesic and/or hyperalgesic state, with or without fever.

9. A pharmaceutical composition according to any one of claims 1 to 8, comprising a combination of dexibuprofen or a pharmaceutically acceptable salt or derivative thereof, codeine or a pharmaceutically acceptable salt or derivative thereof, and paracetamol.

10. A pharmaceutical composition according to any one of claims 1 to 8, comprising a combination of dexibuprofen or a pharmaceutically acceptable salt or derivative thereof, tramadol or a pharmaceutically acceptable salt or derivative thereof, and paracetamol.

11. A pharmaceutical composition according to any one of claims 1 to 9, consisting essentially of dexibuprofen, codeine and paracetamol.

12. A pharmaceutical composition according to any one of claims 1 to 11 , wherein all of the active ingredients are provided in sub-therapeutic amounts.

13. A combination of dexibuprofen in a sub-therapeutic amount, an opiate and a centrally-acting cyclo-oxygenase inhibitor, or pharmaceutically acceptable derivatives or salts thereof, as active ingredients, for use in the treatment of pain, in an algesic and/or hyperalgesic state, with or without fever, the amounts of the active ingredients being selected such that the combination is therapeutically effective.

14. A combination according to claim 13, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 50 mg to 100 mg.

15. A combination according to claim 13, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 70 mg to 80 mg.

16. A combination according to claim 13, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of 100 mg.

17. A combination according to any one of claims 13 to 16, wherein the combination is a composition as defined in any one of claims 1 to 12.

18. A combination according to any one of claims 13 to 17, wherein all of the active ingredients are provided in sub-therapeutic amounts.

19. A combination according to any one of claims 13 to 18, wherein the pain is associated with inflammation.

20. A combination according to any one of claims 13 to 18, wherein the pain is associated with trauma, osteoarthritis, rheumatoid arthritis, non-inflammatory myalgia or dysmenorrhoea.

21. The use of dexibuprofen in a sub-therapeutic amount, an opiate and a centrally- acting cyclo-oxygenase inhibitor, or pharmaceutically acceptable salts or derivatives thereof, as active ingredients, in the manufacture of a medicament for use in a method of treating pain, in an algesic and/or hyperalgesic state, with or without fever.

22. The use according to claim 21, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 50 mg to 100 mg.

23. The use according to claim 21, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 70 mg to 80 mg.

24. The use according to claim 21, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of 100 mg.

25. The use of any one of claims 21 to 24, wherein the medicament is provided in a dosage form selected from the group consisting of tablets, capsules, granules, suspensions, solutions and other liquid forms.

26. The use of claim 25, wherein the medicament is administered orally, rectally, transdermal^, intramuscularly or intravenously.

27. The use of claim 26, wherein the dosage form is administered to a patient from 1 to 4 times a day.

28. The use of claim 25, wherein the medicament is administered as an infusion, continuous or otherwise.

29. A method of treating pain, in an algesic and/or hyperalgesic state, with or without fever, comprising administering to a patient in need thereof a therapeutically effective amount of a combination of dexibuprofen, an opiate and a centrally-acting cyclo-oxygenase inhibitor, or pharmaceutically acceptable salts or derivatives thereof, as active ingredients, wherein the dexibuprofen is provided in a sub-therapeutic amount.

30. A method according to claim 29, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 50 mg to 100 mg.

31. A method according to claim 29, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of from 70 mg to 80 mg.

32. A method according to claim 29, wherein the dexibuprofen or salt or derivative thereof is provided in an amount to give a dose of 100 mg.

33. A method according to any one of claims 29 to 32, wherein the opiate, salt or derivative thereof is selected from the group consisting of codeine, morphine, tramadol, fentanyl and pharmaceutically acceptable salts or derivatives thereof.

34. A method according to any one of claims 29 to 33, wherein the centrally-acting cyclo-oxygenase inhibitor is paracetamol.

35. A method according to any one of claims 29 to 34, comprising administering to a patient in need thereof a combination of dexibuprofen, codeine and paracetamol.

36. A method according to any one of claims 29 to 34, comprising administering to a patient in need thereof a combination of dexibuprofen, tramadol and paracetamol.

37. A method according to claim 35, wherein the codeine is provided in an amount to give a dose from about 10 mg to about 360 mg.

38. A method according to claim 36, wherein the tramadol is provided in an amount to give a dose from about 25 mg to about 500 mg.

39. A method according to claim 34, wherein the paracetamol is provided in an amount to give a dose from about 60 mg to about 4000 mg.

40. A method according to claim 35, wherein the ratio of dexibuprofen to codeine ranges from about 1:1 to about 1 :140.