Topical composition comprising ibuprofen

Abstract

The present invention is directed to a topical gel composition comprising ibuprofen in the form of a mixture of ibuprofen acid and a salt of ibuprofen, a first skin penetration enhancer, a second skin penetration enhancer and water wherein the ibuprofen is capable of providing relief from pain and inflammation for a period of at least 10hrs after application of the composition.

Description

[0001] PAT15719-WO-PCT

[0002] Novel Composition

[0003] The present invention is directed to a novel topical composition. In particular, the present invention is directed to a composition containing an analgesic, such as a non-steroidal antiinflammatory drug (NSAID) having improved local bioavailability following permeation through the layers of the skin of an individual. A preferred composition of the present invention comprises ibuprofen as the active pharmaceutical ingredient.

[0004] Compositions containing NSAIDs in the form of gels, creams and sprays intended for topical application for local to underlying tissues, for the relief of pain and inflammation are known. Transdermal / topical delivery, for local effect of pharmaceutically active compounds (including NSAIDs), was developed to address the problems associated with orally taken drug compositions, e.g. actives breaking down in the body on the first pass through the liver. However, some NSAIDs exhibit undesirable side effects (such as gastric, hepatic, renal and other effects) and, for this reason, there is a continuing need to provide a topical composition which provides an effective amount for therapeutic activity at the local tissue target below the application site while at the same time preventing general uptake in the systemic circulation.

[0005] Voltarol is a diclofenac-containing product that claims 12 hours of pain relief. However, this gel is based on posology rather than efficacy, and it takes a considerable amount of time for the diclofenac to build up in the area applied and maximum efficacy to be achieved. The gel also has an unpleasant smell due to the combination of the excipients and the amine salt of diclofenac.

[0006] The current ibuprofen gels that are available provide pain relief for about 6hrs. There are currently no ibuprofen gels that provide pain relief for 12hrs.

[0007] In addition, it is known that topical ibuprofen-containing compositions which are used for relief from pain and inflammation can cause a mild and short-lived irritation at the site of application. Such irritation can be in the form of redness or erythema and itch or pruritus.PAT15719-WO-PCT

[0008] It would, therefore, be desirable to develop a topical ibuprofen-containing composition which reduces or mitigates the potential for casing any short-term irritancy.

[0009] According to an aspect of the present invention there is provided a topical gel composition comprising ibuprofen in the form of a mixture of ibuprofen acid and a salt of ibuprofen, a first skin penetration enhancer, a second skin penetration enhancer and water wherein the ibuprofen is capable of providing relief from pain and inflammation for a period of at least lOhrs after application of the composition.

[0010] The ibuprofen is capable of providing relief from pain and inflammation for a period of 12hrs.

[0011] The ibuprofen can comprise a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen. Preferably, the ibuprofen can comprise a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen.

[0012] The salt of ibuprofen can be an alkali metal salt, an alkaline earth metal salt or an amine salt. Preferred alkali metals are sodium and potassium. Preferred alkaline earth metal salts are calcium and magnesium. Preferred amine salts are ammonium, lysine.

[0013] The composition can comprise l%w / w - 15%w / w of the ibuprofen. Preferably, the composition can comprise 2%w / w - 10%w / w of the ibuprofen. More preferably, the composition can comprise 3%w / w - 6%w / w of the ibuprofen.

[0014] The composition comprises 45%w / w - 75%w / w of water. Preferably, the composition comprises 50%w / w - 70%w / w of water. More preferably, the composition comprises 55%w / w - 65%w / w of water.

[0015] Preferably, the composition can comprise 0.1%w / w - 5%w / w of the first penetration enhancer. More preferably, the composition can comprise 0.5%w / w - 2%w / w of the first penetration enhancer.PAT15719-WO-PCT

[0016] The first penetration enhancer can be selected from polyoxypropylene stearyl ether, diethylene glycol monoethyl ether (DGME), lauric acid, lauric alcohol or myristyl alcohol.

[0017] Preferably, the composition can comprise l%w / w - 20%w / w of the second penetration enhancer. More preferably, the composition can comprise 5%w / w - 10%w / w of the second penetration enhancer. More preferably, the composition can comprise 6%w / w - 8%w / w of the second penetration enhancer.

[0018] The second penetration enhancer can be selected from propylene glycol, dimethyl sulphoxide oleic acid or oleyl alcohol.

[0019] The weight ratio of the first penetration enhancer and the second penetration enhancer can be from 1:1 to 1:16. Preferably, the weight ratio of the first penetration enhancer and the second penetration enhancer can be from 1:3 to 1:10. More preferably, the weight ratio of the first penetration enhancer and the second penetration enhancer can be from 1:6 to 1:8.

[0020] Preferably, the composition can further comprise 0.1%w / w - 2%w / w of a first rheology modifier. More preferably, the composition can comprise 0.3%w / w - 0.8%w / w of the first rheology modifier.

[0021] The first rheology modifier can be selected from xanthan gum, carbomer or poloxamer.

[0022] Preferably, the composition can further comprise 0.1%w / w - 2%w / w of a second rheology modifier. More preferably, the composition can comprise 0.8%w / w- 1.3%w / w of the second rheology modifier.

[0023] The second rheology modifier which is different to the first rheology modifier can be selected from hydroxyethyl cellulose, hydroxypropyl methyl cellulose, xanthan gum, carbomer or poloxamer.

[0024] The weight ratio of the first rheology modifier and the second rheology modifier can be from 1:1.25 to 1:3. Preferably, the weight ratio of the first rheology modifier and the secondPAT15719-WO-PCT

[0025] rheology modifier can be from 1:1.4 to 1:2. More preferably, the weight ratio of the first rheology modifier and the second rheology modifier can be from 1:1.5 to 1:1.7.

[0026] The composition can comprise l%w / w - 15%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.1%w / w - 2%w / w of hydroxyethyl cellulose and 45%w / w - 75%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:3 to 1:10 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.25 to 1:3.

[0027] The composition can comprise l%w / w - 15%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.125%w / w - 3%w / w of hydroxyethyl cellulose and 45%w / w - 75%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:3 to 1:10 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.25 to 1:3.

[0028] The composition can comprise 2%w / w - 10%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.1%w / w - 2%w / w of hydroxyethyl cellulose and 50%w / w - 70%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.4 to 1:2.

[0029] The composition can comprise 2%w / w - 10%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.2%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.14%w / w - 3%w / w of hydroxyethyl cellulose and 50%w / w - 70%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.4 to 1:2.PAT15719-WO-PCT

[0030] Preferably, the composition can comprise 3%w / w - 6%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.5%w / w - 2%w / w of polyoxypropylene stearate, 5%w / w - 10%w / w of propylene glycol, 0.3%w / w - 0.8%w / w of xanthan gum, 0.8%w / w - 1.3%w / w of hydroxyethyl cellulose and 55%w / w - 65%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.5 to 1:1.7.

[0031] Preferably, the composition can comprise 3%w / w - 6%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.75%w / w - 1.5%w / w of polyoxypropylene stearate, 4.5%w / w - 10%w / w of propylene glycol, 0.3%w / w - 0.8%w / w of xanthan gum, 0.8%w / w - 1.3%w / w of hydroxyethyl cellulose and 55%w / w - 65%w / w of water the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.5 to 1:2.

[0032] The composition can comprise l%w / w - 15%w / w of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.1%w / w -2%w / w of hydroxyethyl cellulose and 45%w / w - 75%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:3 to 1:10 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.25 to 1:3.

[0033] The composition can comprise l%w / w - 15%w / w of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.125%w / w -3%w / w of hydroxyethyl cellulose and 45%w / w - 75%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:3 to 1:10 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.25 to 1:3.

[0034] The composition can comprise 2%w / w - 10%w / w of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate,PAT15719-WO-PCT

[0035] l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.1%w / w -2%w / w of hydroxyethyl cellulose and 50%w / w - 70%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.4 to 1:2.

[0036] The composition can comprise 2%w / w - 10%w / w of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.2%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.14%w / w -3%w / w of hydroxyethyl cellulose and 50%w / w - 70%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.4 to 1:2.

[0037] Preferably, the composition can comprise 3%w / w - 6%w / w of ibuprofen of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.5%w / w - 2%w / w of polyoxypropylene stearate, 5%w / w - 10%w / w of propylene glycol, 0.3%w / w - 0.8%w / w of xanthan gum, 0.8%w / w - 1.3%w / w of hydroxyethyl cellulose and 55%w / w - 65%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.5 to 1:1.7.

[0038] Preferably, the composition can comprise 3%w / w - 6%w / w of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.75%w / w - 1.5%w / w of polyoxypropylene stearate, 4.5%w / w - 10%w / w of propylene glycol, 0.3%w / w - 0.8%w / w of xanthan gum, 0.8%w / w - 1.3%w / w of hydroxyethyl cellulose and 55%w / w - 65%w / w of water the weight ratio of polyoxypropylene stearyl ether and propylene glycol can be from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose can be from 1:1.5 to 1:2.

[0039] The composition can further comprise an emulsifier selected from cetareth 20, cetyl alcohol, cetearyl alcohol, sorbitan monolaurate, sorbitan monooleate, laureth 23, cithrol, steareth 20, a polyoxyethylene sorbitan such as polysorbate 20, polysorbate 80, or a polyoxyethylene alkyl ether such as a Brij® surfactant. The Brij® series of surfactants are polyoxyethylene vegetable-PAT15719-WO-PCT

[0040] based fatty ethers derived from lauryl, cetyl, stearyl, and oleyl ethers which are available from Croda.

[0041] The emulsifier can be present at a level of 0.5%w / w - 5%w / w. Preferably the emulsifier is present in the composition at a level of l%w / w - 2%w / w.

[0042] The composition can further comprise a humectant selected from glycerol, butylene glycol, PEG 4000, PEG 6000 or urea.

[0043] The humectant can be present at a level of 0.5%w / w - 10%w / w. Preferably the humectant is present in the composition at a level of l%w / w - 5%w / w. More preferably, the humectant can be present in the composition at a level of l%w / w - 3%w / w.

[0044] The composition can further comprise a pH adjuster selected from sodium hydroxide, potassium hydroxide, ammonia, ethylenediamine, diisopropanolamine, diethanolamine, triisopropanolamine, triethanolamine, tartaric acid, citric acid, malic acid, lactic acid, hydrochloric acid, phosphoric acid, acetic acid, fumaric acid or maleic acid.

[0045] The pH adjuster can be present at a level of 0.1%w / w - 5%w / w. Preferably the pH adjuster is present in the composition at a level of 0.4%w / w - 0.6%w / w.

[0046] The composition can further include a solvent selected from alcohols. Preferably the solvent is an alcohol selected from C2 - C4 alcohols.

[0047] Preferably the composition comprises the solvent at a level of 15%w / w - 30%w / w. More preferably, the composition comprises the solvent at a level of 20%w / w - 25%w / w.

[0048] The composition can comprise a warming sensate ora cooling sensate selected from menthol, N,2,3-trimethyl-2-(l-methylethyl)-butanamide (WS-23),

[0049] N-(Ethoxycarbonylmethyl)-3-p-menthanecarboxamide (WS-5),

[0050] N-Ethyl-5-Methyl-2-(l- Methylethylj-Cyclohexanecarboxamide (WS-3),PAT15719-WO-PCT

[0051] (lR,2S,5R)-N-(4-Methoxyphenyl)-5-methyl-2-(l-methylethyl)cyclohexanecarboxamide (WS-12), vanillyl butyl ether, isopulegol, eucalyptol, capsicum, capsaicin or methyl salicylate. WS-23, WS-5, WS-3 and WS-12 are available from Symrise under the name Symcool (RTM).

[0052] The composition can comprise the sensate at a level of from 0.1%w / w - 5%w / w. Preferably, the composition can comprise the sensate at a level of 0.5%w / w - 3%w / w.

[0053] Example embodiments of the invention will now be described by way of example only with reference to the accompanying Figure 1 which illustrates the mean cumulative amount of ibuprofen (expressed as a percentage of applied dose) that permeates through a sample of ex vivo adult human abdominal skin over a 12hr period.

[0054] Examples of the composition of the present invention are shown in Table 1.

[0055] Component (% w / w) Exl Ex 2 Ex 3 Ex 4 Ex 5

[0056] Ibuprofen 5.00 5.00 5.00 5.00 5.00 Propylene Glycol 7.07 7.00 7.00 7.00 7.00 Polyoxypropylene Stearyl Ether 1.01 1.00 1.00 1.00 1.00 Glycerin 2.02 2.00 2.00 2.00 2.00 Water 61.05 60.35 60.25 60.15 60.40 Isopropyl Alcohol 20.21 20.00 20.00 20.00 20.00 Xanthan Gum 0.61 0.60 0.60 0.60 0.60 Hydroxy Ethylcellulose 1.01 1.00 1.00 1.00 1.00 Sodium Hydroxide Pellets 0.50 0.50 0.50 0.50 0.50 Cetearyl alcohol 1.52 1.50 1.50 1.50 1.50 Isopulegol - 0.30 0.30 0.30 0.30 Eucalyptol - - 0.10 0.20 0.20 WS-23 - 0.25 0.25 0.25 0.25 WS-5 - 0.50 0.50 0.50 0.25

[0057]

[0058] TOTAL 100.00 100.00 100.00 100.00 100.00

[0059] Table 1

[0060] The compositions can be made in the following way.

[0061] A mixture of the emulsifier in isopropyl alcohol was prepared and to this mixture was added polyoxxypropylene stearyl ether. The sensate was then added to this mixture. A mixture of hydroxyethyl cellulose and xanthan gum was prepared and added to this mixture to form aPAT15719-WO-PCT

[0062] first composition. Separately, an aqueous solution of sodium hydroxide was added1of the required amount of ibuprofen. Glycerol, propylene glycol and the remaining amount of ibuprofen were then added to form a second composition. The first and second compositions were then combined with stirring. The stirring was maintained until the gel was formed. The gel was typically formed in less than about 30mins. The first composition and the second composition were prepared at room temperature.

[0063] In vitro human skin permeation tests were performed to determine the permeability of the compositions of the present invention. The results of these tests and the permeability of an existing product (Deep Relief Anti-Inflammatory Gel) are shown in Figure 1 and Table 2 below.

[0064] Mean ibuprofen detected at 12hr

[0065] Composition

[0066] (%w / w of amount applied)

[0067] Example 1 28.00

[0068] Example 2 32.00

[0069] Example 3 35.00

[0070] Example 4 29.00

[0071] Example 5 25.00

[0072] Comparison 18.00

[0073]

[0074] Table 2

[0075] The in vitro permeability tests were performed as follows. A section of ex vivo adult human abdominal skin having a thickness of 500pm + / - 100pm and a dosing area of 0.6cm2in a vertical diffusion cell having a volume of 2ml was prepared. A 6mg sample of the composition of the present invention was applied to the ex vivo adult human abdominal skin and allowed to penetrate the layers of the ex vivo adult human abdominal skin over a period of 12hrs into a solution of 0.5%w / v of a polyoxyethylene (20) oleyl ether (sold as Brij 98) in phosphate buffered saline. 200pl samples of the composition were taken at 0, 1, 2, 4, 6, 8 and 12hrs. The amount of ibuprofen in each sample was measured. The tests were repeated 6 times for each composition and an average value for the mean cumulative amount of ibuprofen in the that has permeated through the ex vivo adult human abdominal skin was calculated for eachPAT15719-WO-PCT

[0076] of the above time points. The tests were performed at 25°C. An existing product (Deep Relief Anti-Inflammatory Gel) containing 5% w / w ibuprofen was tested as a comparison. The existing product also contains menthol, carbomer, propylene glycol, diisopropanolamine and water.

[0077] As can be seen from Figure 1 and Table 2, the compositions of the present invention show significant improvement in the amount of ibuprofen that permeates through the ex vivo adult human abdominal skin over a 12hr period compared to an existing commercial composition.

[0078] The compositions of the present invention were assessed for potential local cutaneous irritation. The Cumulative Irritation Patch Test (CIPT) is an established and internationally recognised methodology for determining a formulation's intrinsic propensity to induce skin irritation under controlled, typically occlusive, conditions. The compositions of Examples 1 -5 were evaluated to characterise and rank their cumulative irritation potential. A commercially marketed ibuprofen topical product was included as a reference comparator to contextualise the irritation profile of the investigational formulations as well as placebo, standard positive and negative controls were incorporated to confirm methodological validity. The commercially marketed product contained 5% ibuprofen, menthol, carbomer, propylene glycol, diisopropanolamine, alcohol and water. The placebo compositions did not contain any ibuprofen. The positive control contained 0.1% sodium lauryl sulphate (SLS) -this is a well-established control composition used in irritancy studies. The negative control was the occlusive patch only with no topical composition.

[0079] The compositions tested were applied to the skin of individuals and occlusive patches were applied thereon. Across all evaluable timepoints, each of Examples 1-5 demonstrated lower cumulative irritation scores than the commercial reference product as measured using the Berger and Boman scale. The inclusion of placebo formulations, containing no active pharmaceutical ingredient, further enabled attribution of irritancy. These placebo formulations — along with the negative control — exhibited minimal irritation, thereby demonstrating that ibuprofen itself was the primary contributor to any observed skin reactions. Importantly, the formulation's drug-delivery system did not meaningfully increase irritation under the conditions tested.PAT15719-WO-PCT

[0080] Despite achieving enhanced delivery of ibuprofen into and through the skin — at levels exceeding those typical of existing commercial products — the formulations do so without increasing cutaneous irritation risk.

[0081] The compositions of the present invention are capable of providing controlled permeation of ibuprofen so that optimal efficacy is achieved as quickly as possible. In addition, the compositions of the present invention are capable of providing a continuous gradient of movement though the skin such that there is sustained release over 12 hours.

[0082] An advantage of the present invention is that there is provided an aqueous gel compositions which contain ibuprofen and are capable of providing improved efficacy in treating pain and inflammation and are also capable of reducing the potential for any unacceptable local irritation at the site of application.

[0083] Further modifications can be made without departing from the scope of the invention described herein.

Claims

PAT15719-WO-PCTClaims:

1. A topical gel composition comprising ibuprofen in the form of a mixture of ibuprofen acid and a salt of ibuprofen, a first skin penetration enhancer, a second skin penetration enhancer and water wherein the ibuprofen is capable of providing relief from pain and inflammation for a period of at least lOhrs after application of the composition.

2. A composition as claimed in Claim 1 wherein the ibuprofen is capable of providing relief from pain and inflammation for a period of 12hrs.

3. A composition as claimed in Claim 1 or Claim 2 wherein the ibuprofen comprises a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen.

4. A composition as claimed in Claim 3 wherein the ibuprofen comprises a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen.

5. A composition as claimed in any of the preceding Claims wherein the salt of ibuprofen is an alkali metal salt, an alkaline earth metal salt or an amine salt.

6. A composition as claimed in any of the preceding Claims wherein the composition comprises l%w / w- 15%w / w of the ibuprofen.

7. A composition as claimed in Claim 6 wherein the composition comprises 3%w / w - 6%w / w of the ibuprofen.

8. A composition as claimed in any of the preceding Claims wherein the composition comprises 45%w / w - 75%w / w of water.

9. A composition as claimed in Claim 8 wherein the composition comprises 55%w / w - 65%w / w of water.

10. A composition as claimed in any of the preceding Claims wherein the composition comprises 0.1%w / w - 5%w / w of the first skin penetration enhancer.PAT15719-WO-PCT11. A composition as claimed in Claim 10 wherein the composition comprises 0.5%w / w - 2%w / w of the first skin penetration enhancer.

12. A composition as claimed in any of the preceding Claims wherein the first skin penetration enhancer is selected from polyoxypropylene stearyl ether, diethylene glycol monoethyl ether (DGME), lauric acid or myristyl alcohol.

13. A composition as claimed in any of the preceding Claims wherein the composition comprises l%w / w -20%w / w of the second skin penetration enhancer.

14. A composition as claimed in Claim 13 wherein the composition comprises 5%w / w - 10%w / w of the second skin penetration enhancer.

15. A composition as claimed in any of the preceding Claims wherein the second skin penetration enhancer is selected from propylene glycol or oleyl alcohol.

16. A composition as claimed in any of the preceding Claims wherein the weight ratio of the first penetration enhancer and the second skin penetration enhancer is from 1:1 to 1:16.

17. A composition as claimed in Claim 16 wherein the weight ratio of the first penetration enhancer and the second penetration enhancer is from 1:6 to 1:8.

18. A composition as claimed in any of the preceding Claims wherein the composition further comprises 0.1%w / w - 2%w / w of a first rheology modifier.

19. A composition as claimed in Claim 18 wherein the composition comprises 0.3%w / w - 0.8%w / w of the first rheology modifier.

20. A composition as claimed in Claim 18 or Claim 19 wherein the first rheology modifier is selected from xanthan gum, carbomer or poloxamer.

21. A composition as claimed in any of the preceding Claims wherein the composition further comprises 0.1%w / w - 2%w / w of a second rheology modifier.PAT15719-WO-PCT22. A composition as claimed in Claim 21 wherein the composition the composition comprises 0.8%w / w- 1.3%w / w of the second rheology modifier.

23. A composition as claimed in Claim 21 or Claim 22 wherein the second rheology modifier which is different to the first rheology modifier is selected from hydroxyethyl cellulose, xanthan gum, carbomer or poloxamer.

24. A composition as claimed in any of Claims 21 - 23 wherein the weight ratio of the first rheology modifier and the second rheology modifier is from 1:1.25 to 1:3.

25. A composition as claimed in Claim 24 wherein the weight ratio of the first rheology modifier and the second rheology modifier is from 1:1.5 to 1:1.7.

26. A composition as claimed in Claim 24 wherein the composition comprises l%w / w - 15%w / w of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.1%w / w - 2%w / w of hydroxyethyl cellulose and 45%w / w - 75%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol is from 1:3 to 1:10 and the weight ratio of xanthan gum and hydroxyethyl cellulose is from 1:1.25 to 1:3.

27. A composition as claimed in Claim 26 wherein the composition comprises 3%w / w - 6%w / w of ibuprofen of ibuprofen as a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.5%w / w - 2%w / w of polyoxypropylene stearate, 5%w / w - 10%w / w of propylene glycol, 0.3%w / w - 0.8%w / w of xanthan gum, 0.8%w / w - 1.3%w / w of hydroxyethyl cellulose and 55%w / w - 65%w / w of water the weight ratio of polyoxypropylene stearyl ether and propylene glycol is from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose is from 1:1.5 to 1:1.7.

28. A composition as claimed in Claim 24 wherein the composition comprises l%w / w - 15%w / w of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.1%w / w - 5%w / w of polyoxypropylene stearate, l%w / w - 20%w / w of propylene glycol, 0.1%w / w - 2%w / w of xanthan gum, 0.1%w / w - 2%w / w ofPAT15719-WO-PCThydroxyethyl cellulose and 45%w / w - 75%w / w of water wherein the weight ratio of polyoxypropylene stearyl ether and propylene glycol is from 1:3 to 1:10 and the weight ratio of xanthan gum and hydroxyethyl cellulose is from 1:1.25 to 1:3.

29. A composition as claimed in Claim 28 wherein the composition comprises 3%w / w - 6%w / w of ibuprofen of ibuprofen as a 1:1 mixture by weight of ibuprofen acid and a salt of ibuprofen, 0.5%w / w - 2%w / w of polyoxypropylene stearate, 5%w / w - 10%w / w of propylene glycol, 0.3%w / w - 0.8%w / w of xanthan gum, 0.8%w / w - 1.3%w / w of hydroxyethyl cellulose and 55%w / w - 65%w / w of water the weight ratio of polyoxypropylene stearyl ether and propylene glycol is from 1:6 to 1:8 and the weight ratio of xanthan gum and hydroxyethyl cellulose is from 1:1.5 to 1:1.7.

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