Novel composition

Abstract

The present invention is directed to a topical aqueous gel composition comprising ibuprofen, and a combination of a first skin penetration enhancer and a second skin penetration enhancer wherein the combination of skin enhancers allows the composition to maintain a mean rate of permeation of ibuprofen through ex vivo adult human abdominal skin of at least 6 µg / cm2 / hr for a period of 2 – 12hr after application to the ex vivo adult human abdominal skin.

Description

[0001] PAT15718-WO-PCT

[0002] Novel Composition

[0003] The present invention is directed to a novel combination of skin penetration enhancers and their use to improve the permeation of an active pharmaceutical ingredient in a topical composition through the skin. In particular, the present invention is directed to a composition containing an analgesic, such as a non-steroidal anti-inflammatory 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. Accordingly, there is a need to provide an ibuprofen gel that can provide pain relief for a period of up to 12hrs.PAT15718-WO-PCT

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

[0008] According to a first aspect of the present invention there is provided a topical gel composition comprising ibuprofen, and a combination of a first skin penetration enhancer, a second skin penetration enhancer and water wherein the combination of first and second skin penetration enhancers allows the composition to maintain a mean rate of in vitro permeation of ibuprofen through ex vivo adult human abdominal skin of at least 6 pg / cm2 / hr for a period of 2 - 12hrs after application to the ex vivo adult human abdominal skin.

[0009] Preferably, the mean rate of in vitro permeation of ibuprofen is between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin.

[0010] The in vitro permeation rate of the ibuprofen was measured using a vertical diffusion cell or Franz cell using the method set out below.

[0011] Preferably, the peak in vitro permeation rate of the ibuprofen following application of the composition is 15pg / cm2 / hr - 22.5pg / cm2 / hr to the ex vivo adult human abdominal skin.

[0012] Preferably, the peak in vitro permeation rate is between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

[0013] Preferably, the peak in vitro permeation rate of the ibuprofen following application of the composition is 15pg / cm2 / hr - 22.5pg / cm2 / hr between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

[0014] The ibuprofen can comprise a mixture of ibuprofen acid and a salt of ibuprofen. The ibuprofen can comprise a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen.PAT15718-WO-PCT

[0015] Preferably, the ibuprofen comprises a 1:1 mixture by weight of ibuprofen acid and the salt of ibuprofen.

[0016] The topical aqueous gel composition comprises a 1:1 combination of ibuprofen acid and a salt of ibuprofen, and a combination of a polyoxypropylene glycol stearyl ether and propylene glycol wherein the combination of polyoxypropylene glycol stearyl ether and propylene glycol allows the composition to maintain a mean rate of in vitro permeation of ibuprofen through the ex vivo adult human abdominal skin of at least 6 pg / cm2 / hr for a period of 2 - 12hr after application to the ex vivo adult human abdominal skin and a mean rate of in vitro permeation of ibuprofen of between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin.

[0017] Preferably, the topical aqueous gel composition comprises ibuprofen in the form of a 1:1 mixture of ibuprofen acid and a salt of ibuprofen, and a combination of a first skin penetration enhancer and a second skin penetration enhancer wherein the combination of the first and second skin penetration enhancers allows the composition to maintain an rate of in vitro permeation of ibuprofen through the ex vivo adult human abdominal skin of between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin and wherein the ibuprofen has a peak in vitro permeation rate of 15pg / cm2 / hr - 22.5pg / cm2 / hr between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

[0018] More preferably, the topical aqueous gel composition comprises ibuprofen in the form of a 1:1 mixture of ibuprofen acid and a salt of ibuprofen, and a combination of a polyoxypropylene stearyl ether and propylene glycol wherein the combination of polyoxypropylene stearyl ether and propylene glycol allows the composition to maintain an rate of in vitro permeation of ibuprofen through the ex vivo adult human abdominal skin of between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin and wherein the ibuprofen has a peak in vitro permeation rate of 15pg / cm2 / hr - 22.5pg / cm2 / hr between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.PAT15718-WO-PCT

[0019] The salt of ibuprofen can be in the form of 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The first penetration enhancer can be selected from polyoxypropylene stearyl ether, diethylene glycol monoethyl ether (DGME), lauric acid, lauric alcohol or myristyl alcohol.

[0024] 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.

[0025] The second penetration enhancer can be selected from propylene glycol, dimethyl sulphoxide oleic acid or oleyl alcohol.

[0026] 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.PAT15718-WO-PCT

[0027] 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.

[0028] The first rheology modifier can be selected from xanthan gum, carbomer or poloxamer.

[0029] 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.

[0030] 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.

[0031] 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 second 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.

[0032] The composition can comprise l%w / w - 15%w / w 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 2%w / w - 10%w / w 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.PAT15718-WO-PCT

[0034] The composition can comprise 2%w / w - 10%w / w 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.

[0035] Preferably, the composition can comprise 3%w / w - 6%w / w 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 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.

[0036] Preferably, the composition can comprise 3%w / w - 6%w / w 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.

[0037] The composition can further include a solvent selected from alcohols. Preferably the solvent is an alcohol selected from C2 - C4 alcohols.

[0038] 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.

[0039] According to a second aspect of the present invention there is provided the use of a combination of skin penetration enhancers comprising a first skin penetration enhancer and a second skin penetration enhancer to facilitate the permeation of ibuprofen from a topical ibuprofen-containing composition through ex vivo adult human abdominal skin wherein thePAT15718-WO-PCT

[0040] in vitro permeation rate of the ibuprofen is at least 6 pg / cm2 / hr for a period of 2 - 12hr after application to the ex vivo adult human abdominal skin.

[0041] Preferably, the mean rate of in vitro permeation of ibuprofen is between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin.

[0042] The permeation rate of the ibuprofen was measured using a vertical diffusion cell or Franz cell using the method set out below.

[0043] Preferably, the peak in vitro permeation rate of the ibuprofen following application of the composition is 15pg / cm2 / hr- 22.5pg / cm2 / hr.

[0044] Preferably, the peak permeation rate is between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

[0045] Preferably, the peak in vitro permeation rate of the ibuprofen following application of the composition is 15pg / cm2 / hr - 22.5pg / cm2 / hr between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

[0046] The ibuprofen can comprise a mixture of ibuprofen acid and a salt of ibuprofen. The ibuprofen can comprise a 1:2 to 2:1 mixture by weight of ibuprofen acid and a salt of ibuprofen. Preferably, the ibuprofen comprises a 1:1 mixture by weight of ibuprofen acid and the salt of ibuprofen.

[0047] The salt of ibuprofen can be in the form of 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.

[0048] 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.PAT15718-WO-PCT

[0049] 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.

[0050] 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.

[0051] The first penetration enhancer can be selected from polyoxypropylene stearyl ether, diethylene glycol monoethyl ether (DGME), lauric acid, lauric alcohol or myristyl alcohol.

[0052] 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.

[0053] The second penetration enhancer can be selected from propylene glycol, dimethyl sulphoxide oleic acid or oleyl alcohol.

[0054] 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.

[0055] 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.

[0056] The first rheology modifier can be selected from xanthan gum, carbomer or poloxamer.PAT15718-WO-PCT

[0057] 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.

[0058] The second rheology modifier which is different from the first rheology modifier can be selected from hydroxyethyl cellulose, xanthan gum, carbomer or poloxamer.

[0059] 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 second 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.

[0060] The composition can comprise l%w / w - 15%w / w 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.

[0061] The composition can comprise 2%w / w - 10%w / w 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.

[0062] The composition can comprise 2%w / w - 10%w / w 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.PAT15718-WO-PCT

[0063] Preferably, the composition can comprise 3%w / w - 6%w / w 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 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.

[0064] Preferably, the composition can comprise 3%w / w - 6%w / w 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.

[0065] The composition can further include a solvent selected from alcohols. Preferably the solvent is an alcohol selected from C2 - C4 alcohols.

[0066] 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.

[0067] For the avoidance of doubt unless specified otherwise the ratios as set out in the present specification are the weight ratios of the respective components.

[0068] 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 the ex vivo adult human abdominal skin over a 12hr period.PAT15718-WO-PCT

[0069] Examples of the composition of the present invention are shown in Table 1.

[0070] Component (% w / w) Exl Ex 2 Ex 3 Ex 4 Ex 5

[0071] 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

[0072]

[0073] TOTAL 100.00 100.00 100.00 100.00 100.00

[0074] Table 1

[0075] The compositions can be made in the following way.

[0076] 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 a 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.PAT15718-WO-PCT

[0077] WS-23 is N,2,3-trimethyl-2-(l-methylethyl)-butanamide and WS-5 is N- (Ethoxycarbonylmethyl)-3-p-menthanecarboxamide. These are available from Symrise under the name Symcool (RTM).

[0078] 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 Figures 1 and Table 2 below.

[0079] Example Mean Mean Mean Mean Mean Mean Permeation Permeation Permeation Permeation Permeation Permeation (lhr) (2hr) (4hr) (6hr) (8hr) (12hr) 1 4.58 12.10 12.51 12.07 12.75 9.11 2 4.14 11.99 13.97 17.05 14.61 11.53 3 5.96 16.90 19.24 19.88 12.41 10.77 4 7.31 14.88 16.11 15.50 8.29 6.48 5 5.21 13.75 14.14 13.00 9.06 7.57

[0080]

[0081] Comparative 2.24 6.26 7.30 7.04 6.38 6.13

[0082] Table 2

[0083] The 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 cumulative amount of ibuprofen that permeated through the ex vivo adult human abdominal skin was calculated for each 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 contained menthol, carbomer, propylene glycol, diisopropanolamine and water.PAT15718-WO-PCT

[0084] 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 ex vivo human abdominal skin over a 12hr period compared to an existing commercial topical gel composition.

[0085] 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.

[0086] 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.

[0087] 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, thePAT15718-WO-PCT

[0088] 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.

[0089] 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.

[0090] Further modifications can be made without departing from the scope of the invention described herein.

Claims

PAT15718-WO-PCTCLAIMS:

1. A topical aqueous gel composition comprising ibuprofen, and a combination of a first skin penetration enhancer and a second skin penetration enhancer wherein the combination of skin enhancers allows the composition to maintain a mean rate of permeation of ibuprofen through ex vivo adult human abdominal skin of at least 6 pg / cm2 / hr for a period of 2 - 12hr after application to the ex vivo adult human abdominal skin.

2. The use of a combination of skin penetration enhancers comprising a first skin penetration enhancer and a second skin penetration enhancer to facilitate the permeation of ibuprofen from a topical ibuprofen-containing aqueous gel composition through ex vivo adult human abdominal skin wherein the permeation rate of the ibuprofen is at least at least 6 pg / cm2 / hr for a period of 2 - 12hr after application to the ex vivo adult human abdominal skin.

3. The composition or use as claimed in Claim 1 or Claim 2 wherein the mean rate of permeation of ibuprofen is between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin.

4. The composition or use as claimed in Claim 3 wherein the peak permeation rate of the ibuprofen following application of the composition is 15pg / cm2 / hr-22.5pg / cm2 / hr of the composition to the ex vivo adult human abdominal skin.

5. The composition or use as claimed in any of the preceding Claims wherein the peak permeation rate is between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

6. The composition or use as claimed in any of the preceding Claims wherein the ibuprofen can comprise a mixture of ibuprofen acid and a salt of ibuprofen.

7. The composition or use as claimed in Claim 6 wherein the ibuprofen can comprise a 1:2 to 2:1 mixture by weight of ibuprofen acid and the salt of ibuprofen.PAT15718-WO-PCT8. The composition or use as claimed in Claim 7 wherein the ibuprofen comprises a 1:1 mixture by weight of ibuprofen acid and the salt of ibuprofen.

9. The composition or use as claimed in Claim 8 wherein the topical aqueous gel composition comprises ibuprofen in the form of a 1:1 mixture of ibuprofen acid and a salt of ibuprofen, and a combination of a first skin penetration enhancer and a second skin penetration enhancer wherein the combination of skin enhancers allows the composition to maintain a rate of permeation of ibuprofen through the ex vivo adult human abdominal skin of between 7.5pg / cm2 / hr and 25pg / cm2 / hr for a period of 2 - 8hrs after application to the ex vivo adult human abdominal skin and wherein the ibuprofen has a peak permeation rate of 15pg / cm2 / hr- 22.5pg / cm2 / hr between 2 - 6 hrs after application of the composition to the ex vivo adult human abdominal skin.

10. The composition or use as claimed in any of the preceding Claims wherein the composition can comprise l%w / w- 15%w / w of the ibuprofen.

11. The composition or use as claimed in Claim 10 wherein the composition can comprise 3%w / w - 6%w / w.

12. The composition or use as claimed in any of the preceding Claims wherein the composition comprises 45%w / w - 75%w / w of water.

13. The composition or use as claimed in Claim 12 wherein the composition comprises 55%w / w - 65%w / w of water.

14. The composition or use as claimed in any of the preceding Claims wherein the composition can comprise 0.1%w / w - 5%w / w of the first penetration enhancer.

15. The composition or use as claimed in Claim 14 the composition can comprise 0.5%w / w - 2%w / w of the first penetration enhancer.

16. The composition or use as claimed in any of the preceding Claims wherein the first penetration enhancer can be selected from polyoxypropylene stearyl ether, diethylene glycol monoethyl ether (DGME), lauric acid or myrsityl alcohol .PAT15718-WO-PCT17. The composition or use as claimed in any of the preceding Claims wherein the composition can comprise l%w / w - 20%w / w of the second penetration enhancer.

18. The composition or use as claimed in Claim 17 wherein the composition can comprise 5%w / w- 10%w / w of the second penetration enhancer.

19. The composition or use as claimed in any of the preceding Claims wherein the second penetration enhancer can be selected propylene glycol or oleyl alcohol.

20. The composition or use as claimed in any of the preceding Claims wherein the weight ratio of the first penetration enhancer and the second penetration enhancer can be from 1:1 to 1:16.

21. The composition or use as claimed in Claim 20 wherein the weight ratio of the first penetration enhancer and the second penetration enhancer can be from 1:6 to 1:8.

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