Topical gel composition comprising an nsaid, two penetraton enhancers, two rheology modifiers and water

Abstract

The present invention is directed to a topical gel composition comprising an NSAID, a first penetration enhancer, a second penetration enhancer, a first rheology modifier, a second rheology modifier and water.

Description

[0001] Novel Composition

[0002] 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 permeation properties through the layers of the skin. A preferred composition of the present invention comprises ibuprofen as the active pharmaceutical ingredient.

[0003] 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.

[0004] 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 amine API.

[0005] In developing effective topical compositions, the principal problem to be solved is to enable the active ingredient to penetrate the skin, of which the stratum corneum is, by its nature, an effective barrier medium. As a result, efforts in developing topical compositions for enhanced skin penetration of NSAIDS, efforts have hitherto been directed principally at increasing the solubility of the NSAID in the composition as a whole, that is, before application to the skin. More recently, however, compositions have been developed which include a volatile and a nonvolatile solvent system so that, on application of the composition to the skin, the volatile solvent evaporates and as a result increases the concentration of the NSAID in the non-volatile solvent. The phase which incorporates the non-volatile solvent is commonly referred to as the residual phase.

[0006] Due to the desire to optimise the level of saturation in the residual phase, rather than the absolute concentration, it is important to employ a residual phase solvent or solvent blend which has a relatively low solvating power for the NSAID, such that the saturated concentration is relatively low and in consequence the concentration of the NSAID in the residual phase is more likely to achieve saturation or even super-saturation as the volatile ingredients evaporate, thus optimising NSAID permeation and driving skin penetration. It is also desirable for the NSAID to be lipid- soluble, to enable or enhance penetration of the stratum corneum.

[0007] Subsequently, development of transdermal technology was driven by the development of patches. The technology maintained the drug at saturation levels and included a moderately polar solvent, but with an enhancer. As a result, drug solubility and diffusivity in the stratum corneum barrier layer was increased. As the moderately polar solvent increased the solubility of the enhancer in the stratum corneum barrier and the enhancer increased the diffusivity of the polar solvent, synergy was often found with this "co-enhancer" technology.

[0008] Propylene glycol is an excellent solvent for many drugs and has been widely used to enhance the skin penetration of range of drugs, including antivirals, corticosteroids, testosterone, antihistamines, cardiovasculars and nonsteroidals including ibuprofen. However, a high concentration is often required for propylene glycol to achieve an enhancing effect. At such concentrations the propylene glycol-containing composition is extremely hygroscopic and thus tacky to the touch which limits consumer and patient acceptance and compliance.

[0009] Fatty acids have been used as penetration enhancers. However, propylene glycol is immiscible with many fatty acid derivatives, for example isopropyl myristate, such that the mixture is a two-phase system. This gives rise to the potential for pharmaceutical stability problems.Totally miscible systems have some potential advantages as co-enhancer systems and studies have been done using propylene glycol and a fatty acid derivative to which a cosolvent, such as Transcutol (RTM), is added. However, cosolvent enhancers such as Transcutol (RTM) or dimethyl isosorbide, are not as effective as propylene glycol in enhancing skin penetration.

[0010] Propylene glycol can be replaced by enhancers such as Transcutol (RTM) or dimethyl isosorbide. However, these are not as effective and suffer from poor aesthetics.

[0011] WO 02 / 11768 discloses compositions which comprise a fatty alcohol, propylene glycol and Transcutol (RTM). The compositions further include carbomer as a gelling agent. As propylene glycol penetrates into and through the stratum corneum barrier of the skin much faster than the fatty alcohol, much higher doses of propylene glycol are required.

[0012] Ibuprofen has moderately good skin penetration. The onset, intensity and duration of local analgesic and anti-inflammatory activity may be improved by use of skin penetration enhancers, including propylene glycol. However, ibuprofen is a low melting point drug, melting at around 70°C, and consequently has relatively high solubility in most solvents. For example, it has been shown that the saturated solubility of ibuprofen in propylene glycol is in excess of 40% w / v whereas that in water is only approximately 0.014% w / v. Thus, the use of propylene glycol alone has the disadvantage that at 5% of ibuprofen (the amount normally contained in topical products) the drug is at a low level of saturation (of approximately l / 8th saturation) which serves to reduce the overall skin penetration of ibuprofen from propylene glycol-based systems.

[0013] In addition, it is known that topical NSAID-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 NSAID-containing composition which reduces or mitigates the potential for casing any short-term irritancy.According to an aspect of the present invention there is provided a topical gel composition comprising an NSAID, a first penetration enhancer, a second penetration enhancer, a first rheology modifier, a second rheology modifier and water.

[0014] The NSAID can be selected from ibuprofen, ketoprofen, flurbiprofen, diclofenac and naproxen. A preferred NSAID is ibuprofen.

[0015] The NSAID is preferably in the form of a mixture of the NSAID acid and an NSAID salt. The NSAID can comprise a 1:2 to 2:1 mixture by weight of NSAID acid and an NSAID salt. Preferably, the NSAID comprises a 1:1 mixture by weight of NSAID acid and the NSAID salt.

[0016] 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.

[0017] The composition can comprise l%w / w - 15%w / w of the NSAID. Preferably, the composition can comprise 2%w / w - 10%w / w of the NSAID. More preferably, the composition can comprise 3%w / w - 6%w / w of the NSAID.

[0018] 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.

[0019] 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.

[0020] The first penetration enhancer can be selected from polyoxypropylene stearyl ether, diethylene glycol monoethyl ether (DGME), lauric acid, lauric alcohol or myristyl alcohol.

[0021] 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 secondpenetration enhancer. More preferably, the composition can comprise 6%w / w - 8%w / w of the second penetration enhancer.

[0022] The second penetration enhancer can be selected from propylene glycol, dimethyl sulphoxide oleic acid or oleyl alcohol.

[0023] 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.

[0024] Preferably, the composition can comprise 0.1%w / w - 2%w / w of the first rheology modifier. More preferably, the composition can comprise 0.3%w / w - 0.8%w / w of the first rheology modifier.

[0025] The first rheology modifier can be selected from xanthan gum, carbomer or poloxamer.

[0026] Preferably, the composition can comprise 0.1%w / w - 2%w / w of the second rheology modifier. More preferably, the composition can comprise 0.8%w / w- 1.3%w / w of the second rheology modifier.

[0027] 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.

[0028] 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.

[0029] 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 ofxanthan 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.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.

[0034] 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.

[0035] The composition can further comprise a humectant selected from glycerol, butylene glycol, PEG 4000, PEG 6000 or urea.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] The composition can further include a solvent selected from alcohols. Preferably the solvent is an alcohol selected from C2 - C4 alcohols.

[0040] 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.

[0041] The composition can comprise a warming sensate ora cooling sensate selected from menthol, N,2,3-trimethyl-2-(l-methylethyl)-butanamide (WS-23),N-(Ethoxycarbonylmethyl)-3-p-menthanecarboxamide (WS-5),

[0042] N-Ethyl-5-Methyl-2-(l- Methylethyl)-Cyclohexanecarboxamide (WS-3),

[0043] (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).

[0044] 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.

[0045] The composition can comprise:

[0046] (a) l%w / w - 15%w / w of an NSAID;

[0047] (b) l%w / w - 20%w / w of a first penetration enhancer;

[0048] (c) 0.1%w / w - 5%w / w of a second penetration enhancer;

[0049] (d) 0.1%w / w - 2%w / w of a first rheology modifier;

[0050] (e) 0.1%w / w - 2%w / w of a second rheology modifier; and

[0051] (f) 45%w / w - 75%w / w of water.

[0052] The composition can comprise:

[0053] (a) 2%w / w - 10%w / w of an NSAID;

[0054] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0055] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0056] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0057] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0058] (f) 50%w / w - 70%w / w of water.

[0059] The composition can comprise:

[0060] (a) 3%w / w - 6%w / w of an NSAID;

[0061] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0062] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0063] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0064] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0065] (f) 55%w / w - 65%w / w of water.The composition can comprise:

[0066] (a) 3%w / w - 6%w / w of an NSAID;

[0067] (b) 6%w / w - 8%w / w of a first penetration enhancer;

[0068] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0069] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0070] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0071] (f) 55%w / w - 65%w / w of water.

[0072] The composition can comprise:

[0073] (a) l%w / w - 15%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0074] (b) l%w / w - 20%w / w of a first penetration enhancer;

[0075] (c) 0.1%w / w - 5%w / w of a second penetration enhancer;

[0076] (d) 0.1%w / w - 2%w / w of a first rheology modifier;

[0077] (e) 0.1%w / w - 2%w / w of a second rheology modifier; and

[0078] (f) 45%w / w - 75%w / w of water.

[0079] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0080] The composition can comprise:

[0081] (a) 2%w / w - 10%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0082] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0083] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0084] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0085] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0086] (f) 50%w / w - 70%w / w of water.

[0087] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0088] The composition can comprise:

[0089] (a) 3%w / w- 6%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0090] (b) 5%w / w - 10%w / w of a first penetration enhancer;(c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0091] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0092] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0093] (f) 55%w / w - 65%w / w of water.

[0094] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0095] The composition can comprise:

[0096] (a) 3%w / w- 6%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0097] (b) 6%w / w - 8%w / w of a first penetration enhancer;

[0098] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0099] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0100] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0101] (f) 55%w / w - 65%w / w of water.

[0102] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0103] The composition can comprise:

[0104] (a) l%w / w - 15%w / w of ibuprofen;

[0105] (b) l%w / w - 20%w / w of propylene glycol;

[0106] (c) 0.1%w / w - 5%w / w of polyoxypropylene stearyl ether;

[0107] (d) 0.1%w / w - 2%w / w of xanthan gum;

[0108] (e) 0.1%w / w - 2%w / w of hydroxy ethylcellulose; and

[0109] (f) 45%w / w - 75%w / w of water.

[0110] The composition can comprise:

[0111] (a) 2%w / w - 10%w / w of ibuprofen;

[0112] (b) 5%w / w - 10%w / w of propylene glycol;

[0113] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0114] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0115] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0116] (f) 50%w / w - 70%w / w of water.The composition can comprise:

[0117] (a) 3%w / w - 6%w / w of ibuprofen;

[0118] (b) 5%w / w - 10%w / w of propylene glycol;

[0119] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0120] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0121] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0122] (f) 55%w / w - 65%w / w of water.

[0123] The composition can comprise:

[0124] (a) 3%w / w - 6%w / w of ibuprofen;

[0125] (b) 6%w / w - 8%w / w of propylene glycol;

[0126] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0127] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0128] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0129] (f) 55%w / w - 65%w / w of water.

[0130] The composition can comprise:

[0131] (a) l%w / w - 15%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0132] (b) l%w / w - 20%w / w of propylene glycol;

[0133] (c) 0.1%w / w - 5%w / w of polyoxypropylene stearyl ether;

[0134] (d) 0.1%w / w - 2%w / w of xanthan gum;

[0135] (e) 0.1%w / w - 2%w / w of hydroxy ethylcellulose; and

[0136] (f) 45%w / w - 75%w / w of water.

[0137] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0138] The composition can comprise:

[0139] (a) 2%w / w - 10%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0140] (b) 5%w / w - 10%w / w of propylene glycol;

[0141] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0142] (d) 0.3%w / w - 0.8%w / w of xanthan gum;(e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0143] (f) 50%w / w - 70%w / w of water.

[0144] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0145] The composition can comprise:

[0146] (a) 3%w / w - 6%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0147] (b) 5%w / w - 10%w / w of propylene glycol;

[0148] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0149] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0150] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0151] (f) 55%w / w - 65%w / w of water.

[0152] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0153] The composition can comprise:

[0154] (a) 3%w / w - 6%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0155] (b) 6%w / w - 8%w / w of propylene glycol;

[0156] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0157] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0158] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0159] (f) 55%w / w - 65%w / w of water.

[0160] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0161] The composition can consist essentially of:

[0162] (a) l%w / w - 15%w / w of an NSAID;

[0163] (b) l%w / w - 20%w / w of a first penetration enhancer;

[0164] (c) 0.1%w / w - 5%w / w of a second penetration enhancer;

[0165] (d) 0.1%w / w - 2%w / w of a first rheology modifier;

[0166] (e) 0.1%w / w - 2%w / w of a second rheology modifier; and

[0167] (f) 45%w / w - 75%w / w of water.The composition can consist essentially of:

[0168] (a) 2%w / w - 10%w / w of an NSAID;

[0169] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0170] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0171] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0172] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0173] (f) 50%w / w - 70%w / w of water.

[0174] The composition can consist essentially of:

[0175] (a) 3%w / w - 6%w / w of an NSAID;

[0176] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0177] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0178] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0179] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0180] (f) 55%w / w - 65%w / w of water.

[0181] The composition can consist essentially of:

[0182] (a) 3%w / w - 6%w / w of an NSAID;

[0183] (b) 6%w / w - 8%w / w of a first penetration enhancer;

[0184] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0185] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0186] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0187] (f) 55%w / w - 65%w / w of water.

[0188] The composition can consist essentially of:

[0189] (a) l%w / w - 15%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0190] (b) l%w / w - 20%w / w of a first penetration enhancer;

[0191] (c) 0.1%w / w - 5%w / w of a second penetration enhancer;

[0192] (d) 0.1%w / w - 2%w / w of a first rheology modifier;

[0193] (e) 0.1%w / w - 2%w / w of a second rheology modifier; and

[0194] (f) 45%w / w - 75%w / w of water.Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0195] The composition can consist essentially of:

[0196] (a) 2%w / w - 10%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0197] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0198] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0199] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0200] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0201] (f) 50%w / w - 70%w / w of water.

[0202] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0203] The composition can consist essentially of:

[0204] (a) 3%w / w- 6%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0205] (b) 5%w / w - 10%w / w of a first penetration enhancer;

[0206] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0207] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0208] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0209] (f) 55%w / w - 65%w / w of water.

[0210] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.

[0211] The composition can consist essentially of:

[0212] (a) 3%w / w- 6%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;

[0213] (b) 6%w / w - 8%w / w of a first penetration enhancer;

[0214] (c) 0.5%w / w - 2%w / w of a second penetration enhancer;

[0215] (d) 0.3%w / w - 0.8%w / w of a first rheology modifier;

[0216] (e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and

[0217] (f) 55%w / w - 65%w / w of water.

[0218] Preferably the NSAID is in the form of a 1:1 mixture of an NSAID acid and an NSAID salt.The composition can consist essentially of:

[0219] (a) l%w / w - 15%w / w of ibuprofen;

[0220] (b) l%w / w - 20%w / w of propylene glycol;

[0221] (c) 0.1%w / w - 5%w / w of polyoxypropylene stearyl ether; (d) 0.1%w / w - 2%w / w of xanthan gum;

[0222] (e) 0.1%w / w - 2%w / w of hydroxy ethylcellulose; and

[0223] (f) 45%w / w - 75%w / w of water.

[0224] The composition can consist essentially of:

[0225] (a) 2%w / w - 10%w / w of ibuprofen;

[0226] (b) 5%w / w - 10%w / w of propylene glycol;

[0227] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether; (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0228] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and (f) 50%w / w - 70%w / w of water.

[0229] The composition can consist essentially of:

[0230] (a) 3%w / w - 6%w / w of ibuprofen;

[0231] (b) 5%w / w - 10%w / w of propylene glycol;

[0232] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether; (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0233] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and (f) 55%w / w - 65%w / w of water.

[0234] The composition can consist essentially of:

[0235] (a) 3%w / w - 6%w / w of ibuprofen;

[0236] (b) 6%w / w - 8%w / w of propylene glycol;

[0237] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether; (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0238] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and (f) 55%w / w - 65%w / w of water.The composition can consist essentially of:

[0239] (a) l%w / w - 15%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0240] (b) l%w / w - 20%w / w of propylene glycol;

[0241] (c) 0.1%w / w - 5%w / w of polyoxypropylene stearyl ether;

[0242] (d) 0.1%w / w- 2%w / w of xanthan gum;

[0243] (e) 0.1%w / w - 2%w / w of hydroxy ethylcellulose; and

[0244] (f) 45%w / w - 75%w / w of water.

[0245] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0246] The composition can consist essentially of:

[0247] (a) 2%w / w - 10%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0248] (b) 5%w / w - 10%w / w of propylene glycol;

[0249] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0250] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0251] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0252] (f) 50%w / w - 70%w / w of water.

[0253] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0254] The composition can consist essentially of:

[0255] (a) 3%w / w - 6%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0256] (b) 5%w / w - 10%w / w of propylene glycol;

[0257] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0258] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0259] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0260] (f) 55%w / w - 65%w / w of water.

[0261] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0262] The composition can consist essentially of:(a) 3%w / w - 6%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;

[0263] (b) 6%w / w - 8%w / w of propylene glycol;

[0264] (c) 0.5%w / w - 2%w / w of polyoxypropylene stearyl ether;

[0265] (d) 0.3%w / w - 0.8%w / w of xanthan gum;

[0266] (e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and

[0267] (f) 55%w / w - 65%w / w of water.

[0268] Preferably the ibuprofen is in the form of a 1:1 mixture of ibuprofen acid and ibuprofen salt.

[0269] According to a second aspect of the present invention there is provided the use of a topical gel as described in the first aspect for the treatment of pain and inflammation in an individual.

[0270] According to a third aspect of the present invention there is provided a method of treating pain and inflammation in an individual comprising the step of applying a topical gel as described in the first aspect of the present invention to the skin of an individual.

[0271] 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.

[0272] 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 skin over a 12hr period.Examples of the composition of the present invention are shown in Table 1.

[0273] Component (% w / w) Exl Ex 2 Ex 3 Ex 4 Ex 5

[0274] 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

[0275]

[0276] TOTAL 100.00 100.00 100.00 100.00 100.00

[0277] Table 1

[0278] The compositions can be made in the following way.

[0279] 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.

[0280] 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.The in vitro human skin permeation rate of the ibuprofen was measured using a vertical diffusion cell or Franz cell using the method set out below.

[0281] The tests were performed as follows. A section of human abdominal skin having a thickness of 500pm + / - 100pm and a dosing area of 0.6cm2in the vertical diffusion cell having a volume of 2cm3was prepared. A 6mg sample of the composition of the present invention was applied to the skin and allowed to penetrate the layers of the skin over a period of 12hrs into a receptor solution (RS) 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 sample that has permeated through the 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 contains menthol, carbomer, propylene glycol, diisopropanolamine and water.

[0282] Mean ibuprofen detected at 12hr

[0283] Composition

[0284] (%w / w of amount applied)

[0285] Example 1 28.00

[0286] Example 2 32.00

[0287] Example 3 35.00

[0288] Example 4 29.00

[0289] Example 5 25.00

[0290] Comparison 18.00

[0291]

[0292] Table 2

[0293] 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 skin over a 12hr period compared to an existing commercial composition.

[0294] The compositions of the present invention were assessed for potential local cutaneous irritation. The Cumulative Irritation Patch Test (CIPT) is an established and internationallyrecognised 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.

[0295] 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.

[0296] 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.

[0297] An advantage of the present invention is that there is provided aqueous gel compositions which contain an NSAID such as 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.Further modifications can be made without departing from the scope of the invention described herein.

Claims

CLAIMS:

1. A topical gel composition comprising an NSAID, a first penetration enhancer, a second penetration enhancer, a first rheology modifier, a second rheology modifier and water.

2. A composition as claimed in Claim 1 wherein the NSAID is selected from ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen.

3. A composition as claimed in Claim 2 wherein the NSAID is ibuprofen.

4. A composition as claimed in any of the preceding Claims wherein the NSAID is in the form of a mixture of an NSAID acid and an NSAID salt.

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

6. A composition as claimed in Claim 5 wherein the composition comprises 3%w / w - 6%w / w of the NSAID.

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

8. A composition as claimed in Claim 7 wherein the composition comprises 55%w / w - 65%w / w of water.

9. A composition as claimed in any of the preceding Claims where the composition comprises 0.1%w / w - 5%w / w of the first penetration enhancer.

10. A composition as claimed in Claim 9 wherein the composition comprises 0.5%w / w - 2%w / w of the first penetration enhancer.

11. A composition as claimed in any of the preceding Claims wherein the first penetration enhancer is selected to be polyoxypropylene stearyl ether.

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

13. A composition as claimed in any of the preceding Claim 12 wherein the composition comprises 5%w / w- 10%w / w of the second penetration enhancer.

14. A composition as claimed in any of the preceding Claims wherein the second penetration enhancer is selected to be propylene glycol.

15. A composition 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.

16. A composition as claimed in Claim 15 wherein the weight ratio of the first penetration enhancer and the second penetration enhancer is from 1:6 to 1:8.

17. A composition as claimed in any of the preceding Claims wherein the first rheology modifier is different to the second rheology modifier.

18. A composition as claimed in any of the preceding Claims wherein the composition comprises 0.1%w / w - 2%w / w of the 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 any of the preceding Claims wherein the first rheology modifier is selected to be xanthan gum.

21. A composition as claimed in any of the preceding Claims wherein the composition comprises 0.1%w / w - 2%w / w of the second rheology modifier.

22. A composition as claimed in Claim 21 wherein the composition comprises 0.8%w / w - 1.3%w / w of the second rheology modifier.

23. A composition as claimed in any of the preceding Claims wherein the second rheology modifier is selected to be hydroxyethyl cellulose.

24. A composition as claimed in any of the preceding Claims 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, 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.

27. A composition as claimed in Claim 25 wherein the composition comprises 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.

28. A composition as claimed in Claim 1 wherein the composition comprises:(a) l%w / w - 15%w / w of an NSAID;(b) l%w / w - 20%w / w of a first penetration enhancer;(c) 0.1%w / w - 5%w / w of a second penetration enhancer;(d) 0.1%w / w - 2%w / w of a first rheology modifier;(e) 0.1%w / w - 2%w / w of a second rheology modifier; and(f) 45%w / w - 75%w / w of water.

29. A composition as claimed in Claim 28 wherein the composition comprises:(a) 3%w / w - 6%w / w of an NSAID;(b) 5%w / w - 10%w / w of a first penetration enhancer;(c) 0.5%w / w - 2%w / w of a second penetration enhancer;(d) 0.3%w / w - 0.8%w / w of a first rheology modifier;(e) 0.8%w / w - 1.3%w / w of a second rheology modifier; and(f) 55%w / w - 65%w / w of water.

30. A composition as claimed in Claim 28 wherein the composition comprises:(a) l%w / w - 15%w / w of ibuprofen;(b) l%w / w - 20%w / w of propylene glycol;(c) 0.1%w / w - 5%w / w of polyoxypropylene stearyl ether;(d) 0.1%w / w - 2%w / w of xanthan gum;(e) 0.1%w / w - 2%w / w of hydroxy ethylcellulose; and(f) 45%w / w - 75%w / w of water.

31. A composition as claimed in Claim 29 wherein the composition comprises:(a) 3%w / w - 6%w / w of ibuprofen;(b) 5%w / w - 10%w / w propylene glycol;(c) 0.5%w / w - 2%w / w polyoxypropylene stearyl ether;(d) 0.3%w / w - 0.8%w / w of xanthan gum;(e) 0.8%w / w - 1.3%w / w of hydroxy ethylcellulose; and(f) 55%w / w - 65%w / w of water.

32. A composition as claimed in Claim 1 wherein the composition comprises:(a) l%w / w - 15%w / w of an NSAID in the form of a 1:2 to 2:1 mixture of an NSAID acid and an NSAID salt;(b) l%w / w - 20%w / w of a first penetration enhancer;(c) 0.1%w / w - 5%w / w of a second penetration enhancer;(d) 0.1%w / w - 2%w / w of a first rheology modifier;(e) 0.1%w / w - 2%w / w of a second rheology modifier; and(f) 45%w / w - 75%w / w of water.

33. A composition as claimed in Claim 32 wherein the composition comprises:(a) l%w / w - 15%w / w of ibuprofen in the form of a 1:2 to 2:1 mixture of ibuprofen acid and ibuprofen salt;(b) l%w / w - 20%w / w of a propylene glycol;(c) 0.1%w / w - 5%w / w of polyoxypropylene stearyl ether;(d) 0.1%w / w-2%w / w of xanthan gum;(e) 0.1%w / w - 2%w / w of hydroxy ethylcellulose; and(f) 45%w / w - 75%w / w of water.

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