Composition for use in treatment of for example inflammatory disorders

Abstract

Herein describes a composition for use in the treatment of an inflammatory disorder comprising: 35 wt% to 87 wt% water; 1 wt% to 10 wt% benzyl alcohol; 1 wt% to 5 wt% oleic acid; 1 wt% to 5 wt% amine base; and 10 wt% to 50 wt% glycol ether, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid.

Description

[0001] Title: Composition for use in treatment of for example inflammatory disorders

[0002] Field:

[0003] This disclosure relates to a composition for use in therapy, the composition being especially suitable for the treatment of inflammatory disorders.

[0004] Background:

[0005] It is already well established that NSAIDs can be used for the treatment of a wide number of inflammatory conditions and relief of pain, especially in joints. There are well documented problems with oral systemic delivery of NSAIDs as they can cause significant side effects such as stomach bleeding and cardiovascular problems (see e.g. Abigail Davis, John Robson. The dangers of NSAIDs: look both ways. British Journal of General Practice 2016; 66 (645): 172- 173. doi: 10.3399 / bjgpl6X684433; and Zeng C, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med 2018;52:642-650. doi: 10.1136 / bjsports-2017-098043). There is a significant advantage to delivering the NSAIDs directly to the local area where the pain and inflammation is located e.g. in joints or surrounding tissue. Transdermal delivery can lead to significant and effective levels of NSAIDs in the targeted tissues and joints, with much lower systemic uptake of the drugs and hence reduced side effects. However, the delivery of NSAIDs topically (for example transdermally) is currently poor, with significantly lower levels achieved in the target regions versus systemic administration, e.g. taking the NSAIDs orally. There is an unmet medical need to provide a compositions which treat inflammatory disorders, whilst being effective and avoiding side effects, e.g. side effects of NSAIDs given via systemic administration. Further, it is desired to identify compositions that can be used to deliver NSAIDs more effectively through the skin i.e. transdermally.

[0006] Various reviews have shown that essential oils can have anti-inflammatory activity (Zuo, Xu, Gu, Yinuo, Wang, Chao, Zhang, Jinrong, Zhang, Jing, Wang, Guoqiang, Wang, Fang. A Systematic Review of the Anti-Inflammatory and Immunomodulatory Properties of 16 Essential Oils of Herbs, Evidence-Based Complementary and Alternative Medicine, 2020, 8878927. doi.org / 10.1155 / 2020 / 8878927; and Girao, Deysen & Cardoso, Camila & Silva, Francisco. (2024). Effect of essential oils on pain management: what do we know and where do we go?. Brazilian Journal of Health Aromatherapy and Essential Oil., doi. org / 10.62435 / 2965-7253. bjhae.2024.bjhae2). Cajeput and clove oils have been studied as anti-inflammatory agents (see e.g. Sirirat Reungsuwat, Siriwoot Sookkhee, Chintana Itthidecharon and Phenphichar Wanachantararak. Investigation of Cajuput and Lemongrass Essential Oils Supplemented in Alcohol-Free Mouthwash: Anti-Inflammation on Human Gingival Fibroblast Cells In Vitro. TRENDS IN SCIENCES 2023; 20(8): 6752 doi. org / 10.48048 / tis.2023.6752; and Han, X., & Parker, T. L. (2017). Anti-inflammatory activity of clove (Eugenia caryophyllata) essential oil in human dermal fibroblasts. Pharmaceutical Biology, 55(1), 1619-1622. https: / / doi.org / 10.1080 / 13880209.2017.1314513) and are amongst the ingredients of Olbas Oil and Tiger Balm which have been used extensively to treat inflammatory conditions and in the relief of pain in joints. Also, colchicine (a small molecule natural product originally derived from the autumn crocus Colchicum autumnale) has been used to treat inflammatory conditions and is commonly used in treating inflammation caused by gout (Terkeltaub, R.A., et al., High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum, 2010. 62(4): p. 1060-8).

[0007] In the prior art there remains a challenge to help resolve gout attacks. Gout is a disease caused by precipitation of monosodium urate (MSU) crystals within the joints and surrounding tissue. Gout may be associated with a very painful inflammatory response, and can be seriously debilitating. Good delivery of NSAIDs to the joints and surrounding tissues can help relieve the symptoms of gout i.e. the pain and inflammation, but does not in itself treat the underlying cause of gout - the presence of MSU crystals within the cavity of the joint and surrounding tissue, e.g. within the synovial fluid. It is thought that in a patient with gout the MSU crystals act as a source of solid friction in joints that would be low friction in the absence of gout. There is an unmet medical need to provide compositions which treat gout by treating the cause of the disorder, e.g. compositions that dissolve MSU crystals in-situ within the joints and surrounding tissues.

[0008] There are many established excipients and ingredients that are used to make topical formulations. For example, there is an USA Food and Drug Administration list of known and safe excipients which is publicly available. Many current formulations using the known excipients do not achieve the desired drug delivery and / or MSU solubility enhancement.

[0009] Brief description of the figures:

[0010] Figure 1 : Shows the improvement in MSU solubility in a laboratory system that imitates topical application of the invention versus current commercial products.

[0011] Figure 2: Improvement in transdermal diclofenac drug delivery in a laboratory system that imitates the effect of the topical application of the invention versus current commercial products.

[0012] Figure 3: Improvement in transdermal ibuprofen drug delivery in a laboratory system that imitates the effect of the topical application of the invention versus current commercial products.

[0013] Summary of the invention:

[0014] In an aspect, the present invention provides a composition for use in therapy comprising:

[0015] 35 wt% to 87 wt% water;

[0016] 1 wt% to 10 wt% benzyl alcohol;

[0017] 1 wt% to 5 wt% oleic acid;

[0018] 1 wt% to 5 wt% amine base; and

[0019] 10 wt% to 50 wt% glycol ether, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid.

[0020] Suitably the composition comprises 35 wt% to 65 wt% water. Preferably the composition comprises 35 wt% to 50 wt% water.

[0021] Suitably the composition comprises 15 wt% to 50 wt% glycol ether. Preferably the composition comprises 15 wt% to 45 wt% glycol ether.

[0022] Suitably the composition comprises 30 wt% to 40 wt% glycol ether.

[0023] Suitably the glycol ether comprises 2-(2-ethoxyethoxy)ethanol.

[0024] Suitably the glycol ether comprises polyethylene glycol 200.

[0025] Suitably the glycol ether comprises 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200. Preferably the glycol ether comprises 30 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol and 1 wt% to 5 wt% polyethylene glycol 200.

[0026] Suitably the glycol ether comprises 33 wt% to 38 wt% 2-(2-ethoxy ethoxy )ethanol and 2 wt% polyethylene glycol 200. Suitably the glycol ether consists of 33 wt% to 38 wt% 2-(2- ethoxyethoxy)ethanol and 2 wt% polyethylene glycol 200.

[0027] Suitably the composition comprises 3 wt% to 7 wt% benzyl alcohol. Preferably the composition comprises 4 wt% to 6 wt% benzyl alcohol. More preferably the composition comprises 5 wt% benzyl alcohol.

[0028] Suitably the composition comprises 1.3 wt% to 3.0 wt% oleic acid. Preferably the composition comprises 1.5 wt% to 2.7 wt% oleic acid. More preferably the composition comprises 2 wt% oleic acid.

[0029] Suitably the amine base is tris(hydroxymethyl)aminomethane, diethylamine, triethanolamine. Preferably the amine base is triethanolamine.

[0030] Suitably the composition comprises menthol. Suitably the composition comprises 1 wt% to 5 wt% menthol. Preferably the composition comprises 2 wt% menthol.

[0031] Suitably the composition comprises propan-2-ol. Suitably the composition comprises 1 wt% to 5 wt% propan-2-ol. Preferably the composition comprises 2 wt% propan-2-ol.

[0032] Suitably the composition comprises propylene glycol. Suitably the composition comprises 1 wt% to 5 wt% propylene glycol. Preferably the composition comprises 2 wt% propylene glycol. Suitably the composition comprises carbomer. Suitably the composition comprises 1 wt% to 3 wt% carbomer. Preferably the composition comprises 1 wt% to 2 wt% carbomer.

[0033] Suitably the composition comprises one or more non-steroidal anti-inflammatory drug (NSAID). Suitably the composition comprises 0.1 wt% to 10 wt% of one or more NSAID. Preferably the composition comprises 0.5 wt% to 7 wt% of one or more NSAID.

[0034] Suitably the one or more NSAID comprises diclofenac, ibuprofen, salicylic acid, ketorolac, ketoprofen, naproxen or celecoxib.

[0035] Suitably the NSAID is diclofenac. Suitably the one or more NSAID is diclofenac.

[0036] Suitably the NSAID is ibuprofen. Suitably the one or more NSAID is ibuprofen.

[0037] Suitably the NSAID is salicylic acid. Suitably the one or more NSAID is salicylic acid.

[0038] Suitably the composition comprises one or more herbal essential oil. Suitably the composition comprises 0.5 wt% to 5 wt% of one or more herbal essential oil.

[0039] Suitably the one or more herbal essential oil comprises bergamot oil, eucalyptus oil, jasmine oil, camomile oil, lavender oil, peppermint oil, rosemary oil, sandalwood oil, cajeput oil or clove oil. Preferably the one or more herbal essential oil comprises cajeput and / or clove oil. More preferably the one or more herbal essential oil comprises cajeput and clove oil. Most preferably the one or more herbal essential oil consists of cajeput and clove oil.

[0040] Suitably the composition comprises colchicine. Suitably the composition comprises 0.5 wt% to 5 wt% of colchicine.

[0041] Suitably the pH of the composition is 6.0 to 8.0. Preferably the pH of the composition is 6.5 to 7.5.

[0042] Preferably the composition is for use in therapy wherein the therapy is the treatment of an inflammatory disorder.

[0043] Suitably the inflammatory disorder is one or more of gout, arthritis, dermatomyositis, myositis, synovitis, tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, osteitis, osteomyelitis, spondylitis, periostitis and chondritis.

[0044] Suitably the inflammatory disorder is gout. It is especially preferred that the inflammatory disorder is gout.

[0045] Suitably the composition is a topical composition. Preferably the composition is a transdermal composition. All embodiments of the composition provided herein are disclosed as being for use in therapy. Further, all embodiments of the composition provided herein are disclosed as being for use in the treatment of an inflammatory disorder. Moreover, all embodiments of the composition provided herein are disclosed as being for use in the treatment of an inflammatory disorder.

[0046] In another aspect the present invention provides a method of treatment of an inflammatory disorder according to any other aspect which comprises administering to a subject an effective amount of the composition according to any other aspect.

[0047] In another aspect the present invention provides use of the composition according to any other aspect in the manufacture of a medicament for the treatment of an inflammatory disorder according to any other aspect.

[0048] Compositions of the disclosure may provide improved delivery of active ingredients to the target tissue, for example improved delivery of NSAIDs and / or herbal essential oils and / or colchicine. This improved delivery may be improved transdermal delivery (see e.g. figures 2 and 3). Without being bound by theory this advantage may be achieved by the relative amounts of water, benzyl alcohol, oleic acid, amine base and glycol ether present in the compositions. By having high delivery rates of active ingredients such as NSAIDs and / or herbal essential oils and / or colchicine, compositions of the disclosure are especially suitable for the treatment of inflammatory conditions generally, including inter alia gout. Compositions of the disclosure may also improve solubility of MSU in vivo, for example in joints and surrounding tissues, making the compositions especially suitable for the treatment of gout. This advantage may be achieved when the compositions are used transdermally (see e.g. figure 1). It is thought that this advantage may be achieved by dissolving MSU crystals within tissues affected by gout, arising from the particular relative amounts of water, benzyl alcohol, oleic acid, amine base and glycol ether present in the compositions. Compositions of the disclosure may also be associated with the advantage of reduced flammability. This advantage may be attributable to the high water content of the compositions. Compositions of the disclosure may also have the advantage of improved skin kindness / reduced risk of irritation to the skin. This advantage may be achieved by the high water content of the compositions and / or neutral pH. Compositions of the disclosure may be associated with the advantage of improved stability. This advantage is thought to be achieved by the particular relative amounts of water, benzyl alcohol, oleic acid, amine base and glycol ether present in the compositions. Compositions of the disclosure may also be associated with improved patient safety and patient convenience. This advantage may be achieved by the use of an efficacious composition transdermal composition, rather than invasive lavage procedures which involve breaking the skin.

[0049] It is desirable to have a significant level (>10%) of water in a topical formulation. Many of the known excipients are organic molecules, for example organic solvents, and organic molecules / solvents are often flammable. Commonly prior art formulations comprise a large proportion of organic molecules and little / no water, and are flammable. There have been cases where flammable formulation with low levels of water (or no water) have soaked into patients clothes or dressing, and finally caught fire causing serious injury. It is therefore desirable to provide a non-flammable composition for the treatment of inflammatory disorders.

[0050] Known formulations may cause skin irritation and contact dermatitis arising from drying out the skin. It is therefore desirable to provide a composition for the treatment of an inflammatory disorders that is associated with a lower risk of drying out the skin. In other words, it is desirable to provide a composition which is more skin kind.

[0051] The inventors have found it is desirable to have a pH neutral formulation as acidic or alkaline topical formulations can also cause skin irritation and contact dermatitis.

[0052] Formulations for treatment of inflammatory disorders are available in a variety of different forms, and commonly topical formulations are emulsions. Emulsions may be associated with benefits such as a high concentration of drug can be achieved, but also may have a relatively short shelf-life. Emulsions may separate over time (e.g. separating into an organic phase and an aqueous phase) which can lead to reduction in the efficacy of the medicine such as reduced drug delivery, or increased rates of decomposition. As such there is a need to provide a composition that can both deliver a pharmaceutically effective amount of drug that is storage stable. There is a need to provide an efficacious composition that is storage stable.

[0053] A study has shown some improvement in MSU solubility during a medical process to wash out a joint with a water-based solution (Tamasi, G., Cini, R., Gregorkiewitz, M., Lorenzini, S., Marcolongo, R., & Cavallo, G. (2013). The dissolution of monosodium urate monohydrate crystals: formulation of a biocompatible buffer solution with potential use in the treatment of gouty arthropathies. Rheumatology Reports, 5(1), e4. https: / / doi.org / 10.4081 / rr.2013.e4). This is commonly known as joint ‘lavage’ meaning washing of a joint. This is different from the present invention; the prior art process involves a medical process to inject and then remove a solution (buffer or water) into a joint. This can physically wash out some MSU crystals, or can encourage the MSU to dissolve by temporarily replacing the synovial fluid (which has poor MSU solubility due to the high concentration of sodium ions) with an aqueous solution with no sodium ions. This ‘improvement’ in MSU solubility is known in the literature (i.e. since the Kippen paper in 1974). It does not show or suggest what combination of solubility enhancers could improve solubility in blood or synovial fluids "in vivo’, i.e. in an aqueous solution with around 0.15mol / L sodium ions. Mannitol has been shown to have a positive effect on the lavage process i.e. improving MSU solubility in an aqueous buffer used to wash out a joint. However, as shown in Example 2 below, mannitol actually reduces MSU solubility in a medium that imitates body fluids, and would therefore have a negative effect on MSU solubility in vivo. Therefore, the improvement in MSU solubility in body fluids demonstrated in this invention is not demonstrated or predictable by studies on an invasive skin-breaking joint lavage process, as MSU solubility in in-vivo systems is different. As such, studies have shown that there can be no reasonable expectation that additives or reaction conditions that successfully improve the solubility of MSU under “lavage” conditions necessarily improve solubility in vivo. The applicants believe there has been no prior art that describes the application of a topical formulation comprising a combination of excipients to help improve the MSU solubility in vivo. Most gout treatments focus on reducing the inherent levels of urate in the blood, or on treating the symptom of inflammation. One area of treatment using enzymes such as uricase- derivatives focuses on decreasing the blood urate concentration by causing increased reaction of urate in the blood to products which do not cause gout. This leads to reduced concentrations of urate in the blood. An example of this approach is pegloticase (Krystexxa). This approach is not encouraging the existing crystals to ‘re-dissolve’ by enhancing the solubility of MSU in vivo. The treatment using enzymes approach is associated with the disadvantages of systemic administration (e.g. side effects arising from systemic administration). Topical administration is not suitable for the treatment using enzymes approach due to the low skin permeability of the enzymes used.

[0054] Some prior art describes a concept of taking ‘natural’ acids or bases orally to help remove the crystals that cause gout (such as sodium bicarbonate or apple cider vinegar - see for example Trang Thu Nguyen; Lan Thi Ngoc Nguyen; Nam Hoai Nguyen; Dung Van Hoang. The efficacy of sodium bicarbonate for treatment of gout. Journal of Medical Research'. 124-129, 2007). The applicants are of the opinion that these disclosures are flawed. Often these disclosures focus on eating / drinking sodium carbonate or bicarbonate, or drinking vinegar such as apple cider vinegar. There is scientific data to show that taking acids or bases orally has very little effect on the blood and body fluids pH, so the applicant’s put forward that it is not credible that imbibing acids or bases could have an effect on pH in the stomach that can pass from the stomach to the inflamed areas such as the joints. Often in these flawed disclosures the concept is that eating a basic food can help the ‘uric acid crystals’ to dissolve. This is again very unlikely, and it is known that the crystals that cause gout are monosodium urate crystals, not uric acid crystals, and as described in Kippen et al, small changes in pH from physiological pH (7.4) do not have a significant effect on the solubility of MSU in body fluids such as blood or synovial fluids.

[0055] There is also prior art disclosing the use of excipients / ingredients / solvents to improve the solubility of drugs (active pharmaceutical ingredients) in formulations (see e.g. Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, Porter CJ. Strategies to address low drug solubility in discovery and development. Pharmacological reviews. 2013;65:315-499). Although some these disclosures provide comments alleging how solubility of NSAIDs can be improved within pharmaceutical formulations, they do not describe how increased amounts of NSAIDs can be delivered to the relevant site of action in vivo. The improvement of solubility per se of the drugs (NSAIDs) in the formulations is not claimed as novel in this patent / invention. One advantage of compositions of the present disclosure is they can be used to deliver NSAIDs topically with surprising transdermal delivery. Another advantage of the invention is solubility enhancement of an agent (e.g. the solid salt MSU) that causes a disease (e.g. gout), and the solubility enhancement is within the strict constraints of the media where the MSU crystallises within the body i.e. blood or synovial fluids. These fluids have high levels of Na ions and also controlled pH (around 7.4). So precedence that a solvent / excipient can improve solubility of a drug in a formulation or water is not relevant in predicting which excipient combinations can improve the solubility of the disease-causing MSU salt in a medium that imitates "in vivo’ i.e. blood or synovial fluid. Further, the prior art is not relevant to predicting whether a solubility enhancing agent can penetrate the skin in sufficient amount to achieve the solubility enhancement of MSU in vivo.

[0056] The inventors have found that compositions of the disclosure are always a single phase. The single phase nature of the compositions of the disclosure has been determined by visual inspection, light microscopy and centrifugation (i.e. a single phase is present following centrifugation). Used herein the term “single phase” or “one phase” means a substance without a discernible phase boundary, for example a mixture fully dissolved in a liquid solution without any solids and without a discernible phase boundary between oil and water phases. Single phase systems contrasts with bi-phasic systems such as an emulsion, micro-emulsion, ‘emugel’, or liposomes, where there are two phases present. Most bi-phasic systems can be observed as ‘cloudy or opaque’ suspensions / solutions, except true microemulsions. Bi-phasic systems are mostly less stable than single phase solutions. Single phase solutions are often more stable when exposed to non-ambient temperatures such as storage in a fridge (around 4°C) or in the sun (up to around 40-50°C). Single phase solutions are often more stable to storage for a prolonged period.

[0057] In this disclosure, the NSAID may be selected from diclofenac, ibuprofen, salicylic acid, ketorolac, ketoprofen, naproxen or celecoxib. The NSAID may be added as the free acid form, but will generally be neutralised ‘in-situ’ with a base i.e. amine. The NSAID may also be added as a pharmaceutically acceptable salt form. In a preferred embodiment, the NSAID is either diclofenac or ibuprofen. It is also preferred to avoid the sodium salt of an NSAID as sodium has been shown to decrease the solubility of monosodium urate (MSU) in bodily-like fluids (a manifestation of the ‘common-ion effect’) and this can promote precipitation of MSU which leads to worse gout attacks. The preferred range by weight for diclofenac is from 0.5-5%. In a more preferred embodiment the diclofenac weight is 0.93% or 1.86%. In a more preferred embodiment the diclofenac weight is 0.93%. In a more preferred embodiment the diclofenac weight is 1.86%. The preferred range by weight for ibuprofen is from 5-10%. In a more preferred embodiment the ibuprofen weight is either 5% or 10%. In a more preferred embodiment the ibuprofen weight is 5%. In a more preferred embodiment the ibuprofen weight is 10%.

[0058] In compositions of the disclosure water is included in greater than or equal to 35% weight. This is in strong contrast to prior art formulations where water is often absent, or at relatively low levels (0-20%). Many non-aqueous excipients are relatively volatile and flammable ‘organic’ solvents which can result in a flammable product. There have been cases where flammable formulations with low levels of water (or no water) have soaked into patients clothes or dressings, and finally caught fire causing serious injury. Therefore, a formulation with a significant level of water is desirable as it reduces the flammability and associated risk. Topical formulations with higher water content, e.g. >20%, also have lower risk of drying out the skin and causing skin irritation and contact dermatitis. It is also desirable to have a pH neutral formulation as acidic or alkaline topical formulations can also cause skin irritation and contact dermatitis. Suitably all acidic components neutralised to make the formulation pH neutral. Despite the benefits of compositions having a relatively high water content, preparing high water content compositions is associated with numerous technical challenges. It is not possible to simply add water to known compositions to achieve the benefits of the disclosure, because prior art compositions are carefully formulated and typically not compatible with higher water content - i.e. addition of water to known compositions would result in loss of efficacy, making them no longer suitable for treatment of inflammatory disorders. In general, the challenges of preparing a high water content composition for treating inflammatory disorders include increased risk of separation of emulsion into separate phases, reduced stability of the composition, reduced efficacy of the composition due to e.g. dilution by the water, reduced efficacy due to e.g. lower hydrophobicity of the composition and associated reduction in interaction with hydrophobic tissues / regions of the body. The inventors have surprisingly found that compositions of the present disclosure specifically have a relatively high water content without being associated with the generally expected disadvantages.

[0059] The invention provides solutions to the technical challenges of forming a single-phase stable topical formulation, with a significant water content to reduce flammability and potential skin irritation, with improved transdermal NS AID delivery and which can improve solubility of monosodium urate which is the cause of gout. It was impossible for a skilled person to predict what combination and levels of the excipient and ingredients used in this disclosure would deliver these technical advantages. Further, the applicants believe there is no prior art which describes an effective topical formulation that can improve MSU solubility in vivo i.e. in the actual body fluids where MSU is known to cause gout.

[0060] Compositions of the disclosure include benzyl alcohol. Benzyl alcohol has a number of roles in the composition, acting as a cosolvent which in the context of the composition leads to a stable single phase product, as well as a skin penetration enhancer, a preservative inhibiting microbial growth and contamination, and increasing the solubility of MSU in vivo.

[0061] Compositions of the disclosure include oleic acid. Oleic acid acts as a skin penetration enhancer and increases the solubility of MSU in vivo.

[0062] Compositions of the disclosure include amine base. Amine base neutralises the composition making it kind to the skin and reduces the risk of any potential skin irritation. Amine base has been observed by the inventors to also increase the stability of the composition, without being bound by theory it is thought that this is achieved by making the composition close to neutral pH. Further the combination of oleic acid and amine base in the composition forms a soft soap which enables the presence of a single phase despite there being a mixture of relatively hydrophobic components (including oleic acid) and relatively hydrophilic components (including water).

[0063] Compositions of the disclosure include glycol ether (such as 2-(2-ethoxyethoxy)ethanol, polyethylene glycol 200, a mixture thereof, or others). Glycol ethers have been observed by the inventors to be skin penetration enhancers in the context of the composition. Further, glycol ethers increase the solubility of MSU in vivo.

[0064] Compositions of the disclosure may include propan-2-ol. Propan-2-ol has a beneficial combination of properties which makes the composition especially suitable for treatment. Specifically propan-2-ol acts as a skin penetration enhancer, increases the solubility of MSU in vivo, and acts as a cosolvent in the composition contributing to the phase stability of the composition.

[0065] Compositions of the disclosure may include carbomer. Carbomer also imparts beneficial properties onto the composition. Carbomer may act to thicken the composition making it convenient to use and apply to the skin.

[0066] Compositions of the disclosure may include menthol. Menthol in the context of the composition imparts a number of beneficial properties to the composition. Compositions of the disclosure comprising menthol are especially suitable for pain relief as they have a cooling effect on the skin, having an anti-inflammatory effect and also have a pleasant odour.

[0067] Compositions of the disclosure may include NSAIDs. Compositions comprising NSAIDs have especially strong anti-inflammatory effects in vivo.

[0068] Compositions of the disclosure may include colchicine. Compositions comprising colchicine have especially strong anti-inflammatory effects in vivo.

[0069] Collectively the ingredients of the composition act synergistically to give rise to the benefits of the invention. The unique combination of the composition specified herein maximise the improvement of MSU solubility in vivo, enhance penetration through the skin, maintain a stable single phase formulation, prevent microbial contamination (preserving the formulation), present a convenient gel for easy application and use on the skin, and can exert an antiinflammatory effect in vivo.

[0070] For at least these reasons the applicants believe compositions described herein are novel, inventive, non-obvious and solve a number of technical challenges.

[0071] The amine base may be present in a range from 1 to 5% by weight. This is adjusted to result in a pH neutral formulation, based on the molarity of acidic components in the formulations. The acidic components can include the NSAID (if present), a fatty acid and / or carbomers. In a preferred embodiment, the amine is a tertiary amine. Acceptable amines can include di ethylamine, triethylamine, triethanolamine or tromethamine. In a most preferred embodiment of the invention the amine is triethanolamine.

[0072] Suitably compositions of the disclosure may comprise one or more of propylene glycol, dipropylene glycol, 1,5 propanediol butylene glycol, polyethylene glycols (i.e. PEG), PEG- 200, PEG-300, PEG-400, and / or glycerol. In preferred embodiments, the compositions comprise propylene glycol and / or polyethylene glycol-200. In preferred embodiment, the compositions comprise propylene glycol and polyethylene glycol-200.

[0073] In a preferred embodiment, the glycol ether is present in the range 20-45% by weight. In a preferred embodiment the glycol ether comprises 2-(2-ethoxyethoxy)ethanol also known as Transcutol-P (Gattefosse, France).

[0074] The compositions of the disclosure may further comprise aryl and / or alkyl alcohols which are not benzyl alcohol, in an amount in the range of 1-10 wt%, in addition to benzyl alcohol. Suitably, compositions of the disclosure may comprise one or more of methanol, ethanol, propan-l-ol, propan-2-ol (isopropanol), butanol, phenol, 4-hydroxyphenol or 4-hydoxybenzyl alcohol. In a preferred embodiment of the invention the aryl and alky alcohols which are not benzyl alcohol is propan-2-ol.

[0075] The compositions of the disclosure comprise 1 wt% to 10 wt% benzyl alcohol. Suitably the composition comprises 3 wt% to 7 wt% benzyl alcohol. Preferably the composition comprises 4 wt% to 6 wt% benzyl alcohol. More preferably the composition comprises 5 wt% benzyl alcohol.

[0076] The compositions of the disclosure contain oleic acid in the range of 1-5% by weight. It will be understood that one or more of stearic acid, palmitic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, oleic acid or linoleic acid may be used as a suitable alternative. The compositions of the disclosure may comprise stearic acid, palmitic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, and / or linoleic acid.

[0077] The composition may comprise one or more herbal essential oils in the range 0.5-10% by weight. Used herein the term herbal essential oil refers to an oil extracted from a plant. Suitably the one or more herbal essential oils may be one or more pharmaceutically acceptable herbal essential oils. The choice of herbal essential oils can include Bergamot, Eucalyptus, Jasmine, Camomile, Lavender, Peppermint, Rosemary, Sandalwood, Cajeput or Clove. The formulation may comprise between 0-5% herbal essential oils. In a preferred embodiment of the invention the herbal essential oils are cajeput and clove.

[0078] The composition may comprise colchicine in the range 0.5-10% by weight.

[0079] Suitably the composition contains carbomers 1-10% by weight. In the present disclosure the term carbomer means a polymer of acrylic acid, i.e. a polymer with the formula (CEE- CHCO2H)n. There are various grades of carbomer available commercial which would be well known to a skilled person. Suitably the carbomers can be acidic or pre-neutralised.

[0080] Detailed description:

[0081] Compositions may show an unexpected and surprising increase in transdermal delivery of the NS AID active ingredient through full thickness skin. This may be due to the combination and relative amounts of excipients in the formulations. Compositions may show an unexpected and surprising increase in the in vitro solubility of monosodium urate (MSU) which the known cause of the disease gout i.e. when delivered transdermally into a fluid system that imitates in vivo body fluids such as blood or synovial fluids. Compositions may surprisingly be present in one phase, even though it contains up to 87% water, with organic ingredients such as glycols and fatty acids that are commonly known to ‘not dissolve’ in aqueous systems. Compositions have a high content of water i.e. >35% which may lead to lower skin irritation and lower flammability of the formulation.

[0082] Gout is an inflammatory arthritis disease that is caused by crystals of monosodium urate forming within joints or surrounding tissue within the body. These crystals cause a very painful inflammatory response (a ‘gout attack’). A very important and urgent technical challenge is to help the MSU crystals to re-dissolve within the joints or surrounding tissue. This will help resolve the initial gout attack and also prevent re-occurrence or long-term formation of MSU deposits in the joints or surrounding tissue (known as tophi). This technical challenge has not been address in the prior art. The challenge is to provide a topical formulation that can increase the solubility of the MSU crystals without requiring major medical intervention. This means improving the solubility for this MSU salt, in the actually conditions that are within the body fluids. Further, this improvement in solubility must be achieved using a composition that at least the active constituents of which can penetrate through the skin and into the joints and surrounding tissues.

[0083] In a very early paper, Kippen et al. showed that the MSU crystals were forming in body fluids such as synovial fluids or blood. He showed that there were two major factors that influence MSU solubility in these body fluids - the pH and the level of sodium (Na) ions (e.g. from salt, NaCl) in the fluids. It is well known that MSU has a higher solubility in pure water than in body fluids, body fluids have in general around 0.15 mol / litre sodium ions. This effect can be assigned to the known ‘common ion effect’ where Na ions in solution can reduce the solubility of other sodium salts due to them sharing a common ion. Secondly, Kippen showed that between pH 6 to 10, the solubility of MSU in a buffer containing around 0.15mol / l NaCl stays broadly constant. At pH lower than 6 or higher than 10, the solubility can increase significantly. These observations are critical as if one wished to increase the solubility of MSU within the body (in vivo), one must show an increase in MSU solubility in a solution with body-like levels of NaCl (i.e. around 0.15mol / l) and at body-like pH i.e. 7.4. Whilst in may be possible to temporarily change the local concentration of Na ions in the body, or change the pH slightly, it is not safe to change the pH in the body to lower than 6 or higher than 10 for any significant length of time. It is also very dangerous to reduce the levels of Na ions within the body as Na plays a significant role within cells and the body as a whole. Therefore, there is a difficult technical challenge in the treatment of gout, namely to increase MSU solubility in body fluids with Na levels at around 0.15mol / litre and pH at around 7.4 without disturbing the Na levels or the pH. This specific set of body -fluids covering blood and synovial fluids may be modelled using phosphate buffered saline (PBS) in laboratory trials. The PBS used should have Na levels at around 0.15mol / litre (from added NaCl) and should keep pH around pH 7.4 in order to closely reflect body conditions. It is not easily predictable which solvents or co-solvents will improve the solubility of a specific salt of an organic compound (such as the sodium salt of uric acid, MSU). There are various solvents that are known to help solubility of a number of drugs (active pharmaceutical compounds) in pharmaceutical formulations or free solution, but this is not the same as the technical challenge of improving the solubility of MSU in the body -like fluids, e.g. in PBS of pH 7.4. As is shown below in Table 2 of Example 2, some well-known solvents have little or no effect on the MSU solubility, some have a positive effect on solubility and a few even have a negative effect. Therefore it is not predictable which excipients will achieve the desired effect (i.e. improving MSU solubility) and it was surprising which combination of excipients gave the final best results as shown in Figure 1. In fact, many of the excipients used in the topical formulation of this invention were also present in the other commercial formulations tested which showed very little effect on the MSU solubility.

[0084] A second technical challenge is to deliver the improvement in MSU solubility into the joints or affected tissue in a safe and user-friendly manner. Patients do not want to have to go to a surgery or hospital to have a medical professional inject their painful joints, or to have the joint ‘washed out’ (known as joint lavage). Both of these involve medical professionals breaking the skin, which is a strong natural barrier and this is not an ideal way of treating the disease. Therefore, it is preferred to deliver the improvement transdermally directly to the affect areas, normally a joint or surrounding tissue. It is not obvious what combination of excipients / ingredients will achieve both the transdermal delivery and then improve the MSU solubility after delivery through the skin. This is the second technical challenge that the invention solves in this area as the results shown for MSU solubility directly in vials (table 2) are confirmed in Franz-cell experiments where the formulation is delivering the improvement in solubility after passing transdermally through the skin.

[0085] Hooper and He (Hooper MW, He L; Journal of Pain Research 2022, 15: 1825-1835) discloses compositions having the ingredients of the present disclosure. Hooper and He does not disclose or teach the relative amounts of the ingredients, so it would not be possible to reproduce the results seen in the paper without further information. Hooper and He does not disclose or teach that a single phase can be obtained. Hooper and He does not disclose or teach that a single phase composition can be useful for storage stability. Hooper and He does not disclose or teach that a high water content composition can be used (i.e. greater than 35% water), nor that this is useful to reduce flammability of the compositions, nor that this may be useful to make the composition more skin kind. Hooper and He does not disclose or teach that an efficacious composition that is pH neutral can be obtained, nor that this may be useful to make the composition more skin kind.

[0086] Suitably the composition may be a single phase. Suitably the composition may be stable at room temperature for at least 3 months, preferably the composition may be stable at room temperature for at least 6 months, more preferably the composition may be stable at room temperature for at least one year. Suitably NSAIDs may be present as racemates. Suitably NSAIDs may be present as scalemic mixtures. Suitably NSAIDs may be present as single enantiomers. Suitably NSAIDs may exist as stereoisomers. Suitably NSAIDs may be present in the composition as a single stereoisomer. Suitably NSAIDs may be present in the composition as a mixture of stereoisomers.

[0087] Suitably NSAIDs may be free acids. Suitably NSAIDs may be free bases. Suitably NSAIDs may be pharmaceutically acceptable salts. Suitably NSAIDs may comprise a mixture of pharmaceutically acceptable salts. Suitably herbal essential oils may comprise free acids. Suitably herbal essential oils may comprise pharmaceutically acceptable salts or mixtures thereof.

[0088] Suitably compositions show improved delivery of the NSAIDs through the skin to the target area of the body. Suitably compositions show improved delivery of the NSAIDs through the skin to the target area of the body relative to commercially available topical formulations.

[0089] Suitably compositions increase the solubility of MSU in vivo. Suitably compositions increase the solubility of MSU in joints, for example in the synovial fluid of joints. Suitably compositions increase the solubility of MSU in the surrounding of tissues joints. Suitably compositions increase the solubility of MSU in joints and surrounding tissues. Suitably the increase the solubility of MSU in vivo is greater than 1%, preferably greater than 2%, more preferably greater than 3%, even more preferably greater than 5%, most preferably greater than 10%.

[0090] Suitably compositions cause a larger percentage increase in solubility of MSU in PBS buffer at 37 °C than at 25 °C. Suitably compositions cause a larger percentage increase in solubility of MSU in PBS buffer at 37 °C than at 25 °C wherein the percentage increase in solubility at 37 °C is at least twice the percentage increase in solubility at 25 °C. Suitably compositions cause a larger percentage increase in solubility of MSU in PBS buffer (5 mM phosphate, 0.14 M sodium, pH 7.4) at 37 °C than at 25 °C. Suitably compositions cause a larger percentage increase in solubility of MSU in PBS buffer (5 mM phosphate, 0.14 M sodium, pH 7.4) at 37 °C than at 25 °C wherein the percentage increase in solubility at 37 °C is at least twice the percentage increase in solubility at 25 °C.

[0091] Suitably compositions provide an analgesic effect. Suitably compositions provide an analgesic effect and treat gout. Suitably compositions are kind to skin. Suitably compositions are nonflammable.

[0092] Suitably the composition for use in therapy comprises:

[0093] 35 wt% to 87 wt% water;

[0094] 1 wt% to 10 wt% benzyl alcohol;

[0095] 1 wt% to 5 wt% oleic acid;

[0096] 1 wt% to 5 wt% amine base; and

[0097] 10 wt% to 50 wt% 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0098] Suitably the composition for use in therapy comprises:

[0099] 35 wt% to 87 wt% water;

[0100] 1 wt% to 10 wt% benzyl alcohol;

[0101] 1 wt% to 5 wt% oleic acid;

[0102] 1 wt% to 5 wt% triethanolamine; and

[0103] 10 wt% to 50 wt% 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0104] Suitably the composition for use in therapy comprises:

[0105] 35 wt% to 85 wt% water;

[0106] 1 wt% to 10 wt% benzyl alcohol;

[0107] 1 wt% to 5 wt% oleic acid;

[0108] 1 wt% to 5 wt% triethanolamine;

[0109] 1 wt% to 5 wt% menthol;

[0110] 1 wt% to 5 wt% propan-2-ol; and

[0111] 10 wt% to 50 wt% 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0112] Suitably the composition for use in therapy comprises:

[0113] 35 wt% to 83 wt% water;

[0114] 1 wt% to 10 wt% benzyl alcohol;

[0115] 1 wt% to 5 wt% oleic acid;

[0116] 1 wt% to 5 wt% triethanolamine;

[0117] 1 wt% to 5 wt% menthol;

[0118] 1 wt% to 5 wt% propylene glycol;

[0119] 1 wt% to 3 wt% carbomer;

[0120] 1 wt% to 5 wt% propan-2-ol; and

[0121] 10 wt% to 50 wt% 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout. Suitably the composition for use in therapy comprises:

[0122] 35 wt% to 50 wt% water;

[0123] 1 wt% to 10 wt% benzyl alcohol;

[0124] 1.5 wt% to 2.7 wt% oleic acid;

[0125] 1 wt% to 5 wt% triethanolamine;

[0126] 1 wt% to 5 wt% menthol;

[0127] 1 wt% to 5 wt% propylene glycol;

[0128] 1 wt% to 3 wt% carbomer;

[0129] 1 wt% to 5 wt% propan-2-ol; and

[0130] 10 wt% to 50 wt% 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0131] Suitably the composition for use in therapy comprises:

[0132] 35 wt% to 50 wt% water;

[0133] 1 wt% to 10 wt% benzyl alcohol;

[0134] 1.5 wt% to 2.7 wt% oleic acid;

[0135] 1 wt% to 5 wt% triethanolamine;

[0136] 1 wt% to 5 wt% menthol;

[0137] 1 wt% to 5 wt% propylene glycol;

[0138] 1 wt% to 3 wt% carbomer;

[0139] 1 wt% to 5 wt% propan-2-ol; and

[0140] 10 wt% to 50 wt% 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0141] Suitably the composition for use in therapy comprises:

[0142] 35 wt% to 50 wt% water;

[0143] 1 wt% to 10 wt% benzyl alcohol;

[0144] 1.5 wt% to 2.7 wt% oleic acid;

[0145] 1 wt% to 5 wt% triethanolamine;

[0146] 1 wt% to 5 wt% menthol;

[0147] 1 wt% to 5 wt% propylene glycol;

[0148] 1 wt% to 3 wt% carbomer;

[0149] 1 wt% to 5 wt% propan-2-ol; and

[0150] 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol; and

[0151] 2 wt% polyethylene glycol 200 wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0152] Suitably the composition for use in therapy comprises:

[0153] 35 wt% to 50 wt% water;

[0154] 1 wt% to 10 wt% benzyl alcohol;

[0155] 1.5 wt% to 2.7 wt% oleic acid;

[0156] 1 wt% to 5 wt% triethanolamine;

[0157] 1 wt% to 5 wt% menthol;

[0158] 1 wt% to 5 wt% propylene glycol;

[0159] 1 wt% to 3 wt% carbomer;

[0160] 1 wt% to 5 wt% propan-2-ol;

[0161] 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol; and

[0162] 2 wt% polyethylene glycol 200 wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0163] Suitably the composition for use in therapy comprises:

[0164] 35 wt% to 50 wt% water;

[0165] 1 wt% to 10 wt% benzyl alcohol;

[0166] 1.5 wt% to 2.7 wt% oleic acid;

[0167] 1 wt% to 5 wt% triethanolamine;

[0168] 1 wt% to 5 wt% menthol;

[0169] 1 wt% to 5 wt% propylene glycol;

[0170] 1 wt% to 3 wt% carbomer;

[0171] 1 wt% to 5 wt% propan-2-ol;

[0172] 0.1 wt% to 10 wt% of the one or more NSAID, preferably wherein the NSAID is diclofenac or ibuprofen;

[0173] 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol; and

[0174] 2 wt% polyethylene glycol 200 wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0175] Suitably the composition for use in therapy comprises:

[0176] 35 wt% to 50 wt% water;

[0177] 1 wt% to 10 wt% benzyl alcohol;

[0178] 1.5 wt% to 2.7 wt% oleic acid;

[0179] 1 wt% to 5 wt% triethanolamine;

[0180] 1 wt% to 5 wt% menthol;

[0181] 1 wt% to 5 wt% propylene glycol;

[0182] 1 wt% to 3 wt% carbomer; 1 wt% to 5 wt% propan-2-ol;

[0183] 0.5 wt% to 5 wt% of one or more herbal essential oil, preferably wherein the one or more herbal essential oil comprises cajeput and clove oil;

[0184] 33 wt% to 38 wt% 2-(2-ethoxy ethoxy jethanol; and

[0185] 2 wt% polyethylene glycol 200 wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0186] Suitably the composition for use in therapy comprises:

[0187] 35 wt% to 50 wt% water;

[0188] 1 wt% to 10 wt% benzyl alcohol;

[0189] 1.5 wt% to 2.7 wt% oleic acid;

[0190] 1 wt% to 5 wt% triethanolamine;

[0191] 1 wt% to 5 wt% menthol;

[0192] 1 wt% to 5 wt% propylene glycol;

[0193] 1 wt% to 3 wt% carbomer;

[0194] 1 wt% to 5 wt% propan-2-ol;

[0195] 0.1 wt% to 10 wt% of the one or more NSAID, preferably wherein the NSAID is diclofenac or ibuprofen;

[0196] 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol; and

[0197] 2 wt% polyethylene glycol 200 wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; wherein the pH of the composition is 6.0 to 8.0; wherein the composition is a topical composition, preferably a transdermal composition; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0198] Suitably the composition for use in therapy comprises:

[0199] 35 wt% to 50 wt% water;

[0200] 1 wt% to 10 wt% benzyl alcohol;

[0201] 1.5 wt% to 2.7 wt% oleic acid;

[0202] 1 wt% to 5 wt% triethanolamine;

[0203] 1 wt% to 5 wt% menthol;

[0204] 1 wt% to 5 wt% propylene glycol;

[0205] 1 wt% to 3 wt% carbomer;

[0206] 1 wt% to 5 wt% propan-2-ol;

[0207] 0.5 wt% to 5 wt% of one or more herbal essential oil, preferably wherein the one or more herbal essential oil comprises cajeput and clove oil;

[0208] 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol; and

[0209] 2 wt% polyethylene glycol 200 wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid; wherein the pH of the composition is 6.0 to 8.0; wherein the composition is a topical composition, preferably a transdermal composition; preferably wherein the therapy is the treatment of an inflammatory disorder, more preferably wherein the inflammatory disorder is gout.

[0210] In a preferred embodiment the composition comprises one or more non-steroidal antiinflammatory drug (NSAID), more preferably 0.1 wt% to 10 wt% of the one or more NSAID, even more preferably 0.5 wt% to 7 wt% of the one or more NSAID, wherein the composition is for use in the treatment of an inflammatory disorder, for example wherein the inflammatory disorder is one or more of gout, arthritis, dermatomyositis, myositis, synovitis, tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, osteitis, osteomyelitis, spondylitis, periostitis and chondritis.

[0211] In a preferred embodiment the composition comprises one or more herbal essential oil, optionally 0.5 wt% to 5 wt% of the one or more herbal essential oil, wherein the composition is for use in the treatment of an inflammatory disorder, for example wherein the inflammatory disorder is one or more of gout, arthritis, dermatomyositis, myositis, synovitis, tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, osteitis, osteomyelitis, spondylitis, periostitis and chondritis.

[0212] A preferred embodiment provides a composition for use in the treatment of gout comprising: 35 wt% to 87 wt% water;

[0213] 1 wt% to 10 wt% benzyl alcohol;

[0214] 1 wt% to 5 wt% oleic acid;

[0215] 1 wt% to 5 wt% amine base; and

[0216] 10 wt% to 50 wt% glycol ether, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid.

[0217] A preferred embodiment provides a composition comprising 0.5 wt% to 5 wt% of colchicine for use in the treatment of gout.

[0218] It is preferred that compositions of the disclosure for use in treatment of inflammatory conditions (such as those not limited to gout) comprise one or more non-steroidal antiinflammatory drug (NSAID).

[0219] Optionally the listed ingredients sum to 100 wt%. Optionally the weight balance of ingredients in the composition is made up to 100 wt% by the presence of water.

[0220] Used herein the term Transcutol refers to 2-(2-ethoxyethoxy)ethanol. Used herein the term tromethamine refers to tris(hydroxymethyl)aminomethane. Used herein the term Diclofenac refers to [2-(2,6-dichloroanilino)phenyl]acetic acid. Used herein the term Ibuprofen refers to 2-(4-isobutylphenyl)propanoic acid. Used herein the term Salicylic acid refers to 2- Hydroxybenzoic acid. Used herein the term Triethanolamine refers to N(CH2CH2OH)3. Used herein the term Kolliphor RH40 refers to Polyoxyl 40 hydrogenated castor oil. Used herein the term Polysorbate 20 refers to Polyoxyethylene (20) sorbitan monolaurate. Used herein the term Triacetin refers to 1,2, 3 -triacetoxypropane. Used herein the terms composition and formulation are interchangeable. Used herein the term glycol ether refers to an ether derived from a glycol, for example alkyl ethers of glycols, such as monoalkyl ethers or dialkyl ethers of glycols, preferably wherein the glycol is ethylene glycol, propylene glycol, an oligomer of ethylene glycol, an oligomer of propylene glycol, a polymer of ethylene glycol, or a polymer of propylene glycol. Used herein oleic acid refers to (9Z)-octadecenoic acid. Used herein benzyl alcohol refers to phenylmethanol. Used herein the term colchicine refers to N-[(7S)-l,2,3,10- tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide.

[0221] Used herein the term inflammatory disorder refers to diseases which involve excess inflammation, e.g. where the body’s immune system causes inflammation unnecessarily through attacking the body’s own cells and / or tissues. Inflammatory disorders are well known in the field and the skilled person is readily able to identify inflammatory disorders.

[0222] Used herein the terms “treatment” and “therapy” refer to any degree of alleviation of symptoms in a condition, i.e. they may be curative, or they may reduce one or more symptoms of a condition like partial reduction of a pain, further they may be prophylactic or act on on-going conditions.

[0223] The novel and surprising aspects of the disclosure are shown by reference to the following Examples.

[0224] Examples:

[0225] Example 1

[0226] Various compositions of this disclosure are shown below in table 1. These show the percentage by weight of each component in the formulations.

[0227]

[0228] All of the above formulations are single phase systems suitable for use as a topical formulation. This is surprising and many previous formulations in the prior art are either two-phase systems such as the ‘emugel’ formulations (emulsion-gels) i.e. emulsions; or have low levels of water (less than 20%, commonly less than 10%) to avoid forming two-phase systems. In the absence of the information provided herein it is not obvious how to keep a topical formulation with higher levels of water (35 wt% to 87 wt%) and significant levels of organic solvents that are generally non-miscible with water (such as oleic acid, glycols etc) in one phase. The inventors have surprisingly found that compositions of the present disclosure (e.g. Fl, F2, F3, F4 and F5) are of a single phase. Without being bound by theory the unique combination and relative amounts of the ingredients result in formulations of the disclosure being of a single phase.

[0229] Each of the topical formulations have a significant level of water content (>35 wt%), much larger than most prior art compositions. This may be associated with the advantage that the formulations are non-flammable. Further this may be associated with the advantage that the will lead to lower skin irritation.

[0230] All the formulations Fl -F5 are pH neutral i.e. measured pH is around 7. This may be associated with the significant advantage of lower skin irritation.

[0231] Example 2

[0232] Improved monosodium urate (MSU) solubility in media that is a suitable lab-trial for blood or synovial fluid i.e. within the body / joints

[0233] Solubility enhancement of monosodium urate crystals in phosphate buffered saline

[0234] A phosphate buffered saline diluent was prepared by dissolving 8.2 g of NaCl and 0.68 g of KH2PO4 in 500 mL of deionised water in a 1 L flask. An NaOH solution was prepared by dissolving 0.399 g of NaOH in 100 mL of deionised water. 39.1 mL of the 0.1 M NaOH solution was then added to the 1 L flask and the volume was made up to 1 L with deionised water. The pH was adjusted to 7.4. The resultant PBS buffer was 5 mM phosphate, 0.14 M sodium and pH 7.4. Approximately 5 mg of monosodium urate crystals was then suspended in 4.75 mL of the phosphate buffered saline diluent in a vial. A 0.25 mL amount of a solubility enhancer was then added to the suspension of monosodium urate crystals. This provided a 5% by volume solubility enhancer experiment, unless otherwise indicated in Table 2 below. Where a different percentage is indicated in Table 2, the amounts of the phosphate buffered saline diluent and the solubility enhancer were varied to provide a total volume of 5 mL with the specified % by volume of the solubility enhancer. In the case of the solubility enhancer being a mix of components, equal portions by volume of each component was added, unless indicated otherwise. This was then stirred for about 16 hours.

[0235] A sample of the supernatant was then taken, filtered using standard techniques (e.g. a syringe filter), and analysed by high-performance liquid chromatography (HPLC) to determine the concentration of uric acid / urate present in solution. The results are shown below in Table 2.

[0236] All samples were analysed using a HPLC system equipped with a variable wavelength UV detector and a reversed phase column (5 pm ODS2, 4.6 mm x 150 mm, Waters Spherisorb). The mobile phase was 35 mM sodium acetate in water with pH adjusted to 5.0 using acetic acid. The flow rate was set at 1 mL / min and UV detection at a wavelength of 292 nm. Sample injection volume was 50.0 pL and all operations were carried out at 25°C. Standard solutions of MSU were made up in the range of 15-250 pg / mL and analysed as above. The peak area correlated linearly with the MSU concentration in the tested range of 15-250 pg / mL, with an average correlation coefficient of 0.993.

[0237] Although the present examples have been carried out at room temperature (25°C) for convenience, the observed increases in solubility of MSU would correlate similarly to those that would be observed at 37°C (as explained by Kippen et al., “Factors affecting urate solubility in vitro”, Annals of Rheumatic Diseases, 1974, 33, 313-317).

[0238] As explained by Kippen et al. the above-described phosphate buffered saline diluent system is representative of the solubility of monosodium urate (MSU) in the synovial fluid and plasma of a patient. able 2. Solubility enhancement of MSU crystals in phosphate buffered saline solution

[0239] In Table 2, % vs control refers to the concentration of urate in the sample containing solubility enhancer as a percentage of the concentration of urate in the control sample without solubility enhancer. A value of greater than 100% therefore indicates that the solubility enhancer increases the solubility of MSU and a value of less than 100% therefore indicates that the solubility enhancer decreases the solubility of MSU.

[0240] From Table 2, it can be observed that some well-known solvents (or solubility enhancers) such as methanol, acetone or acetonitrile have very little effect on the MSU solubility even when added at 5% (which would be a high level to achieve transdermally). Other solvents that are commonly considered to solubilise a wide range of substances in high solubilities, such as dimethyl sulfoxide, do not show the highest solubility enhancement. Some mixtures of solvents can actually show an additive effect, such as PEG 200 / Transcutol which showed better increase than the solvents alone (when added at 2.5%). The results in Table 2 demonstrate that it is not possible for someone skilled in the art to just predict which solvents / excipients would improve the MSU solubility in PBS by just looking at the prior art or by performing routine tests and extrapolating the results. The results in Table 2 contributed to solving the technical challenge of improving MSU solubility in-vivo.

[0241] Table 2 also shows the effect of adding some solid solubility enhancers. These could be delivered via a topical formulation transdermally as dissolved in the formulation. These results re-enforce the learning from Kippen et al - changing the pH to below 5 (e.g. salicylic acid at pH 2.9) increases the MSU solubility significantly. Also increasing the pH above 10 e.g. tromethamine and especially sodium carbonate can increase the MSU solubility significantly. However, subjecting the body to extremes of pH is very dangerous and not a viable solution to the technical problem of increasing MSU solubility in vivo. Adding sodium bicarbonate can only shift the pH to around 8-9, and this does not increase the MSU solubility significantly. In fact the main effect is to lower the MSU solubility due to the increased concentration of sodium ions, as also described in Kippen et al. Therefore, delivering sodium bicarbonate transdermally will have the undesired effect of decreasing MSU solubility which can cause more MSU to crystallise and will make gout attacks more frequent. So sodium bicarbonate is also not a viable solution to the technical problem of increasing MSU solubility in vivo.

[0242] Both sodium carbonate and sodium bicarbonate lower the MSU solubility when adjusted back to normal body pH (7.4), presumably due to the increased sodium ion concentration. Menthol and mannitol both have little effect on the MSU solubility.

[0243] Further, Table 2 shows tromethamine can increase the MSU solubility when adjusted back to body pH (7.4). Table 2 also shows salicylic acid can increase the MSU solubility when adjusted back to body pH (7.4). These results were surprising to the inventors and are not indicated by the prior art.

[0244] In summary the results of this example demonstrate what solubility enhancers can give rise to overall increase in MSU solubility under physiological conditions is impossible to predict in the absence of the information provided herein.

[0245] Example 3

[0246] Confirmation of solubility enhancement of monosodium urate crystals at room temperature and 37 °C

[0247] Some vial-based solubility assessments were run following the same method as described in Example 2, but were run at both 25°C and at 37°C in a water bath overnight. Results are shown in Table 3. These data provide confirmation that compositions of the disclosure cause an increase in MSU solubility at 25 °C (room temperature) under close to physiological conditions. These data provide confirmation that compositions of the disclosure cause an increase in MSU solubility at body -like temperature of 37 °C under close to physiological conditions. Surprisingly the inventors have found that the compositions of the disclosure cause a larger increase in MSU solubility at body temperature than at room temperature.

[0248] The data in this example relating to F3 demonstrate that compositions of the disclosure containing an NSAID may be useful in the treatment of the inflammatory disorder gout. The data in this example relating to F4 demonstrate that compositions of the disclosure not containing an NSAID may be useful in the treatment of the inflammatory disorder gout.

[0249] Table 3. Solubility enhancement of MSU crystals in phosphate buffered saline solution at 25 °C and 37 °C.

[0250] Example 4: In vitro skin permeation with Franz cells and MSU solubility assessment

[0251] Pig’s ears (pink) were sourced from a local abattoir as a waste product from the food industry and processed within 1 day of sourcing. As no human product or animal testing were used, the experiments did not raise ethical compliance issues. Full thickness pig’s ears skin was removed from the cartilage and frozen at -20°C until use. The skin was thawed, any excess fat was removed from under the skin and it was cut to ~2cm diameter circles for use directly in the Franz cell experiments. Each formulation was tested in minimum in duplicate, and a control was always used. Skin samples were clamped between the donor and receiver cells and placed with the outside skin surface facing up i.e. in contact with the donor sample.

[0252] Static Franz cells were used with an exposed skin diameter of 0.7cm (1.05cm2surface area, supplied by Soham Scientific, Soham, UK). The cells had a receiver volume of 10ml and stir bars were added to the cells. lOmg of monosodium urate (MSU) mono-hydrate (Sigma- Aldrich) was added to each cell (i.e. Img / ml - this is a large excess of MSU as the control solubility for MSU in PBS at 25°C in 0.04mg / ml. This will allow any increase or decrease in the equilibrium MSU solubility to be achieved in the receiver cell). Phosphate buffered saline (PBS) was used as the receiving media (pH 7.4, phosphate buffer strength 0.01N, sodium concentration adjusted to 0.14mol / L with sodium chloride). All experiments were carried out at room temperature (20-25°C). Samples of the receiver media were removed after 72 hours, and filtered through a 0.2 micron syringe filter before being analysed by HPLC for urate and drug content (either ibuprofen or diclofenac as relevant).

[0253] 1ml of each product / formulation was placed in the donor cell - this always gave full coverage of the skin, and provided sink conditions for the formulations. 1ml PBS was applied as a control for all control runs, and this cell was used as the ‘ 100%’ level for MSU solubility in PBS.

[0254] HPLC analyses of sample from receptor media

[0255] Linearity for ibuprofen, diclofenac and MSU was established over the ranges analysed and specificity for each component was established when a single HPLC method was used (e.g. to analyse both diclofenac and MSU content). Ibuprofen and MSU were analysed separately for each relevant sample using separate HPLC methods. Where needed, the excipients in each formulation / product were also tested for specificity to confirm that they didn’t interfere with the determination of concentrations of the drugs and MSU.

[0256] HPLC methods:

[0257] MSU content: Mobile phase: pH 5 acetate buffer 0.035M. HPLC column: Supelco OSIL LC5, 15cm x 4.6mm, 5pm. Flow rate: Iml / min. Detector: UV set @ 292nm. Inj = lOpl. Urate peak at ~ 2.45mins. Run time 5mins.

[0258] MSU and diclofenac content: Mobile phase A (MPA): pH 5 acetate buffer 0.035M. Mobile phase B (MPB): acetonitrile. T=0: 100% MPA; T=6mins to T=6.5mins gradient to 60% MPA: 40% MPB; T=14mins to T=14.5mins gradient to 100% MPA. Run time 18mins. HPLC column: Supelco OSIL LC5, 15cm x 4.6mm, 5pm. Flow rate: Iml / min. Inj = lOpl. Detector: UV set @ 292nm. Urate peak at ~ 2.45mins, diclofenac peak at ~11.3mins.

[0259] Ibuprofen content: Mobile phase A (MPA): pH 3 buffer (from 1ml NEt3 + 0.5ml cone, phosphoric acid in 1 litre DI water). Mobile phase B (MPB): acetonitrile. Run with 50% MPA and 50% MPB. Run time 8 mins. HPLC column: Supelco OSIL LC5, 15cm x 4.6mm, 5pm. Flow rate: Iml / min. Inj = lOpl. Detector: UV set @ 220nm. Ibuprofen peak at ~ 4.9mins.

[0260] Seven commercial products and three compositions of the disclosure were used for this study, alongside a control of just phosphate buffered saline (PBS). The components of the formulations are shown below.

[0261] • Boots ibuprofen gel 5% (‘BO ibuprofen gel 5%’, The Boots Company PLC, Nottingham, UK) : ibuprofen, carbomer, diisopropanolamine, propylene glycol, ethanol and water

[0262] • Radian B ibuprofen gel 5% (‘RB ibuprofen gel 5%’, Thornton & Ross Ltd, Huddersfield, UK): ibuprofen, hydroxyethyl cellulose, sodium hydroxide, benzyl alcohol, isopropyl alcohol, water

[0263] • Ibuleve ibuprofen gel 5% (‘IB ibuprofen gel 5%’, Diomed Developments Ltd, Hitchin, UK): ibuprofen, carbomer, di ethylamine, IMS, water, propylene glycol

[0264] • Ibuleve ibuprofen gel 10% (‘IB ibuprofen gel 10%’, Diomed Developments Ltd, Hitchin, UK): ibuprofen, carbomer, di ethylamine, IMS, water • Nurofen ibuprofen gel 10% (‘NU ibuprofen gel 10%’, Reckitt Benckiser Healthcare, Slough, UK): ibuprofen, hydroxy ethyl cellulose, sodium hydroxide, benzyl alcohol, isopropyl alcohol, water

[0265] • Voltarol diclofenac Emugel 1.16% (‘VO diclofenac gel 1%’, GlaxoSmithKline, Brentford, UK): diclofenac di ethylammonium, carbomer, macrogol cetostearyl ether, cocoyl capryl ocaprate, isopropyl alcohol, liquid paraffin, perfume, propylene glycol, water

[0266] • Voltarol diclofenac Emugel 2.32% (‘VO diclofenac gel 2%’, GlaxoSmithKline, Brentford, UK): diclofenac di ethylammonium, carbomer, butylhydroxytoluene, diethylamine, macrogol cetostearyl ether, cocoyl capryl ocaprate, isopropyl alcohol, liquid paraffin, perfume, oleyl alcohol, propylene glycol, water

[0267] • Formulation 2, Example 1 (‘F2’): ibuprofen, menthol, triethanolamine, benzyl alcohol, oleic acid, isopropyl alcohol, propylene glycol, PEG-200, carbomer, transcutol (diethylene glycol monoethyl ether), water

[0268] • Formulation 3, Example 1 (‘F3’): diclofenac, menthol, triethanolamine, benzyl alcohol, oleic acid, isopropyl alcohol, propylene glycol, PEG-200, carbomer, transcutol (diethylene glycol monoethyl ether), water

[0269] • Formulation 4, Example 1 (‘F4’): menthol, triethanolamine, benzyl alcohol, oleic acid, isopropyl alcohol, propylene glycol, PEG-200, carbomer, transcutol (diethylene glycol monoethyl ether), water

[0270] Figure 1 shows the improvement in MSU solubility in PBS after compositions of the disclosure were applied to full-thickness (pig’s) skin in a Franz-cell experiment. The range of solubility improvements are 20-26% for formulations 2 to 4 prepared according to Example 1. In contrast, the commercial topical formulations tested had little or no effect on MSU solubility, with the change in MSU solubility being between -1% to +3%. This illustrates the technical advantage of compositions of the disclosure of increasing the solubility of MSU in this model of in-vivo fluids. This illustrates the technical advantage of compositions of the disclosure in increasing the solubility of MSU can be achieved transdermally. This illustrates the technical advantage of compositions of the disclosure in treating gout, a serious inflammatory disease.

[0271] Many of the ingredients are common to both the commercial formulations and the formulations of this invention, such as diclofenac, ibuprofen, propylene glycol, isopropyl alcohol, benzyl alcohol, carbomer, water. Many ingredients are also very similar such as alkylamines, oleic acid / oleyl alcohol. However, despite the similar ingredients used in the formulations, there is a significant difference in the observed effect on MSU solubility after transdermal delivery. This re-enforces that it is not obvious to a skilled person which solvents / ingredients would achieve the desired effect and the results achieved by this invention are surprising and novel

[0272] It is a clear technical challenge to improve delivery of non-steroidal anti-inflammatory drugs (NSAIDs) transdermally, that is through the skin. This mode of drug delivery reduces the known and serious side effects of oral delivery i.e. via the stomach, as the drug is targeted to the inflamed area, without causing serious problems in the stomach or cardiovascular systems. However, current commercial products do not deliver the NSAIDs well enough from the topical formulations, so oral NSAID delivery is still commonly used to achieve high enough levels of NSAIDs in the affected regions. Therefore, it is a clear and desirable technical challenge to improve the permeation of the NSAIDs through the skin.

[0273] A well-accepted and established measure of drug permeation in a laboratory setting is using Franz-cells and full thickness pig’s skin as the barrier membrane. Improved drug permeability in this laboratory test has been well correlated with improved permeability in humans, i.e. through live human skin. Therefore, improved drug permeability results (such as those shown in Figures 2 and 3) in the experiment described in this Example shows a significant advance in the technical challenge of NSAID transdermal delivery.

[0274] Figure 2 shows the transdermal delivery results for diclofenac (an efficacious NSAID) in this Example from the two leading commercial topical formulations containing diclofenac (Voltarol ‘ 1%’ and Voltarol ‘2%’). These data are compared with a composition of the disclosure, specifically ‘F2’ as prepared in Example 1 which contains the same amount of diclofenac as Voltarol ‘ 1%’ (all the % values are equivalent to the % of the sodium diclofenac salt, even though different salts are used i.e. the ‘ 1%’ actually contain 0.93 wt% diclofenac free acid). F2 surprisingly shows 3.4 times as much diclofenac delivery as the equivalent commercial product Voltarol ‘ 1%’ (i.e. containing 0.93 wt% diclofenac) and even 1.4 times more drug delivery than the commercial product containing twice as much diclofenac. This illustrates the technical advantage from this invention in delivering diclofenac transdermally. These data demonstrate that formulation of the disclosure can achieve improved transdermal delivery of NSAIDs. These data demonstrate that formulation of the disclosure can achieve improved transdermal delivery of diclofenac.

[0275] Figure 3 shows the transdermal delivery of ibuprofen (an efficacious NSAID) in the Example from the three leading commercial topical formulations containing ibuprofen (Ibuleve, Radian B and Boots). This is compared with a composition of the disclosure, specifically ‘F3’ as prepared in Example 1. All the topical formulations (Ibuleve, Radian B, Boots and F3) contain 5 wt% ibuprofen. F3 shows between 4 and 1.3 time more ibuprofen delivery through the skin than the commercial products. This illustrates the technical advantage from this invention in delivering ibuprofen transdermally. These data demonstrate that formulation of the disclosure can achieve improved transdermal delivery of NSAIDs. These data demonstrate that formulation of the disclosure can achieve improved transdermal delivery of ibuprofen.

[0276] The above Examples (Examples 1-4) show the clear technical advantages of this invention over the prior art and over currently available commercial topical NSAID products.

Claims

Claims:

1. A composition for use in therapy comprising:35 wt% to 87 wt% water;1 wt% to 10 wt% benzyl alcohol;1 wt% to 5 wt% oleic acid;1 wt% to 5 wt% amine base; and10 wt% to 50 wt% glycol ether, wherein the molar amount of amine base is equal to or greater than the molar amount of oleic acid.

2. The composition for use according to claim 1 wherein the composition comprises 35 wt% to 65 wt% water, preferably 35 wt% to 50 wt% water.

3. The composition for use according to claim 1 or 2 wherein the composition comprises 15 wt% to 50 wt% glycol ether, preferably 15 wt% to 45 wt% glycol ether.

4. The composition for use according to claim 3 wherein the composition comprises 30 wt% to 40 wt% glycol ether.

5. The composition for use according to any preceding claim wherein the glycol ether comprises 2-(2-ethoxyethoxy)ethanol.

6. The composition for use according to any preceding claim wherein the glycol ether comprises polyethylene glycol 200.

7. The composition for use according to any preceding claim wherein the glycol ether comprises 2-(2-ethoxyethoxy)ethanol and polyethylene glycol 200, preferably 30 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol and 1 wt% to 5 wt% polyethylene glycol 200.

8. The composition for use according to any preceding claim wherein the glycol ether comprises 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol and 2 wt% polyethylene glycol 200, optionally wherein the glycol ether consists of 33 wt% to 38 wt% 2-(2-ethoxyethoxy)ethanol and 2 wt% polyethylene glycol 200.

9. The composition for use according to any preceding claim wherein the composition comprises 3 wt% to 7 wt% benzyl alcohol, preferably 4 wt% to 6 wt% benzyl alcohol, more preferably 5 wt% benzyl alcohol.

10. The composition for use according to any preceding claim wherein the composition comprises 1.3 wt% to 3.0 wt% oleic acid, preferably 1.5 wt% to 2.7 wt% oleic acid, more preferably 2 wt% oleic acid.

11. The composition for use according to any preceding claim wherein the amine base is tris(hydroxymethyl)aminomethane, diethylamine, triethanolamine, preferably wherein the amine base is triethanolamine.

12. The composition for use according to any preceding claim wherein the composition further comprises menthol, optionally 1 wt% to 5 wt% menthol, preferably 2 wt% menthol.

13. The composition for use according to any preceding claim wherein the composition further comprises propan-2-ol, optionally 1 wt% to 5 wt% propan-2-ol, preferably 2 wt% propan-2-ol.

14. The composition for use according to any preceding claim wherein the composition further comprises propylene glycol, optionally 1 wt% to 5 wt% propylene glycol, preferably 2 wt% propylene glycol.

15. The composition for use according to any preceding claim wherein the composition further comprises carbomer, optionally 1 wt% to 3 wt% carbomer, preferably 1 wt% to 2 wt% carbomer.

16. The composition for use according to any preceding claim wherein the composition further comprises one or more non-steroidal anti-inflammatory drug (NSAID), optionally 0.1 wt% to 10 wt% of the one or more NSAID, preferably 0.5 wt% to 7 wt% of the one or more NSAID.

17. The composition for use according to claim 16 wherein the one or more NSAID comprises diclofenac, ibuprofen, salicylic acid, ketorolac, ketoprofen, naproxen or celecoxib.

18. The composition for use according to claim 17 wherein the NSAID is diclofenac.

19. The composition for use according to claim 17 wherein the NSAID is ibuprofen.

20. The composition for use according to claim 17 wherein the NSAID is salicylic acid.

21. The composition for use according to any preceding claim wherein the composition further comprises one or more herbal essential oil, optionally 0.5 wt% to 5 wt% of the one or more herbal essential oil.

22. The composition for use according to claim 21 wherein the one or more herbal essential oil comprises bergamot oil, eucalyptus oil, jasmine oil, camomile oil, lavender oil, peppermint oil, rosemary oil, sandalwood oil, cajeput oil or clove oil, preferably wherein the one or more herbal essential oil comprises cajeput and / or clove oil, more preferably wherein the one or more herbal essential oil comprises cajeput and clove oil.

23. The composition for use according to any preceding claim wherein the composition further comprises colchicine, optionally 0.5 wt% to 5 wt% of colchicine.

24. The composition for use according to any preceding claim wherein the pH of the composition is 6.0 to 8.0, preferably 6.5 to 7.5.

25. The composition for use according to any preceding claim wherein the therapy is the treatment of an inflammatory disorder.

26. The composition for use according to claim 25 wherein the inflammatory disorder is one or more of gout, arthritis, dermatomyositis, myositis, synovitis, tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, osteitis, osteomyelitis, spondylitis, periostitis and chondritis.

27. The composition for use according to claim 26 wherein the inflammatory disorder is gout.

28. The composition for use according to any preceding claim wherein the composition is a topical composition, preferably wherein the composition is a transdermal composition.

29. A method of therapy according to any of the preceding claims which comprises administering to a subject an effective amount of the composition according to any of the preceding claims.

30. The method of claim 29 wherein the therapy is the treatment of an inflammatory disorder, preferably wherein the inflammatory disorder is gout.

31. Use of the composition according to any of the preceding claims in the manufacture of a medicament according to any of the preceding claims.

32. The use of claim 31 wherein the medicament for the treatment of an inflammatory disorder, preferably wherein the inflammatory disorder is gout.

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