Diclofenac preparations

Abstract

A single-phase hydroalcoholic gel for localized drug delivery comprising diclofenac epolamine or diclofenac diethylammonium in a concentration of about 0.5% to about 1.5% w / w, a C2-C4 monoalcohol in a concentration of about 12% to about 15% w / w, a C2-C4 polyalcohol in a concentration of about 2.5% to about 7.5% w / w, a gelling agent, optionally a pH adjusting agent, and water, wherein the pH of the entire composition is about 6.5 to about 8.5. The composition is for use in the localized treatment of pain.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of priority to European Patent Application No. 22154688.0, filed February 2, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to a formulation for topical delivery of diclofenac. Specifically, the present disclosure relates to a gel formulation comprising about 0.5% to 1.5% (w / w) of diclofenac diethylammonium salt. [Background technology]

[0003] Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) of the acetate class that is widely used in topical or transdermal products. Emulsion gels, also called emulgels, are oil-in-water emulsions with a gelled aqueous phase. Emulgel formulations are a successful format for topical delivery of diclofenac. Despite the market success of emulgel, recent patient reports suggest that some users are dissatisfied with some of its attributes. The inventors have overcome these shortcomings, and the present disclosure provides a topical diclofenac product that has similar advantages to existing products, but also has (sensory) attributes that satisfy evolving consumer preferences. Summary of the Invention

[0004] a) diclofenac epolamine or diclofenac diethylammonium at a concentration of about 0.5% to about 1.5% w / w; b) a C2-C4-monoalcohol in a concentration of about 12% to about 15% w / w; c) a C2-C4-polyhydric alcohol in a concentration of about 2.5% to about 7.5% w / w; d) a gelling agent; e) optionally a pH adjuster; f) water The present invention provides a single-phase hydroalcoholic gel for local drug delivery comprising:

[0005] In one embodiment, component b) is isopropanol.

[0006] In one embodiment, component c) is propylene glycol.

[0007] In one embodiment, components b) and c) combined are present in a concentration of about 15% to about 25% w / w.

[0008] In one embodiment, components b) and c) combined are present in a concentration of about 15% to about 20% w / w.

[0009] In one embodiment, the ratio of component b) to component c) is from about 1:1 to about 5:2.

[0010] In one embodiment, component b) is present in a concentration of about 12% to about 13% w / w.

[0011] In one embodiment, component c) is present in a concentration of about 4% to about 6% w / w.

[0012] In one embodiment, component d) is a carbomer gelling agent.

[0013] In one embodiment, component e) is a basic drug.

[0014] In one embodiment, component a) is diclofenac diethylammonium.

[0015] In one embodiment, component f) is present in a concentration greater than about 70% w / w.

[0016] In one embodiment, component d) is present in a concentration of about 0.7% to about 1.5% w / w.

[0017] In one embodiment, the gel is substantially free of permeation enhancers.

[0018] In one embodiment, the gel is substantially free of emulsifiers.

[0019] In one embodiment, the gel is substantially free of humectants.

[0020] In one embodiment, the gel does not contain a lipophilic phase.

[0021] In one embodiment, the viscosity of the gel is from about 1 Pa.S to about 5 Pa.S.

[0022] In one embodiment, the gel has a drying time on the skin of less than 120 seconds.

[0023] In one embodiment, the gel has a cumulative permeation in an in vitro skin permeation test that allows bridging the literature data of Voltaren 1.16% diclofenac diethylammonium emulgel, taking into account its well-established use registration according to Annex I of Directive 2001 / 83 / EC.

[0024] In one embodiment, the gel is transparent.

[0025] In one embodiment, the gel comprises: a) diclofenac diethylammonium at a concentration of about 1% to about 1.2% w / w; b) isopropanol, at a concentration of about 12% to about 13% w / w; c) propylene glycol, at a concentration of about 4% to about 6% w / w; d) Carbomer, at a concentration of about 0.7% to about 1.5% w / w; e) diethylamine, at a concentration of about 0.7% to about 1.3% w / w; f) optionally one or more of a fragrance, a pH adjuster, a gelling agent, an emollient, a humectant, a preservative, a chelating agent, an antioxidant, and / or a colorant; It essentially consists of:

[0026] In one embodiment, the gel is provided in an applicator pack for direct application to the skin.

[0027] In one embodiment, the gel is for use in a method for providing a cooling sensation to mammalian skin at the site of application.

[0028] In one embodiment, the gel is for use in treating a human suffering from joint pain, osteoarthritis pain, back pain, knee pain, ankle pain, neck pain, muscle pain, sprains, and / or inflammation.

[0029] In one embodiment, the gel is applied to the skin at the application site at a dose of 2 grams on the upper extremities or 4 grams on the lower extremities, the gel is rubbed or massaged into the skin until the application site is dry, and the application is repeated 3 to 4 times every 24 hours until treatment is discontinued. [Brief description of the drawings]

[0030] [Figure 1] Representative photographs of compositions of the present disclosure compared to Voltaren 1.16% Emulgel. [Diagram 2] Representative depiction of a composition of the present disclosure on a typical dosage card for a topical product. [Diagram 3] Representative depiction of Voltaren 1.16% Emulgel on a typical dosage card for a topical product. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] An example of a topical diclofenac formulation is Voltaren Arthritis Pain (Diclofenac Sodium Topical Gel, 1% (NSAID)-Arthritis Painkiller), which contains 1% w / w diclofenac sodium and has been approved in the United States as an over-the-counter (OTC) drug since 2020. Another topical diclofenac formulation contains 1.16% w / w diclofenac diethylammonium salt (equivalent to 1% diclofenac sodium salt), which is sold as Voltaren or Voltarol 1.16% Emulgel. Voltaren 1.16% Emulgel has been sold in Europe since 1985. Voltaren Arthritis Pain and Voltaren 1.16% Emulgel are emulgels. Emulgel forms have been described in combination with the active pharmaceutical ingredient (API) diclofenac, for example in US 4917886.

[0032] According to US4917886, the described emulgel formulations provide easier solubility of active ingredients and associated higher active ingredient concentrations compared to conventional topical formulations such as gels or creams. Another advantageous property of emulgels is described as the presence of a lipid phase that provides fat-restoring properties. The combination of the lipid phase with a gelled aqueous phase allows the formulation to be massaged in, while at the same time, direct absorption into the skin is experienced as a pleasant property.

[0033] The existing Voltaren 1% or 1.16% Emulgel products are successful commercial products, however, over time consumers develop preferences and some attributes of these commercial formulations are not attractive to some consumers.

[0034] Recent patient reports and consumer preference studies suggest that some patients find the products too greasy. Some users report that the products leave a sticky residue at the application site. Some users report that they find application "messy" due to the need to apply a product containing fatty ingredients to the hands and then wash the hands to remove the fatty ingredients from the hands.

[0035] Additionally, colored or opaque products are more difficult to dose with traditional dosing cards used for topical products because they cover the scale or measurement area.

[0036] Additionally, some consumers prefer clear or transparent gels, which are perceived as modern, clean, fresh, and natural. However, Voltaren Arthritis Pain and Voltaren 1.16% Emulgel are opaque to white in color.

[0037] Additionally, some consumers have expressed a preference for topical products for the treatment of pain that, in addition to efficient drug delivery, provide a cooling sensation at the application site, which is perceived as a marker of rapid onset of pain relief or immediate action of the formulation.

[0038] Therefore, the inventors sought to improve these attributes of the formulation while keeping modifications compared to the current Voltaren 1% or 1.16% Emulgel products to a minimum. This approach was adopted to maintain the favorable properties of the Voltaren 1% or 1.16% Emulgel products that patients are familiar with and value. It was also adopted from a patient safety perspective: by limiting modifications to existing marketed products with excellent safety profiles, the risk of adverse events caused by new compositions is reduced. Furthermore, for products similar or equivalent to already approved products, the registration of new pharmaceuticals by regulatory authorities may be easier. Furthermore, this approach allows leveraging existing supply chains and manufacturing capabilities.

[0039] Another object of the present invention was to provide a product which could be registered under the criteria of "well established use", relying on Voltaren 1.16% Emulgel as a comparator product.

[0040] The compositions disclosed herein are compositions for local drug delivery. This means that the compositions contain an active pharmaceutical ingredient (API) and are intended to be applied onto the skin of a patient who needs treatment with the API. The composition is an effective vehicle for the API to penetrate the skin. This is necessary for the API to reach the site of action. Thus, the compositions disclosed herein allow the API to penetrate through the skin to the site of action, such as a joint. Effective delivery of the API through the skin can be measured in preclinical experiments, which are further described herein.

[0041] Single-phase hydroalcoholic gels for topical drug delivery are provided. Single phase should be understood as a composition that contains a single phase, as opposed to multi-phase compositions such as emulsions, creams, suspensions, etc. In this case, the single phase is a continuous phase that contains water. Hydroalcoholic gels mean that the gel contains a combination of water as a continuous phase and one or more water-miscible alcohols, and optionally additional water-miscible excipients. This is a completely different delivery format compared to, for example, the multi-phase emulgels previously described herein, or creams and ointments that are also traditionally used for topical delivery. These multi-phase systems contain a continuous phase that is hydrophilic (emulgels) or lipophilic (creams) and a dispersed phase that is dispersed in the continuous phase. The dispersed phase in these multi-phase systems refracts light. This makes the multi-phase systems appear opaque or colored, usually opaque white. The single-phase compositions disclosed herein do not contain a dispersed phase that refracts light. Thus, the compositions disclosed herein are transparent.

[0042] The compositions disclosed herein comprise an API that is a pharma- ceutically acceptable salt of diclofenac.Preferably, a salt of diclofenac with an organic base or ammonia is used.For example, ammonium salt, alkylamine salt, dimethylamine, diethylamine, trimethylamine and cyclic amine salt, such as epolamine (hydroxyethylpyrrolidine salt), can be used.Preferably, the compositions disclosed herein comprise diclofenac diethylammonium salt.

[0043] In some embodiments, the compositions described herein are substantially free of additional API.This means that in these embodiments, there is no second or further API in the composition.In a preferred embodiment, diclofenac is the only API in the composition.For example, the composition does not contain additional NSAID such as ibuprofen.

[0044] In the present disclosure, substantially free should be understood to mean that no additional components with a certain functionality are added to the formulation. For example, substantially free of permeation enhancers means that no permeation enhancers are added to the composition. However, this does not exclude additional components explicitly listed in the present disclosure. Also, in pharmaceutical compositions, many components perform more than one function. Thus, the additional components listed herein may perform certain other functionalities in addition to their functionality described herein. For example, a solvent is described as an additional component in some embodiments of the compositions described herein, but may also act as a permeation enhancer. In this example, substantially free of permeation enhancers would not exclude the presence of this solvent in the composition of the present disclosure. Additionally, the composition may contain small or trace amounts of certain compounds. For example, this may occur due to impurities or decomposition products. These small or trace amounts are also not encompassed by this term, and such compositions would still be considered to be substantially free of the compounds.

[0045] The compositions of the present disclosure may include diclofenac salts at a concentration of about 0.5% w / w to about 1.5% w / w of diclofenac sodium equivalent.

[0046] The compositions of the present disclosure may contain diclofenac diethylammonium in a concentration of about 0.58% w / w to about 1.75% w / w, which is equivalent to about 0.5% w / w to about 1.5% w / w diclofenac sodium.

[0047] Preferably, the composition comprises diclofenac diethylammonium in a concentration of about 1% to about 1.2% w / w. In some embodiments, the composition may comprise diclofenac diethylammonium in a concentration of about 1% w / w, 1.01% w / w, 1.02% w / w, 1.03% w / w, 1.04% w / w, 1.05% w / w, 1.06% w / w, 1.07% w / w, 1.08% w / w, 1.09% w / w, 1.10% w / w, 1.11% w / w, 1.12% w / w, 1.13% w / w, 1.14% w / w, 1.15% w / w, 1.16% w / w, 1.17% w / w, 1.18% w / w, 1.19% w / w, or 1.2% w / w. Especially preferred is diclofenac diethylammonium at a concentration of about 1.16% w / w. If a different pharma- ceutically acceptable salt of diclofenac is used, one skilled in the art will understand that the corresponding equivalent amount is used.

[0048] At higher concentrations, APIs may recrystallize in the final formulation and API crystals may be present in the product. Non-solubilized APIs are lost as they are unable to penetrate the skin. Lost APIs remain on the skin and eventually wash off and end up in wastewater. Furthermore, lost APIs increase the cost of the product without supporting efficacy. The presence of non-solubilized APIs also hinders dosage uniformity, which is unacceptable from a patient safety perspective. Hence, there is a need to prevent API loss from non-solubilized APIs and maintain fully solubilized APIs, including during storage. This is discussed in more detail in a separate paragraph on stability.

[0049] The compositions disclosed herein comprise a C2-C4 monoalcohol. The C2-C4 monoalcohol can be selected from methanol, ethanol, propanol, isopropanol and butanol, and mixtures thereof. In some preferred embodiments, the compositions comprise ethanol and isopropanol, and mixtures thereof. In some embodiments, the compositions comprise isopropanol.

[0050] C2-C4-monoalcohols can act as solubilizers for APIs. Furthermore, C2-C4-monoalcohols have a low evaporation temperature. When applied to the skin, C2-C4-monoalcohols evaporate, which can be perceived as a cooling sensation on the skin. This provides a perception of immediate action, as desired by consumers. These C2-C4-monoalcohols are colorless and transparent, which is beneficial for the blending of clear or transparent gels of the present disclosure. Thus, they are suitable for the formulation of colorless, transparent topical gels that are preferred by consumers. The disclosed C2-C4-monoalcohols also impart antibacterial or antipathogenic activity to the formulation and improve microbial stability.

[0051] In some embodiments, isopropanol is used as the only C2-C4-monoalcohol. It has been found that isopropanol is sufficient to solubilize the API and also provides an immediate cooling sensation to the skin of the user. Furthermore, it has been discovered that isopropanol can be used as the only C2-C4-monoalcohol in the compositions herein without another C2-C4-monoalcohol that evaporates more easily, such as ethanol. This is preferred because it allows the number of different ingredients to be kept low, which facilitates manufacturing, lowers production costs, and simplifies the supply chain. Furthermore, ethanol is regulated in many countries due to tax or ethical and religious reasons.

[0052] The C2-C4-monoalcohol may be present in the composition at a concentration of about 12% w / w to about 15% w / w. In a preferred embodiment, the C2-C4-monoalcohol may be present at a concentration of about 12% w / w to about 13% w / w. In one embodiment, the C2-C4-monoalcohol is present at a concentration of about 12.5% ​​w / w. Alternatively, the C2-C4-monoalcohol may be present in the composition at a concentration of about 12% w / w, about 13% w / w, about 13.5% w / w, about 14% w / w, about 14.5% w / w, or about 15% w / w.

[0053] These concentrations of C2-C4-monoalcohols aid in solubilizing the API. Additionally, these concentrations of C2-C4-monoalcohols produce a sufficient cooling sensation upon application. Lower concentrations of C2-C4-monoalcohols may produce less of a cooling sensation in some cases, e.g., the cooling sensation may be too weak or the cooling sensation may not last long enough.

[0054] If the concentration of C2-C4-monoalcohol exceeds the above range, application of the composition to the skin may result in evaporation of the C2-C4-monoalcohol component. The remainder of the composition on the skin may then be insufficient to solubilize the API. Thus, the API may crystallize on the skin, leaving a thin film or a brittle deposit on the skin. This is undesirable due to the stray API considerations discussed above. This is also undesirable as it would result in an unpleasant user experience. Furthermore, higher concentrations of C2-C4-monoalcohol may be characterized as a hazardous substance under certain regulations, which may require the product to be labeled, stored, and handled under strict scrutiny. This is undesirable as it complicates manufacturing and supply chains and may discourage consumers from using the final product. Alcohol also has a certain odor that may discourage some consumers. In particular, in monophasic hydroalcoholic compositions, it is difficult to incorporate certain fragrances or odor masking agents, since they are often lipophilic, which may result in phase separation, creaming, bead formation, a cloudy or hazy appearance of the product, etc. It is therefore beneficial to keep the concentration of C2-C4-monoalcohols to a necessary minimum in order to avoid the need for the addition of (more) fragrances or odor masking agents. Furthermore, C2-C4-monoalcohols have certain lipolytic properties that may adversely affect the natural fat and ceramide components of the skin, especially human skin. In order to prevent dehydrating and irritating effects on the skin, especially in the absence of a fat-restoring oil phase, formulators may strive to keep the concentration of C2-C4-monoalcohols in topical compositions as low as possible. C2-C4-monoalcohols may also affect the permeation properties of the formulation. However, any such effect on permeation also depends on the other ingredients and the overall composition of the product. The inventors aimed to formulate a composition that has similar permeation properties to those of the existing Voltaren 1% or 1.16% Emulgel products, thereby allowing the podiatry, i.e. dosage and frequency, of the existing products to be maintained.This is explained in more detail in another section below.

[0055] In one embodiment, as previously disclosed, the gel of the present disclosure comprises isopropanol at a concentration of about 12% w / w to about 15% w / w, preferably about 12% w / w to about 13% w / w, and no other added C2-C4-monoalcohols. Isopropanol in these ranges is particularly advantageous as it is sufficient to provide solubilization and cooling while avoiding the adverse effects that may occur in formulations containing C2-C4-monoalcohols at other concentrations. In particular, the inventors have found that compositions containing isopropanol in the recited ranges have permeation properties similar to those of existing Voltaren 1% or 1.16% Emulgel products.

[0056] The compositions disclosed herein include a C2-C4-polyhydric alcohol. The C2-C4-polyhydric alcohol is typically a glycol. The C2-C4-polyhydric alcohol can be selected from ethylene glycol, propylene glycol and 1,3-butylene glycol, and mixtures thereof. Propylene glycol is preferred. In some embodiments, propylene glycol is used as the only C2-C4-polyhydric alcohol. The C2-C4-polyhydric alcohol acts as a solubilizer for the API. In contrast to C2-C4-monoalcohols, the C2-C4-polyhydric alcohols do not evaporate easily when the composition is applied to the skin. Thus, the C2-C4-polyhydric alcohol remains on the skin even after evaporation of the C2-C4-monoalcohol, ensuring that the API remains solubilized. The C2-C4-polyhydric alcohol may also have moisturizing, moisture-retaining properties. This may provide a pleasant skin feel, such as a soft, supple, or nurtured skin feel. C2-C4-polyalcohols may also affect the permeation properties of the formulation. However, this effect on permeation may also depend on other ingredients and the overall composition of the product. As discussed above, the inventors aimed to formulate a composition with permeation properties similar to those of existing Voltaren 1% or 1.16% Emulgel products, which will be described in more detail in another section below.

[0057] The C2-C4-polyhydric alcohol may be present in the composition at a concentration of about 2.5% w / w to about 7.5% w / w. Preferably, the C2-C4-polyhydric alcohol may be present in the composition at a concentration of about 4% w / w to 6% w / w. In one embodiment, the C2-C4-polyhydric alcohol is present at a concentration of about 5% w / w. Alternatively, the C2-C4-polyhydric alcohol may be present at a concentration of about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% w / w, or about 7.5% w / w.

[0058] It has been found that the disclosed concentrations of C2-C4-polyhydric alcohols solubilize the API and keep it solubilized when the C2-C4-monoalcohol evaporates after application of the composition to the skin. The disclosed concentrations have also been found to provide safe compositions that do not cause skin irritation that can sometimes be caused by compositions that contain excessive concentrations of C2-C4-polyhydric alcohols. Furthermore, the disclosed concentrations of C2-C4-polyhydric alcohols do not unduly extend the time that the composition needs to be rubbed or dried on the application area before the user perceives the application area as dry. The disclosed concentrations of C2-C4-polyhydric alcohols result in compositions that have controlled drying times. Furthermore, the disclosed concentrations of C2-C4-polyhydric alcohols result in compositions that feel less sticky on the skin. Compositions containing C2-C4-polyalcohols in the disclosed concentrations can be formulated as clear and transparent gels, without the hazy or cloudy appearance that compositions containing C2-C4-polyalcohols at higher concentrations can have.

[0059] In one embodiment, the composition of the present disclosure comprises propylene glycol at a concentration of about 2.5% w / w to about 7.5% w / w, preferably about 4% w / w to about 6% w / w, without any other additional C2-C4-polyhydric alcohol. Propylene glycol at a concentration of about 2.5% w / w to about 7.5% w / w, preferably about 4% w / w to about 6% w / w, is sufficient to achieve good solubilization of APIs in the above concentration range. At the same time, these concentrations of propylene glycol are low enough to prevent the above adverse effects. Importantly, these concentrations of about 2.5% w / w to about 7.5% w / w, preferably about 4% w / w to 6% w / w, result in a clear, transparent gel.

[0060] In one embodiment, the composition comprises a combination of isopropanol and propylene glycol as the C2-C4-monoalcohol and the C2-C4-polyalcohol.

[0061] The ratio of C2-C4-monoalcohol to C2-C4-polyhydric alcohol can be from about 1:1 to about 5:2. A ratio of C2-C4-monoalcohol to C2-C4-polyhydric alcohol of 5:2 is preferred.

[0062] In some embodiments, the combined total concentration of C2-C4-monoalcohols and C2-C4-polyhydric alcohols is greater than about 15% w / w. The combined total concentration of C2-C4-monoalcohols and C2-C4-polyhydric alcohols is preferably less than about 25% w / w. Expressed as a range, the combined total concentration of C2-C4-monoalcohols and C2-C4-polyhydric alcohols can be from about 15% w / w to about 25% w / w, preferably from about 15% w / w to about 20% w / w. In some cases, the combined total concentration of the C2-C4-monoalcohol and the C2-C4-polyalcohol is about 15% w / w, about 15.5% w / w, about 16% w / w, about 16.5% w / w, about 17% w / w, about 17.5% w / w, about 18% w / w, about 18.5% w / w, about 19% w / w, about 19.5% w / w, about 20% w / w, about 20.5% w / w, about 21% w / w, about 21.5% w / w, about 22% w / w, about 22.5% w / w, about 23% w / w, about 23.5% w / w, about 24% w / w, about 24.5% w / w, or about 25% w / w. In one embodiment, the combined total concentration of C2-C4-monoalcohol and C2-C4-polyalcohol is about 17.5% w / w.

[0063] The composition of the present disclosure also includes a gelling agent. In some embodiments, the composition includes a carbomer gelling agent. Carbomer gelling agents often produce very clear, transparent gels. Carbomer gelling agents are also preferred due to their spreading properties, which are preferred by many consumers, over those of other gelling agents, such as hydroxypropyl methylcellulose. For example, carbomer 974P or carbomer 980 can be used. Carbomer is less likely to form a film or flakes on the skin after the composition is applied onto the skin.

[0064] The carbomer gelling agent may be present in a concentration sufficient to increase the viscosity of the composition. In some embodiments, the carbomer gelling agent may be present in a concentration of about 0.7% w / w to about 1.5% w / w. In one embodiment, the composition of the present disclosure comprises a carbomer in a concentration of about 1.2% w / w. In some embodiments, the carbomer gelling agent may be present in a concentration of about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3%, about 1.4% w / w, or about 1.5% w / w.

[0065] It may be advantageous for the viscosity to be high enough to allow the composition to be dispensed from a tube, without the composition being too runny or dripping. Preferably, the viscosity of the final composition is from about 1 Pa.S to about 5 Pa.S, more preferably from about 1.8 Pa.S to about 4 Pa.S at 20° C. In some cases, the viscosity of the final composition is about 1 Pa.S, about 1.2 Pa.S, about 1.4 Pa.S, about 1.6 Pa.S, about 1.8 Pa.S, about 2 Pa.S, about 2.2 Pa.S, about 2.4 Pa.S, about 2.6 Pa.S, about 2.8 Pa.S, about 3 Pa.S, about 3.2 Pa.S, about 3.4 Pa.S, about 3.6 Pa.S, about 3.8 Pa.S, about 4 Pa.S, about 4.2 Pa.S, about 4.4 Pa.S, about 4.6 Pa.S, about 4.8 Pa.S, or about 5 Pa.S at 20° C. In one embodiment, the viscosity of the final composition is about 20 to about 100 scale units, more preferably about 40 to 80 scale units, measured at 25° C. In some embodiments, the viscosity of the final composition is about 20 to about 100 scale units, about 30 scale units, about 40 scale units, about 40 scale units, about 50 scale units, about 60 scale units, about 70 scale units, about 80 scale units, about 90 scale units, or about 100 scale units, measured at 25°C.

[0066] In this disclosure, when viscosity is given in scale units or scale divisions, it is measured on a Brookfield RVT DV-1 instrument with Helipath spindle C rotating at 50 revolutions per minute (rpm) at a temperature of 25° C., with the scale read after approximately 2 minutes of rotation. When viscosity is given in Pa.s, it is measured on a rotational viscometer such as an MCR 150, MCR51 or equivalent cone and plate viscometer with a conical cone CP 50-1 rotating at approximately 100 rad / s at a temperature of 20° C., with the scale read after approximately 2 minutes of rotation.

[0067] The composition may further include a pH adjuster. The pH adjuster may be a basic agent. In particular, in embodiments including a carbomer gelling agent, the composition includes a basic agent. The basic agent can initiate gelation of the carbomer gelling agent, which is a polyacrylic acid. The basic agent may be present in a concentration sufficient to adjust the pH to about 7 to about 8.5, preferably about 7.5 to about 8.2. The pH measurement is typically performed at 20°C. The basic agent may be any basic agent not inconsistent with the objectives of the present disclosure. For example, aliphatic amines, such as primary, secondary, and tertiary alkanolamines, and primary, secondary, and tertiary alkylamines, may be used. Specific examples include monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, dimethylamine, diethylamine, trimethylamine, and triethylamine. Diethylamine is preferred. Preferably, the API is diclofenac diethylammonium and the basic drug is diethylamine, because diethylamine as a basic drug contains a diethylammonium cation, which is the counter ion of diclofenac diethylammonium salt.

[0068] Alternatively, the basic agent may be inorganic, such as NaOH or ammonia. The basic agent may be provided in an aqueous solution. In one embodiment, the basic agent is ammonia (10-30% w / v in water). The use of an inorganic base may reduce the risk of nitrosamine formation, a storage risk for topical diclofenac products. In embodiments that include a carbomer gelling agent, an ammonia solution is preferred over NaOH because the carbomer gelling agent is ion sensitive and the sodium ions of NaOH may reduce the gelling ability of the carbomer gelling agent, thus necessitating the addition of more carbomer gelling agent to achieve a certain viscosity. Additionally, ammonia may aid in the mixing of a clear, transparent gel, while in some cases, the Na ions may cause the composition to become opalescent.

[0069] The composition also comprises water. The water may be purified water, distilled water or the like. The water may be pharmaceutical grade water. The composition may comprise at least about 70% w / w water. The composition may comprise from about 70% w / w to about 85% w / w water, preferably from about 75% w / w to about 82% w / w water. In one embodiment, the composition comprises about 79% w / w water.

[0070] The composition may typically have a pH of about 7 to about 8.5, preferably about 7.5 to about 8.2. Optionally, a pH adjuster may be used to achieve this pH range. For example, a buffer such as a phosphate buffer may be used. In one embodiment, the pH of the composition is greater than 7.2. pH measurements are typically performed at 20°C.

[0071] The compositions may optionally contain additional excipients, such as flavorings, chelating agents, preservatives, antioxidants, colorants, and the like.

[0072] Examples of fragrances are eucalyptus fragrance, rose fragrance, lavender fragrance, rosemary fragrance, wintergreen fragrance, and mint fragrance.

[0073] Examples of chelating agents are salts of edetic acid, malic acid, fumaric acid and citric acid.

[0074] Examples of preservatives are benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol and sodium metabisulfite.

[0075] Examples of antioxidants are alpha tocopherol and butylated hydroxytoluene.

[0076] Examples of colorants are FD&C Blue #1, D&C Orange #5, and D&C Red #6.

[0077] In one embodiment, a) a pharma- ceutically acceptable salt of an aryl acetic acid nonsteroidal anti-inflammatory analgesic selected from alclofenac, diclofenac, and felbinac; b) a C2-C4-monoalcohol in a concentration of about 12% w / w to about 15% w / w; c) a C2-C4-polyhydric alcohol in a concentration of about 2.5% w / w to about 7.5% w / w; d) carbomer gelling agent; and water A composition is provided comprising:

[0078] In another embodiment, a) diclofenac sodium or diclofenac diethylammonium salt at a concentration of about 0.5% w / w to about 1.5% w / w diclofenac sodium equivalent; b) a C2-C4-monoalcohol in a concentration of about 12% w / w to about 15% w / w; c) a C2-C4-polyhydric alcohol in a concentration of about 2.5% w / w to about 7.5% w / w; d) carbomer gelling agent; e) a basic agent for adjusting the pH of the entire composition to about 7.5 to about 8.5; and f) water A single-phase hydroalcoholic gel for topical drug delivery is provided, comprising:

[0079] In another embodiment, - diclofenac diethylammonium, in a concentration of about 1.16% w / w; isopropanol, at a concentration of about 12% w / w to about 15% w / w; - propylene glycol, in a concentration of about 2.5% w / w to about 7.5% w / w; - a carbomer gelling agent in a concentration of about 0.7% w / w to about 1.5% w / w, - a basic agent for adjusting the pH of the entire composition to a pH of about 7.5 to about 8.5; and - Water, with a concentration of about 70% w / w to about 85% w / w A single-phase hydroalcoholic gel for topical drug delivery is provided, comprising:

[0080] In another embodiment, a) diclofenac diethylammonium at a concentration of about 1.16% w / w; b) isopropanol, at a concentration of about 12% w / w to about 15% w / w; c) propylene glycol, at a concentration of about 2.5% w / w to about 7.5% w / w; d) a carbomer gelling agent at a concentration of about 0.7% w / w to about 1.5% w / w; e) diethylamine to adjust the pH of the entire composition to about 7.5 to about 8.5, and f) Water, at a concentration of about 70% w / w to about 85% w / w and optionally fragrances, pH adjusters, gelling agents, emollients, humectants, preservatives, chelating agents, antioxidants and / or colorants. A composition is provided consisting essentially of:

[0081] In another embodiment, a) diclofenac diethylammonium at a concentration of about 1.16% w / w; b) isopropanol, at a concentration of about 12.5 w / w; c) propylene glycol, at a concentration of about 5% w / w; d) Carbomer, in a concentration of about 0.7% w / w to about 1.5% w / w; e) diethylamine to adjust the pH of the entire composition to about 7.3 to about 8.2, and f) Water, at a concentration of about 70% w / w to about 85% w / w and optionally fragrances, pH adjusters, gelling agents, emollients, humectants, preservatives, chelating agents, antioxidants and / or colorants. A composition is provided consisting essentially of:

[0082] In another embodiment, a) diclofenac diethylammonium at a concentration of about 1.16% w / w; b) isopropanol, at a concentration of about 12.5 w / w; c) propylene glycol, at a concentration of about 5% w / w; d) Carbomer, at a concentration of about 1.2% w / w; e) diethylamine, at a concentration of about 1% w / w; f) a flavoring agent, in a concentration of about 0.1% w / w; and g) Water to be added to make 100% A composition is provided consisting essentially of:

[0083] Preferably, the compositions disclosed herein are substantially free of lipophilic excipients. Preferably, the compositions do not contain a lipophilic or fatty phase. This is to provide consumers with a "fat-free", "messy", "non-greasy" alternative based entirely on water and alcohol. Multi-phase systems that contain a lipophilic phase are typically opaque, milky or cloudy. However, by excluding lipophilic excipients and lipophilic phases in general, it is possible to obtain clear, transparent compositions. However, it is difficult to exclude lipophilic excipients and phases, since such excipients and phases are often used as permeation enhancers, solubilizers or skin conditioning agents in topical formulations. Therefore, it is difficult to successfully formulate a hydrophilic single-phase composition without lipophilic components that provides sufficient long-term solubilization and permeation of APIs and still has desirable sensory attributes, such as ease of application, water retention properties, etc. In particular, the application properties of Voltaren 1.16% Emulgel, which are positively perceived by users, should be preserved.

[0084] Preferably, the compositions disclosed herein are substantially free of permeation enhancers. Typically, permeation enhancers are included in the composition to increase the cumulative permeation and / or flux of the API. However, permeation enhancers may be irritating to the skin. In addition, some permeation enhancers need to be specifically highlighted on the package label. Specifically, the composition may be free of permeation enhancers such as isostearic acid and other fatty acids or acids. Permeation enhancers may result in a cloudy, hazy or milky composition. Specifically, the composition is preferably free of fatty alcohols, fatty acids, isopropyl myristate, isopropyl palmitate and diethyl sebacate. As explained above, the inventors aimed to formulate a composition with permeation properties similar to those of existing Voltaren 1% or 1.16% Emulgel products, which was surprisingly achieved without incorporating permeation enhancers.

[0085] Preferably, the compositions disclosed herein are substantially free of emulsifiers, which can often result in cloudy, hazy or milky compositions and are therefore not preferred.

[0086] Preferably, the compositions disclosed herein are substantially free of humectants.Humectants are often included in topical compositions for their cooling, conditioning and moisture-retaining properties, but they can cause the product to dry out on the skin for a long time.Humectants are therefore not preferred.

[0087] Preferably, the compositions disclosed herein are substantially free of sensates. For example, the compositions may be free of peppermint oil, l-menthol and menthol derivatives, methyl salicylate, ethyl salicylate, glycol monosalicylate, and the like. Preferably, the compositions are substantially free of counterirritants. Preferably, the compositions are substantially free of inductive stimulants. Sensates, counterirritants, and inductive stimulants are often incorporated to provide a "quick-on" sensation, or the cooling sensation described above as a desirable sensory attribute. However, they may also cause haze or phase separation in the formulation. They may also cause irritation. In addition, they may affect the permeation of the composition.

[0088] Characteristics of the Disclosed Compositions The composition is preferably a transparent gel. Preferably, the composition is colorless and transparent. In some embodiments, the composition may be slightly opalescent.

[0089] As discussed above, it is important that the API is completely solubilized. This can be determined by the absence of API crystals. Preferably, the composition does not contain API crystals upon visual inspection by optical microscopy. Preferably, the composition is homogenous upon visual inspection by the naked eye. Preferably, the composition does not contain API crystals over a shelf life of 24 months.

[0090] In one embodiment, the composition is free of crystals when examined under a microscope with a 40x optical zoom. In one embodiment, the composition is free of crystals when examined under a microscope with a 40x optical zoom after storage at 25° C. and 60% relative humidity (RH) for 3 months. In one embodiment, the composition is free of crystals when examined under a microscope with a 40x optical zoom after storage at 40° C. and 75% RH for 3 months.

[0091] Preferably, the composition is homogenous upon visual inspection with an optical microscope.

[0092] The composition of the present disclosure may have a drying time of less than 120 seconds, preferably less than 110 seconds. In one embodiment, the composition of the present invention has a drying time of less than 100 seconds. In some embodiments, the composition has a drying time of 40 seconds or less, 50 seconds or less, 60 seconds or less, 70 seconds or less, 80 seconds or less, 90 seconds or less, 100 seconds or less, 110 seconds or less, or 120 seconds or less. The method of measuring the drying time is described in detail in the Examples section.

[0093] As explained above, the composition of the present disclosure provides desirable sensory attributes. For example, the composition spreads easily on the skin. The composition also provides a cooling sensation when rubbed in, which persists even after rubbing in. The composition does not leave any residue or flakes or films on the skin after drying.

[0094] Cumulative skin penetration In one embodiment, the composition has a cumulative permeation equal to or greater than the cumulative permeation of Voltaren 1.16% diclofenac diethylammonium emulgel in an in vitro skin permeation test.

[0095] In one embodiment, the composition has a cumulative permeation in an in vitro skin permeation test that allows bridging of the literature data of Voltaren 1.16% diclofenac diethylammonium emulgel, taking into account its well-established use registration according to Annex I of Directive 2001 / 83 / EC.

[0096] "Similar permeation characteristics" in the present disclosure means that the permeation profile of the formulation is such that the in vitro skin permeation test results comparing the skin permeation of the formulation with Voltaren 1.16% diclofenac diethylammonium emulgel can be used to bridge literature data for Voltaren 1.16% diclofenac diethylammonium emulgel, taking into account its well-established use registrations pursuant to Annex I of Directive 2001 / 83 / EC.

[0097] Manufacturing method The composition can be prepared as follows: - combining C2-C4 monoalcohols, C2-C4 polyalcohols, the total amount of API, and a portion of water (about 3% to about 4% of the total amount of water); - mixing the combination until the API is completely dissolved to obtain an API phase; - optionally adding, under mixing, additional optional ingredients to the API phase; - Optionally, dilute the basic agent to about 1.5% of the total volume of water; - dispersing the carbomer gelling agent in the remaining amount of water until completely dispersed to obtain a carbomer-water dispersion; - adding a basic agent (optionally diluted) to the carbomer-water dispersion to initiate gelation of the carbomer to obtain an aqueous carbomer gel; -Combine the aqueous carbomer gel and API phase under homogenization.

[0098] definition Unless otherwise indicated, concentrations given in % are % by weight (w / w).

[0099] When the term "about" is applied to a particular value (e.g., "about 200° C.") or range (e.g., "about x to about y"), the value or range should be interpreted as precise as the methods used in the art to measure it.

[0100] Unless otherwise indicated, pH is measured at 20°C.

[0101] Purpose The compositions disclosed herein are suitable for use in the treatment of joint pain, osteoarthritis, muscle pain, back pain and / or inflammation.

[0102] Pharmaceutical Composition / Route of Administration / Dosage The compositions described herein may be useful for treating joint pain, osteoarthritis pain, back pain, knee pain, ankle pain, neck pain, muscle pain, sprains, and / or inflammation. The compositions may be administered to mammals suffering from these conditions. Preferably, the compositions are for the treatment of humans.

[0103] The composition may be applied onto the skin covering the body part of concern. The composition may be rubbed in until the skin feels dry. The composition may be applied 2-4 times per day. In some embodiments, the dose of the composition may include up to 2 grams per application for the upper limbs and up to 4 grams per application for the lower limbs, 2-4 applications per day. Thus, in many cases, the dose may be up to 80 mg of diclofenac sodium equivalent per day for the upper limbs and up to 160 mg of diclofenac sodium equivalent per day for the lower limbs. The method of treatment may include administering a pharma- ceutical effective amount of the composition disclosed herein to a subject in need of administration. The method may include administering the composition to the skin covering a body part that is afflicted with or causes one or more of joint pain, osteoarthritis, muscle pain, back pain, and / or inflammation.

[0104] Further provided is a method for treating joint pain, osteoarthritis pain, back pain, knee pain, ankle pain, neck pain, muscle pain, sprains, and / or inflammation, comprising the steps of: a) applying to the skin of the patient at the application site up to about 2 grams for the upper extremities or up to about 4 grams for the lower extremities of a gel of any of the compositions described herein; b) rubbing or massaging the gel into the skin until it is dry; c) Repeating steps a) and b) 3-4 times per 24 hours until treatment is stopped. Disclosed herein is a method comprising:

[0105] The composition can be provided in a package that includes a means for administration. The composition may be provided in a container that includes an applicator for direct application onto the skin.

[0106] The embodiments described herein can be more easily understood by referring to the following detailed description, examples, and drawings. However, the elements, devices, and methods described herein are not limited to the specific embodiments presented in the detailed description, examples, and drawings. It should be recognized that the exemplary embodiments herein are merely illustrative of the principles of the present invention. Many modifications and adaptations will be readily apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0107] Moreover, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, a range stated as "1.0 to 10.0" should be considered to include any and all subranges beginning with a minimum value equal to or greater than 1.0 and ending with a maximum value equal to or less than 10.0, such as 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9.

[0108] All ranges disclosed herein should also be considered to include the endpoints of the range, unless otherwise specified. For example, the range "between 5 and 10" or "from 5 to 10" or "5 to 10" should generally be considered to include the endpoints 5 and 10.

[0109] Furthermore, unless expressly prohibited by the nature of the present disclosure or related embodiments, it should be understood that a feature or features of one embodiment may generally be applied to other embodiments even if not specifically described or illustrated in such other embodiments. Similarly, the compositions and methods described herein may include any combination of the features and / or steps described herein that is not inconsistent with the objectives of the present disclosure. Many modifications and / or adaptations of the compositions and methods described herein will be readily apparent to those of skill in the art without departing from the subject matter. EXAMPLES

[0110] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0111] Example 1: Formulation Experiments In order to formulate a topical product that addresses the challenges discussed above, the inventors conducted formulation experiments. Formulations with different compositions were produced, see Table 1 below. pH and apparent viscosity were measured, and visual appearance was analyzed by the naked eye. Apparent viscosity was measured with a Brookfield RVT DV-1 device equipped with a Helipath spindle C, rotating at 50 revolutions per minute (rpm) at a temperature of 25°C, and the scale was read after about 2 minutes of rotation. For apparent viscosity, which is shown in scale units according to this measurement method, the values ​​are shown in Table 1. The results are also given in Table 1.

[0112] [Table 1] TIFF2025504985000002.tif255160

[0113] Example 2: In vitro skin permeation study In vitro skin permeation studies were conducted in a preclinical laboratory. Skin permeation studies can be used to determine the qualitative permeation characteristics of a formulation, for example, through human skin. Skin permeation studies can also be used for direct quantitative comparison of the permeation and flux of two given formulations. The purpose of this experiment was to determine whether any of the screened formulations had a similar permeation profile to the reference product. Five of the screened formulations from Example 1, namely formulations 1, 2, 4, 7 and 9, were administered at 10 mg / cm at 0 hours. 2 The formulations were applied to the abdominal skin of human donors at a dose of 0.01 mg / mL. Each formulation was tested on five skin samples from different donors on Franz diffusion cells. The reference product for comparison was Voltaren Emulgel 1.16% (m / m) diclofenac diethylammonium. The composition of Voltaren Emulgel 1.16% (m / m) is given in Table 2. The concentration of diclofenac in the receptor fluid of the Franz cells was measured at t=0, 4 h, 8 h and 24 h, and the endpoint of the study was the cumulative amount of diclofenac permeated at 24 h. The results of the study are given in Table 3.

[0114] [Table 2]

[0115] [Table 3]

[0116] Formulation 7 was found to have the closest cumulative permeation to the reference product.

[0117] Example 3: Sensory Panel Testing To test the sensory attributes of the composition, Formulation 7, in a placebo version for safety reasons, was compared to Voltaren 1.16% diclofenac diethylammonium emulgel in a sensory panel study. Eleven subjects participated in the study. Both products were evaluated on each day, with a 20-minute break in between. Product evaluations were performed in two replicates. Each product was evaluated twice on separate days under different blinding codes. Each panelist had a separate rotation plan, with the leg used randomized across replicates. All panels except one were right-handed. The preparation protocol was as follows: Carefully weigh out 2 g of sample onto a plastic spoon. Distribute the spoons with 2 g of weighed sample to the panelists. The application protocol was as follows: Wash hands and dry thoroughly. Wipe the backs of the legs (calves) with Huggies unscented wipes and allow to dry. Panelists scoop the entire contents of the spoon onto their fingertips. Use your left hand for the left calf and your right hand for the right calf. Apply product to the calf, set a timer, and use your entire hand to rub the sample into the skin in a circular motion until dry. Once dry, stop the timer and note the amount of time it took. Repeat with the second sample using the other leg and other hand.

[0118] This is also the protocol for measuring "drying time" discussed above.

[0119] In addition to dry time, the following attributes were evaluated: ease of absorption (throughout rub-in), ease of spread (throughout rub-in), stickiness (assessable during and at the end), cooling sensation (during and at the end), skin tightness (immediately after rub-in) and residue (immediately after rub-in).

[0120] The results are reproduced in Table 4 below.

[0121] [Table 4]

[0122] Thus, formulation 7 dries in less than 100 seconds, which is comparable to the reference product. This is surprising, since formulation 7 contains less isopropanol, i.e., less volatile solvent. Significantly, formulation 7 is less sticky than the reference product. Formulation 7 also leaves the skin feeling less tight. Formulation 7 spreads significantly easier. This is surprising, since formulation 7 does not contain a fatty phase. Importantly, formulation 7 feels significantly cooler both during and after rubbing.

[0123] Example 4: Visual Appearance As discussed above, the gels disclosed herein have excellent visual appearance. Figure 1 is a representative photograph showing the visual appearance of the composition of the present disclosure (left, labeled "clear gel") compared to Voltaren 1.16% Emulgel (right, labeled "Emulgel"). Figure 2 is a representative depiction of the composition of the present disclosure on a typical dosing card for a topical product. Figure 3 is a representative depiction of Voltaren 1.16% Emulgel on a typical dosing card for a topical product. These dosing cards are often used to measure a specific dose of a topical product. Dosing cards are usually plastic cards that include a printed line of a predetermined length. The printed line is used as a reference. For example, a dosing card may include a printed line of 6 cm in length that corresponds to a predetermined dose. A user can place the dosing card on their skin and then apply a linear product onto the skin that has the same length as the reference line on the dosing card. Alternatively, a user can administer a linear product onto the reference line on the dosing card and then apply the product from the dosing card to the desired skin area. The embodiments of the present disclosure can be described as clear, transparent, transparent or see-through. As is evident from Figure 2, it is even possible to discern the text on the dosing card on the reference line underneath the linear gel. In contrast, as is evident from Figure 3, this is not the case for Voltaren 1.16% Emulgel, which appears white and opaque, thus obscuring the underlying reference line and text.

Claims

1. a) diclofenac epolamine or diclofenac diethylammonium at a concentration of about 0.5% to about 1.5% w / w; b) C at a concentration of about 12% to about 15% w / w 2 ~C 4 -monoalcohols, c) C at a concentration of about 2.5% to about 7.5% w / w 2 ~C 4 polyhydric alcohols, d) gelling agents; e) optionally a pH adjuster; f) water 1. A single-phase hydroalcoholic gel for topical drug delivery comprising:

2. 2. The gel of claim 1, wherein b) is isopropanol.

3. 2. The gel of claim 1, wherein c) is propylene glycol.

4. 10. The gel of claim 1, wherein b) and c) together are present in a concentration of about 15% to about 25% w / w.

5. 5. The gel of claim 4, wherein b) and c) together are present in a concentration of about 15% to about 20% w / w.

6. 2. The gel of claim 1, wherein the ratio of b) to c) is from about 1:1 to about 5:

2.

7. 2. The gel of claim 1, wherein b) is present in a concentration of about 12% to about 13% w / w.

8. 2. The gel of claim 1, wherein c) is present at a concentration of about 4% to about 6% w / w.

9. 10. The gel of claim 1, wherein d) is a carbomer gelling agent.

10. 2. The gel of claim 1, wherein e) is a basic drug.

11. 2. The gel of claim 1, wherein a) is diclofenac diethylammonium.

12. 10. The gel of claim 1, wherein f) is present at a concentration greater than about 70% w / w.

13. 2. The gel of claim 1, wherein d) is present at a concentration of about 0.7% to about 1.5% w / w.

14. The gel of claim 1 , wherein the gel is substantially free of permeation enhancers.

15. 10. The gel of claim 1, wherein the gel is substantially free of emulsifiers.

16. The gel of claim 1 , wherein the gel is substantially free of humectants.

17. 10. The gel of claim 1, wherein the gel does not contain a lipophilic phase.

18. 10. The gel of claim 1, wherein the viscosity of the gel is from about 1 Pa.S to about 5 Pa.S.

19. 10. The gel of claim 1, wherein the gel has a drying time on the skin of less than 120 seconds.

20. 2. The gel according to claim 1, which has a cumulative permeation in an in vitro skin permeation test that allows bridging of literature data for Voltaren 1.16% diclofenac diethylammonium emulgel, taking into account well-established use registrations in accordance with Annex I of Directive 2001 / 83 / EC.

21. 10. The gel of claim 1, wherein the gel is transparent.

22. a) diclofenac diethylammonium at a concentration of about 1% to about 1.2% w / w; b) isopropanol at a concentration of about 12% to about 13% w / w; c) propylene glycol at a concentration of about 4% to about 6% w / w; d) carbomer at a concentration of about 0.7% to about 1.5% w / w; e) diethylamine at a concentration of about 0.7% to about 1.3% w / w; f) optionally one or more of a fragrance, a pH adjuster, a gelling agent, an emollient, a humectant, a preservative, a chelating agent, an antioxidant, and / or a colorant; 10. The gel of claim 1, consisting essentially of

23. 10. The gel of claim 1 provided in an applicator pack for direct application to the skin.

24. 10. The gel of claim 1 for use in a method for providing a cooling sensation to mammalian skin at the site of application.

25. 10. The gel of claim 1 for use in treating a human suffering from joint pain, osteoarthritis pain, back pain, knee pain, ankle pain, neck pain, muscle pain, sprains, and / or inflammation.

26. 26. A gel for use according to claim 24 or 25, wherein the gel is applied to the skin at the application site in a dose of 2 grams for the upper limbs or 4 grams for the lower limbs, the gel is rubbed or massaged into the skin until the application site is dry, and the application is repeated 3 to 4 times in 24 hours until treatment is stopped.

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