Hydroalcoholic single-phase gel composition for topical delivery of diclofenac

Abstract

The present invention discloses a hydroalcoholic single phase gel composition comprising diclofenac or a pharmaceutically acceptable salt of diclofenac. The composition is a single-phase composition, and does not comprise a lipophilic phase. The composition may include at least one non-ionic surfactant. The compositions are useful for the topical delivery of diclofenac. The compositions are useful in the treatment of, for example, pain.

Description

Field of the Invention

[0001] The present invention relates to a formulation for the topical delivery of diclofenac. In particular, the present invention relates to a non-greasy hydroalcoholic gel formulation. Background of the Invention

[0003] Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) of the acetic acid class that is widely used in systemic and topical or transdermal products. Emulgel is an oil-in-water emulsion having a gelled aqueous phase. Emulgel for the topical delivery of diclofenac is commercially available. Recent patient reports indicate that some users are dissatisfied with certain properties of the emulgel. The inventors of the present application have overcome those drawbacks, and the present disclosure provides a topical diclofenac product that has similar advantages of existing products but additionally has properties that meet evolving consumer preferences. Summary of the Invention

[0004] The present invention discloses a hydroalcoholic single-phase gel composition for the topical delivery of diclofenac, which comprises:

[0005] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0006] - A gelling agent,

[0007] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0008] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0009] - A nonionic emulsifier, and

[0010] - Water.

[0011] In one embodiment, the composition comprises diclofenac or a pharmaceutically acceptable salt of diclofenac at a total concentration of about 1.5% w / w to about 2.5% w / w diclofenac sodium equivalent.

[0012] In one embodiment, the composition comprises at least two different nonionic emulsifiers.

[0013] In one embodiment, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 13 to about 17, about 14 to about 16, or about 15. In one embodiment, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 15 to about 19, about 16 to about 18, or about 17.

[0014] In one embodiment, the composition comprises a nonionic emulsifier selected from Macrogol Cetostearyl Ether 20, polysorbate 60, polysorbate 80, isosteareth-20, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20, and combinations of two or more thereof.

[0015] In one embodiment, the composition comprises Macrogol Cetostearyl Ether.

[0016] In one embodiment, the composition comprises a nonionic emulsifier selected from polysorbate 20, laureth-20, and combinations thereof.

[0017] In one embodiment, the composition comprises polysorbate 20.

[0018] In one embodiment, the composition comprises a nonionic emulsifier containing a 2-isopropyl-tetrahydrofuran moiety and comprising one or more oligo(ethylene oxide) ester groups, wherein all of the ethylene oxide units of the oligo(ethylene oxide) ester groups combined contain from 10 to 30, from 14 to 24, or 20 carbon atoms.

[0019] In one embodiment, the composition comprises a first nonionic emulsifier having a hydrophilic-lipophilic balance value of from about 14 to about 16 and a second nonionic emulsifier having a hydrophilic-lipophilic balance value of from about 16 to about 18.

[0020] In one embodiment, the composition comprises a first nonionic emulsifier (which is Macrogol Cetostearyl Ether) and a second nonionic emulsifier (which is polysorbate).

[0021] In one embodiment, the composition comprises a nonionic emulsifier in a total concentration of from about 0.1% w / w to about 5% w / w, from about 1% w / w to about 3.5% w / w, or from about 1.5% w / w to about 3% w / w.

[0022] In one embodiment, the composition comprises isopropanol at a concentration of from about 8% w / w to about 15% w / w.

[0023] In one embodiment, the composition comprises propylene glycol at a concentration of from about 3% w / w to about 15% w / w.

[0024] In one embodiment, the nonionic emulsifier slows the penetration of diclofenac.

[0025] In one embodiment, the composition is substantially free of one or more fats, oils, waxes, occlusives, or carbohydrate-based ointment bases.

[0026] In one embodiment, the composition is substantially free of fats, oils, waxes, occlusives, and carbohydrate-based ointment bases.

[0027] In one embodiment, the composition is substantially free of oil.

[0028] In one embodiment, the composition is substantially free of fat.

[0029] In one embodiment, the composition is substantially free of wax.

[0030] In one embodiment, the composition is substantially free of carbohydrate-based ointment bases.

[0031] In one embodiment, the composition substantially does not form a lipophilic dispersed phase.

[0032] In one embodiment, the gel is transparent.

[0033] In one embodiment, the composition has a pH value of from about 6.5 to about 8.5.

[0034] In one embodiment, the composition has a cumulative penetration amount in an in vitro skin penetration test such that it enables registration in accordance with the well-established use criteria of Annex I of Directive 2001 / 83 / EC based on the literature data of Voltarol Joint Pain Relief Gel 2.32% Diclofenac Diethylammonium.

[0035] The present invention also discloses a composition for use in a method of treating pain of non-severe arthritis of the knee or finger.

[0036] The present invention also discloses the use of a non-ionic emulsifier in reducing the cumulative penetration amount of diclofenac through the skin within 6 hours, 9 hours, 12 hours, or 24 hours in a hydroalcoholic single-phase gel for topical delivery of diclofenac.

[0037] BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0038] Figure 1 : Example of a hydroalcoholic single-phase gel composition when used with a dosing card.

[0039] Figure 2 : Visual representation of the results of Example 2

[0040] Figure 3 : Visual representation of the results of Example 3

[0041] Figure 4 : Visual representation of the results of Example 4 Detailed description of the invention

[0043] Examples of topical diclofenac preparations are Voltaren Arthritis Pain (diclofenac sodium topical gel, 1% (NSAID) - arthritis pain reliever), which contains 1% w / w diclofenac sodium and has been approved as an over-the-counter (OTC) drug in the United States since 2020. Another topical diclofenac preparation contains 1.16% w / w diethylammonium diclofenac (equivalent to 1% of diclofenac sodium salt) and is sold as Voltaren or Voltarol 1.16% Emulgel. Voltarol 1.16% Emulgel has been available in Switzerland since 1974. In some countries, such as the United Kingdom, Voltarol Joint Pain Relief Gel 2.32% is available on the market, which contains 2.32% w / w diethylammonium (DEA) salt of diclofenac (2% w / w diclofenac sodium equivalent). Voltaren Arthritis Pain, Voltarol 1.16% Emulgel and Voltarol Joint Pain Relief are latex gels (emulgels). Emulgels are a special form of topically applied drugs. The emulgel form has been described in combination with the active ingredient (API) diclofenac, for example, in US4917886A.

[0044] According to US4917886A, compared with traditional topical preparations such as gels or creams, the described emulgel preparations provide a more soluble active ingredient and a related higher concentration of the active ingredient. Another advantageous property of emulgels is the presence of a lipid phase, which provides fat-replenishing properties. The combination of the lipid phase and the gelled aqueous phase enables the preparation to be massaged, and at the same time, the experience of direct absorption into the skin is also a pleasant property.

[0045] Existing Voltaren 1%, 1.16% and 2.32% emulgel products are successful commercial products. However, due to the evolving preferences of consumers over time, finding new compositions has become the goal, which can be quickly absorbed by the skin, do not leave oily marks or residues on the application site and hands, and are optically transparent or clear.

[0046] The main goal of the inventors is to find new compositions that are optically transparent or as clear as water. Transparent compositions may be considered modern, clean, fresh and natural. This may increase user compliance. In addition, transparent topical products may be easier to administer for some users. For example, on the dose cards of traditional topical products, the transparent gel does not obscure the scale or measurement area (see Figure 1 ).

[0047] Meanwhile, the beneficial properties of the existing Voltaren 1%, 1.16% and 2.32% emulgel products should not be compromised. The new compositions should contain a similar dose of diclofenac. They should provide similar diclofenac permeation properties. In this way, similar efficacy and safety can be expected. In addition, the beneficial sensory attributes of the existing products, such as a pleasant application experience and a cooling effect, should be maintained or improved.

[0048] For topical compositions containing diclofenac or diclofenac salts, it can be challenging to dissolve the diclofenac (salt) completely and permanently. For example, diclofenac free acid is a weak acid and is poorly soluble in water. For topical compositions containing diclofenac (salt), crystallization or precipitation of the diclofenac (salt) during storage and after application to the skin is a problem, as it can lead to inaccurate dosing or underdosing, and result in "loss" of the API, since the undissolved API is no longer available for skin penetration. Accordingly, there is a need for a solvent system that completely dissolves diclofenac or its salts. In the art, solvent systems containing water, aliphatic C2-C4 monohydric alcohols, and aliphatic diols have been used. For example, Voltarol 2.32% Emulgel contains such a solvent combination. However, hydroalcoholic gels containing the prior art solvent systems fail to achieve the above object. Even if the dissolution of diclofenac or diclofenac salts is achieved, other properties of the gel may get out of control. For example, the skin penetration of diclofenac may be affected. Aliphatic C2-C4 monohydric alcohols can have a penetration enhancing effect. The effect (enhancing or reducing) of aliphatic diols on the penetration rate may depend on their total concentration. Higher concentrations of aliphatic diols also make the composition hazy or turbid, which is unacceptable to the inventors. In addition, other excipients in the given formulation also affect the amount of skin penetration. The above US4917886A describes an emulgel containing a lipophilic phase as an option for enhancing API dissolution. However, since emulgels are generally opaque and the inventors sought to find transparent compositions, a different form was needed. The inventors observed (see Example 1) that hydroalcoholic gel compositions composed of the hydroalcoholic phase of Voltaren 1.16% Emulgel exhibited sufficient API solubility. However, their cumulative penetration amount exceeded that of Voltaren 1.16% Emulgel, such that they did not meet the defined penetration property requirements. Accordingly, the inventors found that hydroalcoholic single-phase gel compositions tend to have a higher API penetration amount compared to emulgels. Without being bound by a particular theory, the inventors believe this is due to the lack of a lipophilic dispersed phase and the higher water activity of compositions containing a high concentration of water. However, the inventors aimed to formulate a composition having penetration properties similar to those of the existing Voltaren 1% or 1.16% Emulgel products. Thus, the dosimetry of the existing products, i.e., the dosing amount and frequency, can be maintained. Accordingly, determining a suitable solvent and its useful concentration is a particular challenge, the solvent and useful concentration of which can completely dissolve diclofenac or diclofenac salts in a single-phase hydroalcoholic composition, thereby forming a transparent gel having the desired application properties and having an acceptable (not too high) cumulative penetration amount.

[0049] Surprisingly, the inventors were able to formulate a hydroalcoholic single-phase gel having a penetration amount very similar to that of an emulgel.

[0050] Accordingly, the present inventors sought to improve the user's sensory experience and convenience while maintaining skin penetration characteristics similar to those of Voltaren Arthritis Pain Relief Patch, Voltaren 1.16% Emulgel, or Voltarol Joint Pain Gel 2.32%. This approach was taken to maintain the beneficial properties of the Voltaren 1%, 1.16%, or 2.32% Emulgel products, which are familiar and appreciated by patients. This was also done in consideration of patient safety. By providing a product with diclofenac penetration characteristics similar to those of commercially available products with excellent safety profiles, the risk of adverse events with the new product was reduced. In addition, it can facilitate the registration and approval of new pharmaceutical products with products similar or comparable to the approved products by regulatory authorities. In one aspect, the present inventors sought to develop a product that could be registered according to the "well-established use" criterion, relying on the published literature data of Voltaren 1% Emulgel or Voltaren 1.16% Emulgel or Voltarol Joint Pain Gel 2.32%.

[0051] Composition

[0052] Hydroalcoholic single-phase composition

[0053] The compositions disclosed herein are compositions for topical drug delivery. This means that the compositions contain an active pharmaceutical ingredient (API). The compositions are designed to be applied to the skin of patients in need of treatment with the API. The compositions are effective vehicles for the penetration of the API through the skin. The compositions disclosed herein allow the API to penetrate through the skin and reach the site of action. The site of action can be, for example, a joint. The process of penetration and passage of the API from the composition through the skin can be determined in sophisticated preclinical experiments, such as those described in the experimental section later in this document. The skin is a complex structure containing multiple tissue layers. Therefore, the skin is an important barrier to the API. For the avoidance of doubt, the compositions of the present disclosure are not for the treatment of skin diseases. In one embodiment, the compositions are not for the treatment of skin diseases.

[0054] The compositions are hydroalcoholic compositions. The term "hydroalcoholic composition" means a composition that is substantially free of oils, waxes, and saturated carbohydrates, but does not exclude the possibility that the composition may contain ingredients with hydrophobic moieties.

[0055] The compositions described herein are specifically hydroalcoholic gels. A "hydroalcoholic gel" refers to a composition that contains a gel continuous phase comprising water and one or more alcohols. In other words, the composition contains a hydroalcoholic continuous phase. For the avoidance of doubt, a hydroalcoholic gel may contain other ingredients in addition to water and alcohol.

[0056] The composition is a single-phase composition. A "single-phase composition" means that diclofenac or a diclofenac salt is mainly or completely dissolved in a solvent system, and the solvents constituting the solvent system are mainly or completely miscible with each other. The single-phase composition is intended to distinguish this composition from emulsions, emulsions, colloidal mixtures, two-phase compositions (such as oil and water), etc. Although only a gelling agent or an emulsifier is present, the composition can be a single-phase composition. In the present disclosure, the gelling agent and the gel network formed by the gelling agent are not regarded as a separate phase or a second phase. In addition, the micelles formed by the aggregation of emulsifier molecules are not regarded as a separate phase or a second phase.

[0057] Compared with traditional ointments, the hydroalcoholic single-phase gel is a different dosage form. An ointment is a single-phase composition containing only a single lipophilic phase. Ointments usually have a thick consistency. Due to their lipophilicity, ointments have a occlusive effect on the skin and may cause a greasy or sticky skin sensation. Ointments usually also produce a warming effect. However, different forms are emulsions, creams and emulsions. An emulsion is a two-phase composition, also called a two-phase system. These two-phase systems include a lipophilic phase and a hydrophilic phase, formulated as a continuous phase and a dispersed phase. An emulsion composition can have a lipophilic continuous phase and a hydrophilic dispersed phase (so-called water-in-oil emulsion or W / O emulsion), or can have a hydrophilic continuous phase and a lipophilic dispersed phase (so-called oil-in-water emulsion or O / W emulsion). Emulsions contain emulsifiers, i.e., molecules having both hydrophilic and lipophilic properties. Therefore, emulsifiers are amphiphilic molecules. The hydrophilic part of the emulsifier molecule is usually called the head group, and the lipophilic part of the emulsifier molecule is usually called the tail group. Emulsifiers help to form and stabilize the dispersion of the lipophilic phase or the hydrophilic phase. Without an emulsifier, an emulsion can only be formed temporarily or has poor stability, manifested as non-mixing / phase separation. This can occur because lipophilic and hydrophilic components are usually immiscible, and the dispersed state is thermodynamically unstable. This non-mixing process can be called phase separation because it results in the separation of the dispersed phase and the continuous phase. Due to the amphiphilic nature of emulsifiers, they stabilize the inherently immiscible phases in a dispersed state. Creams and emulsions are subclasses of emulsions. A cream is an emulsion that can have a lipophilic continuous phase and a hydrophilic dispersed phase (so-called W / O cream), or can have a hydrophilic continuous phase and a lipophilic dispersed phase (so-called O / W cream). Creams are also defined by their semi-solid consistency. An emulsion is an emulsion having a gel continuous phase. Emulsions can also have a lipophilic continuous phase and a hydrophilic dispersed phase (W / O), or can have a hydrophilic continuous phase and a lipophilic dispersed phase (O / W). However, the commercial emulsion form is usually the O / W form. Therefore, in the art and in the present disclosure, when referring to an emulsion, it usually refers to an O / W emulsion.

[0058] The compositions disclosed herein are different from the above-described conventional multiphase systems. The compositions disclosed herein are hydroalcoholic single-phase gels. The compositions disclosed herein comprise a gelled hydroalcoholic continuous phase. In this regard, the compositions described herein are similar to emulsions. However, emulsions also comprise a dispersed lipophilic phase. For example, Voltaren 1% Emulgel, Voltaren 1.16% Emulgel or Voltarol Joint Pain Relief Gel 2.32% Diclofenac DEA comprise a lipophilic dispersed phase comprising, for example, liquid paraffin as the lipophilic HE hydrophobic component. In contrast, the compositions of the present disclosure do not comprise a lipophilic dispersed phase. In emulsions, the lipophilic phase enhances the solubility of the active ingredient (in this case diclofenac (salt)). Thus, in a single-phase hydroalcoholic composition, it is more challenging to dissolve diclofenac and diclofenac salts, especially at elevated API concentrations. Even if a certain amount of diclofenac (salt) is initially dissolved in the solvent or composition, the API may have a strong tendency to recrystallize. Therefore, formulating a hydroalcoholic gel comprising diclofenac (salt) and free of a lipophilic dispersed phase and still achieving complete dissolution of the diclofenac (salt) is a challenge. Formulating a hydroalcoholic single-phase gel is particularly challenging where diclofenac or diclofenac salts are completely dissolved over an extended period of time, during the shelf life and / or during storage.

[0059] The inventors have found a hydroalcoholic single-phase composition comprising a solvent system that can dissolve diclofenac or diclofenac salts. The solvent system comprises water and a mixture of aliphatic C2-C4 monohydric alcohols and aliphatic diols at specific concentrations. Unexpectedly, the inventors have found that by adding a specific concentration of one or more non-ionic emulsifiers to the resulting hydroalcoholic single-phase diclofenac gel, the cumulative permeation of diclofenac can be reduced, and thus the permeation characteristics can be adjusted. In addition, the resulting gel is optically transparent.

[0060] One aspect of conventional multiphase systems is that they typically contain spheres of a certain size. Most multiphase systems contain a dispersed phase, the spheres of which (also referred to as particle size) scatter light and make the multiphase system appear turbid or opaque, typically milky white to opaque white. In contrast, the compositions described herein are clear, transparent, see-through, and / or slightly milky white. Without being bound by a particular theory, the inventors believe that the compositions disclosed herein contain only structures with an average size that is too small to effectively scatter light. This results in a transparent composition. In these embodiments, the nonionic emulsifier can be dissolved in the water continuous phase. According to the inventors' theory, in the disclosed compositions, hydrophilic nonionic emulsifier molecules can associate to form small aggregates starting from a certain concentration in a water-alcohol environment. The lipophilic tail groups of many nonionic emulsifier molecules can associate to form micelles. The tail groups are located in the core of the micelle, while the head groups face outwards, towards the hydrophilic continuous phase. Nevertheless, the compositions of the present disclosure are not opaque but optically transparent. In addition, even though micelles may be present, these compositions are still considered single-phase compositions as defined herein.

[0061] In some embodiments of the composition, the structures formed by the hydrophilic nonionic emulsifier or micelles (if present) have an average spherulite size of less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, or less than about 40 nm. In a particular embodiment of the composition, the structures formed by the hydrophilic nonionic emulsifier or micelles (if present) have an average spherulite size of less than about 50 nm. In one embodiment, the composition does not contain structures (except gelling agents) with an average spherulite size greater than 50 nm. The average spherulite size of the semi-solid composition structure can be measured using a compound microscope with or without particle counting software.

[0062] In one embodiment, the composition has no color. In one embodiment, the composition is colorless. In one embodiment, the compositions disclosed herein are transparent to milky white. In one embodiment, the composition is clear. In one embodiment, the composition does not significantly scatter light in the visible spectrum of the human eye. In one embodiment, the composition does not significantly scatter light in the wavelength range of about 380 nm to about 780 nm. In one embodiment, the composition is light transmissive. In one embodiment, the composition is transparent. In one embodiment, the composition does not contain a disperse phase that scatters light in the visible spectrum of the human eye, and the composition is transparent to milky white. In one embodiment, the compositions of the present disclosure are hydroalcoholic single-phase gels that contain only structures that do not scatter light in the visible spectrum of the human eye. In a particular embodiment of the above embodiments, if micelles are present, their average spherulite size is less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, or less than about 40 nm.

[0063] Advantageously, the optical properties of the compositions described herein have a modern and appealing appearance that attracts many patients and consumers. This "as clear as water" appearance can serve as a visible marker indicating that the composition consists mainly of water, which can also be perceived positively. In addition, it is easier to administer using a dosing card for topical products (such as Figure 1 the dosing card in). When the composition of the present invention is administered on a dosing card, even when the user has dispensed the composition onto the dosing card, they can perceive the dose indicator on the dosing card. This improves dosing safety and dosing accuracy. This also improves the user's dosing skills.

[0064] In the present disclosure, "substantially free of" should be understood as not adding additional ingredients with specific functions to the formulation. For example, "substantially free of penetration enhancers" means not adding penetration enhancers to the composition. However, this does not exclude the ingredients that are explicitly listed in the present disclosure as mandatory or optional or preferred components. Those skilled in the art understand that in a pharmaceutical composition, many ingredients perform more than one function. Thus, in addition to the functions described herein, the ingredients listed as mandatory or optional or preferred components in the present disclosure may also perform certain other functions. For example, a given alcohol described as a component of a composition can act as a solubilizer but can also affect penetration. For example, at certain concentrations it may have a penetration enhancing effect. In this instance, "substantially free of penetration enhancers" does not exclude the presence of such a solvent in the composition of the present disclosure. In addition, the composition may contain trace or trace amounts of certain compounds, for example due to impurities or due to degradation of the ingredients. This is also not included, and such a composition will still be considered "substantially free of" the said compound. "Substantially free of lipophilic excipients" does not exclude the presence of hydrophilic nonionic emulsifiers in the composition. The hydrophilic nonionic emulsifiers used in the compositions of the present invention are not considered lipophilic excipients, although a part of their molecular structure, namely the tail group, is lipophilic. Hydrophilic nonionic emulsifiers are amphiphilic molecules containing lipophilic and hydrophilic parts, where overall, the hydrophilicity predominates and renders the emulsifier hydrophilic and water-soluble.

[0065] The lipophilicity of a compound can be evaluated, for example, by the shake flask method and can be expressed by the logP value. The logP value (partition coefficient or distribution coefficient) indicates how a given molecule partitions between a lipophilic organic phase (usually n-octanol) and a polar aqueous phase (usually deionized water). In some embodiments, the composition is substantially free of excipients (except diclofenac or its salts) having a logP octanol / water value higher than about 3, higher than about 4, higher than about 5, or higher than about 6. Preferably, the composition does not contain a lipophilic or fatty phase. This preferably provides consumers with a water- and alcohol-based "fat-free", "no-messy", "non-greasy" alternative. The composition does not leave lipophilic marks on the application site, hands, or clothes. In addition, the composition is transparent.

[0066] Although the compositions do not contain a lipophilic phase, they contain hydrophilic nonionic emulsifiers. As described above, in conventional multiphase systems, emulsifiers are used to achieve the dispersion of one immiscible phase in another immiscible phase. In compositions without a lipophilic phase, emulsifiers are generally not added because there is no dispersed phase to be stabilized in the aqueous phase and there is no risk of phase separation. Thus, typically, hydroalcoholic compositions in the art do not contain any emulsifiers. Contrary to the art, the compositions of the present disclosure contain hydrophilic nonionic emulsifiers, although they are hydroalcoholic compositions without a lipophilic phase. Emulsifiers have been reported to have a permeation-enhancing effect in multiphase systems (e.g., see Iti Som, Kashish Bhatia, and Mohd. Yasir, “Status of surfactants as penetration enhancers in transdermal drug delivery”, J PharmBioallied Sci., 2012 Jan-Mar; 4(1):2–9; doi:10.4103 / 0975-7406.92724). Contrary to these teachings, in the compositions of the present disclosure, the hydrophilic nonionic emulsifiers have a permeation-reducing effect.

[0067] The inventors unexpectedly found that in the hydroalcoholic compositions of the present disclosure, the nonionic emulsifiers can reduce the cumulative permeation of diclofenac. In one aspect, the nonionic emulsifiers can thus have a permeation-slowing effect on diclofenac or its salts in the hydroalcoholic single-phase compositions of the present disclosure. This is particularly unexpected in view of the teachings in the art regarding the permeation-enhancing effect of nonionic emulsifiers (Iti Som et al., as described above). In addition, the inventors found that a specific combination of nonionic emulsifiers is particularly suitable for reducing the cumulative permeation of diclofenac.

[0068] As can be seen from the Examples section, the inventors found that diclofenac or its salts showed a higher permeation rate in the hydroalcoholic compositions compared to an emulsion gel composition containing the same concentration of API and other excipients (e.g., see Example 1). As discussed above, the inventors sought to provide a composition as safe as the established product Voltarol Joint Pain Relief Gel 2.32% Diclofenac DEA and could rely on their extensive drug safety experience. Thus, in one aspect, the inventors aimed to provide a composition having a permeation profile similar to that of Voltarol Joint Pain Relief Gel 2.32% Diclofenac DEA. Surprisingly, it was found that the cumulative permeation of diclofenac from the hydroalcoholic gel could be adjusted by adding one or more hydrophilic nonionic emulsifiers. In addition, the nonionic emulsifiers do not contain ionizable groups and are relatively insensitive to pH changes. Thus, the nonionic emulsifiers can stabilize the compositions.

[0069] In one embodiment, the composition comprises at least one nonionic emulsifier. In one embodiment, the composition comprises at least two different classes of nonionic emulsifiers. In one embodiment, the composition comprises one or more nonionic emulsifiers. In one embodiment, the composition comprises at least two different nonionic emulsifiers. In another embodiment, the composition comprises two nonionic emulsifiers and no other emulsifiers. In some embodiments, the composition comprises at least two nonionic emulsifiers. In another embodiment, the composition comprises exactly two nonionic emulsifiers.

[0070] In one embodiment, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of from about 13 to about 17, from about 14 to about 16, or about 15. In a particular embodiment, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 15. In one embodiment, the composition comprises a nonionic emulsifier, wherein the one nonionic emulsifier has a hydrophilic-lipophilic balance value of from about 13 to about 17, from about 14 to about 16, or about 15. In any of these embodiments, the nonionic emulsifier may be present at a concentration of from about 0.1% w / w to about 5% w / w, from about 1% w / w to about 3% w / w, from about 1.5% w / w to about 2.5% w / w, or about 2% w / w.

[0071] In some embodiments, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of from about 15 to about 19, from about 16 to about 18, or about 17. In a particular embodiment, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 17. In one embodiment, the composition comprises a nonionic emulsifier, wherein the one nonionic emulsifier has a hydrophilic-lipophilic balance value of from about 15 to about 19, from about 16 to about 18, or about 17. In any of these embodiments, the nonionic emulsifier may be present at a concentration of from about 0.1% w / w to about 5% w / w, from about 0.5% w / w to about 1.5% w / w, from about 0.7% w / w to about 1.3% w / w, or about 1% w / w.

[0072] In another embodiment, the composition comprises a first nonionic emulsifier and a second nonionic emulsifier, wherein the first nonionic emulsifier is different from the second nonionic emulsifier. The first nonionic emulsifier and the second nonionic emulsifier may have the same hydrophile-lipophile balance value or different hydrophile-lipophile balance values. In one embodiment, the composition comprises a first nonionic emulsifier having a hydrophile-lipophile balance value of from about 14 to about 16, and a second nonionic emulsifier having a hydrophile-lipophile balance value of from about 16 to about 18. In another embodiment, the composition comprises at least two nonionic emulsifiers, wherein one of the at least two nonionic emulsifiers has a hydrophile-lipophile balance value of from about 13 to about 17, from about 14 to about 16 or about 15. In a particular embodiment, the composition comprises two nonionic emulsifiers, wherein one of the two nonionic emulsifiers has a hydrophile-lipophile balance value of from about 13 to about 17, from about 14 to about 16 or about 15.

[0073] In another embodiment, the composition comprises at least two nonionic emulsifiers, wherein one of the at least two nonionic emulsifiers has a hydrophile-lipophilic balance value of from about 15 to about 19, from about 16 to about 18 or about 17. In a particular embodiment, the composition comprises two different nonionic emulsifiers, wherein one of the two nonionic emulsifiers has a hydrophile-lipophilic balance value of from about 15 to about 19, from about 16 to about 18 or about 17.

[0074] In a particular embodiment, the composition comprises a first nonionic emulsifier having a hydrophile-lipophile balance value of from about 13 to about 17, from about 14 to about 16 or about 15, and a second nonionic emulsifier having a hydrophile-lipophile balance value of from about 15 to about 19, from about 16 to about 18 or about 17. The concentration of the first nonionic emulsifier present may be from about 0.1% w / w to about 5% w / w, from 1% w / w to about 3% w / w, from about 1.5% w / w to about 2.5% w / w or about 2% w / w. The concentration of the second nonionic emulsifier present may be from about 0.1% w / w to about 5% w / w, from 0.5% w / w to about 1.5% w / w, from about 0.7% w / w to about 1.3% w / w or about 1% w / w. In another particular embodiment, the composition comprises a nonionic emulsifier having a hydrophile-lipophile balance value of about 15 and a nonionic emulsifier having a hydrophile-lipophile balance value of about 17. The concentration of the nonionic emulsifier having a hydrophile-lipophile balance value of about 15 present may be from about 0.1% w / w to about 5% w / w, from 1% w / w to about 3% w / w, from about 1.5% w / w to about 2.5% w / w or about 2% w / w. The concentration of the nonionic emulsifier having a hydrophile-lipophile balance value of about 17 present may be from about 0.1% w / w to about 5% w / w, from 0.5% w / w to about 1.5% w / w, from about 0.7% w / w to about 1.3% w / w or about 1% w / w.

[0075] In one embodiment, the composition comprises a hydrophilic nonionic emulsifier which is an ethoxylated C16 to C18 alcohol. In one embodiment, the composition comprises a nonionic emulsifier selected from polyoxyethylene cetostearyl ether 20, polysorbate 60, polysorbate 80, isosteareth-20, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20, and combinations of two or more thereof. In a particular embodiment, the composition comprises polyoxyethylene cetostearyl ether. In another particular embodiment, the composition comprises polyoxyethylene cetostearyl ether 20. Polyoxyethylene cetostearyl ether 20 is the pharmacopoeial name used in the European Pharmacopoeia (Ph.Eur.). In the United States Pharmacopoeia (USP), the name Polyoxyl 20 cetostearyl ether (USP) is used for the same ingredient. In the International Nomenclature of Cosmetic Ingredients (INCI), the name Ceteareth-20 (INCI) is used for the same ingredient. One trade name of polyoxyethylene cetostearyl ether 20 is Kolliphor CS20. In any of these embodiments, the concentration of the defined nonionic emulsifier present may be from about 0.1% w / w to about 5% w / w, 1% w / w to about 3% w / w, about 1.5% w / w to about 2.5% w / w, or about 2% w / w.

[0076] In one embodiment, the composition comprises a nonionic emulsifier containing a 2-isopropyl-tetrahydrofuran moiety which contains one or more oligo(ethylene oxide) ester groups, wherein all of the ethylene oxide units of the oligo(ethylene oxide) ester group combined contain from about 10 to about 30, about 14 to about 24, or about 20 carbon atoms. In a particular embodiment, the oligo(ethylene oxide) ester group contains a laurate. In another embodiment, the composition comprises polysorbate. In another embodiment, the composition comprises a nonionic emulsifier selected from polysorbate 20, laureth-20, and combinations thereof. In a particular embodiment, the composition comprises polysorbate 20. Polysorbate 20 is the pharmacopoeial name used in Ph.Eur. and USP. One trade name of polysorbate 20 is Kolliphor PS20. In any of these embodiments, the concentration of the defined nonionic emulsifier present may be from about 0.1% w / w to about 5% w / w, 0.5% w / w to about 1.5% w / w, about 0.7% w / w to about 1.3% w / w, or about 1% w / w.

[0077] In one embodiment, the composition comprises a first nonionic emulsifier that is ceteth and a second nonionic emulsifier that is polysorbate. The ceteth may be present in a concentration of about 0.1% w / w to about 5% w / w, about 1% w / w to about 3% w / w, about 1.5% w / w to about 2.5% w / w, or about 2% w / w. The polysorbate may be present in a concentration of about 0.1% w / w to about 5% w / w, 0.5% w / w to about 1.5% w / w, about 0.7% w / w to about 1.3% w / w, or about 1% w / w. In yet another specific embodiment, the composition comprises a combination of ceteth 20 and polysorbate 20. The ceteth 20 may be present in a concentration of about 0.1% w / w to about 5% w / w, about 1% w / w to about 3% w / w, about 1.5% w / w to about 2.5% w / w, or about 2% w / w. The polysorbate 20 may be present in a concentration of about 0.1% w / w to about 5% w / w, about 0.5% w / w to about 1.5% w / w, about 0.7% w / w to about 1.3% w / w, or about 1% w / w.

[0078] In a specific embodiment of any of the above embodiments, one or more of the listed emulsifiers are the only emulsifiers in the composition. In some embodiments, the composition is substantially free of anionic emulsifiers. In some embodiments, the above composition is substantially free of anionic emulsifiers and substantially free of cationic emulsifiers.

[0079] In one embodiment, the composition comprises a nonionic emulsifier in a total concentration of about 0.1% w / w to about 5% w / w, 0.5% w / w to about 4% w / w, about 1% w / w to about 3.5% w / w, or about 1.5% w / w to about 3% w / w. In one embodiment, the composition comprises a nonionic emulsifier in a total concentration of about 2% w / w. In another embodiment, the composition comprises a nonionic emulsifier in a total concentration of about 3% w / w.

[0080] Solvent system

[0081] The compositions disclosed herein comprise a solvent system that includes water, an aliphatic C2-C4 monohydric alcohol, and an aliphatic diol. In one embodiment, the compositions described herein comprise more than about 50% w / w, more than about 60% w / w, or more than about 70% w / w water. In a specific embodiment, the composition comprises from about 65% w / w to about 75% w / w water. In one embodiment, the composition is water-based. In one embodiment, the composition is an aqueous composition. Advantageously, water imparts a cooling effect to the skin. It is also an easily accessible ingredient with a low environmental impact. Additionally, water is a transparent ingredient, which is advantageous given the importance of the optical appearance of the final composition. The water can be purified water, distilled water, or the like. The water can be pharmaceutical-grade water. In one embodiment, the composition comprises water as the composition matrix. As part of the solvent system, water also serves to dissolve diclofenac or a diclofenac salt.

[0082] In addition to water, the solvent system further comprises an aliphatic C2-C4 monohydric alcohol. The composition can comprise a single aliphatic C2-C4 monohydric alcohol or multiple aliphatic C2-C4 monohydric alcohols. In one embodiment, the aliphatic C2-C4 monohydric alcohol is selected from ethanol, propanol, isopropanol, butan-1-ol, and combinations of two or more thereof. In some embodiments, the composition comprises isopropanol. In other embodiments, the composition comprises ethanol. In one embodiment, the composition comprises ethanol, isopropanol, or both. In one embodiment, the composition comprises water, ethanol, and isopropanol. In one embodiment, isopropanol serves as the sole aliphatic C2-C4 monohydric alcohol. In any of the above embodiments, the water and the alcohol are present in the continuous phase of the composition. In some embodiments, the composition comprises a continuous phase that includes water, isopropanol, and optionally ethanol. In a specific embodiment, the composition comprises a continuous phase that includes water and isopropanol.

[0083] Compared to water alone, C2-C4 monohydric alcohols enable better dissolution of diclofenac and diclofenac salts. This is beneficial for the dissolution of diclofenac and reduces the risk of recrystallization. In addition, compared to pure water-based gels, the topical gels produced by aliphatic C2-C4 monohydric alcohols have a shorter drying time. After applying the composition to the skin, the aliphatic C2-C4 monohydric alcohol will evaporate. The evaporation after application to the skin will shorten the drying time. The drying time can be described as the time from applying the topical product to the skin until the skin at the application site feels dry again. In addition, aliphatic C2-C4 monohydric alcohols can impart a distinct cooling effect to the topical composition. After applying the topical composition to the skin, the evaporation of the composition components is driven by the thermal energy at the application site. Therefore, the evaporation process absorbs thermal energy from the application site. Thereby, a cooling sensation is produced on the skin. This cooling effect is beneficial to patients and consumers: "Calor", that is, the affected body part is hot, is one of the main symptoms of the inflammatory process. Therefore, the cooling of the administration site can relieve the inflammatory process and can reduce inflammatory pain. In addition, the cooling can give people the feeling that the topical product takes effect immediately. In addition, aliphatic C2-C4 monohydric alcohols are transparent. Therefore, they are suitable for formulating topical compositions with the desired optical transparency.

[0084] In some specific embodiments, the composition comprises isopropyl alcohol as the only aliphatic C2-C4 monohydric alcohol. In some embodiments, the composition comprises a continuous phase that comprises water and isopropyl alcohol and does not contain ethanol. In some embodiments, the composition comprises a continuous phase that comprises water and isopropyl alcohol and does not contain any other C2-C4 monohydric alcohol. Advantageously, by using isopropyl alcohol as the only aliphatic C2-C4 monohydric alcohol, the number of different components. In these embodiments, no additional aliphatic C2-C4 monohydric alcohol is required to dissolve diclofenac or diclofenac salts and to provide a cooling sensation on the skin. In particular, it is not necessary to add another aliphatic C2-C4 monohydric alcohol that evaporates more easily, such as ethanol. In some embodiments, this may be preferred because ethanol is regulated in many states for tax or ethical reasons. Therefore, in some embodiments, the composition does not contain ethanol.

[0085] Aliphatic C2-C4 monohydric alcohols can be used to reduce the drying time, which is generally beneficial. However, since the alcohol component in the composition also plays a role in API dissolution, the solvent system may not evaporate too easily and sufficient API concentration needs to be maintained during the dissolution process. Therefore, the risk of API crystallization or precipitation after application on the skin is reduced. As a result, the amount of bioavailable API can be increased. This is beneficial for efficacy, patient safety, and environmental safety. This is also preferred because it can reduce the formation of residues on the skin after application and drying. This provides a pleasant experience for the patient. Therefore, the solvent system used in the composition of the present invention also includes an aliphatic diol as a co-solvent.

[0086] In some embodiments, the aliphatic diol can be a C2-C4 polyhydric alcohol. In some embodiments, the composition disclosed herein contains a diol. In one embodiment, the composition contains an aliphatic diol selected from ethylene glycol, propylene glycol, and 1,3-butanediol, and any combination thereof. In some embodiments, propylene glycol is present as the sole aliphatic diol.

[0087] The aliphatic diol or C2-C4 polyhydric alcohol can act as a co-solvent for the API. Compared with the above-mentioned aliphatic C2-C4 monohydric alcohols, the aliphatic diol or C2-C4 polyhydric alcohol is not easily evaporated after application to the skin. Therefore, the aliphatic diol or C2-C4 polyhydric alcohol will remain in the topical composition on the skin, while the aliphatic C2-C4 monohydric alcohol will evaporate. Therefore, the aliphatic diol or C2-C4 polyhydric alcohol can keep the API in a dissolved state after application to the skin.

[0088] In addition, the aliphatic diol or C2-C4 polyhydric alcohol has hygroscopicity. They can impart moisturizing and water-retaining properties to the topical composition. This can provide a pleasant skin feel, such as a soft, smooth, or nourishing skin feel. This also helps to balance the lipid-extracting properties of the C2-C4 monohydric alcohols. These effects are particularly important in single-phase hydroalcoholic compositions because these compositions do not contain a lipophilic phase that can provide emollient or fat-replenishing properties.

[0089] The aliphatic diol or C2-C4 polyhydric alcohol can also affect the permeation properties of the formulation. However, this effect on permeation also depends on their concentration, as well as other ingredients and the overall composition. As mentioned above, the present inventors have attempted to formulate a composition with permeation characteristics similar to those of existing Voltaren 1% or 1.16% or 2.32% emulsion products, which will be explained in more detail in a separate section below.

[0090] The concentration of the aliphatic C2-C4 monohydric alcohol present in the composition may be from about 5% w / w to about 20% w / w. Preferably, the concentration of the aliphatic C2-C4 monohydric alcohol may be from about 8% w / w to about 15% w / w. In one embodiment, the concentration of the aliphatic C2-C4 monohydric alcohol is about 12.5% w / w. In a specific embodiment of any of the above embodiments, the aliphatic C2-C4 monohydric alcohol may be isopropyl alcohol.

[0091] In a specific embodiment, the composition comprises isopropyl alcohol at a concentration of from about 5% w / w to about 20% w / w, from about 8% w / w to about 15% w / w, or about 12.5% w / w. In one embodiment, the composition of the present disclosure comprises isopropyl alcohol at a concentration of from about 5% w / w to about 20% w / w, from about 8% w / w to about 15% w / w, or about 12.5% w / w and does not contain any other aliphatic C2-C4 monohydric alcohol.

[0092] The aliphatic C2-C4 monohydric alcohols within these concentration ranges achieve a balance. On the one hand, high concentrations of C2-C4 monohydric alcohols can be beneficial for API dissolution, microbial preservation, and / or a cooling effect. On the other hand, high concentrations of aliphatic C2-C4 monohydric alcohols may cause the final product to be classified as a hazardous material in certain regulations or may be subject to additional regulatory scrutiny, which may complicate production, supply, and regulatory logistics. In the case of high concentrations of aliphatic C2-C4 monohydric alcohols, the composition may require particularly tight packaging to prevent evaporation of the aliphatic C2-C4 monohydric alcohol during storage. Compositions containing aliphatic C2-C4 monohydric alcohols within the above concentration ranges do not require labeling, storage, and handling under strict scrutiny because they are not classified as hazardous materials and do not require particularly tight packaging. This is desirable because such classification would complicate manufacturing and supply and may discourage consumers from using the final product. Additionally, if the concentration of the aliphatic C2-C4 monohydric alcohol is too high, the API may precipitate at the application site as described above. The aliphatic C2-C4 monohydric alcohols within the said concentration range, in combination with the water and aliphatic diol of the solvent system, can fully dissolve the API. Therefore, the composition reduces the risk of leaving API residues or precipitates on the skin.

[0093] Furthermore, the said concentration can produce a sufficient sense of coolness upon application. The initially emerging sense of coolness can distract the patient from the painful and inflamed area and quickly generate a feeling of pain relief. Physiologically, this can help the patient quickly relieve pain. In particular, the sense of coolness can be felt distinctly or strongly, can appear quickly, and can be perceived persistently.

[0094] Aliphatic monohydric alcohols also have antimicrobial properties. If present in a high enough concentration in a composition, the composition can reduce the risk of microbial contamination and bacterial growth. This is particularly important for compositions containing a high concentration of water (e.g., more than about 50% w / w, more than about 60% w / w, or more than about 65% w / w water).

[0095] On the other hand, aliphatic C2-C4 monohydric alcohols may have an odor that is off-putting to some consumers. Perfumes or other odor masking agents may be needed to mask the alcohol odor. However, in some instances, adding fragrances may be challenging or undesirable. Surprisingly, compositions containing aliphatic C2-C4 monohydric alcohols within the stated concentration range can have a pleasant odor. Thus, they are particularly suitable for formulating into fragrance-free compositions. In a particular embodiment, the composition is fragrance-free.

[0096] On the other hand, the above concentration range also provides skin-friendly compositions. Aliphatic C2-C4 monohydric alcohols have some lipid-extracting (lipolytic) properties. These lipid-extracting properties can affect the skin's natural fat and ceramide components as well as the barrier function. It can have a dehydrating, defatting, and irritating effect on the skin. In some cases, this can lead to dry skin, skin flaking, and / or a feeling of skin tightness. On the other hand, aliphatic C2-C4 monohydric alcohols can have a permeation-enhancing effect on APIs. In conventional topical compositions containing a lipophilic phase, the lipophilic components can balance the dehydrating, defatting, and irritating effects of the alcohol component. As mentioned above, the compositions of the present disclosure do not contain a lipophilic dispersed phase. However, the compositions of the present disclosure are very skin-friendly due to the balanced mixing of their components because they contain an appropriate concentration of aliphatic C2-C4 monohydric alcohols and also contain a co-solvent that is an aliphatic diol.

[0097] The co-solvent, aliphatic diol, or C2-C4 polyol can be present in the composition in an amount of about 2.5% w / w to about 20% w / w. Preferably, the aliphatic diol or C2-C4 polyol can be present in an amount of about 3% w / w to about 15% w / w. In one embodiment, the amount of the aliphatic diol or C2-C4 polyol is about 6% w / w to about 12% w / w. In another embodiment, the amount of the aliphatic diol or C2-C4 polyol is about 8% w / w to about 10% w / w. In one embodiment, the composition contains about 8% w / w of the aliphatic diol. In another embodiment, the composition contains about 10% w / w of the aliphatic diol.

[0098] The benefits of including a certain concentration of aliphatic diols or C2-C4 polyols have been described above. However, the inventors of the present invention have found that a specific concentration range of the aliphatic diols or C2-C4 polyols is particularly useful. The aliphatic diols or C2-C4 polyols within this concentration range produce a composition having a reduced risk of skin irritation. In another aspect, the range produces a composition having an acceptable drying time. In another aspect, the resulting composition has very pleasant skin application properties. For example, they do not feel sticky or greasy. Additionally, the resulting composition is clear, transparent or translucent. In some embodiments, the composition may be milky white. Further, the aliphatic diols or C2-C4 monohydric alcohols also affect the penetration properties of the composition.

[0099] In one embodiment, the composition comprises an aliphatic C2-C4 monohydric alcohol (which is isopropyl alcohol) and an aliphatic diol (which is propylene glycol).

[0100] The total combined amount of the aliphatic C2-C4 monohydric alcohol and the aliphatic diol or C2-C4 polyol is preferably greater than about 10% w / w. The total combined amount of the aliphatic C2-C4 monohydric alcohol and the aliphatic diol or C2-C4 polyol is preferably less than about 30% w / w. In range form, the total combined amount of the aliphatic C2-C4 monohydric alcohol and the aliphatic diol or C2-C4 polyol can be from about 15% w / w to about 25% w / w, preferably from about 19% w / w to about 24% w / w. In one embodiment, the total combined amount of the aliphatic C2-C4 monohydric alcohol and the aliphatic diol C2-C4 polyol is about 20.5% w / w. In one embodiment, the total combined amount of the aliphatic C2-C4 monohydric alcohol and the aliphatic diol or C2-C4 polyol is about 22.5% w / w.

[0101] In certain embodiments, the aliphatic C2-C4 monohydric alcohol is isopropyl alcohol and the aliphatic diol is propylene glycol. In some of these embodiments, the total combined concentration of isopropyl alcohol and propylene glycol is greater than about 10% w / w. The total combined concentration of isopropyl alcohol and propylene glycol is preferably less than about 30% w / w. In range form, the total combined concentration of isopropyl alcohol and propylene glycol can be from about 10% w / w to about 30% w / w, preferably from about 12% w / w to about 25% w / w. In certain embodiments, the total combined concentration of isopropyl alcohol and propylene glycol is about 14% w / w, about 15% w / w, about 15.5% w / w, about 17.5% w / w, about 20% w / w or about 25% w / w.

[0102] In some embodiments, the ratio of the aliphatic diol to the aliphatic C2-C4 monohydric alcohol is from 1:0.5 to 1:2. In some embodiments, the ratio of the aliphatic diol to the aliphatic C2-C4 monohydric alcohol is from 1:0.5 to 1:2, 1:1.9, 1:1.8, 1:1.17, 1:1.16, 1:1.15, 1:1.14, 1:1.13, 1:1.125, 1:1.12, 1:1.11, 1:1, 1:0.9, 1:0.8, 1:0.7 or 1:0.6. In a specific embodiment, the ratio of the aliphatic diol to the aliphatic C2-C4 monohydric alcohol is from 1:1.4 to 1:1. In one specific embodiment, the ratio of the aliphatic diol to the aliphatic C2-C4 monohydric alcohol is 1:1.25. In a specific embodiment of the above embodiments, the aliphatic C2-C4 monohydric alcohol is isopropanol and the aliphatic diol is propylene glycol.

[0103] In other specific embodiments, the composition comprises about 10% w / w, about 11% w / w or about 12.5% w / w isopropanol and about 5% w / w or about 10% w / w propylene glycol. In a specific embodiment, the composition comprises about 12.5% w / w isopropanol and about 10% w / w propylene glycol.

[0104] The compositions disclosed herein comprise an API which is diclofenac or a pharmaceutically acceptable salt of diclofenac. This includes deuterated forms of diclofenac or its salts, wherein one or more hydrogen atoms in the diclofenac molecule are replaced by deuterium atoms (i.e., deuterated diclofenac). In one embodiment, the composition comprises diclofenac, ammonium diclofenac, sodium diclofenac or potassium diclofenac. In one embodiment, the composition comprises a pharmaceutically acceptable inorganic diclofenate. In a specific embodiment, the composition comprises ammonium diclofenac, sodium diclofenac or potassium diclofenac. In another specific embodiment, the composition comprises sodium diclofenac or potassium diclofenac. In another embodiment, the composition comprises sodium diclofenac. In some embodiments, the composition comprises diclofenac or a pharmaceutically acceptable salt of diclofenac as the sole active pharmaceutical ingredient.

[0105] The inventors compared the stability of a conventional emulgel and a hydroalcoholic gel formulation, both of which contained diethylammonium diclofenac. They found that the emulgel showed slower nitrosamine formation compared to the hydroalcoholic composition. Without being bound by a particular theory, the inventors believe that the lipophilic phase and antioxidants that may be present in the lipophilic phase can have a stabilizing effect on secondary amines, thereby slowing down nitrosamine formation. Thus, in the hydroalcoholic single-phase compositions of the present disclosure, inorganic diclofenates such as ammonium diclofenac or sodium diclofenac, potassium diclofenac may be preferred. However, the dissolution of these salts in hydroalcoholic gels may be more challenging than that of organic diclofenates. In addition, counterions, especially Na+ and K + and can interact with certain gelling agents and have a negative impact on their gel formation and thickening effect. For example, this is the case with so-called carbomer gelling agents, which are commonly referred to as "ion-sensitive". However, carbomer gelling agents are preferred gelling agents for the compositions of the present disclosure because the gels they produce have particularly appealing tactile and skin sensations. Surprisingly, the inventors were able to formulate embodiments of the presently disclosed compositions that contain an inorganic diclofenac salt and a carbomer gelling agent, made in a hydroalcoholic single-phase formulation matrix, and still have a suitable viscosity.

[0106] Preferably, the composition is substantially free of additional APIs. This means that no APIs other than diclofenac (or diclofenac salts) are added to the composition. For example, the composition does not contain additional NSAIDs such as ibuprofen. In one embodiment, the composition does not contain an anti-irritant. In one embodiment, the composition is substantially free of anti-irritants.

[0107] In some embodiments, the composition contains diclofenac or a pharmaceutically acceptable salt of diclofenac at a total concentration of about 1.5% w / w to about 2.5% w / w diclofenac sodium equivalent. Generally, in the present disclosure, unless otherwise stated, the concentration of diclofenac salts is given in terms of diclofenac sodium equivalent. In some embodiments, the composition contains diclofenac or a pharmaceutically acceptable salt of diclofenac at a total concentration of about 1.8% w / w to about 2.2% w / w diclofenac sodium equivalent. In some embodiments, the composition contains about 2.32% w / w of the diethylammonium salt of diclofenac. In some embodiments, the composition contains about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2.0% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w or about 2.5% w / w of diclofenac sodium. In a particular embodiment, the composition contains about 2% diclofenac sodium. As mentioned above, the dissolution of higher concentrations of diclofenac or its salts is more challenging. In addition, the concentration of counterions can interfere with the gelling ability of the gelling agent. The disclosed solvent system is suitable for dissolving even the said high concentrations of diclofenac or diclofenac salts, and the resulting hydroalcoholic single-phase gel composition is optically transparent. Even when using carbomer gelling agents, they still have the desired diffusion characteristics and viscosity. In addition, they also have the desired permeation characteristics.

[0108] In alternative embodiments, the compositions of the present disclosure may comprise from about 0.5% w / w to about 1.5% w / w of diclofenac or a diclofenac salt in terms of diclofenac sodium equivalent. In some embodiments, the composition comprises from about 0.8% w / w to about 1.2% w / w of diclofenac or a pharmaceutically acceptable salt of diclofenac in terms of diclofenac sodium equivalent. In one embodiment, the composition comprises from about 0.5% w / w to about 1.5% w / w of diclofenac sodium. Preferably, the composition comprises from about 1% w / w to about 1.2% w / w of diclofenac sodium. Particularly preferred is a concentration of about 1% w / w of diclofenac sodium. In alternative embodiments, the composition comprises about 1.16% w / w of diclofenac diethylammonium salt. In some other embodiments, the composition comprises about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w or about 1.5% w / w of diclofenac sodium.

[0109] Within these concentration ranges, excellent API dissolution can be achieved. After formulation, no visible API crystals remain in the composition. In one embodiment, no crystals of diclofenac or its salts are detected in the composition when examined by visual inspection or using an optical microscope at magnifications of x10, x40, x100, x400, x800 or x1200.

[0110] Preferably, the composition is substantially free of additional API. This means that no additional API is added to the composition other than diclofenac (salt). For example, the composition does not contain additional NSAIDs such as ibuprofen. In one embodiment, the composition does not contain an anti-irritant. In one embodiment, the composition is substantially free of an anti-irritant. In one embodiment, the composition comprises diclofenac or a pharmaceutically acceptable salt of diclofenac as the sole active pharmaceutical ingredient.

[0111] The compositions of the present disclosure may comprise from about 1.5% w / w to about 2.5% w / w, from 1.8% w / w to about 2.2% w / w or from about 1.9% w / w to about 2.1% w / w of diclofenac or a diclofenac salt in terms of diclofenac sodium equivalent. Generally, in the present disclosure, unless otherwise specified, the concentration of diclofenac salts is given in terms of diclofenac sodium equivalent. In one embodiment, the composition comprises from about 1.5% w / w to about 2.5% w / w of diclofenac sodium. Preferably, the composition comprises from about 1.8% to about 2.2% w / w of diclofenac sodium. Particularly preferred is a concentration of about 2% w / w of diclofenac sodium.

[0112] Within these concentration ranges, excellent API dissolution was achieved. After formulation, no visible residual API crystals were present in the composition. In one embodiment, no crystals of diclofenac or its salts were detected in the composition when examined visually or using an optical microscope with magnifications of x10, x40, x100, x400, x800 or x1200.

[0113] The compositions disclosed herein contain a gelling agent. The composition contains a hydroalcoholic continuous phase containing the gelling agent. In one embodiment, the composition contains a gelled hydroalcoholic continuous phase. In one embodiment, the composition is a gel comprising an aqueous continuous phase and a three-dimensional network structure formed by the gelling agent.

[0114] In some embodiments, the compositions of the present disclosure may contain a carbomer gelling agent. Carbomer gelling agents produce very clear and transparent gels. As described above, carbomer gelling agents also produce gels with excellent spreading properties, and many consumers prefer such gels compared to other gels (such as hydroxypropyl methylcellulose gels). For example, Carbomer 974P or Carbomer 980 may be used.

[0115] The amount of carbomer gelling agent present is sufficient to increase the viscosity of the composition. The concentration of the carbomer gelling agent may be from about 1.5% w / w to about 2.5% w / w, from about 1.8% w / w to about 2.2% w / w or about 2% w / w. Preferably, the viscosity is high enough so that the composition can be dosed by the dose from a tube. 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.

[0116] In embodiments containing an acidic gelling agent (such as carbomer), the composition further contains a basic agent. The basic agent initiates the gelling of the acidic gelling agent (such as a carbomer gelling agent, which is polyacrylic acid). The basic agent may be present in a concentration sufficient to adjust the pH to about 6 to about 8.5, preferably about 7.3 to about 8.2. The basic agent may be an aliphatic amine, such as primary, secondary and tertiary alkanolamines and primary, secondary and tertiary alkylamines. For example, monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, dimethylamine, diethylamine, trimethylamine or triethylamine may be used. In an alternative embodiment, the basic agent is an inorganic basic agent. In one embodiment, the basic agent is NaOH, KOH or an ammonia solution. The ammonia solution may be, for example, a 10% or 30% ammonia solution.

[0117] The composition may optionally contain other ingredients such as fragrances, chelating agents, preservatives, stabilizers, antioxidants, colorants, etc.

[0118] In some embodiments, the compositions disclosed herein are substantially free of penetration enhancers. Generally, penetration enhancers are included in compositions to increase the cumulative penetration and / or flux of the API. However, they can irritate the skin. Additionally, some penetration enhancers require special highlighting on the packaging label. Specifically, the composition can be free of isostearic acid and other fatty acids or acids. Penetration enhancers result in turbid, hazy, or milky compositions and are thus not preferred. Specifically, the composition is preferably free of fatty alcohols, fatty acids, isopropyl myristate, isopropyl palmitate, and diethyl sebacate.

[0119] Preferably, the compositions disclosed herein are substantially free of additional humectants such as glycerin. While humectants are often added to topical compositions for their cooling, conditioning, and moisturizing properties, they can cause the product to have a longer drying time on the skin. Thus they are not preferred.

[0120] Preferably, the compositions disclosed herein are substantially free of sensates. For example, the composition can be free of peppermint oil, 1-menthol, and menthol derivatives, methyl salicylate, ethyl salicylate, ethylene glycol monosalicylate, etc. Preferably, the composition is substantially free of anti-irritants. Preferably, the composition is substantially free of inducers. Sensates, anti-irritants, and inducers are typically added to provide a "fast-acting" cooling sensation, which is the preferred sensory attribute described above. However, they can also cause the formulation to be turbid or break. They can also cause irritation. Additionally, they can affect the amount of penetration of the composition.

[0121] Stability

[0122] As described above, it is important that the API is dissolved and remains dissolved. This can be determined by the absence of API crystals. Preferably, the composition is free of API crystals when visually inspected with an optical microscope. Preferably, the composition is homogeneous when visually inspected with the naked eye. Preferably, the composition is free of API crystals during a shelf life of 12, 24, or 36 months. In some embodiments, the composition is homogeneous when visually inspected with an optical microscope at magnifications of x10, x40, x100, x400, x800, or x1200. In some embodiments, after storage for 6, 12, 24, or 36 months under accelerated stability test conditions of 40°C ± 2°C / 75% ± 5% relative humidity, or after storage for 3, 6, 12, 24, or 36 months under long-term stability test conditions of 30°C ± 2°C / 65% ± 5% relative humidity, the composition is homogeneous when visually inspected with an optical microscope at magnifications of x10, x40, x100, x400, x800, or x1200.

[0123] Amount of penetration

[0124] The aim of the present inventors was to find a composition which, in an in vitro skin penetration test over 24 hours, had a therapeutic to reference ratio (T / R) of the cumulative penetration amount between 0.8 and 1.25, with a 90% confidence interval, relative to the reference product Voltarol Joint Pain Relief Gel 2.32% diethylammonium diclofenac. The method for measuring the cumulative skin penetration amount is described in detail in the Examples section. In one embodiment, the composition herein has a cumulative penetration over 24 hours in an in vitro human skin penetration test which meets the acceptance criteria of the draft guideline on the quality and equivalence of topical products CHMP / QWP / 708282 / 2018. In one embodiment, the composition has a cumulative penetration over 24 hours in an in vitro human skin penetration test which meets the acceptance criteria of lines 708 to 710 of the draft guideline on the quality and equivalence of topical products CHMP / QWP / 708282 / 2018. In one embodiment, the composition has a cumulative penetration over 24 hours in an in vitro human skin penetration test, wherein the 90% confidence interval of the mean ratio of the composition to the comparator product Voltarol Joint Pain Relief Gel 2.32% diethylammonium diclofenac is within the acceptance interval of 80.00–125.00%.

[0125] In certain embodiments, the composition has a cumulative penetration over 24 hours in an in vitro human skin penetration test which meets the acceptance criteria of lines 711 to 715 of the draft guideline on the quality and equivalence of topical products CHMP / QWP / 708282 / 2018. In another embodiment, the composition has a cumulative penetration over 24 hours in an in vitro human skin penetration test, wherein the 90% confidence interval of the mean ratio of the composition to the comparator product Voltarol Joint Pain Relief Gel 2.32% diethylammonium diclofenac is within the acceptance interval of 69.84%–143.19%. In cases where there is a higher variability within or between subjects, acceptance criteria with a wider 90% confidence interval may be acceptable.

[0126] In some embodiments, the composition has a cumulative penetration amount in an in vitro skin penetration test which enables registration according to the well - established use criteria of Annex I of Directive 2001 / 83 / EC, based on the literature data of Voltarol Joint Pain Relief Gel 2.32% diethylammonium diclofenac.

[0127] As mentioned above, due to the specific choice of the solvent system and the addition of a hydrophilic non - ionic emulsifier, the penetration amount of the hydroalcoholic single - phase composition can be customized and the cumulative penetration amount can be reduced compared to other hydroalcoholic single - phase gel compositions. This effect can be summarized as a penetration - slowing effect. This effect is also evident from the Examples. Detailed Description

[0128] In one embodiment, a hydroalcoholic single-phase gel composition is provided, comprising:

[0129] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0130] - A gelling agent,

[0131] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0132] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0133] - A non-ionic emulsifier, and

[0134] - Water.

[0135] In one embodiment, a hydroalcoholic single-phase gel composition is provided, comprising:

[0136] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0137] - A gelling agent,

[0138] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0139] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0140] - A non-ionic emulsifier with a hydrophilic-lipophilic balance value of about 14 to about 16, and

[0141] - Water.

[0142] In one embodiment, a hydroalcoholic single-phase gel composition is provided, comprising:

[0143] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0144] - A gelling agent,

[0145] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0146] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0147] - Ceteth-20, and

[0148] - Water.

[0149] In one embodiment, a hydroalcoholic single-phase gel composition is provided, comprising:

[0150] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0151] - A gelling agent,

[0152] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0153] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0154] - A non-ionic emulsifier with a hydrophilic-lipophilic balance value of about 16 to about 18, and

[0155] - Water.

[0156] In one embodiment, there is provided a hydroalcoholic single-phase gel composition comprising:

[0157] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0158] - A gelling agent,

[0159] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0160] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0161] - Polysorbate 20, and

[0162] - Water.

[0163] In another embodiment, there is provided a hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

[0164] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0165] - A gelling agent,

[0166] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0167] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0168] - Water,

[0169] wherein the composition is substantially free of a lipophilic phase.

[0170] In another embodiment, there is provided a hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

[0171] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0172] - A gelling agent,

[0173] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0174] - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w,

[0175] - At least one non-ionic emulsifier at a concentration of about 0.5% w / w to about 4% w / w, and

[0176] - Water.

[0177] In another embodiment, there is provided a hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

[0178] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0179] - A gelling agent,

[0180] - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w,

[0181] - Ethylene glycol at a concentration of about 2.5% w / w to about 20% w / w,

[0182] - A non-ionic emulsifier at a concentration of about 0.5% w / w to about 4% w / w, and

[0183] - Water.

[0184] In another embodiment, there is provided a hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

[0185] - Diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0186] - A gelling agent,

[0187] - Isopropyl alcohol, ethanol or a combination thereof,

[0188] - Propylene glycol,

[0189] - A non-ionic emulsifier, and

[0190] - Water.

[0191] In another embodiment, there is provided a hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

[0192] - Diclofenac or a pharmaceutically acceptable salt of diclofenac at a concentration of about 1.5% w / w to about 2.5% w / w diclofenac sodium equivalent,

[0193] - Carbomer gelling agent,

[0194] - aliphatic C2-C4 monohydric alcohols at a concentration of about 5% w / w to about 20% w / w,

[0195] - C2-C4 polyhydric alcohols at a concentration of about 2.5% w / w to about 20% w / w,

[0196] - nonionic emulsifiers at a concentration of about 0.1% w / w to about 5% w / w, and

[0197] - water, and

[0198] - an alkaline agent for adjusting the pH value of the whole composition to about 6.5 to about 8.5.

[0199] In another embodiment, a composition mainly composed of the following components is provided:

[0200] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0201] - a gelling agent,

[0202] - aliphatic C2-C4 monohydric alcohols,

[0203] - aliphatic diols,

[0204] - nonionic emulsifiers,

[0205] - water, and

[0206] - an alkaline agent for adjusting the pH value of the whole composition to about 6.5 to about 8.5,

[0207] and optionally flavors, chelating agents, preservatives, stabilizers, antioxidants and / or colorants.

[0208] In another embodiment, a composition mainly composed of the following components is provided:

[0209] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0210] - a gelling agent,

[0211] - aliphatic C2-C4 monohydric alcohols,

[0212] - aliphatic diols,

[0213] - a first nonionic emulsifier with a hydrophilic-lipophilic balance value of about 14 to about 16,

[0214] - a second nonionic emulsifier with a hydrophilic-lipophilic balance value of about 16 to about 18,

[0215] - water, and

[0216] - An alkaline agent for adjusting the pH value of the whole composition to about 6.5 to about 8.5,

[0217] and optionally perfume, chelating agent, preservative, stabilizer, antioxidant and / or colorant.

[0218] Preferably, the above composition is substantially free of anionic emulsifier. In some embodiments, the above composition is substantially free of anionic emulsifier and substantially free of cationic emulsifier.

[0219] Manufacturing method

[0220] The composition can be manufactured as follows:

[0221] - In a first container, disperse the gelling agent in a first portion of water until completely dispersed;

[0222] - If it is necessary to initiate the gelling of the gelling agent, add an alkaline agent to the gelling agent dispersion to obtain a gel;

[0223] - In a second container, combine a second portion of water, aliphatic monohydric alcohol, aliphatic diol and non-ionic emulsifier;

[0224] - Disperse diclofenac or a pharmaceutically acceptable salt of diclofenac in the mixture in the second container to obtain an API solution;

[0225] - Combine the gel and the API solution under homogenization.

[0226] Use

[0227] The composition disclosed herein is suitable for treating:

[0228] · Pain, inflammation and swelling in the following parts:

[0229] - Soft tissue injuries: tendon, ligament, muscle and joint trauma, such as those caused by sprains, strains, abrasions and back pain (sports injuries);

[0230] - Local forms of soft tissue rheumatism: tendinitis (such as tennis elbow), bursitis, shoulder-hand syndrome and periarthropathy; and

[0231] · Pain of non-severe arthritis in the knee or finger.

[0232] Pharmaceutical composition / Route of administration / Dose

[0233] The composition can be administered to mammals suffering from arthralgia, osteoarthritis, myalgia, back pain and / or inflammation. Preferably, the composition is for treating humans. The composition can be used to treat pain, inflammation and swelling in soft tissue injuries, such as trauma to tendons, ligaments, muscles and joints, such as those caused by sprains, strains, abrasions and back pain (sports injuries), and / or local forms of soft tissue rheumatism, such as tendinitis (e.g., tennis elbow), bursitis, shoulder-hand syndrome and peripheral arthropathy.

[0234] The composition can also be used to treat pain in non-severe knee or finger arthritis.

[0235] They can be applied to the skin covering the relevant body part. They can be rubbed until the skin feels dry. They can be applied 2 - 4 times a day. The treatment method can include administering a pharmaceutically effective amount of the composition disclosed herein to a subject in need thereof. The method can include applying the composition to the skin covering a body part that has suffered or causes pain, inflammation and swelling in one or more soft tissue injuries, such as trauma to tendons, ligaments, muscles and joints, such as those caused by sprains, strains, abrasions and back pain (sports injuries), and / or local forms of soft tissue rheumatism, such as tendinitis (e.g., tennis elbow), bursitis, shoulder-hand syndrome and peripheral arthropathy or pain in non-severe arthritis.

[0236] The composition can be packaged in a package containing a dosing device. The composition can be contained in a container with an applicator for direct application to the skin.

[0237] The embodiments described herein can be more easily understood with reference 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 only for illustrating the principles of the present invention. Those skilled in the art will readily envision many modifications and adaptations without departing from the spirit and scope of the present invention.

[0238] In addition, all ranges disclosed herein should be understood to encompass any and all sub-ranges subsumed therein. For example, the range “1.0 to 10.0” should be considered to include any and all sub-ranges starting with a minimum value of 1.0 or greater and ending with a maximum value of 10.0 or less, such as 1.0 to 5.3, 4.7 to 10.0 or 3.6 to 7.9.

[0239] Unless otherwise expressly stated, all ranges disclosed herein should also be considered to include the endpoints of the range. For example, a range of “between 5 and 10” or “5 to 10” or “5 - 10” should generally be considered to include the endpoints 5 and 10.

[0240] It should also be understood that one or more features of one embodiment can generally be applied to other embodiments, even if not specifically described or illustrated in other embodiments, unless the characteristics of the present disclosure or the relevant embodiments clearly prohibit it. Similarly, the compositions and methods described herein can include any combination of the features and / or steps described herein that are not inconsistent with the objectives of the present disclosure. Those skilled in the art will readily understand various modifications and / or adjustments of the compositions and methods described herein without departing from the subject matter of the present invention. Unless otherwise stated, concentrations are expressed as %(w / w).

[0241] Unless otherwise stated, concentrations are expressed as %(w / w).

[0242] The term "about" in relation to the numerical value x means, for example, x ± 10%, x ± 5%, x ± 4%, x ± 3%, x ± 2%, x ± 1%.

[0243] pH, viscosity, and HLB are typically measured at 25°C.

[0244] Examples

[0245] The present invention will be described in more detail below by way of examples, but the present invention is not limited by these examples.

[0246] Example 1: Comparison of 24-hour cumulative skin penetration in an emulsion and a hydroalcoholic gel

[0247] In vitro skin penetration studies were conducted in a preclinical laboratory. Skin penetration studies can be used to determine the qualitative penetration characteristics of a formulation through, for example, human skin. They can also be used to directly quantitatively compare the penetration and flux of two given formulations. In Example 1, the cumulative penetration in a hydroalcoholic test formulation was compared with the cumulative penetration of a reference product (an emulsion). At the time point of 0 hours, five test formulations and the reference product were each applied to the abdominal skin of human donors at a dose of 10 mg / cm 2 . Five skin samples from different donors were tested for each formulation on a Franz diffusion cell. The reference product used for comparison was Voltaren Emulgel 1.16% (m / m) diethylammonium diclofenac. The compositions of the test formulations and the reference product Voltaren Emulgel 1.16% (m / m) are listed in Table 1:

[0248] Table 1: Compositions of the reference product and test formulations in Example 1

[0249]

[0250]

[0251] The concentration of diclofenac in the receptor fluid of the Franz cell was measured at time points t = 0 h, 4 h, 8 h, and 24 h, and the study endpoint was the cumulative amount of diclofenac permeated over 24 h.

[0252] The study results are shown in Table 2.

[0253] Table 2: Results of in vitro skin permeation study of Example 1

[0254]

[0255] Surprisingly, the cumulative permeation amounts of all test formulations (Tests 1 to 5) were much higher than that of the reference product. Although the concentration of the active ingredient in all test compositions was the same, the hydroalcoholic formulations (Tests 1 to 5) showed a cumulative permeation amount at 24 h that was approximately 1.7 times (Test 4) to nearly 3 times (Test 5) that of the reference product. This led the inventors to conclude that the absence of a discrete lipophilic phase resulted in a higher cumulative permeation amount over 24 h.

[0256] Example 2: Comparison of cumulative skin permeation amounts of emulsion and hydroalcoholic gel over 24 h

[0257] In a cumulative skin permeation study in a 3 ml permeation cell, the cumulative permeation amount through skin samples from human donors was investigated. Six replicate tests were performed on five different compositions. The cumulative permeation amount was measured at 4 h and 24 h after the application dose. However, the cumulative permeation amount at 4 h was below the measurement threshold in this experiment, and thus no report was made on Example 2. All formulations were applied at a dose of 6 μl to skin samples with a defined surface area. The following formulations were investigated:

[0258] Table 3: Composition and cumulative permeation results of control and test compositions

[0259]

[0260] Voltaren Arthritis Pain is an emulsion composition, while the test compositions F072, F077, F078, and F079 are hydroalcoholic gel compositions without nonionic emulsifier (F072), containing one nonionic emulsifier (F077 and F078), or containing a combination of two nonionic emulsifiers (F079). Voltaren Arthritis Pain was used as the control because it was intended to study the differences between emulsion and hydroalcoholic gel, and because the product was readily available for purchase.

[0261] The results are summarized in the above table and are shown in Figure 2Intuitive display in the middle. The cumulative permeation amount of all test compositions at 24 hours was higher than that of the test composition. It was expected that the cumulative permeation amount of the test composition would be higher than that of the control because the test composition contained more diclofenac sodium (2% w / w instead of 1% w / w). However, the magnitude of the difference was unexpectedly large and exceeded expectations. Interestingly, formulation F072 contained the same types of excipients as the control, except for the lipophilic phase (caprylic / capric triglyceride and mineral oil) and the emulsifier (Kolliphor CS20), and it showed a cumulative permeation amount at 24 hours almost five times higher than that of the control. Unexpectedly, the significant increase in the cumulative permeation amount at 24 hours could be reduced by adding a non-ionic emulsifier. Contrary to the teachings in the art, the non-ionic emulsifier thus had the effect of slowing down permeation. Comparing the cumulative permeation amounts of all test formulations at 24 hours, both Kolliphor PS20 and Kolliphor CS20 had the effect of slowing down permeation, and the effect of Kolliphor CS20 in slowing down permeation was more significant. Formulation F079 (which contained a combination of Kolliphor CS20 and Kolliphor PS20 at a total concentration of 4% w / w) showed the lowest cumulative permeation amount at 24 hours among all test formulations.

[0263] Example 3: Comparison of the cumulative skin permeation amounts of a latex and a hydroalcoholic gel containing 2% w / w epomol diclofenac at 24 hours

[0264] To test the hypothesis that non-ionic emulsifiers exhibit the same effect in compositions containing different diclofenac salts (especially diclofenac salts with organic counterions), the experiment of Example 1 was repeated with test compositions containing epomol diclofenac. The control was the same as in Example 1. Unless otherwise specified, the experimental setup was the same as in Example 1.

[0265] Table 4: Composition and cumulative permeation results of the control and test formulations

[0266]

[0267]

[0268] The results are summarized in the table above and in Figure 3Intuitive display. Interestingly, only formulation DiEp-F004 (the test composition without the lipophilic phase and emulsifier) showed a significantly higher cumulative permeation amount than the control. Surprisingly, the cumulative permeation amounts of all test compositions containing one (DiEp-F005 and DiEp-F006) nonionic emulsifier or two nonionic emulsifiers (DiEp-F007) were even lower than that of the control at 24 hours. Therefore, it seems that the permeation-slowing effect of nonionic emulsifiers is more obvious in compositions containing diclofenac epolamine than in compositions containing diclofenac sodium (Example 2). Interestingly, the cumulative permeation amounts of formulations DiEp-F005, Di-Ep-F006, and DiEp-F007 at 24 hours were very similar. In formulations containing diclofenac epolamine, Kolliphor CS20 and Kolliphor PS20 seem to have a similar permeation-slowing effect. When used in combination at a total concentration of about 4% w / w (DiEp-F007), the cumulative permeation amount at 24 hours was further reduced.

[0269] Example 4: In a non-GLP comparative skin permeation study at different doses, the cumulative skin permeation amounts of latex and hydroalcoholic gels containing 2% w / w diclofenac sodium and different concentrations of nonionic emulsifiers were compared at 24 hours

[0270] Hydroalcoholic compositions containing 2% w / w diclofenac sodium and different levels of nonionic emulsifiers were studied. At the same time, the concentrations of isopropyl alcohol and propylene glycol were varied to study the effect of these components on the cumulative permeation amount. The control was Voltarol Joint Pain Relief Gel, which is also known as Voltaren 2.32% diclofenac diethylamine (DDEA) latex in some markets.

[0271] Stratified abdominal human skin samples (200 - 400 μm) with a trans-epithelial electrical resistance (TEER) value > 7.7 kΩ were mounted in static diffusion cells (exposed area = 0.64 cm 2) and stored under controlled temperature conditions (32 ± 1 °C). Each study formulation was applied in duplicate to skin samples from 6 donors (i.e., total number of skin samples for each formulation = 12 = N). Two experiments were conducted to evaluate the effects of single (t = 0 h) and quadruple (t = 0, 4, 8, 12 h) dosing. The receptor fluid was phosphate buffered saline containing 5% w / v bovine serum albumin. Receptor fluid samples were collected at 0, 2, 4, 8, 16, and 24 h after the first dose, and the diclofenac content was analyzed by LC-MS / MS. The cumulative amount of diclofenac absorbed in the receptor fluid was calculated for each test formulation and two dosing intervals. The cumulative amount of diclofenac absorbed 24 h after the first dose was analyzed. For any post-baseline samples with concentrations below the LOQ, the half value of the limit of quantitation (LOQ) was used. The statistical model used was analysis of variance (ANOVA) on the log-transformed geometric mean and included formulation and donor as fixed effects.

[0272] Table 5: Composition and cumulative permeation results of the reference and test formulations

[0273]

[0274] Table 6: Results of Example 4:

[0275]

[0277]

[0278] The results are summarized in the table above.

[0279] In Example 4, it was observed that the cumulative permeation amount of Composition Test 10 was most similar to that of the reference product. For Tests 10, 11, and 14, the 60% CI of the geometric least-squares mean ratio of the cumulative absorption of diclofenac in the receptor fluid 24 hours after dosing was entirely within the range of 0.67 - 1.50. Therefore, these test formulations were considered to have the most similar permeation characteristics to the control. On the one hand, comparing the results of Tests 9, 13, and 14 (each containing more than 10% w / w propylene glycol) with the results of Tests 10, 11, and 12 (each containing less than 10% w / w propylene glycol), it was evident that the higher the concentration of propylene glycol, the higher the cumulative permeation amount. Comparing only Tests 14 and 13: Tests 13 and 14 had the same composition, except that Test 13 contained only 2.00% w / w Kolliphor CS20, while Test 14 also contained 1.00% w / w Kolliphor PS20 (based on water). The addition of the second nonionic emulsifier decreased the cumulative permeation amount to such an extent that although Test 14 contained more than 10% w / w propylene glycol, the 60% CI of the geometric least-squares mean ratio of its cumulative permeation amount to the cumulative absorption amount of diclofenac in the receptor fluid 24 hours after dosing was entirely within the range of 0.67 - 1.50. Test 12 (a test composition containing two nonionic emulsifiers and only 5% w / w propylene glycol) had the lowest cumulative permeation amount.

Claims

1. A hydroalcoholic single-phase gel composition for local delivery of diclofenac, comprising: - Diclofenac or a pharmaceutically acceptable salt of diclofenac, - A gelling agent, - An aliphatic C2-C4 monohydric alcohol at a concentration of about 5% w / w to about 20% w / w, - An aliphatic diol at a concentration of about 2.5% w / w to about 20% w / w, - A nonionic emulsifier, and - Water.

2. The composition according to claim 1, comprising diclofenac or a pharmaceutically acceptable salt of diclofenac at a total concentration of about 1.5% w / w to about 2.5% w / w of diclofenac sodium equivalent.

3. The composition according to claim 1 or 2, comprising at least two different nonionic emulsifiers.

4. The composition according to any one of the preceding claims, comprising a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 13 to about 17, about 14 to about 16 or about 15. The composition according to any one of the preceding claims, comprising a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 15 to about 19, about 16 to about 18 or about 17.

5. The composition according to any one of the preceding claims, comprising a nonionic emulsifier selected from: ceteth-20, polysorbate 60, polysorbate 80, isosteareth-20, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20 and combinations of two or more thereof.

6. The composition according to any one of the preceding claims, comprising ceteth-20.

7. The composition according to any one of the preceding claims, comprising a nonionic emulsifier selected from polysorbate 20, laureth-20 and combinations thereof.

8. The composition according to any one of the preceding claims, comprising polysorbate 20.

9. The composition according to any one of the preceding claims, comprising a nonionic emulsifier containing a 2-isopropyl-tetrahydrofuran moiety, the nonionic emulsifier comprising one or more oligo(ethylene oxide) ester groups, wherein all the ethylene oxide units of the oligo(ethylene oxide) ester groups combined contain 10 to 30, 14 to 24 or 20 carbon atoms.

10. The composition according to any one of the preceding claims, comprising a first nonionic emulsifier having a hydrophilic-lipophilic balance value of about 14 to about 16, and a second nonionic emulsifier having a hydrophilic-lipophilic balance value of about 16 to about 18.

11. The composition according to any one of the preceding claims, comprising a first nonionic emulsifier which is ceteth-20, and a second nonionic emulsifier which is a polysorbate.

12. The composition according to any one of the preceding claims, comprising a nonionic emulsifier at a total concentration of about 0.1% w / w to about 5% w / w, about 1% w / w to about 3.5% w / w or about 1.5% w / w to about 3% w / w.

13. The composition according to any one of the preceding claims, wherein the nonionic emulsifier slows down the penetration of diclofenac.

14. A composition according to any one of the preceding claims, which has a cumulative permeation amount in an in vitro skin permeation test, said cumulative permeation amount enabling registration in accordance with the literature data of Voltarol Joint Pain Relief Gel 2.32% Diclofenac Diethylamine, in accordance with Annex I of Directive 2001 / 83 / EC, according to well-defined use criteria.

15. A composition according to any one of the preceding claims, for use in a method of treating pain of non-severe arthritis of the knee or finger.

16. Use of a non-ionic emulsifier for reducing the cumulative permeation amount of diclofenac through the skin from a hydroalcoholic single-phase gel for topical delivery of diclofenac within 6 hours, 9 hours, 12 hours or 24 hours.

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