Hydroalcoholic topical diclofenac formulations

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 compositions are useful for the topical delivery of diclofenac. The compositions are useful in the treatment of pain, inflammation, and swelling in, for example, soft tissue injuries.

Description

Field of the Invention

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

[0003] Diclofenac is an acetic acid nonsteroidal anti-inflammatory drug (NSAID) widely used in topical or transdermal products. Emulsion gels (also known as emulsions) are oil-in-water emulsions with a gelled aqueous phase. Emulsions (Emulgel) are commercially available for topical delivery of diclofenac. Recent patient reports indicate that some users are dissatisfied with certain attributes of emulsions. The inventors of the present application have overcome those shortcomings, and the present disclosure provides a topical diclofenac product that has similar advantages to existing products, but additionally has attributes that meet evolving consumer preferences. Summary of the invention

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

[0005] - diclofenac or a pharmaceutically acceptable salt of diclofenac in a concentration of about 0.5% w / w to about 1.5% w / w diclofenac sodium equivalent,

[0006] - Gelling agents,

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

[0008] - aliphatic diols in a concentration of about 2% w / w to about 10% w / w,

[0009] - a hydrophilic nonionic emulsifier in a concentration of about 1% w / w to about 2% w / w, and

[0010] - water.

[0011] In one embodiment, the composition comprises diclofenac sodium.

[0012] In one embodiment, the composition comprises diclofenac sodium at a concentration of about 1% w / w.

[0013] In one embodiment, the nonionic emulsifier has a hydrophile-lipophile balance value of about 13 to about 17, about 14 to about 16, or about 15.

[0014] In one embodiment, the nonionic emulsifier is an ethoxylated C16 to C18 alcohol.

[0015] In one embodiment, the nonionic emulsifier is 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 a combination of two or more thereof.

[0016] In one embodiment, the composition comprises polyethylene glycol cetearyl alcohol ether.

[0017] In one embodiment, the nonionic emulsifier slows the permeation of diclofenac.

[0018] In one embodiment, the composition does not comprise fats, oils, waxes, occlusives, or carbohydrate-based ointment bases.

[0019] In one embodiment, the composition is substantially free of oil.

[0020] In one embodiment, the composition is substantially free of fat.

[0021] In one embodiment, the composition is substantially free of wax.

[0022] In one embodiment, the composition is substantially free of carbohydrate-based ointment bases.

[0023] In one embodiment, the composition does not substantially form a lipophilic dispersed phase.

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

[0025] In one embodiment, the composition has a pH of about 6.5 to about 8.5.

[0026] In one embodiment, the composition comprises an aliphatic C2-C4 monohydric alcohol at a concentration of about 8% w / w to about 18% w / w or about 10% w / w to about 15% w / w.

[0027] In one embodiment, the composition comprises the aliphatic diol at a concentration of about 3% w / w to about 8% w / w or about 3% w / w to about 5% w / w.

[0028] In one embodiment, the aliphatic C2-C4 monohydric alcohol is isopropanol.

[0029] In one embodiment, the aliphatic diol is propylene glycol.

[0030] In one embodiment, the composition comprises isopropanol as the only aliphatic C2-C4 monoalcohol and propylene glycol as the only aliphatic diol.

[0031] In one embodiment, the composition has a cumulative permeation in an in vitro skin permeation test that allows registration according to Annex I to Directive 2001 / 83 / EC under well established criteria for use based on literature data for Voltaren Arthritis Pain (diclofenac sodium topical gel, 1% (NSAID)-arthritis pain reliever) or Voltaren diclofenac diethylamine 1.16% gel.

[0032] The present invention also discloses compositions for use in methods of relieving pain, inflammation and swelling in soft tissue injuries, localized forms of soft tissue rheumatism, and relieving pain in non-severe arthritis of the knee or fingers.

[0033] Description of Figures / Charts

[0034] Figure 1 : An embodiment of a composition according to the present disclosure when used with a dosage card.

[0035] Figure 2 : Graphical representation of the results of Example 2

[0036] Figure 3 : Graphical representation of the results of Example 3 DETAILED DESCRIPTION OF THE INVENTION

[0038] An example of a topical diclofenac formulation is Voltaren Arthritis Pain (diclofenac sodium topical gel, 1% (NSAID)-arthritis pain reliever), which contains 1% w / w diclofenac sodium and is approved as an over-the-counter (OTC) drug in the United States since 2020. Another topical diclofenac formulation contains 1.16% w / w diclofenac diethylammonium salt (equivalent to 1% diclofenac sodium salt), sold as Voltaren or Voltarol 1.16% emulsion. Voltaren 1.16% emulsion has been on the market in Europe since 1974. Voltaren Arthritis Pain and Voltaren 1.16% emulsion are emulsion gels (emulsions). The emulsion form has been described in combination with the active ingredient (API) diclofenac, for example, in US4917886A.

[0039] According to US4917886A, the described emulsion formulations provide more soluble active ingredients and associated higher active ingredient concentrations compared to conventional topical formulations such as gels or creams. Another advantageous property of the emulsion is the presence of a lipid phase, which provides fat recovery properties. The combination of the lipid phase with the gelled aqueous phase enables the formulation to be massaged, while experiencing direct absorption into the skin is also a pleasant property.

[0040] The existing Voltaren 1% or 1.16% emulsion products are successful commercial products. However, as consumer preferences continue to evolve over time, it has become a goal to find new compositions that are quickly absorbed into the skin, do not leave oily marks or residues on the application site and hands, and are optically transparent or clear.

[0041] A primary goal of the inventors was to find new compositions that were optically transparent or clear like water. Transparent compositions may be perceived as modern, clean, fresh, and natural. This may increase user compliance. Additionally, transparent topical products may be easier to administer for some users. For example, on traditional topical product dosage cards, a clear gel would not obscure the scale or measurement area (see Figure 1 ).

[0042] At the same time, the favorable properties of the existing Voltaren 1% or 1.16% emulsion products should not be compromised. The new compositions should contain similar diclofenac dosages. They should provide similar diclofenac penetration characteristics. In this way, similar efficacy and safety can be expected. In addition, the beneficial sensory attributes of the existing products, such as pleasant application experience and cooling effect, should be maintained or improved.

[0043] For topical compositions containing diclofenac or diclofenac salts, it may be challenging to completely and permanently dissolve diclofenac (salt). 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 diclofenac (salt) during storage and after application to the skin is a problem because it may lead to inaccurate or insufficient dosing and cause API "loss" because undissolved API is no longer available to penetrate the skin. Therefore, a solvent system that completely dissolves diclofenac or its salt is needed. In the art, a solvent system containing water, aliphatic C2-C4 monohydric alcohol and aliphatic diol has been used. For example, Voltarol 1.16% emulsion contains such a solvent combination. However, hydroalcoholic gels containing prior art solvent systems cannot achieve the above purposes. Even if dissolution of diclofenac or diclofenac salts is achieved, other properties of the gel may be 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 (enhancement or reduction) of aliphatic diols on the permeation rate may depend on their total concentration. A higher concentration of aliphatic diols can also make the composition hazy or turbid, which is unacceptable to the inventors. In addition, other excipients in a given formulation can also affect the amount of skin permeation. The above-mentioned US4917886A describes an emulsion containing a lipophilic phase as an option for enhancing API dissolution. But since emulsions are usually opaque, and the inventors are trying to find a transparent composition, a different form is required. The inventors observed (see Example 1) that the hydroalcoholic gel composition composed of the hydroalcoholic phase of Voltaren 1.16% emulsion exhibited sufficient API solubility. However, their cumulative permeation exceeded the cumulative permeation of Voltaren 1.16% emulsion, so that they did not meet the defined permeation characteristics requirements. Therefore, the inventors found that compared with emulsions, hydroalcoholic single-phase gel compositions tend to have higher API permeation. Without being bound by a particular theory, the inventors believe that this is due to the lack of a lipophilic dispersed phase and that the composition containing a high concentration of water has a higher water activity. However, the inventors aimed to formulate a composition with similar penetration characteristics to the existing Voltaren 1% or 1.16% emulsion products. In this way, the posology of the existing products, i.e., the dosage and frequency of administration, could be maintained. Therefore, it was a particular challenge to determine a suitable solvent and a useful concentration thereof that would allow complete dissolution of diclofenac or diclofenac salt in a single-phase hydroalcoholic composition, thereby forming a transparent gel with the desired application characteristics and an acceptable (not too high) cumulative penetration.

[0044] Surprisingly, the inventors were able to formulate a hydroalcoholic single phase gel with a penetration capacity very similar to that of an emulsion.

[0045] Therefore, the inventors seek to improve the sensory experience and convenience of the user while maintaining skin penetration properties similar to Voltaren Arthritis Pain Relief Cream or Voltaren 1.16% Emulsion. This approach is adopted to maintain the favorable characteristics of the Voltaren 1% or 1.16% Emulsion products, which are familiar and appreciated by patients. This is also taken with patient safety in mind. By providing a product with diclofenac penetration characteristics similar to commercially available products with excellent safety characteristics, the risk of new products causing adverse events is reduced. In addition, it can facilitate the registration and approval of new drug products by regulatory agencies for products that are similar or comparable to approved products. In one aspect, the inventors seek to develop a product that can be registered according to the "well-established use" standard, relying on published literature data for Voltaren 1% Emulsion or Voltaren 1.16% Emulsion.

[0046] Composition

[0047] Hydroalcoholic single phase composition

[0048] The composition disclosed herein is a composition for topical delivery of diclofenac. This means that the composition comprises diclofenac as an active pharmaceutical ingredient (API). The composition is intended to be applied to the skin of a patient who needs to be treated with the API. The composition is an effective vehicle for the penetration of the API into the skin. The composition disclosed herein allows 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 of the API from the composition through the skin can be determined in complex preclinical experiments, such as the experiments described later in the experimental section herein. The skin is a complex structure comprising multiple tissue layers. Therefore, the skin constitutes an important barrier to the API. For the avoidance of doubt, the composition of the present disclosure is not used to treat skin diseases. In one embodiment, the composition is not used to treat skin diseases.

[0049] The composition is a hydroalcoholic composition. The term "hydroalcoholic composition" means a composition that is substantially free of oils, waxes and saturated carbohydrates, but does not exclude that the composition may contain ingredients containing hydrophobic moieties.

[0050] The compositions described herein are specifically hydroalcoholic gels. "Hydroalcoholic gel" refers to a composition comprising a gel continuous phase comprising water and one or more alcohols. In other words, the composition comprises a hydroalcoholic continuous phase. For the avoidance of doubt, a hydroalcoholic gel may comprise other ingredients in addition to water and alcohol.

[0051] The composition is a single-phase composition. "Single-phase composition" means that diclofenac or diclofenac salt is mainly or completely dissolved in the solvent system, and the solvents constituting the solvent system are mainly or completely miscible together. The single-phase composition is intended to distinguish the present composition from emulsions, latexes, colloid mixtures, two-phase compositions (such as oil and water), etc. Although only a gelling agent or an emulsifier is present, the present 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 considered as a separate phase or a second phase. In addition, micelles formed by the aggregation of emulsifier molecules are not considered as a separate phase or a second phase.

[0052] Compared with traditional ointments, hydroalcoholic single-phase gels are a different form of administration. Ointments are single-phase compositions containing only a single lipophilic phase. Ointments usually have a thick consistency. Due to their lipophilicity, ointments have an occlusive effect on the skin and may cause a greasy or sticky skin feel. Ointments usually also produce a warming effect. However, different forms are emulsions, creams and emulsions. Emulsions are two-phase compositions, also known as two-phase systems. These two-phase systems include a lipophilic phase and a hydrophilic phase, formulated as a continuous phase and a dispersed phase. Emulsion compositions can have a lipophilic continuous phase and a hydrophilic dispersed phase (so-called water-in-oil emulsions or W / O emulsions), or they can have a hydrophilic continuous phase and a lipophilic dispersed phase (so-called oil-in-water emulsions or O / W emulsions). Emulsions contain emulsifiers, i.e. molecules with 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 dispersions of lipophilic or hydrophilic phases. Without emulsifiers, emulsions can only be formed temporarily or have poor stability, showing immiscible / phase separation. This can happen because lipophilic and hydrophilic components are generally immiscible and the dispersed state is thermodynamically unstable. This immiscible process can be called phase separation because it causes the dispersed phase and the continuous phase to separate. Since emulsifiers have amphiphilic properties, they stabilize the inherently immiscible phases in the dispersed state. Creams and emulsions are subclasses of emulsions. Creams are emulsions that can have a lipophilic continuous phase and a hydrophilic dispersed phase (so-called W / O creams) or a hydrophilic continuous phase and a lipophilic dispersed phase (so-called O / W creams). Creams are also defined by their semi-solid consistency. Emulsions are emulsions with 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 latex form is usually an O / W form. Therefore, in the art and in the present disclosure, when referring to a latex, it is usually an O / W latex.

[0053] The composition disclosed herein is different from the conventional multiphase system described above. The composition disclosed herein is a hydroalcoholic single-phase gel. The composition disclosed herein comprises a gelled hydroalcoholic continuous phase. In this respect, the composition described herein is similar to an emulsion. However, the emulsion also comprises a dispersed lipophilic phase. For example, Voltaren 1% emulsion and Voltaren 1.16% emulsion comprise a lipophilic dispersed phase, comprising, for example, liquid paraffin as a lipophilic hydrophobic component. In contrast, the composition disclosed herein does not comprise a lipophilic dispersed phase. In the emulsion, the lipophilic phase enhances the solubility of the active ingredient (in this case, diclofenac (salt)). Therefore, in a single-phase hydroalcoholic composition, dissolving diclofenac and diclofenac salts is more challenging. Even if a certain amount of diclofenac (salt) is initially dissolved in a solvent or composition, the API may also have a strong tendency to recrystallize. Therefore, it is a challenge to formulate a hydroalcoholic gel comprising diclofenac (salt) and not containing a lipophilic dispersed phase and still achieve complete dissolution of diclofenac (salt). It is particularly challenging to formulate hydroalcoholic single-phase gels in which diclofenac or diclofenac salts are completely dissolved over an extended period of time, during shelf life and / or during storage.

[0054] The present inventors have discovered a hydroalcoholic single-phase composition comprising a solvent system in which diclofenac or a diclofenac salt can be dissolved. The solvent system comprises water and a mixture of aliphatic C2-C4 monohydric alcohol and aliphatic diol at a specific concentration. Unexpectedly, the present inventors have found that by adding a hydrophilic nonionic emulsifier at a specific concentration to the resulting hydroalcoholic single-phase diclofenac gel, the cumulative permeation of diclofenac can be reduced, thereby adjusting the permeation characteristics. In addition, the resulting gel is optically transparent.

[0055] One aspect of conventional multiphase systems is that they typically contain spheres of a certain sphere size. Most multiphase systems contain a dispersed phase whose sphere size scatters light and makes the multiphase system look turbid or opaque, typically milky to opaque white. In contrast, the compositions described herein are clear, transparent, see-through, and / or slightly milky. Without being bound by a particular theory, the inventors believe that the compositions disclosed herein contain only structures whose average size is too small to effectively scatter light. This results in a transparent composition. In these embodiments, the nonionic emulsifier can be dissolved in the aqueous continuous phase. According to the inventors' theory, in the disclosed composition, the 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 outward, toward the hydrophilic continuous phase. Nevertheless, the compositions disclosed herein are not opaque, but optically transparent. Furthermore, even though micelles may be present, these compositions are still considered single-phase compositions as defined herein.

[0056] In some embodiments of the composition, the structure formed by the hydrophilic nonionic emulsifier or micelle (if present) has an average spherulite size lower than about 100nm, lower than about 90nm, lower than about 80nm, lower than about 70nm, lower than about 60nm, lower than about 50nm or lower than about 40nm. In a specific embodiment of the composition, the structure formed by the hydrophilic nonionic emulsifier or micelle (if present) has an average spherulite size lower than about 50nm. In one embodiment, the composition does not include a structure (except gelling agent) with an average spherulite size higher than 50nm. The average spherulite size of the semi-solid composition structure can be measured with a compound microscope with or without particle counting software.

[0057] In one embodiment, the composition has no color. In one embodiment, the composition is colorless. In one embodiment, the composition disclosed herein is 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 380nm to about 780nm. In one embodiment, the composition is light-transmitting. In one embodiment, the composition is transparent. In one embodiment, the composition does not contain a dispersed phase that scatters light in the visible spectrum of the human eye, and the composition is transparent to milky white. In one embodiment, the composition of the present disclosure is a hydroalcoholic single-phase gel that only contains structures that do not scatter light in the visible spectrum of the human eye. In specific embodiments of the above embodiments, if micelles are present, their average spherical particle size is less than about 100nm, less than about 90nm, less than about 80nm, less than about 70nm, less than about 60nm, less than about 50nm or less than about 40nm.

[0058] Advantageously, the optical attributes of the compositions described herein provide a modern and attractive appearance that appeals to many patients and consumers. This "clear as water" appearance can serve as a visible marker that the composition consists primarily of water, which can also be perceived positively. In addition, the use of dosage cards (e.g., Figure 1 When the composition of the present invention is administered on a dosage card, the user can sense the dosage indicator on the dosage card even when the composition has been discharged onto the dosage card. This improves administration safety and administration accuracy. This also improves the patient's administration skills.

[0059] Preferably, the compositions disclosed herein are substantially free of lipophilic excipients. In the present disclosure, "substantially free" is understood to mean that no additional ingredients with specific functions are added to the formulation. For example, "substantially free of penetration enhancers" means that no penetration enhancers are added to the composition. However, this does not exclude the ingredients explicitly listed as mandatory or optional or preferred components in the present disclosure. It is understood by those skilled in the art that in pharmaceutical compositions, many ingredients play more than one function. Therefore, in addition to the functions described herein, the ingredients listed herein as mandatory or optional or preferred components may also play certain other functions. For example, a given alcohol described as a component of the composition may act as a solubilizer, but may also affect penetration, for example, it may have a penetration enhancing effect at certain concentrations. In this example, "substantially free of penetration enhancers" does not exclude the presence of such solvents in the compositions of the present disclosure. In addition, the composition may contain trace amounts or traces of certain compounds, for example, due to impurities or due to component degradation. This is also not included, and such compositions will still be considered to be "substantially free of" the compounds. "Substantially free of lipophilic excipients" does not exclude the presence of hydrophilic nonionic emulsifiers in the composition. The hydrophilic nonionic emulsifier used in the composition of the present invention is not considered a lipophilic excipient, although part of its molecular structure, i.e. the tail group, is lipophilic. The hydrophilic nonionic emulsifier is an amphiphilic molecule comprising a lipophilic and a hydrophilic part, wherein overall, the hydrophilicity predominates and makes the emulsifier hydrophilic and water-soluble.

[0060] The lipophilicity of a compound can be evaluated, for example, by a shake bottle method, and can be expressed by a logP value. The logP value (partition coefficient or distribution coefficient) indicates how a given molecule is distributed 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 salt) having a logP octanol / water value greater than about 3, greater than about 4, greater than about 5, or greater than about 6. Preferably, the composition does not contain a lipophilic or fatty phase. This preferably provides consumers with a "fat-free", "no-messy", "non-greasy" alternative based on water and alcohol. The composition does not leave lipophilic marks on the application site, hands, or clothing. In addition, the composition is transparent.

[0061] Although the compositions do not contain a lipophilic phase, they contain a hydrophilic nonionic emulsifier. As described above, in conventional multiphase systems, emulsifiers are used to achieve the dispersion of an immiscible phase in another immiscible phase. In compositions without a lipophilic phase, emulsifiers are generally not added because there is no need for a dispersed phase that is stable in an aqueous phase, and there is no risk of phase separation. Therefore, the hydroalcoholic compositions of the art generally do not contain any emulsifier. In contrast to the art, the compositions of the present disclosure contain a hydrophilic nonionic emulsifier, although they are hydroalcoholic compositions without a lipophilic phase. It is reported that emulsifiers have a penetration enhancing effect in a multiphase system (e.g., see Iti Som, Kashish Bhatia and Mohd. Yasir, "Status of surfactants as penetration enhancers in transdermal drug delivery", J Pharm Bioallied 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 emulsifier has a permeation-reducing effect.

[0062] The present inventors have surprisingly found that in the hydroalcoholic compositions of the present disclosure, hydrophilic nonionic emulsifiers can reduce the cumulative permeation of diclofenac. In one aspect, such hydrophilic nonionic emulsifiers can therefore have a permeation slowing effect on diclofenac or a salt thereof in the hydroalcoholic compositions of the present disclosure. This is particularly surprising in view of the teachings in the art regarding the permeation enhancing effect of nonionic emulsifiers (Iti Som et al., supra).

[0063] As can be seen from the Examples section, the inventors have found that diclofenac or its salts show a higher penetration rate in a hydroalcoholic composition compared to an emulsion composition containing the same concentration of API and other excipients (e.g., see Example 1). As discussed above, the inventors seek to provide a composition that is as safe as the existing products Voltaren 1% emulsion or Voltaren 1.16% emulsion, and can rely on its rich drug safety experience. Therefore, in one aspect, the inventors seek to provide a composition having a penetration curve similar to Voltaren 1% emulsion or Voltaren 1.16% emulsion. Surprisingly, it was found that the cumulative penetration of diclofenac from the hydroalcoholic gel can be adjusted by adding a hydrophilic nonionic emulsifier. In addition, the nonionic emulsifier does not contain an ionizable group and is relatively insensitive to pH changes. Therefore, the nonionic emulsifier can stabilize the composition.

[0064] In one embodiment, the composition comprises at least one hydrophilic nonionic emulsifier. In one embodiment, the composition comprises a single class of hydrophilic nonionic emulsifiers. In one embodiment, the composition comprises a single hydrophilic nonionic emulsifier. In one embodiment, the composition comprises only one hydrophilic nonionic emulsifier.

[0065] In one embodiment, the composition comprises a hydrophilic nonionic emulsifier having an HLB of about 13 to about 17, about 14 to about 16, or about 15. In a specific embodiment, the composition comprises a hydrophilic nonionic emulsifier having an HLB of about 15. In one embodiment, the composition comprises one hydrophilic nonionic emulsifier, wherein the one hydrophilic nonionic emulsifier has an HLB of about 13 to about 17, about 14 to about 16, or about 15.

[0066] In one embodiment, the composition comprises a hydrophilic nonionic emulsifier which is an ethoxylated C16 to C18 alcohol. In another embodiment, the hydrophilic nonionic emulsifier is selected from cetostearyl 20, polysorbate 60, polysorbate 80, isosteareth 20, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20, and a combination of two or more thereof.

[0067] In one specific embodiment, the composition comprises cetostearyl ether. In another specific embodiment, the composition comprises cetostearyl 20. Cetostearyl 20 is the pharmacopoeia name used by 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 for cetostearyl 20 is Kolliphor CS 20.

[0068] In one embodiment, the composition comprises a total concentration of about 0.5% w / w to about 4% w / w, about 0.8% w / w to about 3% w / w, or about 1% w / w to about 2% w / w of a hydrophilic nonionic emulsifier. In one embodiment, the composition comprises a total concentration of about 1% w / w of a nonionic emulsifier. In another embodiment, the composition comprises a total concentration of about 2% w / w of a nonionic emulsifier.

[0069] Solvent system

[0070] The compositions disclosed herein comprise a solvent system comprising 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, more than about 70% w / w, or more than about 80% w / w of water. In a specific embodiment, the composition comprises about 65% w / w to about 75% w / w of water. In another embodiment, the composition comprises about 70% w / w to about 80% w / w of 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 a readily available ingredient with a low environmental impact. In addition, water is a transparent ingredient, which is advantageous in view of the importance of the optical appearance of the above-mentioned final composition. The water may be purified water, distilled water, or the like. The water may be pharmaceutical grade water. In one embodiment, the composition comprises water as a composition matrix. As part of the solvent system, water also serves to dissolve diclofenac or diclofenac salts.

[0071] In addition to water, the solvent system also includes an aliphatic C2-C4 monoalcohol. The composition may include a single aliphatic C2-C4 monoalcohol or multiple aliphatic C2-C4 monoalcohols. In one embodiment, the aliphatic C2-C4 monoalcohol is selected from ethanol, propanol, isopropanol, butan-1-ol and a combination of two or more thereof. In some embodiments, the composition includes isopropanol. In other embodiments, the composition includes ethanol. In one embodiment, the composition includes ethanol, isopropanol or both. In one embodiment, the composition includes water, ethanol and isopropanol. In one embodiment, isopropanol is used as the only aliphatic C2-C4 monoalcohol. In any of the above embodiments, water and alcohol are present in the continuous phase of the composition. In some embodiments, the composition includes a continuous phase, and the continuous phase includes water, isopropanol and optional ethanol. In a specific embodiment, the composition includes a continuous phase, and the continuous phase includes water and isopropanol.

[0072] Compared to water alone, C2-C4 monoalcohols allow better dissolution of diclofenac and diclofenac salts. This facilitates the dissolution of diclofenac and reduces the risk of recrystallization. In addition, aliphatic C2-C4 monoalcohols produce topical gels with shorter drying times compared to pure water-based gels. After application of the composition to the skin, the aliphatic C2-C4 monoalcohol evaporates. Evaporation after application to the skin reduces the drying time. Drying time can be described as the time from application of the topical product to the skin until the skin at the application site feels dry again. In addition, aliphatic C2-C4 monoalcohols can impart a significant cooling effect to the topical composition. After application of the topical composition to the skin, the evaporation of the composition ingredients is driven by the thermal energy of the application site. Therefore, the evaporation process absorbs thermal energy from the application site. As a result, a cooling sensation is generated on the skin. This cooling effect is beneficial to patients and consumers: "Calor", i.e., heating of the affected body part, is one of the main symptoms of inflammatory processes. Therefore, cooling of the application site can alleviate the inflammatory process and can reduce inflammatory pain. In addition, the cooling effect can give a person a feeling that the topical product is immediately effective. In addition, aliphatic C2-C4 monohydric alcohols are transparent. Therefore, they are suitable for formulating topical compositions with desired optical clarity.

[0073] In some embodiments, the composition comprises isopropanol as the only aliphatic C2-C4 monoalcohol. In some embodiments, the composition comprises a continuous phase comprising water and isopropanol and is free of ethanol. Advantageously, by using isopropanol as the only aliphatic C2-C4 monoalcohol, the number of different ingredients can be kept low, which is conducive to the production and supply logistics of the topical composition. In these embodiments, no additional aliphatic C2-C4 monoalcohol is required to dissolve diclofenac or diclofenac salt and provide a cooling sensation on the skin. In particular, there is no need to add another aliphatic C2-C4 monoalcohol 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 comprise ethanol.

[0074] Aliphatic C2-C4 monohydric alcohols can be used to reduce 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 needs to maintain sufficient API concentration during the dissolution process. Therefore, the risk of API crystallization or precipitation after application on the skin is reduced. Therefore, 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 patients. Therefore, the solvent system used in the composition of the present invention also includes an aliphatic diol as a co-solvent.

[0075] In some embodiments, the aliphatic diol can be a C2-C4 polyol. In some embodiments, the composition disclosed herein comprises a diol. In one embodiment, the composition comprises an aliphatic diol selected from ethylene glycol, propylene glycol and 1,3-butylene glycol, and any combination thereof. In some embodiments, propylene glycol exists as the only aliphatic diol.

[0076] The aliphatic diol or C2-C4 polyol can act as a co-solvent for the API. Compared to the aliphatic C2-C4 monohydric alcohol described above, the aliphatic diol or C2-C4 polyol is less likely to evaporate after application to the skin. Therefore, the aliphatic diol or C2-C4 polyol 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 polyol can keep the API in a dissolved state after application to the skin.

[0077] In addition, aliphatic diols or C2-C4 polyols are hygroscopic. They can impart moisturizing, water-retaining properties to topical compositions. This can provide a pleasant skin feel, such as a soft, supple or nourished skin feel. This also helps to balance the lipid extraction 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-restoring properties.

[0078] Aliphatic diols or C2-C4 polyols 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 inventors attempted to formulate a composition having permeation characteristics similar to the existing Voltaren 1% or 1.16% emulsion products, which will be explained in more detail in a separate section below.

[0079] In some embodiments, the aliphatic C2-C4 monoalcohol is present in the composition at a concentration of about 5% w / w to about 20% w / w. Preferably, the aliphatic C2-C4 monoalcohol is present at a concentration of about 8% w / w to about 18% w / w. In one embodiment, the aliphatic C2-C4 monoalcohol is present at a concentration of about 10% w / w to about 15% w / w. In a specific embodiment, the aliphatic C2-C4 monoalcohol is present at a concentration of about 10% w / w, about 11% w / w, about 12.5% ​​w / w, about 15% w / w, or about 20% w / w. In a specific embodiment of any of the above embodiments, the aliphatic C2-C4 monoalcohol is isopropanol or ethanol or a combination of the two.

[0080] In a specific embodiment, the composition comprises isopropyl alcohol at a concentration of about 5% w / w to about 20% w / w, about 8% w / w to about 18% w / w, or about 10% w / w to about 15% w / w. In a specific embodiment, the composition comprises isopropyl alcohol at a concentration of about 10% w / w, about 11% w / w, about 12.5% ​​w / w, about 15% w / w, or about 20% w / w. In one embodiment, the composition of the present disclosure comprises isopropyl alcohol at a concentration of about 5% w / w to about 20% w / w, about 8% w / w to about 18% w / w, or about 10% w / w to about 15% w / w, and does not comprise any other aliphatic C2-C4 monohydric alcohol.

[0081] Aliphatic C2-C4 monoalcohols within these concentration ranges strike a balance. On the one hand, high concentrations of aliphatic C2-C4 monoalcohols can facilitate API dissolution, antimicrobial and / or cooling effects. On the other hand, high concentrations of aliphatic C2-C4 monoalcohols 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 monoalcohols, the composition may require particularly tight packaging to avoid evaporation of the aliphatic C2-C4 monoalcohol during storage. Compositions containing aliphatic C2-C4 monoalcohols within the above concentration range do not need to be labeled, stored and handled under strict scrutiny because they are not classified as hazardous goods and do not require particularly tight packaging. This is ideal because such classifications can complicate manufacturing and supply and may prevent consumers from using the final product. In addition, if the concentration of the aliphatic C2-C4 monoalcohol is too high, the API may precipitate at the application site as described above. The concentration range of the C2-C4 monoalcohol combined with the water and aliphatic diol of the solvent system can fully dissolve the API. Therefore, the composition can reduce the risk of API crystallization during storage and after application. The composition can reduce the risk of leaving API residues or precipitates on the skin. In addition, the concentration can produce a sufficient cooling sensation when applied. The initial cooling sensation can distract the patient's attention from the painful inflamed area and quickly produce a feeling of pain relief. This physiologically helps the patient to relieve pain quickly. In particular, the cooling sensation can feel obvious or strong, can appear quickly and can be perceived for a long time. The aliphatic C2-C4 monoalcohol also has antimicrobial properties. If the composition contains a sufficiently high concentration, the risk of microbial contamination and bacterial growth of the composition will be reduced. This is particularly important for compositions containing high concentrations of water (e.g., water content exceeding about 60% w / w, exceeding about 70% w / w, or exceeding about 80% w / w).

[0082] On the other hand, aliphatic C2-C4 monoalcohols may have an odor that puts some consumers off. Perfumes or other odor masking agents may be needed to cover up the alcohol odor. However, in some instances, adding fragrances may be challenging or unwelcome. Surprisingly, compositions comprising aliphatic C2-C4 monoalcohols within the concentration range can have a pleasant odor. Therefore, they are particularly suitable for being formulated into fragrance-free compositions. In a particular embodiment, the composition is fragrance-free.

[0083] On the other hand, the above concentration ranges also provide skin-friendly compositions. Aliphatic C2-C4 monoalcohols have some lipid extraction (lipolysis) properties. These lipid extraction properties affect the natural fat and ceramide components of the skin and the barrier function. They can have dehydrating, defatting and irritating effects on the skin. In some cases, this can lead to dry skin, skin desquamation and / or skin tightness. On the other hand, aliphatic C2-C4 monoalcohols can have a penetration enhancing effect on API. In conventional topical compositions comprising a lipophilic phase, the lipophilic component can balance the dehydrating, defatting and irritating effects of the alcohol component. As described above, the compositions of the present disclosure do not include a lipophilic dispersed phase. However, the compositions of the present disclosure are very skin-friendly due to the balanced mixing of their ingredients because they contain aliphatic C2-C4 monoalcohols at appropriate concentrations and also contain a co-solvent that is an aliphatic diol.

[0084] Cosolvent (aliphatic diol or C2-C4 polyol) can be present in the composition at a concentration of about 2%w / w to about 10%w / w. Preferably, aliphatic diol or C2-C4 polyol can be present in the composition at a concentration of about 3%w / w to about 8%w / w, or a concentration of about 3%w / w to about 5%w / w. In one embodiment, the concentration of aliphatic diol or C2-C4 polyol is about 5%w / w. In one embodiment, the concentration of aliphatic diol or C2-C4 polyol is about 3%w / w. In a specific embodiment, the composition comprises propylene glycol from about 3%w / w to about 5%w / w.

[0085] The benefits of including a certain concentration of aliphatic diols or C2-C4 polyols have been described above. The present inventors 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 the concentration range produce compositions with reduced risk of skin irritation. In another aspect, the range produces compositions with acceptable drying times. In another aspect, the resulting compositions have very pleasant skin application properties. For example, they do not feel sticky or greasy. In addition, the resulting compositions are clear, transparent or see-through. In some embodiments, the composition can be milky white. In addition, the aliphatic diol concentration can also affect the penetration characteristics of the composition.

[0086] In one embodiment, the composition comprises an aliphatic C2-C4 monohydric alcohol which is isopropanol and an aliphatic diol which is propylene glycol.

[0087] The total combined concentration of the aliphatic C2-C4 monool and the aliphatic diol is preferably greater than about 10% w / w. The total combined concentration of the aliphatic C2-C4 monool and the C2-C4 polyol is preferably less than about 30% w / w. Expressed as a range, the total combined concentration of the aliphatic C2-C4 monool and the aliphatic diol can be from about 10% w / w to about 30% w / w, preferably from about 12% w / w to about 25% w / w. In a particular embodiment, the total combined concentration of the aliphatic C2-C4 monool and the C2-C4 polyol 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.

[0088] In certain embodiments, the aliphatic C2-C4 monohydric alcohol is isopropanol and the aliphatic diol is propylene glycol. In some of these embodiments, the total combined concentration of isopropanol and propylene glycol is greater than about 10% w / w. The total combined concentration of isopropanol and propylene glycol is preferably less than about 30% w / w. Expressed as a range, the total combined concentration of isopropanol 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 isopropanol 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.

[0089] In some embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:2 to 1:4.5. In some embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:2 to 1:4.2, 1:4, 1:3.7, 1:3 or 1:2.5. In specific embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:2, 1:2.5, 1:3, 1:3.7, 1:4 or 1:4.2. In specific embodiments of the above embodiments, the aliphatic C2-C4 monoalcohol is isopropanol and the aliphatic diol is propylene glycol.

[0090] In other specific embodiments, the composition comprises about 10% w / w, about 11% w / w, or about 12.5% ​​w / w isopropanol and about 3% w / w or about 5% w / w propylene glycol. In a specific embodiment, the composition comprises about 12.5% ​​w / w isopropanol and about 5% w / w propylene glycol.

[0091] The composition disclosed herein comprises an API, which is diclofenac or a pharmaceutically acceptable salt of diclofenac. This includes a deuterated form of diclofenac or a salt thereof, wherein one or more hydrogen atoms in the diclofenac molecule are replaced by a deuterium atom (i.e., deuterated diclofenac). In one embodiment, the composition comprises diclofenac, diclofenac ammonium, diclofenac sodium, diclofenac potassium, or a combination thereof. In one embodiment, the composition comprises a pharmaceutically acceptable inorganic diclofenac salt. In a specific embodiment, the composition comprises diclofenac ammonium, diclofenac sodium, or diclofenac potassium. In another specific embodiment, the composition comprises diclofenac sodium or diclofenac potassium. In another embodiment, the composition comprises diclofenac sodium. In some embodiments, the composition comprises diclofenac or a pharmaceutically acceptable salt of diclofenac as the sole active pharmaceutical ingredient.

[0092] The inventors compared the stability of conventional latex and hydroalcoholic gel formulations, both of which contained diclofenac diethylammonium. They found that the latex 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 the formation of nitrosamines. Therefore, in the hydroalcoholic single-phase composition of the present disclosure, inorganic diclofenac salts, such as diclofenac ammonium or diclofenac sodium, diclofenac potassium may be preferred. However, the dissolution of these salts in hydroalcoholic gels may be more challenging than organic diclofenac salts. In addition, counterions, especially Na + and K + , can interact with certain gelling agents and negatively affect their gel forming and viscosity increasing effects. This is the case, for example, with the so-called carbomer gelling agents, which are often 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 a particularly appealing tactile and skin feel. Surprisingly, the inventors were able to formulate an embodiment of the presently disclosed composition, comprising an inorganic diclofenac salt and a carbomer gelling agent, in a hydroalcoholic single phase formulation base, and still have a suitable viscosity.

[0093] Preferably, the composition is substantially free of additional API. This means that, apart from diclofenac (or diclofenac salt), no API is 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 an anti-irritant.

[0094] The composition of the present disclosure may include diclofenac or a diclofenac salt in a concentration of about 0.5% w / w to about 1.5% w / w diclofenac sodium equivalent. Typically, in the present disclosure, unless otherwise specified, the concentration of diclofenac salt is given as diclofenac sodium equivalent. In some embodiments, the composition comprises diclofenac or a pharmaceutically acceptable salt of diclofenac in a total concentration of about 0.8% w / w to about 1.2% w / w diclofenac sodium equivalent. In one embodiment, the composition comprises diclofenac sodium in a concentration of about 0.5% w / w to about 1.5% w / w. Preferably, the composition comprises diclofenac sodium in a concentration of about 1% w / w to about 1.2% w / w. Particularly preferred is diclofenac sodium in a concentration of about 1% w / w. In an alternative embodiment, the composition comprises about 1.16% w / w 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 diclofenac sodium.

[0095] In these concentration ranges, excellent API dissolution is achieved. After formulation, no API crystals are visible in the composition. In one embodiment, no crystals of diclofenac or its salt are detected in the composition by naked eye inspection or by optical microscopy at a magnification of x10, x40, x100, x400, x800 or x1200.

[0096] The composition disclosed herein comprises a gelling agent. The composition comprises a gelled hydroalcoholic continuous phase. In other words, the composition is a gel comprising an aqueous continuous phase and a three-dimensional network structure formed by a gelling agent.

[0097] In some embodiments, the compositions of the present disclosure may include a carbomer gelling agent. Carbomer gelling agents can produce clear and transparent gels. They can also produce gels with excellent diffusion properties, which many consumers prefer over other gels (e.g., hydroxypropyl methylcellulose gels). For example, carbomer 974P or carbomer 980 can be used.

[0098] The amount of carbomer gelling agent present is sufficient to increase the viscosity of the composition. The concentration of carbomer gelling agent can be 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. In a specific embodiment, the concentration of carbomer gelling agent is about 1.6% w / w. Preferably, the viscosity is high enough to allow the composition to be dosed from a tube. Preferably, the viscosity of the final composition is about 2000 cP to about 16000 cP. In a specific embodiment, the viscosity of the composition is about 6000 cP to about 12000 cP.

[0099] In an embodiment comprising an acidic gelling agent (e.g., carbomer), the composition further comprises an alkaline agent. The alkaline agent initiates the gelling of the acidic gelling agent (e.g., carbomer gelling agent, which is polyacrylic acid). The alkaline agent may be present in a concentration suitable for adjusting the pH to about 6 to about 8.5, about 7.3 to about 8.2, or about 7 to about 8. The alkaline agent may be an aliphatic amine, such as a primary, secondary, or tertiary alkanolamine and a primary, secondary, or tertiary alkylamine. For example, monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, dimethylamine, diethylamine, trimethylamine, or triethylamine may be used. In an alternative embodiment, the alkaline agent is an inorganic alkaline agent. In one embodiment, the alkaline agent is NaOH, KOH, or an ammonia solution. The ammonia solution may be, for example, a 10% or 30% ammonia solution.

[0100] The composition may optionally contain other ingredients, such as flavors, chelating agents, preservatives, stabilizers, antioxidants, colorants, and the like.

[0101] In some embodiments, the compositions disclosed herein are substantially free of penetration enhancers. Typically, penetration enhancers are included in the composition to increase the cumulative penetration and / or flux of the API. However, they may irritate the skin. In addition, some penetration enhancers need to be particularly highlighted on the package label. Specifically, the composition may be free of isostearic acid and other fatty acids or acids. Penetration enhancers can produce turbid, blurred or milky compositions, and are therefore not preferred. Specifically, the composition preferably does not contain fatty alcohols, fatty acids, isopropyl myristate, isopropyl palmitate, and diethyl sebacate.

[0102] Preferably, the compositions disclosed herein are substantially free of additional humectants, such as glycerin. Although humectants are often added to topical compositions for their cooling, conditioning and moisturizing properties, they can cause the product to take longer to dry on the skin. Therefore, they are not preferred.

[0103] Preferably, the composition disclosed herein is substantially free of sensate. For example, the composition may be free of peppermint oil, l-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 stimulants. Sensates, anti-irritants and stimulants are usually added to provide a "quick-acting" cooling sensation, which is the preferred sensory attribute described above. However, they can also cause the preparation to be turbid or physically unstable. They can also cause irritation. In addition, they can affect the amount of penetration of the composition.

[0104] stability

[0105] As described above, it is important that the API is completely dissolved. This can be demonstrated 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 within a shelf life of 12, 24 or 36 months. In some embodiments, the composition is homogeneous when visually inspected with an optical microscope at a magnification of x10, x40, x100, x400, x800 or x1200. In some embodiments, the composition is homogeneous as visually inspected using an optical microscope at a magnification of x10, x40, x100, x400, x800, or x1200 after storage under accelerated stability testing conditions of 40°C±2°C / 75%±5% relative humidity for 6, 12, 24, or 36 months, or under long-term stability testing conditions of 30°C±2°C / 65%±5% relative humidity for 3, 6, 12, 24, or 36 months.

[0106] Penetration

[0107] The inventors aim to find a composition having a therapeutic to reference ratio (T / R) of cumulative permeation over 24 hours in an in vitro skin permeation test relative to a reference product, Voltaren Emulsion (diclofenac diethylammonium topical gel, 1.16% (NSAID)) between 0.8 and 1.25 with a confidence interval of 90%. The method for measuring cumulative skin permeation is described in detail in the Examples section. In one embodiment, the composition herein has a cumulative permeation over 24 hours in an in vitro human skin permeation test that meets the acceptance criteria of the draft guideline for quality and equivalence of topical products CHMP / QWP / 708282 / 2018. In one embodiment, the composition has a cumulative permeation over 24 hours in an in vitro human skin permeation test that meets the acceptance criteria of lines 708 to 710 of the draft guideline for quality and equivalence of topical products CHMP / QWP / 708282 / 2018. In one embodiment, the composition has a cumulative permeation over 24 hours in an in vitro human skin permeation test, wherein the 90% confidence interval of the mean ratio of the composition to the comparator product Voltaren Emulgel (diclofenac diethylammonium topical gel, 1.16%) is within the acceptance interval of 80.00-125.00%.

[0108] In a specific embodiment, the composition has a cumulative permeation over 24 hours in an in vitro human skin permeation test that meets the acceptance criteria of the draft guidance on quality and equivalence of topical products CHMP / QWP / 708282 / 2018, lines 711 to 715. In another embodiment, the composition has a cumulative permeation over 24 hours in an in vitro human skin permeation test, wherein the 90% confidence interval of the mean ratio of the composition to the comparator product Voltaren Emulsion (diclofenac diethylammonium topical gel, 1.16%) is within the acceptance interval of 69.84%–143.19%. In cases where there is high intra-subject or intra-donor variability, a wider acceptance criterion of a 90% confidence interval may be accepted.

[0109] In some embodiments, the composition has a cumulative permeation in an in vitro skin permeation test that enables registration according to Annex I of Directive 2001 / 83 / EC under well-established criteria for use based on literature data for Voltaren Arthritis Pain Cream (Diclofenac Sodium Topical Gel, 1% (NSAID)-Arthritis Pain Relief) or Voltaren Diclofenac Diethylamine 1.16% Gel.

[0110] As described above, due to the specific selection of the solvent system and the addition of the hydrophilic nonionic emulsifier, the permeation amount of the hydroalcoholic single phase composition can be customized, and the cumulative permeation amount can be reduced compared with other hydroalcoholic single phase gel compositions. This effect can be summarized as a permeation slowing effect. This effect can also be clearly seen from the examples.

[0111] Preferably, the compositions disclosed herein are substantially free of anionic emulsifiers. In some embodiments, the compositions are substantially free of anionic emulsifiers and substantially free of cationic emulsifiers. Specific implementation plan

[0112] In one embodiment, there is provided a hydroalcoholic single phase gel composition comprising:

[0113] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0114] - aliphatic C2-C4 monohydric alcohols,

[0115] - aliphatic diols,

[0116] - a hydrophilic nonionic emulsifier, and

[0117] -water.

[0118] In one embodiment, there is provided a hydroalcoholic single phase gel composition comprising:

[0119] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0120] - aliphatic C2-C4 monohydric alcohols,

[0121] - aliphatic diols,

[0122] - a hydrophilic nonionic emulsifier having an HLB of about 14 to about 16, and

[0123] -water.

[0124] In one embodiment, there is provided a hydroalcoholic single phase gel composition comprising:

[0125] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0126] - aliphatic C2-C4 monohydric alcohols,

[0127] - aliphatic diols,

[0128] - Ceteareth-20, and

[0129] -water.

[0130] In another embodiment, there is provided a hydroalcoholic single phase gel composition for topical delivery of diclofenac comprising:

[0131] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0132] - aliphatic C2-C4 monohydric alcohols,

[0133] - aliphatic diols,

[0134] - a hydrophilic nonionic emulsifier, and

[0135] -water,

[0136] wherein the composition does not comprise a lipophilic phase.

[0137] In another embodiment, there is provided a hydroalcoholic single phase composition for topical delivery of diclofenac comprising:

[0138] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0139] - gelling agent,

[0140] - aliphatic C2-C4 monohydric alcohols,

[0141] - aliphatic diols,

[0142] - a hydrophilic nonionic emulsifier in a concentration of about 0.5% w / w to about 4% w / w, and

[0143] -water.

[0144] In another embodiment, there is provided a hydroalcoholic single phase composition for topical delivery of diclofenac comprising:

[0145] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0146] - gelling agent,

[0147] - aliphatic C2-C4 monohydric alcohols,

[0148] -ethylene glycol,

[0149] - a hydrophilic nonionic emulsifier in a concentration of about 1% w / w to about 2% w / w, and

[0150] -water.

[0151] In another embodiment, there is provided a hydroalcoholic single phase gel composition for topical delivery of diclofenac comprising:

[0152] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0153] - Gelling agents,

[0154] - isopropyl alcohol, ethanol or a combination thereof,

[0155] - Propylene glycol,

[0156] - hydrophilic nonionic emulsifiers, and

[0157] - water.

[0158] In another embodiment, there is provided a hydroalcoholic single phase gel composition for topical delivery of diclofenac comprising:

[0159] - diclofenac or a pharmaceutically acceptable salt of diclofenac in a concentration of about 0.5% w / w to about 1.5% w / w diclofenac sodium equivalent,

[0160] - Carbomer gelling agent,

[0161] - an aliphatic C2-C4 monohydric alcohol in a concentration of about 5% w / w to about 20% w / w,

[0162] - a C2-C4 polyol in a concentration of about 2.5% w / w to about 7.5% w / w,

[0163] - a hydrophilic nonionic emulsifier in a concentration of about 0.5% w / w to about 4% w / w,

[0164] - Water, and

[0165] - an alkaline agent at a concentration suitable to adjust the pH of the overall composition to a pH of from about 6.5 to about 8.5.

[0166] In another embodiment, there is provided a hydroalcoholic single phase gel composition for topical delivery of diclofenac comprising:

[0167] - diclofenac sodium or diclofenac potassium at a concentration of about 1% w / w diclofenac sodium equivalent,

[0168] - isopropyl alcohol in a concentration of about 5% w / w to about 20% w / w,

[0169] - propylene glycol in a concentration of about 2.5% w / w to about 7.5% w / w,

[0170] - Hydrophilic nonionic emulsifier, which is an ethoxylated C 16 To C 18 alcohol, at a concentration of about 1% w / w to about 2% w / w,

[0171] - a carbomer gelling agent in a concentration of about 1% w / w to about 2% w / w,

[0172] - an alkaline agent at a concentration suitable for adjusting the pH of the overall composition to a pH of from about 6.5 to about 8.5, and

[0173] - Water in a concentration of about 60% w / w to about 80% w / w.

[0174] In another embodiment, a hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, consisting essentially of the following ingredients:

[0175] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0176] - Gelling agents,

[0177] - Aliphatic C2-C4 monohydric alcohols,

[0178] - aliphatic diols,

[0179] - Hydrophilic nonionic emulsifier,

[0180] - Water, and

[0181] - Alkaline agents,

[0182] - and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants and / or coloring agents, wherein the pH of the total composition is from about 6.5 to about 8.5.

[0183] In another embodiment, a composition is provided, which consists essentially of the following ingredients:

[0184] - diclofenac or a pharmaceutically acceptable salt of diclofenac,

[0185] - Gelling agents,

[0186] - Aliphatic C2-C4 monohydric alcohols,

[0187] - aliphatic diols,

[0188] - a nonionic emulsifier having an HLB of about 14 to about 16,

[0189] - Water, and

[0190] - Alkaline agents,

[0191] - and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants and / or coloring agents, wherein the pH of the total composition is from about 6.5 to about 8.5.

[0192] In another embodiment, a composition is provided, which consists essentially of the following ingredients:

[0193] - Diclofenac sodium,

[0194] - Carbomer gelling agent,

[0195] - Isopropyl alcohol,

[0196] - Propylene glycol,

[0197] - Macrogol cetearyl ether,

[0198] - Water, and

[0199] - Alkaline agents,

[0200] and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants and / or coloring agents.

[0201] Preferably, the above-mentioned composition is substantially free of anionic emulsifiers. In some embodiments, the above-mentioned composition is substantially free of anionic emulsifiers and substantially free of cationic emulsifiers.

[0202] Manufacturing method

[0203] The composition can be prepared as follows:

[0204] - In a first container, disperse the gelling agent in the first portion of water until completely dispersed;

[0205] - if it is necessary to initiate neutralization of the gelling agent, adding an alkaline agent to the gelling agent dispersion in order to obtain a gel;

[0206] - In a second container, combine a second portion of the water, aliphatic monohydric alcohol, aliphatic diol, and nonionic emulsifier;

[0207] - dissolving diclofenac or a pharmaceutically acceptable salt of diclofenac in the mixture in the second container to obtain an API solution;

[0208] - Combine the gelling agent dispersion and API solution under homogenization / mixing.

[0209] use

[0210] The compositions disclosed herein are useful for relieving pain, inflammation and swelling from soft tissue injuries, localized forms of soft tissue rheumatism, and for relieving pain from non-severe arthritis of the knees or fingers.

[0211] Drug composition / administration route / dosage

[0212] The composition can be applied to mammals suffering from pain, inflammation and swelling in soft tissue injuries, localized forms of soft tissue rheumatism, and pain in non-severe arthritis of the knee or fingers. Preferably, the composition is used to treat humans. The composition is used to relieve pain, inflammation and swelling in soft tissue injuries, localized forms of soft tissue rheumatism, and pain in non-severe arthritis of the knee or fingers.

[0213] They can be applied to the affected area. They can be rubbed until the skin feels dry. They can be applied 3-4 times a day. Typical dosages of the composition include about 20 mg to about 40 mg diclofenac sodium (equivalent) per application. The method of treatment may include administering a pharmaceutically effective amount of the composition disclosed herein to a subject in need thereof. The method may include applying the composition to the skin covering a body part that suffers from or causes one or more of soft tissue injuries, local soft tissue rheumatism, pain, inflammation and swelling, and for relieving pain in non-severe arthritis of the knee or fingers.

[0214] The composition may be contained in a package comprising an administration device.The composition may be contained in a container comprising an applicator for direct application to the skin.

[0215] With reference to the following detailed description, examples and accompanying drawings, the embodiments described herein can be more easily understood. However, the elements, devices and methods described herein are not limited to the specific embodiments presented in the detailed description, examples and accompanying drawings. It should be appreciated that the exemplary embodiments herein are only used to illustrate the principles of the present invention. Those skilled in the art will easily appreciate many modifications and adjustments without departing from the spirit and scope of the present invention.

[0216] In addition, all ranges disclosed herein are to be understood to encompass any and all subranges contained therein. For example, the range "1.0 to 10.0" is to be considered to include any and all subranges 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.

[0217] 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 endpoints 5 and 10.

[0218] 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 related embodiments clearly prohibit. Similarly, the compositions and methods described herein can include any combination of features and / or steps described herein that are not inconsistent with the purpose of the present disclosure. Those skilled in the art will readily appreciate the various modifications and / or adjustments of the compositions and methods described herein without departing from the subject matter of the present invention. Unless otherwise indicated, concentrations are expressed in % (w / w).

[0219] Unless otherwise stated, concentrations are expressed in % (w / w).

[0220] The term “about” in connection with a numerical value x means, for example, x±10%, x±5%, x±4%, x±3%, x±2%, x±1%.

[0221] pH, viscosity and HLB are typically measured at 25°C.

[0222] Example

[0223] The present invention is described in more detail below by way of examples, but the present invention is not limited to these examples.

[0224] Example 1: Comparison of 24-hour cumulative skin permeation in latex and hydroalcoholic gel

[0225] In this example, the commercial product Voltaren Emulsion 1.16% (m / m) diclofenac diethylammonium was reformulated without the addition of a lipophilic phase (Tests 1-5) and the cumulative permeation of the compositions was compared.

[0226] In vitro skin permeation studies were performed in the preclinical laboratory. Skin permeation studies can be used to determine the qualitative permeation characteristics of a formulation through, for example, human skin. They can also be used to directly quantitatively compare the permeation and flux of two given formulations. The cumulative permeation of diclofenac in the hydroalcoholic test formulations was compared to the cumulative permeation of the reference product (latex). At time point 0 hours, the five test formulations and the reference product were each exposed to 10 mg / cm 2 The dose was applied to abdominal skin of human donors. Each formulation was tested on five skin samples from different donors in a Franz diffusion cell. The reference product used for comparison was Voltaren Emulgel 1.16% (m / m) diclofenac diethylammonium. The composition of the test formulations and the reference product Voltaren Emulgel 1.16% (m / m) are listed in Table 1:

[0227] Table 1: Composition of the reference product and test formulation in Example 1

[0228]

[0229] The concentration of diclofenac in the Franz cell receptor fluid 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.

[0230] The research results are shown in Table 2.

[0231] Table 2: Results of in vitro skin permeation study of Example 1

[0232]

[0233] Surprisingly, the cumulative permeation of all test formulations (tests 1 to 5) was much higher than that of the reference product. Although the concentration of active ingredient in all test compositions was the same, the hydroalcoholic formulations (tests 1 to 5) showed a cumulative permeation of about 1.7 times (test 4) to nearly 3 times (test 5) the cumulative permeation of the reference product at 24 hours. This led the inventors to conclude that the absence of a dispersed lipophilic phase resulted in a higher cumulative permeation over 24 hours.

[0234] Example 2: Comparison of Cumulative Skin Permeation of Emulsions and Hydroalcoholic Gels Containing 1% w / w Diclofenac Sodium and Different Concentrations of Nonionic Emulsifiers over 24 Hours

[0235] Hydroalcoholic single-phase compositions containing 1% w / w diclofenac sodium and different levels of non-ionic emulsifiers were studied. At the same time, the concentrations of isopropyl alcohol and propylene glycol were varied to study the effect of these ingredients on the cumulative permeation amount. The reference product was Voltaren Arthritis Pain Relief Cream. Cumulative skin permeation studies were performed in 3 ml permeation cells. The cumulative permeation amount through skin samples from human donors was studied. Five different compositions were tested in 6 replicates. The cumulative permeation amount was measured 4 hours (hrs) and 24 hours after the application of the dose. If the cumulative permeation amount at 4 hours was below the measurement threshold, it was not reported. All formulations were applied at a dose of 10µl on skin samples with a specified surface area.

[0236] Table 3: Composition of reference product and test formulation and cumulative permeation results of Example 2

[0237]

[0238] The results are summarized in the table above and in Figure 2 Intuitive display.

[0239] The tests conducted on the 1% diclofenac sodium hydroalcoholic gel composition compared to the emulsion control (Example 1) showed the following trends: In the hydroalcoholic gel without lipophilic phase and emulsifier, the permeation rate was increased compared to the emulsion composition (compare the cumulative permeation of Test 2 and Test 3 with the control at 24 hours). In the absence of a dispersed lipophilic phase, diclofenac sodium permeates faster. The addition of a hydrophilic nonionic emulsifier to the hydroalcoholic single phase gel (such as in Test 1) unexpectedly had the effect of slowing the permeation (compare the cumulative permeation of Test 2 and Test 3 with Test 1 at 24 hours).

[0240] Example 3: Comparison of Cumulative Skin Permeation of 1% w / w Diclofenac Epolamide Emulsion and Hydroalcoholic Gel over 24 Hours

[0241] Cumulative skin permeation studies were performed in 3 ml permeation cells to test the hypothesis that nonionic emulsifiers have a permeation-retarding effect in hydroalcoholic compositions containing different diclofenac salts, such as diclofenac salts containing organic counterions. Cumulative permeation through skin samples from human donors was studied. Five different compositions were tested in six replicates. Cumulative permeation was measured 4 hours (hrs) and 24 hours after application of the dose. If the cumulative permeation at 4 hours was below the measurement threshold, it was not reported. All formulations were applied at a dose of 10 µl on skin samples with a defined surface area.

[0242] The formulation tested in this Example 3 is a hydroalcoholic composition containing 1% w / w diclofenac epolamide. At the same time, the concentrations of isopropyl alcohol and propylene glycol were changed to study the effects of these ingredients on the cumulative permeation amount. Table 4 shows the composition of the reference product (Voltaren Arthritis Pain Relief Cream) and the test formulations (Test 1, Test 2, Test 3) of Example 3, as well as the results of the cumulative permeation experiment.

[0243] Table 4: Composition of reference product and test formulation and cumulative permeation results of Example 2

[0244]

[0245] The results are summarized in Table 4 and are Figure 3 Intuitive display.

[0246] Test 1 and Test 2 are very similar compositions, except that Test 2 does not contain any nonionic emulsifier, while Test 1 contains 1.5% w / w Kolliphor CS 20. Comparing the cumulative permeation at 24 hours between Test 1 and Test 2, the nonionic emulsifier also has a slowing effect in the composition containing 1% w / w diclofenac epolamide. The cumulative permeation at 24 hours is comparable between Test 2, Test 3 and the control. Test 2 and Test 3 do not contain any lipophilic phase and emulsifier, but contain different concentrations of isopropyl alcohol and propylene glycol than the control: 18% w / w for Test 2 and 20% w / w for Test 3. The difference in the cumulative permeation at 24 hours between Test 2 and Test 3 is not significant. The cumulative permeation at 24 hours between Test 2 and Test 3 is not significantly higher than that of the control. Although the permeation is significantly higher due to the absence of a fat phase and an emulsifier, the trend of higher permeation in the hydroalcoholic gel seems to be balanced or offset by the use of the organic counterion diclofenac and the higher concentration of propylene glycol.

[0247] Example 4: Comparison of the 24-hour in vitro cumulative skin permeation of emulsions and hydroalcoholic gels containing 1% w / w diclofenac sodium and different concentrations of non-ionic emulsifiers in a non-GLP skin permeation comparison study

[0248] A hydroalcoholic composition containing 1% w / w diclofenac sodium and different levels of nonionic emulsifiers was studied. At the same time, the concentrations of isopropyl alcohol and propylene glycol were varied to study the effect of these ingredients on the cumulative permeation. The reference product was the same as in Examples 2 and 3.

[0249] Full-thickness human skin (abdomen) samples were obtained from six female donors aged between 43 and 69 years. The skin was stored in a freezer set at -20°C. The skin was cut to a depth of 200-400 μm using an electric skin extractor, and split-thickness skin was prepared from the samples. Split-thickness skin samples (200-400 µm) with transepithelial electrical resistance (TEER) values ​​>7.7 kΩ were mounted in static diffusion cells (nominal volume 5 ml, exposed area = 0.64 cm 2 ) and stored under controlled temperature conditions (32 ± 1°C). Each research formulation was applied in duplicate to skin samples from 6 donors (i.e., the total number of skin samples for each formulation = 12). The receptor fluid was phosphate-buffered saline containing 5% w / v bovine serum albumin. Before use, the receptor fluid was degassed by ultrasound and stored at a temperature of about +4°C. Receptor fluid samples were collected at 0, 2, 4, 8, 16, and 24 hours after the first dose, and the diclofenac content was analyzed by LC-MS / MS. The cumulative absorption of diclofenac in the receptor fluid of each test formulation and two dosing intervals was calculated. The cumulative absorption of diclofenac 24 hours after the first dose was analyzed. For any post-baseline sample with a concentration below LOQ, the half value of the limit of quantification (LOQ) was used. The statistical model used was an analysis of variance (ANOVA) of the logarithmic transformed geometric mean, and included formulation and donor as fixed effects.

[0250] The test formulations and control were applied to human split-graft specimens using a positive displacement pipette. The formulations were then applied at 10 (mg / cm 2 ) was evenly applied to the surface of the stratum corneum of the skin at an application rate of . Table 5 shows the composition of the reference product (Voltaren Arthritis Pain Relief Cream) and the test formulations (F3 and F5) in Example 4, and Table 6 shows the results.

[0251] Table 5: Composition and cumulative permeation results of the reference product and the test formulation

[0252]

[0253] Table 6: Results of Example 4:

[0254]

[0255] In Example 4, no statistically significant difference was observed between formulation F3 and the reference product in terms of cumulative permeation at 24 hours. This means that the addition of an emulsifier has a permeation-slowing effect on the hydroalcoholic composition. This permeation-slowing effect is so pronounced that the cumulative permeation of F3 at 24 hours is similar to that of the reference product, even though F3 is a hydrophilic composition and the reference product is an emulsion. A higher cumulative permeation would be expected from a hydrophilic composition (see Example 1). Surprisingly, the nonionic emulsifier did not further enhance the cumulative permeation. On the contrary, the addition of a nonionic emulsifier seems to balance the permeation-enhancing effect of the lack of a dispersed lipophilic phase. Interestingly, the cumulative permeation of F5, which contains a total concentration of 3% w / w emulsifier, is even significantly lower than that of the reference product at 24 hours. Therefore, the inventors conclude that the permeation-slowing effect of nonionic emulsifiers in hydrophilic compositions is dose-dependent. Adding more nonionic surfactants can produce a more pronounced permeation-slowing effect.

Claims

1. A hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising: - diclofenac or a pharmaceutically acceptable salt of diclofenac in a concentration of about 0.5% w / w to about 1.5% w / w diclofenac sodium equivalent, - Gelling agents, - an aliphatic C2-C4 monohydric alcohol in a concentration of about 5% w / w to about 20% w / w, - aliphatic diols in a concentration of about 2% w / w to about 10% w / w, - a hydrophilic nonionic emulsifier in a concentration of about 1% w / w to about 2% w / w, and - water.

2. A composition according to claim 1, comprising diclofenac sodium.

3. A composition according to claim 1 or 2 comprising diclofenac sodium in a concentration of about 1% w / w.

4. A composition according to claim 1, 2 or 3, wherein the nonionic emulsifier has a hydrophilic-lipophilic balance value of from about 13 to about 17, from about 14 to about 16 or about 15.

5. A composition according to any one of the preceding claims, wherein the nonionic emulsifier is an ethoxylated C 16 To C 18 alcohol.

6. The composition according to any one of claims 1 to 4, wherein the nonionic emulsifier is selected from the group consisting of cetostearyl 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.

7. A composition according to any one of the preceding claims comprising polyethylene glycol cetearyl alcohol ether.

8. A composition according to any one of the preceding claims, wherein the non-ionic emulsifier slows the penetration of diclofenac.

9. A composition according to any preceding claim which is substantially free of one or more of fats, oils, waxes, occlusives, or carbohydrate-based ointment bases.

10. A composition according to any preceding claim, wherein the gel is transparent.

11. A composition according to any one of the preceding claims, wherein the pH of the composition is from about 6.5 to about 8.

5.

12. A composition according to any one of the preceding claims comprising the aliphatic C2-C4 monoalcohol in a concentration of from about 8% w / w to about 18% w / w or from about 10% w / w to about 15% w / w.

13. A composition according to any one of the preceding claims comprising the fatty diol in a concentration of from about 3% w / w to about 8% w / w or from about 3% w / w to about 5% w / w.

14. A composition according to any one of the preceding claims comprising isopropanol as the only aliphatic C2-C4 monoalcohol and propylene glycol as the only aliphatic diol.

15. A composition according to any of the preceding claims which has a cumulative permeation in an in vitro skin permeation test which allows registration according to Annex I to Directive 2001 / 83 / EC under well-established criteria for use based on literature data for Voltaren Arthritis Pain Cream (Diclofenac Sodium Topical Gel, 1% (NSAID)-Arthritis Pain Relief) or Voltaren Diclofenac Diethylamine 1.16% Gel.

16. A composition according to any one of the preceding claims for use in a method for relieving pain, inflammation and swelling in soft tissue injuries, localised forms of soft tissue rheumatism and for relieving pain in non-severe arthritis of the knee or fingers.

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