Hydroalcoholic single-phase gel compositions for topical delivery of diclofenac

Abstract

A hydroalcoholic single-phase gel composition containing diclofenac or a pharmaceutically acceptable salt of diclofenac is disclosed. The composition is a single-phase composition and does not contain a lipophilic phase. The composition may contain at least one nonionic surfactant. The composition is useful for topical delivery of diclofenac. The composition can be used, for example, to treat pain.

Description

[Technical Field]

[0001] The present disclosure relates to formulations for the topical delivery of diclofenac. Specifically, the disclosure relates to formulations that are non-greasy hydroalcoholic gels. [Background technology]

[0002] Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the acetic acid class that is widely used in systemic products as well as topical or transdermal products. Emulsion gels, also known as emulgels, are oil-in-water emulsions with a gelled aqueous phase. Emulgels for topical delivery of diclofenac are commercially available. Recent patient reports suggest that some users are dissatisfied with some of the attributes of emulgels. The inventors have overcome these shortcomings, and the present disclosure provides a topical diclofenac product that has similar advantages to existing products but also has additional attributes that meet evolving consumer preferences. Summary of the Invention

[0003] - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - non-ionic emulsifiers, and - water A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is disclosed, comprising:

[0004] In one embodiment, the composition comprises a total concentration of diclofenac or a pharmaceutically acceptable salt of diclofenac equivalent to about 1.5% w / w to about 2.5% w / w of diclofenac sodium.

[0005] In one embodiment, the composition comprises at least two different non-ionic emulsifiers.

[0006] 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.

[0007] In one embodiment, the composition comprises a nonionic emulsifier selected from the group consisting of macrogol cetostearyl ether 20, polysorbate 60, polysorbate 80, isosteareth 20, PEG-60 almond glyceryl fatty acid, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20, and combinations of two or more thereof.

[0008] In one embodiment, the composition comprises macrogolcetostearyl ether.

[0009] In one embodiment, the composition comprises a non-ionic emulsifier selected from the group of polysorbate 20, laureth-20, and combinations thereof.

[0010] In one embodiment, the composition comprises polysorbate 20.

[0011] In one embodiment, the composition comprises a nonionic emulsifier comprising a 2-isopropyl-tetrahydrofuran moiety comprising one or more oligo(ethylene oxide) ester groups, wherein all of the ethylene oxide units of the oligo(ethylene oxide) ester groups in combination contain from 10 to 30, 14 to 24, or 20 carbon atoms.

[0012] In one embodiment, the composition comprises 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.

[0013] In one embodiment, the composition comprises a first non-ionic emulsifier that is macrogolcetostearyl ether and a second non-ionic emulsifier that is a polysorbate.

[0014] In one embodiment, the composition comprises a total concentration of non-ionic emulsifiers 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.

[0015] In one embodiment, the composition comprises isopropanol at a concentration of about 8% w / w to about 15% w / w.

[0016] In one embodiment, the composition comprises propylene glycol at a concentration of about 3% w / w to about 15% w / w.

[0017] In one embodiment, the non-ionic emulsifier retards the permeation of diclofenac.

[0018] In one embodiment, the composition is substantially free of one or more of fats, oils, waxes, occlusive agents, or carbohydrate-based ointment bases.

[0019] In one embodiment, the composition is substantially free of fats, oils, waxes, occlusive agents, and carbohydrate-based ointment bases.

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

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

[0022] In one embodiment, the composition is substantially free of waxes.

[0023] In one embodiment, the composition is substantially free of carbohydrate-based ointment bases.

[0024] In one embodiment, the composition is substantially free of a lipophilic dispersed phase.

[0025] In one embodiment, the gel is clear.

[0026] In one embodiment, the composition has a pH of about 6.5 to about 8.5.

[0027] In one embodiment, the composition has a cumulative permeation in an in vitro skin permeation test that allows for reliance on literature data for Voltarol Joint Pain Relief 2.32% diclofenac diethylammonium for registration under well-established use criteria pursuant to Annex I of Directive 2001 / 83 / EC.

[0028] Compositions for use in methods for treating non-severe arthritic pain in the knees or fingers are also disclosed.

[0029] The use of a non-ionic emulsifier to reduce the cumulative permeation of diclofenac through the skin over a 6-hour, 9-hour, 12-hour or 24-hour period from a hydroalcoholic single-phase gel for topical delivery of diclofenac is also disclosed. [Brief explanation of the drawings]

[0030] [Figure 1] 1 is an example of a hydroalcoholic single phase gel composition when used with a dosing card. [Figure 2] Visual representation of the results of Example 2. [Figure 3] Visual representation of the results of Example 3. [Figure 4] Visual representation of the results of Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0031] An example of a topical diclofenac formulation is Voltaren Arthritis Pain (diclofenac sodium topical gel, 1% (NSAID) - arthritis analgesic), which contains 1% w / w diclofenac sodium and has been approved in the United States as an over-the-counter (OTC) drug since 2020. Another topical diclofenac formulation contains 1.16% w / w diclofenac diethylammonium salt (equivalent to 1% diclofenac sodium salt), which is sold as Voltaren or Voltarol 1.16% Emulgel. Voltaren 1.16% Emulgel has been sold in Switzerland since 1974. In some countries, such as the UK, Voltarol Joint Pain Relief 2.32% Gel is commercially available, containing 2.32% w / w diclofenac diethylammonium (DEA) salt (equivalent to 2% w / w diclofenac sodium). Voltaren Arthritis Pain, Voltaren 1.16% Emulgel, and Voltarol Joint Pain Relief are emulsion gels (emulgels). Emulgels are a specific form for topical application of drugs. Emulgel forms are described, for example, in US Pat. No. 4,917,886 A in combination with the active ingredient (API) diclofenac.

[0032] According to US4917886A, the described emulgel formulations provide easier dissolution of the active ingredient and an associated higher concentration of the active ingredient compared to conventional topical formulations such as gels or creams. Another advantageous property of emulgels is described as the presence of a lipid phase that provides fat-restoring properties. The combination of the lipid phase with the gelled aqueous phase allows the formulation to be massaged in, while at the same time, direct absorption into the skin is experienced as a pleasant property.

[0033] The existing Voltaren 1%, 1.16%, and 2.32% Emulgel products are successful marketed products, but as consumer preferences evolve over time, the objective became to identify new compositions that are not only rapidly absorbed into the skin without leaving an oily mark or residue at the application site and on the hands, but are also visually clear or crystal clear.

[0034] It was the inventors' primary objective to find new compositions that are visually clear, or water-clear. Clear compositions may be perceived as modern, clean, fresh, and natural. This may improve user compliance. Furthermore, clear topical products may be easier for some users to administer. For example, on a conventional dosing card for a topical product, the clear gel does not obscure the scale or measuring area (see FIG. 1).

[0035] At the same time, the advantageous properties of the existing Voltaren 1%, 1.16%, or 2.32% Emulgel products should not be compromised. The new compositions should contain a similar diclofenac dosage. The new compositions should provide a similar diclofenac permeation profile, thereby enabling similar efficacy and safety to be expected. Furthermore, the beneficial sensory attributes of the existing products, such as a pleasant stretching experience and cooling effect, should be maintained or improved.

[0036] For topical compositions containing diclofenac or diclofenac salts, it can be difficult to completely and permanently solubilize the diclofenac (salt). For example, diclofenac free acid is a weak acid and poorly soluble in water. For topical compositions containing diclofenac (salts), crystallization or precipitation of diclofenac (salts) during storage and after application to the skin is a concern because it can lead to inaccurate or insufficient dosing and can also result in "loss" of the API because the unsolubilized API is no longer available for permeation through the skin. Therefore, a solvent system that completely solubilizes diclofenac or its salts is needed. Solvent systems containing water, an aliphatic C2-C4 monoalcohol, and an aliphatic diol have been used in the art. For example, Voltarol 2.32% emulgel contains such a combination of solvents. However, hydroalcoholic gels containing solvent systems in the art cannot achieve the above objectives. Even if solubilization of diclofenac or diclofenac salts is achieved, other gel properties may not function properly. For example, diclofenac skin permeation may be affected. Aliphatic C2-C4 monoalcohols may have a permeation-enhancing effect. The effect (enhancement or decrease) of aliphatic diols on the permeation rate may depend on their total concentration. Furthermore, a high concentration of aliphatic diols may cause the composition to become cloudy or opaque, which is unacceptable to the inventors. Furthermore, other excipients in a given formulation may also affect skin permeation. The above-cited US Pat. No. 4,917,886 A describes an emulgel containing a lipophilic phase as an option for enhancing API solubilization. However, emulgels are typically opaque, and the inventors sought to find a transparent composition, necessitating a different format. The inventors observed that a hydroalcoholic gel composition consisting of a hydroalcoholic phase of Voltaren 1.16% emulgel exhibited sufficient API solubilization (see Example 1). However, their cumulative permeation exceeded that of Voltaren 1.16% Emulgel to such an extent that they did not meet the prescribed permeation property requirements.Thus, the present inventors have found that hydroalcoholic single-phase gel compositions tend to have higher API permeation rates compared to emulgels. Without being bound by any particular theory, the present inventors believe this is due to the lack of a lipophilic dispersed phase and the higher water activity of compositions containing high concentrations of water. However, the present inventors aimed to formulate a composition with permeation properties similar to those of existing Voltaren 1% or 1.16% emulgel products, thereby maintaining the podiatry, i.e., dosage and frequency, of the existing products. Therefore, it was particularly difficult to identify suitable solvents and their useful concentrations that would completely solubilize diclofenac or diclofenac salts in a single-phase hydroalcoholic composition capable of forming a clear gel with desired application properties and acceptable (not too high) cumulative permeation.

[0037] Surprisingly, the inventors were able to formulate a single-phase hydroalcoholic gel with permeation properties very similar to those of an emulgel.

[0038] Therefore, the inventors sought to improve the user's sensory experience and convenience while maintaining similar skin permeation characteristics to Voltaren Arthritis Pain, Voltaren 1.16% Emulgel, or Voltarol Joint Pain Relief 2.32% Gel. This approach was adopted to maintain the advantageous properties of Voltaren 1%, 1.16%, or 2.32% Emulgel products, which patients are familiar with and appreciate. This approach was also adopted from the perspective of patient safety. Providing a product with a diclofenac permeation profile similar to commercially available products with excellent safety profiles reduces the risk of adverse events caused by new products. Furthermore, products similar or equivalent to already approved products may facilitate the registration and approval of new drugs by regulatory authorities. In one aspect, the inventors sought to develop a product that could be registered under the criterion of "well-established use" based on published literature data for Voltaren 1% Emulgel, Voltaren 1.16% Emulgel, or Voltarol Joint Pain Relief 2.32% Gel.

[0039] composition Hydroalcoholic single-phase composition 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 a patient in need of treatment with the API. The compositions are an effective vehicle for the API to penetrate the skin. The compositions disclosed herein allow the API to penetrate through the skin to the site of action, which can be, for example, a joint. The penetration of the API from the composition through the skin can be determined through sophisticated preclinical experiments, such as those described in the Experimental Section later herein. The skin is a complex structure containing several tissue layers. Therefore, the skin is a significant barrier for the API. For the avoidance of doubt, the compositions disclosed herein are not intended for the treatment of a dermal condition. In one embodiment, the composition is not for the treatment of a dermal condition.

[0040] The composition is a hydroalcoholic composition. The term "hydroalcoholic composition" is intended to refer to a composition that is essentially free of oils, waxes, and saturated carbohydrates, and does not exclude that the composition may include components that include hydrophobic moieties.

[0041] The compositions specifically described herein are hydroalcoholic gels. "Hydroalcoholic gel" means a composition comprising a gelled continuous phase comprising water and one or more alcohols. In other words, the composition comprises a hydroalcoholic continuous phase. For the avoidance of doubt, hydroalcoholic gels may comprise additional components in addition to water and alcohol(s).

[0042] The composition is a single-phase composition. A "single-phase composition" means that diclofenac or a diclofenac salt is largely or completely dissolved in the solvent system, and the solvents comprising the solvent system are largely or completely miscible. The term "single-phase composition" is intended to distinguish the composition from emulsions, emulsifiers, colloidal mixtures, two-phase compositions (e.g., oil and water), and the like. The composition may be a single-phase composition despite the mere presence of a gelling agent or emulsifier. For purposes of this disclosure, the gelling agent and the gel network formed by the gelling agent are not considered a separate or second phase. Furthermore, micelles formed by clustered emulsifier molecules are not considered a separate or second phase.

[0043] Hydroalcoholic single-phase gels are a different delivery format compared to traditional ointments. Ointments are single-phase compositions containing only a single lipophilic phase. Ointments typically have a high viscosity. Due to their lipophilicity, ointments have an occlusive effect on the skin and may cause a greasy or sticky feeling on the skin. Ointments typically also provide a warming effect. Further different formats are emulsions, creams, and emulsion gels. Emulsions are two-phase compositions, also called two-phase systems. These two-phase systems contain 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 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 both hydrophilic and lipophilic properties. Thus, emulsifiers are amphiphilic molecules. The hydrophilic portion of an emulsifier molecule is usually referred to as the head group, and the lipophilic portion of an emulsifier molecule is usually referred to as the tail group. Emulsifiers help form and stabilize dispersions of lipophilic or hydrophilic phases. Without emulsifiers, emulsions would only form temporarily or would have insufficient stability, as evidenced by immiscibility / phase separation. This can occur because lipophilic and hydrophilic components are usually immiscible and the dispersed state is thermodynamically unstable. This immiscibility process can be called phase separation, as it results in the separation of the dispersed and continuous phases. Due to the amphiphilic nature of emulsifiers, they stabilize the otherwise immiscible phases in the dispersed state. Creams and emulgels are subgroups of emulsions. Creams are emulsions that can have either 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. Emulgels are emulsions with a gelled continuous phase. Emulgels can also have a lipophilic continuous phase and a hydrophilic dispersed phase (W / O), or a hydrophilic continuous phase and a lipophilic dispersed phase (O / W). However, commercially available emulgel forms are usually O / W forms.Therefore, in the art and in this disclosure, when an emulgel is mentioned, it is typically an O / W emulgel.

[0044] The compositions disclosed herein differ from the conventional multiphase systems described above. The compositions disclosed herein are hydroalcoholic single-phase gels. The compositions disclosed herein contain a gelled hydroalcoholic continuous phase. In this regard, the compositions described herein are similar to emulgels. However, emulgels further contain a dispersed lipophilic phase. For example, Voltaren 1% Emulgel, Voltaren 1.16% Emulgel, and Voltarol Joint Pain Relief 2.32% Diclofenac DEA contain a lipophilic dispersed phase, for example, containing liquid paraffin as both lipophilic and hydrophobic components. In contrast, the compositions disclosed herein do not contain a lipophilic dispersed phase. In emulgels, the lipophilic phase enhances the solubility of the active ingredient, in this case, diclofenac (salt). Therefore, it is more difficult to solubilize diclofenac and diclofenac salts in a single-phase hydroalcoholic composition, especially when the API concentration is high. Even if a certain amount of diclofenac (salt) is initially solubilized in a solvent or composition, the API may have a strong tendency to recrystallize. Therefore, it is difficult to formulate a hydroalcoholic gel containing diclofenac (salt) without using a lipophilic dispersed phase and still achieve complete solubilization of the diclofenac (salt). It is particularly difficult to formulate a hydroalcoholic single-phase gel in which diclofenac or a diclofenac salt is completely solubilized over an extended period of time, over shelf life, and / or during storage.

[0045] The present inventors have identified a hydroalcoholic single-phase composition containing a solvent system capable of solubilizing diclofenac or a diclofenac salt. The solvent system comprises a mixture of water, a specific concentration of an aliphatic C2-C4 monoalcohol, and a specific concentration of an aliphatic diol. Unexpectedly, the present inventors have found that the incorporation of specific concentrations of one or more nonionic emulsifiers into the resulting hydroalcoholic single-phase diclofenac gel can reduce the cumulative permeation of diclofenac and tailor its permeation characteristics. Furthermore, the resulting gel is visually transparent.

[0046] One aspect of conventional multiphase systems is that they typically contain globules of a certain size. Most multiphase systems contain dispersed phases with globule sizes (also called particle sizes) that scatter light and make the multiphase system appear cloudy or opaque, usually milky to opaque white. In contrast, the compositions described herein are clear, transparent, see-through, and / or slightly opalescent. Without being bound by any particular theory, the inventors suggest 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 may be solubilized in the aqueous continuous phase. According to the inventors' theory, in the disclosed compositions, hydrophilic nonionic emulsifier molecules can associate to form small aggregates at certain concentrations in a water-alcoholic environment. The lipophilic tail groups of some nonionic emulsifier molecules can associate to form micelles. The tail groups are located in the core of the micelles, and the head groups face outward toward the hydrophilic continuous phase. Nevertheless, the compositions of the present disclosure are not opaque but visually transparent. Furthermore, even if micelles may be present, the compositions are still considered to be single-phase compositions as defined herein.

[0047] In some embodiments of the composition, the structures or micelles formed by the hydrophilic nonionic emulsifier, if present, have an average globule 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 one particular embodiment of the composition, the structures or micelles formed by the hydrophilic nonionic emulsifier, if present, have an average globule size of less than about 50 nm. In one embodiment, the composition does not contain any structures, excluding the gelling agent, with an average globule size greater than 50 nm. The average globule size of the structures in the semi-solid composition can be measured using a compound microscope with or without particle counting software.

[0048] In one embodiment, the composition is uncolored. In one embodiment, the composition is colorless. In one embodiment, the compositions disclosed herein are clear to opalescent. In one embodiment, the composition is clear. In one embodiment, the composition does not significantly scatter light in the human visible spectrum. 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 sheer. In one embodiment, the composition is transparent. In one embodiment, the composition does not contain a dispersed phase that scatters light in the human visible spectrum, and the composition is clear to opalescent. In one embodiment, the composition of the present disclosure is a single-phase hydroalcoholic gel containing only structures that do not scatter light in the human visible spectrum. In certain of the above embodiments, micelles, if present, have an average globule 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.

[0049] Advantageously, the visual attributes of the compositions described herein have a modern and attractive appearance that appeals to many patients and consumers. Such a "water-clear" appearance can be a visual marker that the composition is primarily water, which can also be perceived positively. Furthermore, the composition is easier to administer using a dosage card for a topical product, such as the dosage card in FIG. 1. When administering the compositions of the present invention on a dosage card, the user can perceive the dose indicator on the dosage card even if the composition has already been dispensed onto the dosage card. This improves dosing safety and dosage accuracy. This also improves the patient's dosing technique.

[0050] In the present disclosure, "substantially free" should be understood to mean that no additional components with a certain functionality are added to the formulation. For example, "substantially free of permeation enhancers" means that no permeation enhancers are added to the composition. However, this does not exclude components explicitly listed in the present disclosure as essential, optional, or preferred. Those skilled in the art will understand that many components in pharmaceutical compositions perform more than one function. Thus, a component listed herein as essential, optional, or preferred may perform certain other functionality in addition to its functionality described herein. For example, a given alcohol listed as a component of a composition may act as a solubilizer, but may also affect permeation, e.g., have a permeation-enhancing effect depending on the concentration. In this example, "substantially free of permeation enhancers" would not exclude the presence of this solvent in the compositions of the present disclosure. Furthermore, a composition may contain minor or trace amounts of a certain compound, for example, due to impurities or due to component degradation. This is also not included, and such compositions would still be considered "substantially free" of the 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 present compositions are not considered lipophilic excipients, even though the tail groups that are part of their molecular structure are lipophilic. Hydrophilic nonionic emulsifiers are amphiphilic molecules that contain a lipophilic portion and a hydrophilic portion, and overall, the hydrophilic properties predominate, making the emulsifier hydrophilic and water-soluble.

[0051] The lipophilicity of a compound can be evaluated, for example, by the shake-flask method and expressed as a logP value. The logP value (partition coefficient or distribution coefficient) is a measure of how a given molecule partitions between a lipophilic organic phase (typically n-octanol) and a polar aqueous phase (typically deionized water). In some embodiments, the composition is substantially free of excipients (except for diclofenac or a salt thereof) 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 is preferable to provide consumers with a "non-fat," "non-messy," and "non-greasy" alternative to water- and alcohol-based products. The composition does not leave lipophilic residues on the application site, hands, or clothing. Furthermore, the composition is transparent.

[0052] Although the composition does not contain a lipophilic phase, it does contain a hydrophilic nonionic emulsifier. As explained above, in conventional multiphase systems, emulsifiers are used to achieve dispersion of one immiscible phase within another. In compositions without a lipophilic phase, there is no dispersed phase that needs to be stabilized by an aqueous phase, and therefore no risk of phase separation, so emulsifiers are generally not incorporated. Therefore, hydroalcoholic compositions in the art typically do not contain emulsifiers. In contrast to this technology, the composition of the present disclosure is a hydroalcoholic composition without a lipophilic phase, but it does contain a hydrophilic nonionic emulsifier. Emulsifiers have also been reported to have a penetration-enhancing effect in multiphase systems (see, for example, 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). In contrast to these teachings, in the compositions of the present disclosure, the hydrophilic nonionic emulsifier has a permeation reducing effect.

[0053] The present inventors have surprisingly found that in the hydroalcoholic compositions of the present disclosure, nonionic emulsifiers can reduce the cumulative permeation of diclofenac. Thus, in one aspect, nonionic emulsifiers can have a permeation-retarding effect on diclofenac or its salts in the hydroalcoholic single-phase compositions of the present disclosure. This is particularly surprising in light of the teachings in the art (Iti Som et al., referenced above) regarding the permeation-enhancing effect of nonionic emulsifiers. Furthermore, the present inventors have found that certain combinations of nonionic emulsifiers are particularly suitable for reducing the cumulative permeation of diclofenac.

[0054] As is evident from the Examples section, the inventors have found that diclofenac or its salts exhibit a higher permeation rate from hydroalcoholic compositions compared to emulgel compositions containing the same concentrations of API and other excipients (see, e.g., Example 1). As discussed above, the inventors sought to provide a composition that is as safe as the established product, Voltarol Joint Pain Relief 2.32% Diclofenac DEA, and that can rely on its extensive drug safety experience. Thus, in one aspect, the inventors aimed to provide a composition with a permeation profile similar to that of Voltarol Joint Pain Relief 2.32% Diclofenac DEA. Surprisingly, it was found that the cumulative permeation of diclofenac from hydroalcoholic gels can be adjusted by incorporating one or more hydrophilic nonionic emulsifiers. Furthermore, nonionic emulsifiers do not contain ionizable groups and are relatively insensitive to changes in pH. Therefore, nonionic emulsifiers can stabilize the composition.

[0055] 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 yet another embodiment, the composition comprises two nonionic emulsifiers and no additional emulsifiers. In some embodiments, the composition comprises at least two nonionic emulsifiers. In another embodiment, the composition comprises exactly two nonionic emulsifiers.

[0056] In one embodiment, the composition comprises a non-ionic emulsifier having a hydrophilic-lipophilic balance value of about 13 to about 17, about 14 to about 16, or about 15. In one particular embodiment, the composition comprises a non-ionic emulsifier having a hydrophilic-lipophilic balance value of about 15. In one embodiment, the composition comprises one non-ionic emulsifier, wherein the one non-ionic emulsifier has a hydrophilic-lipophilic balance value of about 13 to about 17, about 14 to about 16, or about 15. In any of these embodiments, the described non-ionic emulsifier 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.

[0057] In some embodiments, 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. In one particular embodiment, the composition comprises a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 17. In one embodiment, the composition comprises one nonionic emulsifier, wherein the one nonionic emulsifier has a hydrophilic-lipophilic balance value of about 15 to about 19, about 16 to about 18, or about 17. In any of these embodiments, the described nonionic emulsifier 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.

[0058] 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 and second nonionic emulsifiers may have the same or different lipophilic balance values. In one embodiment, the composition comprises 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. In yet another embodiment, the composition comprises at least two nonionic emulsifiers, wherein one of the at least two nonionic emulsifiers has a hydrophilic-lipophilic balance value of about 13 to about 17, about 14 to about 16, or about 15. In one particular embodiment, the composition comprises two nonionic emulsifiers, wherein one of the two nonionic emulsifiers has a hydrophilic-lipophilic balance value of from about 13 to about 17, from about 14 to about 16, or about 15.

[0059] In another embodiment, the composition comprises at least two nonionic emulsifiers, wherein one of the at least two nonionic emulsifiers has a hydrophilic-lipophilic balance value of from about 15 to about 19, from about 16 to about 18, or about 17. In one particular embodiment, the composition comprises two different nonionic emulsifiers, wherein one of the two nonionic emulsifiers has a hydrophilic-lipophilic balance value of from about 15 to about 19, from about 16 to about 18, or about 17.

[0060] In one particular embodiment, the composition comprises a first nonionic emulsifier having a hydrophilic-lipophilic balance value of about 13 to about 17, about 14 to about 16, or about 15, and a second nonionic emulsifier having a hydrophilic-lipophilic balance value of about 15 to about 19, about 16 to about 18, or about 17. The first nonionic emulsifier may be present at a concentration of 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. The second nonionic emulsifier may be present at 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 another specific embodiment, the composition comprises one non-ionic emulsifier having a hydrophilic-lipophilic balance value of about 15 and one non-ionic emulsifier having a hydrophilic-lipophilic balance value of about 17. The non-ionic emulsifier having a hydrophilic-lipophilic balance value of about 15 may be present at a concentration of 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. The non-ionic emulsifier having a hydrophilic-lipophilic balance value of about 17 may be present at 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.

[0061] In one embodiment, the composition comprises a hydrophilic nonionic emulsifier that is an ethoxylated C16-C18 alcohol. In one embodiment, the composition comprises a nonionic emulsifier selected from the group consisting of macrogol cetostearyl ether 20, polysorbate 60, polysorbate 80, isosteareth 20, PEG-60 almond glyceryl, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20, and combinations of two or more thereof. In a specific embodiment, the composition comprises macrogol cetostearyl ether. In another specific embodiment, the composition comprises macrogol cetostearyl ether 20. Macrogol cetostearyl ether 20 is the official name used by the European Pharmacopoeia (Ph.Eur.). The United States Pharmacopoeia (USP) uses the name Polyoxyl 20 Cetostearyl Ether (USP) for the same ingredient. The International Nomenclature of Cosmetic Ingredients (INCI) uses the name Ceteareth-20 (INCI) for the same ingredient. One trade name for macrogol cetostearyl ether 20 is Kolliphor CS 20. In any of these embodiments, the specified nonionic emulsifier may be present in a concentration of 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.

[0062] In one embodiment, the composition comprises a nonionic emulsifier comprising a 2-isopropyl-tetrahydrofuran moiety containing one or more oligo(ethylene oxide) ester groups, wherein all ethylene oxide units in the oligo(ethylene oxide) ester groups, in combination, contain from about 10 to about 30, from about 14 to about 24, or about 20 carbon atoms. In a particular embodiment, the oligo(ethylene oxide) ester groups comprise a lauric acid ester. In another embodiment, the composition comprises a polysorbate. In another embodiment, the composition comprises a nonionic emulsifier selected from the group consisting of polysorbate 20, laureth-20, and combinations thereof. In a particular embodiment, the composition comprises polysorbate 20. Polysorbate 20 is the official name used in Ph.Eur. and USP. One trade name for polysorbate 20 is Corifol PS 20. In any of these embodiments, the specified non-ionic emulsifier may be present at 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.

[0063] In one embodiment, the composition comprises a first nonionic emulsifier that is macrogol cetostearyl ether and a second nonionic emulsifier that is a polysorbate. The macrogol cetostearyl ether may be present at 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 at 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 cetostearyl ether 20 and polysorbate 20. Cetostearyl Ether 20 may be present at 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. Polysorbate 20 may be present at 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.

[0064] In certain embodiments of any of the above embodiments, the listed emulsifier(s) are the only emulsifier(s) in the composition. In some embodiments, the composition is substantially free of anionic emulsifiers. In some embodiments, the composition is substantially free of anionic emulsifiers and substantially free of cationic emulsifiers.

[0065] In one embodiment, the composition comprises a total concentration of non-ionic emulsifier(s) 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 total concentration of non-ionic emulsifier(s) of about 2% w / w. In another embodiment, the composition comprises a total concentration of non-ionic emulsifier(s) of about 3% w / w.

[0066] Solvent System The compositions disclosed herein comprise a solvent system including water, an aliphatic C2-C4 monoalcohol, and an aliphatic diol. In one embodiment, the compositions described herein comprise greater than about 50% w / w, greater than about 60% w / w, or greater than about 70% w / w water. In a particular embodiment, the compositions comprise about 65% w / w to about 75% w / w water. In one embodiment, the compositions are water-based. In one embodiment, the compositions are aqueous compositions. Advantageously, water provides a cooling effect to the skin. Water is also a readily available ingredient with low environmental impact. Furthermore, water is a clear ingredient, which is advantageous given the importance of the visual appearance of the final composition, as discussed above. The water may be purified water, distilled water, or the like. The water may be pharmaceutical-grade water. In one embodiment, the compositions comprise water as the base of the composition. As part of the solvent system, water also plays a role in solubilizing diclofenac or a diclofenac salt.

[0067] In addition to water, the solvent system includes an aliphatic C2-C4 monoalcohol. The composition can 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 combinations 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, the water and alcohol(s) are present in a continuous phase of the composition. In some embodiments, the composition includes a continuous phase including water, isopropanol, and optionally ethanol. In one particular embodiment, the composition includes a continuous phase including water and isopropanol.

[0068] Compared to water alone, the C2-C4 monoalcohol(s) provide better solubilization of diclofenac and diclofenac salts. This promotes diclofenac solubilization and reduces the risk of recrystallization. Furthermore, the aliphatic C2-C4 monoalcohol(s) result in a topical gel with a reduced drying time compared to pure water-based gels. When the composition is applied to the skin, the aliphatic C2-C4 monoalcohol(s) may evaporate. Evaporation after application to the skin reduces the drying time. Drying time can be described as the time elapsed between application of a topical product to the skin and the skin at the application site feeling dry again. Furthermore, the aliphatic C2-C4 monoalcohol(s) may impart a noticeable cooling effect to the topical composition. After application of the topical composition to the skin, evaporation of the composition components is driven by thermal energy from the application site. Thus, the evaporation process draws thermal energy from the application site, resulting in a cooling sensation on the skin. This cooling effect is beneficial to patients and consumers: "calor," i.e., fever in the affected body area, is one of the primary symptoms of the inflammatory process. Therefore, cooling the administration site can calm the inflammatory process and reduce inflammatory pain. Furthermore, cooling can provide a perception of immediate action of the topical product. Furthermore, aliphatic C2-C4 monoalcohols are transparent. Therefore, aliphatic C2-C4 monoalcohols are suitable for formulating topical compositions with the desired visual transparency.

[0069] In some specific embodiments, the composition contains isopropanol as the only aliphatic C2-C4 monoalcohol. In some embodiments, the composition contains a continuous phase containing water and isopropanol and no ethanol. In some embodiments, the composition contains a continuous phase containing water and isopropanol and no other C2-C4 monoalcohols. Advantageously, by using isopropanol as the only aliphatic C2-C4 monoalcohol, different numbers of C2-C4 monoalcohols can be obtained. In these embodiments, no additional aliphatic C2-C4 monoalcohol is required to solubilize the diclofenac or diclofenac salt and provide a cooling sensation to the skin. Notably, the addition of another aliphatic C2-C4 monoalcohol, such as ethanol, which evaporates more easily, is not required. This may be preferable in some embodiments because ethanol is restricted in many countries for tax or ethical reasons. Thus, in some embodiments, the composition is ethanol-free.

[0070] Aliphatic C2-C4 monoalcohols are useful for shortening drying time, which can be generally beneficial. However, because the alcohol component(s) of the composition also play a role in API solubilization, the solvent system must not evaporate too easily and a sufficient concentration of the API must be maintained in a solubilized state. This reduces the risk of API crystallization or precipitation after application on the skin. This can increase the amount of API that is bioavailable. This is advantageous for efficacy, patient safety, and environmental safety. This is also preferable because it can reduce the formation of residue on the skin after application and drying. This provides a pleasant patient experience. Therefore, the solvent system used in the present composition further includes an aliphatic diol as a cosolvent.

[0071] The aliphatic diol, in some embodiments, can be a C2-C4 polyhydric alcohol. In some embodiments, the compositions disclosed herein include a glycol. In one embodiment, the composition includes an aliphatic diol selected from the group consisting of ethylene glycol, propylene glycol, and 1,3-butylene glycol, and any combination thereof. In some embodiments, propylene glycol is present as the only aliphatic diol.

[0072] The aliphatic diol or C2-C4 polyhydric alcohol can act as a co-solubilizer for the API. In contrast to the aliphatic C2-C4 monoalcohol(s) discussed above, the aliphatic diol or C2-C4 polyhydric alcohol does not readily evaporate after application onto the skin. Therefore, the aliphatic diol or C2-C4 polyhydric alcohol remains in the topical composition on the skin, while the aliphatic C2-C4 monoalcohol(s) evaporate. The aliphatic diol or C2-C4 polyhydric alcohol can thereby maintain the API in a solubilized state after application onto the skin.

[0073] Additionally, aliphatic diols or C2-C4 polyhydric alcohols are hygroscopic. They can impart moisturizing, moisture-retaining properties to topical compositions. This can provide a pleasant skin feel, such as a soft, supple, or nurturing skin feel. This can also help balance the lipid extraction properties of the C2-C4 monoalcohol(s). These effects are particularly important in single-phase hydroalcoholic compositions because they do not contain a lipophilic phase that can provide emollient or fat-restoring properties.

[0074] The aliphatic diol or C2-C4 polyhydric alcohol may also affect the permeation properties of the formulation. However, this effect on permeation also depends on their concentration, as well as on the other ingredients and the overall composition. As discussed above, the inventors sought to formulate a composition with permeation properties similar to those of the existing Voltaren 1%, 1.16%, or 2.32% Emulgel products, which are described in more detail in another section below.

[0075] The aliphatic C2-C4 monoalcohol(s) may be present in the composition at a concentration of about 5% w / w to about 20% w / w. Preferably, the aliphatic C2-C4 monoalcohol(s) may be present at a concentration of about 8% w / w to about 15% w / w. In one embodiment, the aliphatic C2-C4 monoalcohol(s) are present at a concentration of about 12.5% ​​w / w. In certain embodiments of any of the above embodiments, the aliphatic C2-C4 monoalcohol(s) may be isopropanol.

[0076] In certain embodiments, the composition comprises isopropanol at a concentration of about 5% w / w to about 20% w / w, 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 isopropanol at a concentration of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 12.5% ​​w / w, and is free of other aliphatic C2-C4 monoalcohols.

[0077] These concentration ranges of aliphatic C2-C4 monoalcohol(s) are balanced. On the one hand, high concentrations of C2-C4 monoalcohol(s) may be beneficial for API solubilization, microbial preservation, and / or cooling effect. On the other hand, high concentrations of aliphatic C2-C4 monoalcohol(s) may result in the final product being classified as hazardous under some regulations or may be subject to additional regulatory scrutiny, potentially complicating production, supply, and regulatory logistics. When the concentration of aliphatic C2-C4 monoalcohol is high, the composition may require particularly stringent packaging to avoid evaporation of the aliphatic C2-C4 monoalcohol during storage. Compositions containing aliphatic C2-C4 monoalcohol(s) in the above concentration ranges are not classified as hazardous and therefore do not require labeling, storage, or handling under strict supervision, nor do they require particularly stringent packaging. This is desirable because such classification may complicate manufacturing and supply and may discourage consumers from using the final product. Furthermore, if the concentration of the aliphatic C2-C4 monoalcohol(s) is too high, precipitation of the API at the application site may occur, as described above. The concentration ranges described for the aliphatic C2-C4 monoalcohol(s) can sufficiently solubilize the API in combination with water and the aliphatic diol of the solvent system. Therefore, the composition has a reduced risk of leaving residue or precipitation of the API on the skin.

[0078] Furthermore, the concentrations described can provide a sufficient cooling sensation upon application. The initial onset of the cooling sensation distracts the patient from the painful, inflamed area, and the onset of pain relief is felt immediately. This physiologically aids the patient by providing rapid pain relief. In particular, the cooling sensation can be perceived as having a rapid onset, being noticeable or strong, and being long-lasting.

[0079] Aliphatic monoalcohols also have antimicrobial properties. When included in a composition at a sufficiently high concentration, the composition has a reduced risk of microbial contamination and bacterial growth. This is particularly important for compositions containing high concentrations of water, such as greater than about 50% w / w, greater than about 60% w / w, or greater than about 65% w / w water.

[0080] In another aspect, the aliphatic C2-C4 monoalcohol(s) may have an odor that may put off some consumers. A fragrance or other odor-masking agent may be required to mask the alcohol odor. However, incorporating a fragrance may be difficult or undesirable in some instances. Surprisingly, compositions comprising aliphatic C2-C4 monoalcohol(s) within the described concentration ranges may have a pleasant odor. Thus, they are particularly suitable for formulation as fragrance-free compositions. In one particular embodiment, the composition is fragrance-free.

[0081] In yet another aspect, the above concentration ranges also provide skin-friendly compositions. The aliphatic C2-C4 monoalcohol(s) have some lipid-extracting (lipolytic) properties. These lipid-extracting properties can affect the skin's natural fat and ceramide components and barrier function. They can have dehydrating, degreasing, and irritating effects on the skin. In some cases, this can cause dry skin, flaky skin, and / or a tight feeling on the skin. On the other hand, the aliphatic C2-C4 monoalcohol(s) can have a permeation-enhancing effect on the API. In conventional topical compositions containing a lipophilic phase, the lipophilic components can balance the dehydrating, degreasing, and irritating effects of the alcohol components. As discussed above, the compositions of the present disclosure do not contain a lipophilic dispersed phase. Nevertheless, the compositions of the present disclosure are very skin-friendly due to the balanced blend of ingredients, because the compositions of the present disclosure contain a suitable concentration of aliphatic C2-C4 monoalcohol and further contain a cosolvent that is an aliphatic diol.

[0082] The cosolvent aliphatic diol or C2-C4 polyalcohol may 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 polyalcohol may be present in the composition in an amount of about 3% w / w to about 15% w / w. In one embodiment, the aliphatic diol or C2-C4 polyalcohol is present in an amount of about 6% w / w to about 12% w / w. In yet another embodiment, the aliphatic diol or C2-C4 polyalcohol is present in an amount of about 8% w / w to about 10% w / w. In one embodiment, the composition comprises about 8% w / w of the aliphatic diol. In another embodiment, the composition comprises about 10% w / w of the aliphatic diol.

[0083] The benefits of including a specific concentration of an aliphatic diol or C2-C4 polyhydric alcohol are described above. However, the inventors have found that a specific concentration range of the aliphatic diol or C2-C4 polyhydric alcohol described is particularly useful. The aliphatic diol or C2-C4 polyhydric alcohol described in the concentration range results in a composition with a reduced risk of skin irritation. In another aspect, the described range results in a composition with an acceptable dry time. In yet another aspect, the resulting composition has very pleasant skin application characteristics. For example, the resulting composition is not perceived as sticky or greasy. Furthermore, the resulting composition is clear, transparent, or sheer. In some embodiments, the composition can be opalescent. Furthermore, the aliphatic diol or C2-C4 monoalcohol also affects the permeability characteristics of the composition.

[0084] In one embodiment, the composition comprises an aliphatic C2-C4 monoalcohol that is isopropanol and an aliphatic diol that is propylene glycol.

[0085] The combined total amount of the aliphatic C2-C4 monoalcohol and the aliphatic diol or C2-C4 polyhydric alcohol is preferably greater than about 10% w / w. The combined total amount of the aliphatic C2-C4 monoalcohol and the aliphatic diol or C2-C4 polyhydric alcohol is preferably less than about 30% w / w. Expressed as a range, the combined total amount of the aliphatic C2-C4 monoalcohol and the aliphatic diol or C2-C4 polyhydric alcohol 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 combined total amount of the aliphatic C2-C4 monoalcohol and the aliphatic diol or C2-C4 polyhydric alcohol is about 20.5% w / w. In one embodiment, the combined total amount of the aliphatic C2-C4 monoalcohol and the aliphatic diol or C2-C4 polyhydric alcohol is about 22.5% w / w.

[0086] In certain embodiments, the aliphatic C2-C4 monoalcohol is isopropanol and the aliphatic diol is propylene glycol. In some of these embodiments, the combined total concentration of isopropanol and propylene glycol is greater than about 10% w / w. The combined total concentration of isopropanol and propylene glycol is preferably less than about 30% w / w. Expressed as a range, the combined total 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 combined total 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.

[0087] In some embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:0.5 to 1:2. In some embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 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 certain embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:1.4 to 1:1. In one particular embodiment, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:1.25. In certain of the above embodiments, the aliphatic C2-C4 monoalcohol is isopropanol and the aliphatic diol is propylene glycol.

[0088] 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, hi certain embodiments, the composition comprises about 12.5% ​​w / w isopropanol and about 10% w / w propylene glycol.

[0089] The compositions disclosed herein include an API that is diclofenac or a pharmaceutically acceptable salt of diclofenac. This includes deuterated forms of diclofenac or its salts, in which one or more hydrogen atoms in the diclofenac molecule have been replaced with deuterium atoms (i.e., deuterated diclofenac). In one embodiment, the composition includes diclofenac, diclofenac ammonium, diclofenac sodium, or diclofenac potassium. In one embodiment, the composition includes a pharmaceutically acceptable inorganic salt of diclofenac. In a specific embodiment, the composition includes diclofenac ammonium, diclofenac sodium, or diclofenac potassium. In another specific embodiment, the composition includes diclofenac sodium or diclofenac potassium. In yet another embodiment, the composition includes diclofenac sodium. In some embodiments, the composition includes diclofenac or a pharmaceutically acceptable salt of diclofenac as the only active pharmaceutical ingredient.

[0090] The present inventors compared the stability of a conventional emulgel and a hydroalcoholic gel formulation, both of which contained diclofenac diethylammonium. The inventors found that the emulgel exhibited slower nitrosamine formation than the hydroalcoholic composition. Without being bound by any particular theory, the inventors believe that the lipophilic phase, and any antioxidants that may be present in the lipophilic phase, may have a stabilizing effect on secondary amines, thereby slowing nitrosamine formation. Therefore, inorganic diclofenac salts, such as diclofenac ammonium, diclofenac sodium, or diclofenac potassium, may be preferred in the hydroalcoholic single-phase compositions of the present disclosure. However, these salts may be more difficult to solubilize in hydroalcoholic gels than organic diclofenac salts. Furthermore, counterions, particularly Na+ and K+, may interact with certain gelling agents, adversely affecting their gel-building and thickening effects. This is the case, for example, with so-called carbomer gelling agents, which are often referred to as "ion-sensitive." However, carbomer gelling agent is a preferred gelling agent for the compositions of the present disclosure because it provides gels with particularly appealing tactile and skin feel. The inventors have surprisingly been able to formulate embodiments of the presently disclosed compositions comprising an inorganic diclofenac salt and a carbomer gelling agent in a hydroalcoholic single-phase formulation base that still has a suitable viscosity.

[0091] Preferably, the composition is substantially free of additional API(s). This means that no API(s) are added to the composition in addition to diclofenac (or a diclofenac salt). For example, the composition does not contain an additional NSAID, such as ibuprofen. In one embodiment, the composition is free of counterirritants. In one embodiment, the composition is substantially free of counterirritants.

[0092] In some embodiments, the composition contains a total concentration of diclofenac or a pharmaceutically acceptable salt of diclofenac equivalent to about 1.5% w / w to about 2.5% w / w of diclofenac sodium. Generally, in this disclosure, unless otherwise specified, diclofenac salt concentrations are given as diclofenac sodium equivalents. In some embodiments, the composition contains a total concentration of diclofenac or a pharmaceutically acceptable salt of diclofenac equivalent to about 1.8% w / w to about 2.2% w / w of diclofenac sodium. In some embodiments, the composition contains about 2.32% w / w of diclofenac diethylammonium salt. 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 certain embodiments, the composition contains about 2% diclofenac sodium. As discussed above, the higher the concentration of diclofenac or its salts, the more difficult it is to solubilize. Furthermore, the concentration of counterions can interfere with the gelling ability of the gelling agent. The disclosed solvent system is suitable for solubilizing even the described high concentrations of diclofenac or diclofenac salts, and the resulting hydroalcoholic single-phase gel compositions are visually transparent. They still possess the desired spreading properties and viscosity, even when a carbomer gelling agent is used. Additionally, they have desirable transmission properties.

[0093] In alternative embodiments, the compositions of the present disclosure may contain diclofenac or a diclofenac salt at a concentration equivalent to about 0.5% w / w to about 1.5% w / w of diclofenac sodium. In some embodiments, the compositions contain a total concentration of diclofenac or a pharmaceutically acceptable salt of diclofenac equivalent to about 0.8% w / w to about 1.2% w / w of diclofenac sodium. In one embodiment, the composition contains diclofenac sodium at a concentration of about 0.5% w / w to about 1.5% w / w. Preferably, the composition contains diclofenac sodium at a concentration of about 1% w / w to about 1.2% w / w. Particularly preferred is a diclofenac sodium concentration of about 1% w / w. In an alternative embodiment, the composition contains diclofenac diethylammonium salt at about 1.16% w / w. 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.

[0094] Within these described concentration ranges, excellent API solubilization is achieved. No visible crystals of the API remain in the composition after formulation. In one embodiment, no crystals of diclofenac or its salts are detectable in the composition when examined with the naked eye or with an optical microscope having a magnification of 10x, 40x, 100x, 400x, 800x, or 1200x.

[0095] Preferably, the composition is substantially free of additional API(s). This means that no APIs are added to the composition in addition to diclofenac (salt). For example, the composition does not contain an additional NSAID, such as ibuprofen. In one embodiment, the composition is free of counterirritants. In one embodiment, the composition is substantially free of counterirritants. In one embodiment, the composition comprises diclofenac or a pharmaceutically acceptable salt of diclofenac as the only active pharmaceutical ingredient.

[0096] The compositions of the present disclosure may contain diclofenac or a diclofenac salt at a concentration equivalent to about 1.5% w / w to about 2.5% w / w, 1.8% w / w to about 2.2% w / w, or about 1.9% w / w to about 2.1% w / w of diclofenac sodium. Generally, in this disclosure, unless otherwise specified, the concentration of the diclofenac salt is expressed as the diclofenac sodium equivalent. In one embodiment, the composition contains diclofenac sodium at a concentration of about 1.5% w / w to about 2.5% w / w. Preferably, the composition contains diclofenac sodium at a concentration of about 1.8% w / w to about 2.2% w / w. Particularly preferred is a diclofenac sodium concentration of about 2% w / w.

[0097] Within these concentration ranges, excellent API solubilization is achieved. No visible crystals of the API remain in the composition after formulation. In one embodiment, no crystals of diclofenac or its salts are detectable in the composition when examined with the naked eye or with an optical microscope having a magnification of 10x, 40x, 100x, 400x, 800x, or 1200x.

[0098] The compositions disclosed herein comprise a gelling agent. The compositions comprise a hydroalcoholic continuous phase comprising the gelling agent. In one embodiment, the compositions comprise a gelled hydroalcoholic continuous phase. In one embodiment, the composition is a gel comprising an aqueous continuous phase and a three-dimensional network formed by the gelling agent.

[0099] In some embodiments, the compositions of the present disclosure may include a carbomer gelling agent. Carbomer gelling agents produce very clear, transparent gels. As mentioned above, carbomer gelling agents also produce gels with superior spreading properties that are preferred by many consumers over other gels, such as hydroxypropyl methylcellulose gels. For example, carbomer 974P or carbomer 980 can be used.

[0100] The carbomer gelling agent may be present in an amount sufficient to increase the viscosity of the composition. The carbomer gelling agent may be present in a concentration of about 1.5% w / w to about 2.5% w / w, about 1.8% w / w to about 2.2% w / w, or about 2% w / w. Preferably, the viscosity is high enough to allow the composition to be administered through a tube. Preferably, the viscosity of the final composition is about 1 Pa.S to about 5 Pa.S, more preferably about 1.8 Pa.S to about 4 Pa.S.

[0101] In embodiments including an acidic gelling agent such as carbomer(s), the composition further includes a basic agent. The basic agent initiates gelation of the acidic gelling agent, such as the 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, or tertiary alkanolamine, and 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 basic agent is an inorganic basic agent. In one embodiment, the basic agent is NaOH, KOH, or ammonia solution. The ammonia solution may be, for example, a 10% or 30% ammonia solution.

[0102] The compositions may optionally contain additional ingredients such as fragrances, chelating agents, preservatives, stabilizers, antioxidants, colorants, and the like.

[0103] In some embodiments, the compositions disclosed herein are substantially free of permeation enhancers. Typically, permeation enhancers are included in the compositions to increase the cumulative permeation and / or flux of the API. However, permeation enhancers can be irritating to the skin. Furthermore, some permeation enhancers must be specifically highlighted on the package label. Specifically, the compositions may be free of isostearic acid and other fatty acids or acids. Permeation enhancers can result in a cloudy, hazy, or milky composition and are therefore undesirable. Specifically, the compositions preferably do not include fatty alcohols, fatty acids, isopropyl myristate, isopropyl palmitate, and diethyl sebacate.

[0104] Preferably, the compositions disclosed herein are substantially free of added humectants, such as glycerol. Humectants are often included in topical compositions for their cooling, conditioning, and moisture-retaining properties, but humectants can result in the product taking longer to dry on the skin. Therefore, humectants are not preferred.

[0105] Preferably, the compositions disclosed herein are substantially free of sensates. For example, the compositions may be free of peppermint oil, l-menthol and menthol derivatives, methyl salicylate, ethyl salicylate, glycol monosalicylate, and the like. Preferably, the compositions are substantially free of counterirritants. Preferably, the compositions are substantially free of inductive stimulants. Sensates, counterirritants, and inductive stimulants are often incorporated to provide the "fast-acting" cooling sensation described above as a desirable sensory attribute. However, they may also cause clouding or breakdown of the formulation. They may also cause irritation. Furthermore, they may affect the permeation of the composition.

[0106] stability As discussed above, it is important that the API is solubilized and remains solubilized. This can be determined by the absence of API crystals. Preferably, the composition does not contain API crystals upon visual inspection with an optical microscope. Preferably, the composition is homogeneous upon visual inspection with the unaided eye. Preferably, the composition does not contain API crystals over a shelf life of 12, 24, or 36 months. In some embodiments, the composition is homogeneous upon visual inspection with an optical microscope having a magnification of 10x, 40x, 100x, 400x, 800x, or 1200x. In some embodiments, the composition is homogenous upon visual inspection by light microscopy having a magnification of 10x, 40x, 100x, 400x, 800x, or 1200x after storage under accelerated stability test conditions at 40°C ± 2°C / 75% ± 5% relative humidity for 6, 12, 24, or 36 months, or under long-term stability test conditions at 30°C ± 2°C / 65% ± 5% relative humidity for 3, 6, 12, 24, or 36 months.

[0107] transparent The inventors' objective was to discover a composition that provides a cumulative permeation treatment to reference ratio (T / R) over 24 hours in an in vitro skin permeation study with a 90% CI between 0.8 and 1.25 relative to the reference product, Voltarol Joint Pain Relief 2.32% Diclofenac Diethylammonium. Methods for measuring cumulative skin permeation are described in detail in the Examples section. In one embodiment, the compositions herein have a cumulative permeation over 24 hours in an in vitro human skin permeation study that meets the acceptance criteria of the Draft Guideline on Quality and Comparability of Topical Products, CHMP / QWP / 708282 / 2018, lines 708-710. In one embodiment, the composition has a cumulative permeation over 24 hours in an in vitro human skin permeation study where the 90% confidence interval for the ratio of the means of the composition and the comparator product, Voltarol Joint Pain Relief 2.32% Diclofenac Diethylammonium, is within an acceptance interval of 80.00 to 125.00%.

[0108] In certain embodiments, the composition has an accumulation over 24 hours in an in vitro human skin permeation study that meets the acceptance criteria of the Draft Guideline on Quality and Comparability of Topical Products, CHMP / QWP / 708282 / 2018, lines 711-715. In another embodiment, the composition has an accumulation over 24 hours in an in vitro human skin permeation study where the 90% confidence interval for the ratio of the mean of the composition and the comparator product, Voltarol Joint Pain Relief 2.32% Diclofenac Diethylammonium, is within an acceptance interval of 69.84% to 143.19%. In cases where there is high intra-subject or intra-donor variability, wider acceptance criteria for the 90% confidence interval may be acceptable.

[0109] In some embodiments, the composition has a cumulative permeation in an in vitro skin permeation test that allows bridging to literature data for Voltarol Joint Pain Relief 2.32% Diclofenac Diethylammonium for registration under well-established criteria for use pursuant to Annex I of Directive 2001 / 83 / EC.

[0110] As explained above, by the specific selection of the solvent system and the inclusion of a hydrophilic nonionic emulsifier, the permeation of the hydroalcoholic single-phase composition can be tuned, resulting in a reduction in cumulative permeation compared to other hydroalcoholic single-phase gel compositions. This effect can be summarized as a permeation retardation effect. This effect is also evident from the examples.

[0111] Specific Embodiments In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - non-ionic emulsifiers, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0112] In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 14 to about 16, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0113] In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - Macrogol cetostearyl ether 20, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0114] In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, a nonionic emulsifier having a hydrophilic-lipophilic balance value of about 16 to about 18, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0115] In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - Polysorbate 20, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0116] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - water, 1. A hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising: A hydroalcoholic single phase gel composition is provided, wherein the composition is substantially free of a lipophilic phase.

[0117] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - at least one non-ionic emulsifier in a concentration of about 0.5% w / w to about 4% w / w, and - water A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0118] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, glycol in a concentration of about 2.5% w / w to about 20% w / w, a non-ionic emulsifier at a concentration of about 0.5% w / w to about 4% w / w, and - water A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0119] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, isopropanol, ethanol, or a combination thereof; - propylene glycol, - non-ionic emulsifiers, and - water A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0120] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac in a concentration equivalent to about 1.5% w / w to about 2.5% w / w of diclofenac sodium, - carbomer gelling agent, an aliphatic C2-C4 monoalcohol in a concentration of about 5% w / w to about 20% w / w, - a C2-C4 polyhydric alcohol in a concentration of about 2.5% w / w to about 20% w / w, a non-ionic emulsifier at a concentration of about 0.1% w / w to about 5% w / w, and - Water, and - A basic agent for adjusting the pH of the entire composition to about 6.5 to about 8.5 A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0121] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - aliphatic C2-C4 monoalcohols, aliphatic diols, - non-ionic emulsifiers, - Water, and a basic agent for adjusting the pH of the entire composition to a pH of about 6.5 to about 8.5; and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants, and / or coloring agents. A composition consisting essentially of:

[0122] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - aliphatic C2-C4 monoalcohols, aliphatic diols, a first nonionic emulsifier having a hydrophilic-lipophilic balance value of from about 14 to about 16, a second nonionic emulsifier having a hydrophilic-lipophilic balance value of from about 16 to about 18, - Water, and a basic agent for adjusting the pH of the entire composition to a pH of about 6.5 to about 8.5; and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants, and / or coloring agents. A composition consisting essentially of:

[0123] Preferably, the composition is substantially free of anionic emulsifiers, hi some embodiments, the composition is substantially free of anionic emulsifiers and substantially free of cationic emulsifiers.

[0124] Manufacturing method The composition can be prepared as follows: - in a first container, dispersing the gelling agent in a first portion of water until completely dispersed; - adding a basic agent to the gelling agent dispersion when needed to initiate the gelling of the gelling agent to obtain a gel; - combining in a second container a second portion of the water, the aliphatic monoalcohol, the aliphatic diol and the non-ionic emulsifier(s); - dispersing diclofenac or a pharmaceutically acceptable salt of diclofenac into the mixture in a second container to obtain an API solution; - Combine the gel and API solution under homogenization.

[0125] Purpose The compositions disclosed herein are suitable for use in the treatment of: Pain, inflammation and swelling in: - Soft tissue injuries: injuries to tendons, ligaments, muscles and joints, e.g. sprains, strains, bruises and back pain (sports injuries) - Localized forms of soft tissue rheumatism: tendonitis (e.g., tennis elbow), bursitis, shoulder-hand syndrome and periarthropathy, and -Minor arthritic pain in the knees or fingers.

[0126] Pharmaceutical Composition / Route of Administration / Dosage The composition can be administered to mammals suffering from joint pain, osteoarthritis, muscle pain, back pain and / or inflammation. Preferably, the composition is for the treatment of humans. The composition is useful for treating pain, inflammation and swelling in soft tissue injuries such as tendon, ligament, muscle and joint trauma due to, for example, sprains, strains, contusions and back pain (sports injuries), and / or localized soft tissue rheumatism such as tendonitis (e.g., tennis elbow), bursitis, shoulder-hand syndrome and periarthritis.

[0127] The compositions are also useful for treating mild arthritic pain in the knees or fingers.

[0128] The composition can be applied to the skin overlying the body part of concern. The composition may be rubbed in until the skin feels dry. The composition may be applied two to four times per day. A method of treatment may include administering a pharmaceutically effective amount of a composition disclosed herein to a subject in need thereof. The method may include administering the composition to the skin overlying a body part that is suffering from or causing one or more of the following: soft tissue injuries, such as trauma to tendons, ligaments, muscles, and joints due to, for example, sprains, strains, bruises, and back pain (sports injuries); and / or pain, inflammation, and swelling in tendonitis (e.g., tennis elbow), bursitis, shoulder-hand syndrome, and localized soft tissue rheumatism, such as periarthritis; or non-severe arthritic pain.

[0129] The composition can be provided in a package that includes a means for administration. The composition may be provided in a container that includes an applicator for direct application onto the skin.

[0130] The embodiments described herein can be more readily understood by 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 merely illustrative of the principles of the present invention. Many modifications and adaptations will be readily apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0131] Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein. For example, a range stated as "1.0 to 10.0" should be considered to include any and all subranges beginning with a minimum value greater than or equal to 1.0 and ending with a maximum value less than or equal to 10.0, such as 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9.

[0132] All ranges disclosed herein should also be considered to include the endpoints of the range unless otherwise specified. For example, a range "between 5 and 10" or "from 5 to 10" or "5 to 10" should generally be considered to include the endpoints 5 and 10.

[0133] Furthermore, unless expressly prohibited by the nature of the present disclosure or related embodiments, it should be understood that a feature or features of one embodiment may generally be applied to other embodiments even if not specifically described or exemplified in such other embodiments. Similarly, the compositions and methods described herein may include any combination of the features and / or steps described herein that is not inconsistent with the objectives of the present disclosure. Many modifications and / or adaptations of the compositions and methods described herein will be readily apparent to those of skill in the art without departing from the present subject matter. Unless otherwise indicated, concentrations are given in % (w / w).

[0134] Unless otherwise indicated, concentrations are given in % (w / w).

[0135] The term "about" in reference to a numerical value x means, for example, x±10%, x±5%, x±4%, x±3%, x±2%, x±1%.

[0136] pH, viscosity and HLB are typically measured at 25°C. [Example]

[0137] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0138] Example 1: Comparison of Cumulative Skin Permeation in Emulgel and Hydroalcoholic Gel over 24 Hours In vitro skin permeation studies were conducted in preclinical laboratories. Skin permeation studies can be used to determine, for example, the qualitative permeation characteristics of a formulation through human skin. Skin permeation studies can also be used for direct quantitative comparison of the permeation and flux of two given formulations. In Example 1, the cumulative permeation of a hydroalcoholic test formulation was compared with that of an emulgel reference product. Five test formulations and the reference product were each measured at 10 mg / cm at time 0. 2 The test formulations were applied to the abdominal skin of human donors at a dose of 0.01 mg / mL. Each formulation was tested on five skin samples from different donors on Franz diffusion cells. The reference product for comparison was Voltaren Emulgel 1.16% (m / m) diclofenac diethylammonium. The compositions of the test formulations and the reference product Voltaren Emulgel 1.16% (m / m) are listed in Table 1:

[0139] [Table 1]

[0140] The concentration of diclofenac in the receptor fluid of the Franz cells was measured at t=0, 4, 8 and 24 hours, and the endpoint of the study was the cumulative amount of diclofenac permeated at 24 hours.

[0141] The results of the study are given in Table 2.

[0142] [Table 2]

[0143] Surprisingly, the cumulative permeation of all test formulations, Test 1 to Test 5, significantly exceeded that of the reference product. Although the concentration of the active ingredient was the same in all tested compositions, the hydroalcoholic formulations, Test 1 to Test 5, showed cumulative permeation at 24 hours that was approximately 1.7 times (Test 4) to almost 3 times (Test 5) higher than that of the reference product. This led the inventors to conclude that the absence of a dispersed lipophilic phase results in a higher cumulative permeation at 24 hours.

[0144] Example 2: Comparison of Cumulative Skin Permeation in Emulgel and Hydroalcoholic Gel over 24 Hours In cumulative skin permeation studies using 3 ml permeation cells, cumulative permeation through skin samples from human donors was studied.Five different compositions were tested in sextuplicate.Cumulative permeation was measured 4 hours and 24 hours after application of the dose.However, the cumulative permeation at 4 hours was below the measurement threshold in this experiment, and therefore is not reported in Example 2.All formulations were applied at a dose of 6 microliters onto skin samples with a defined surface area.The following formulations were studied:

[0145] [Table 3]

[0146] Voltaren Arthritis Pain was an emulgel composition, while test compositions F072, F077, F078, and F079 were hydroalcoholic gel compositions containing no nonionic emulsifier (F072), one nonionic emulsifier (F077 and F078), or a combination of two nonionic emulsifiers (F079). Voltaren Arthritis Pain was used as a comparator because the study was intended to study the differences between emulgel and hydroalcoholic gel and because the product was readily available commercially.

[0147] The results are summarized in the table above and visualized in Figure 2. All test compositions exhibited higher cumulative permeation at 24 hours than the test compositions. Because the test compositions contained more diclofenac sodium (2% w / w instead of 1% w / w), it was expected that the cumulative permeation from the test compositions would be higher than that of the comparator. However, the magnitude of the difference was surprisingly large and unexpected. Interestingly, formulation F072, which contains the same excipient types as the comparator except for the lipophilic phase (cocoyl caprylocaprate and mineral oil) and emulsifier (Coriphor CS 20), exhibited a cumulative permeation at 24 hours that was nearly five-fold higher than that of the comparator. Unexpectedly, this significant increase in cumulative permeation at 24 hours could be reduced by the incorporation of a nonionic emulsifier. Thus, contrary to teachings in the art, nonionic emulsifiers may have a permeation-retarding effect. Comparing the cumulative permeation at 24 hours of all tested formulations, both Corifol PS 20 and Corifol CS 20 have permeation retarding effect, with the permeation retarding effect of Corifol CS 20 being more pronounced. Formulation F079, which contains a combination of Corifol CS 20 and Corifol PS 20 at a total concentration of 4% w / w, showed the lowest cumulative permeation at 24 hours among all tested formulations.

[0148] Example 3: Comparison of Cumulative Skin Permeation Over 24 Hours in Emulgel and Hydroalcoholic Gel Containing 2% w / w Diclofenac Epolamine To test the hypothesis that nonionic emulsifiers would have the same effect in compositions containing various salts of diclofenac, particularly diclofenac salts with organic counterions, the experiment of Example 1 was repeated with a test composition containing diclofenac epolamine. The comparator was the same as in Example 1. Unless otherwise specified, the experimental setup was the same as in Example 1.

[0149] [Table 4]

[0150] The results are summarized in the table above and visualized in Figure 3. Interestingly, only formulation DiEp-F004, the test composition without a lipophilic phase or emulsifier, showed significantly higher cumulative permeation than the comparator. Surprisingly, all test compositions containing one nonionic emulsifier (DiEp-F005 and DiEp-F006) or two nonionic emulsifiers (DiEp-F007) showed a cumulative permeation at 24 hours that was much lower than that of the comparator. Therefore, the permeation retarding effect of nonionic emulsifiers appears to be much more pronounced in the compositions containing diclofenac epolamine than in the compositions containing diclofenac sodium (Example 2). Interestingly, formulations DiEp-F005, DiEp-F006, and DiEp-F007 showed very similar cumulative permeation at 24 hours. In the formulations containing diclofenac epolamine, Corifol CS 20 and Corifol PS 20 appear to have similar permeation retarding effects. When used in combination at a total concentration of about 4% w / w (DiEp-F007), the cumulative permeation at 24 hours was further reduced.

[0151] Example 4: Comparison of Cumulative Skin Permeation Over 24 Hours in Emulgels and Hydroalcoholic Gels Containing 2% w / w Diclofenac Sodium and Various Concentrations of Non-ionic Emulsifiers in a Non-GLP Comparative Skin Permeation Study at Various Posologies Hydroalcoholic compositions containing 2% w / w diclofenac sodium and varying levels of nonionic emulsifier were studied. Concurrently, concentrations of isopropanol and propylene glycol were varied to study the effect of these ingredients on cumulative permeation. The comparator was Voltarol Joint Pain Relief, also known as Voltaren 2.32% Diclofenac Diethylamine (DDEA) Emulgel in some markets.

[0152] Split-thickness abdominal human skin samples (200–400 μm) with transepithelial electrical resistance (TEER) values ​​>7.7 kΩ were mounted in static diffusion cells (exposed area = 0.64 cm2) and maintained under controlled temperature conditions (32 ± 1°C). Each study formulation was applied in duplicate to skin samples from six donors (i.e., total skin samples per formulation = 12 = N). Two experiments were conducted to evaluate the effects of single (t = 0 h) and four (t = 0, 4, 8, and 12 h) dosing. The receptor fluid was phosphate-buffered saline with 5% bovine serum albumin. Receptor fluid samples were collected at 0, 2, 4, 8, 16, and 24 h after the first dose and analyzed for diclofenac content by LC-MS / MS. Cumulative absorption of diclofenac in the receptor fluid was calculated for each test formulation and for both dosing intervals. Cumulative absorption of diclofenac was analyzed 24 hours after the first dose. For any post-baseline samples with concentrations below the LOQ, half the limit of quantitation (LOQ) was used. The statistical model used was analysis of variance (ANOVA) on log-transformed geometric means, including formulation and donor as fixed effects.

[0153] [Table 5]

[0154] [Table 6]

[0155] The results are summarized in the table above.

[0156] In Example 4, it was observed that the cumulative permeation of Composition Test 10 was most similar to that of the reference product. In Tests 10, 11, and 14, the 60% CI of the geometric least squares mean ratios of the cumulative absorption of diclofenac in the receptor fluid 24 hours after administration was entirely within 0.67 to 1.50. Therefore, these test formulations are considered to have permeation characteristics most similar to the comparator. On the other hand, when 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 is clear that higher concentrations of propylene glycol result in higher cumulative permeation. Comparing Test 14 and Test 13 alone, Test 13 and Test 14 have identical compositions, except that Test 13 contains only 2.00% w / w Corifol CS 20, while Test 14 additionally contains 1.00% w / w Corifol PS 20 (due to water). The addition of a second nonionic emulsifier reduces cumulative permeation, even to the extent that Test 14, which contains more than 10% w / w propylene glycol, has a cumulative permeation whose 60% CI for the geometric least-squares mean ratio of cumulative absorption of diclofenac in the receptor fluid 24 hours after administration is entirely within 0.67 to 1.50. Test 12, the test composition containing two nonionic emulsifiers and only 5% w / w propylene glycol, had the lowest cumulative permeation.

Claims

1. - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - Aliphatic C at a concentration of about 5% w / w to about 20% w / w 2 ~C 4 Monoalcohol, - an aliphatic diol in a concentration of about 2.5% w / w to about 20% w / w, - non-ionic emulsifiers, and - water 1. A hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

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

3. 3. The composition of claim 1, comprising at least two different nonionic emulsifiers.

4. The composition of any one of claims 1 to 3, 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 of any one of claims 1 to 3, 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. 5. The composition of claim 1, further comprising a nonionic emulsifier selected from the group consisting of macrogol cetostearyl ether 20, polysorbate 60, polysorbate 80, isosteareth 20, PEG-60 almond glyceryl fatty acid, PEG-20 methyl glucose sesquistearate, oleth-20, steareth-20, and combinations of two or more thereof.

6. The composition according to any one of claims 1 to 5, comprising macrogolcetostearyl ether.

7. The composition of any one of claims 1 to 6, comprising a non-ionic emulsifier selected from the group consisting of polysorbate 20, laureth-20, and combinations thereof.

8. The composition according to any one of claims 1 to 7, comprising polysorbate 20.

9. 9. The composition of claim 1, comprising a nonionic emulsifier comprising a 2-isopropyl-tetrahydrofuran moiety comprising one or more oligo(ethylene oxide) ester groups, wherein all of the ethylene oxide units of the oligo(ethylene oxide) ester groups in combination contain 10 to 30, 14 to 24, or 20 carbon atoms.

10. 10. The composition of any one of claims 1 to 9, comprising 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.

11. 11. The composition of any one of claims 1 to 10, comprising a first non-ionic emulsifier that is macrogolcetostearyl ether and a second non-ionic emulsifier that is a polysorbate.

12. 12. The composition of any one of claims 1 to 11, comprising a non-ionic emulsifier in 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 of any one of claims 1 to 12, wherein the non-ionic emulsifier retards the permeation of diclofenac.

14. 14. The composition of any one of claims 1 to 13, having a cumulative permeation in an in vitro skin permeation test that allows for reliance on literature data for Voltarol Joint Pain Relief 2.32% Diclofenac Diethylammonium for registration under well-established criteria of use pursuant to Annex I of Directive 2001 / 83 / EC.

15. A composition according to any one of claims 1 to 14 for use in a method for the treatment of non-severe arthritic pain in the knees or fingers.

16. Use of a non-ionic emulsifier to reduce the cumulative permeation of diclofenac through the skin over a 6-hour, 9-hour, 12-hour or 24-hour period from a hydroalcoholic single-phase gel for topical delivery of diclofenac.

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