Hydroalcoholic topical diclofenac preparation

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 is useful for the topical delivery of diclofenac. The composition can be used, for example, to treat pain, inflammation, and swelling in soft tissue injuries.

Description

[Technical Field]

[0001] The present disclosure relates to hydroalcoholic 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 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 satisfy evolving consumer preferences. Summary of the Invention

[0003] - diclofenac or a pharmaceutically acceptable diclofenac salt in a concentration equivalent to about 0.5% w / w to about 1.5% w / w of diclofenac sodium, - 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% w / w to about 10% w / w, a hydrophilic non-ionic emulsifier at a concentration of about 1% w / w to about 2% w / w, and - water A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is disclosed, comprising:

[0004] In one embodiment, the composition comprises diclofenac sodium.

[0005] In one embodiment, the composition comprises diclofenac sodium in a concentration of about 1% w / w.

[0006] In one embodiment, the nonionic emulsifier has a hydrophilic-lipophilic balance value of from about 13 to about 17, from about 14 to about 16, or about 15.

[0007] In one embodiment, the non-ionic emulsifier is an ethoxylated C16-C18 alcohol.

[0008] In one embodiment, the nonionic emulsifier is 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.

[0009] In one embodiment, the composition comprises macrogolcetostearyl ether.

[0010] In one embodiment, the non-ionic emulsifier retards the permeation of diclofenac.

[0011] In one embodiment, the composition does not contain fats, oils, waxes, occlusive agents, or carbohydrate-based ointment bases.

[0012] In one embodiment, the composition is substantially free of oil.

[0013] In one embodiment, the composition is substantially free of fat.

[0014] In one embodiment, the composition is substantially free of waxes.

[0015] In one embodiment, the composition is substantially free of carbohydrate-based ointment bases.

[0016] In one embodiment, the composition is substantially free of a lipophilic dispersed phase.

[0017] In one embodiment, the gel is clear.

[0018] In one embodiment, the composition has a pH of about 6.5 to about 8.5.

[0019] In one embodiment, the composition comprises an aliphatic C2-C4 monoalcohol at a concentration of about 8% w / w to about 18% w / w or about 10% w / w to about 15% w / w.

[0020] In one embodiment, the composition comprises an aliphatic diol at a concentration of about 3% w / w to about 8% w / w or about 3% w / w to about 5% w / w.

[0021] In one embodiment, the aliphatic C2-C4 monoalcohol is isopropanol.

[0022] In one embodiment, the aliphatic diol is propylene glycol.

[0023] In one embodiment, the composition comprises isopropanol as the only aliphatic C2-C4 monoalcohol and propylene glycol as the only aliphatic diol.

[0024] In one embodiment, the composition has a cumulative permeation in an in vitro skin permeation test that allows for reliance on literature data for Voltaren Arthritis Pain (diclofenac sodium topical gel, 1% (NSAID) - arthritis pain reliever) or Voltaren Diclofenac Diethylamine 1.16% gel for registration under well-established use criteria pursuant to Annex I of Directive 2001 / 83 / EC.

[0025] Also disclosed are compositions for use in methods for relieving pain, inflammation, and swelling in soft tissue injuries, localized forms of soft tissue rheumatism, and for relieving pain from mild arthritis of the knees or fingers. [Brief explanation of the drawings]

[0026] [Figure 1] 1 is an example of a composition according to the present disclosure when used with a dosing card. [Figure 2] Graphical representation of the results of Example 2 [Figure 3] Graphical representation of the results of Example 3 DETAILED DESCRIPTION OF THE INVENTION

[0027] An example of a topical diclofenac formulation is Voltaren Arthritis Pain (Diclofenac Sodium Topical Gel, 1% (NSAID) - Arthritis Pain Reliever), which contains 1% w / w diclofenac sodium and has been approved in the United States as an over-the-counter (OTC) drug since 2020. Another topical diclofenac formulation contains 1.16% w / w diclofenac diethylammonium salt (equivalent to 1% diclofenac sodium salt), which is sold as Voltaren or Voltarol 1.16% Emulgel. Voltaren 1.16% Emulgel has been sold in Europe since 1974. Voltaren Arthritis Pain and Voltaren 1.16% Emulgel are emulsion gels (emulgels). Emulgel formulations are described, for example, in US Pat. No. 4,917,886 A in combination with the active ingredient (API) diclofenac.

[0028] 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.

[0029] The existing Voltaren 1% or 1.16% Emulgel products are successful commercial 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.

[0030] 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).

[0031] At the same time, the advantageous properties of the existing Voltaren 1% or 1.16% 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 ensuring similar efficacy and safety. Furthermore, the beneficial sensory attributes of the existing products, such as a pleasant stretching experience and cooling effect, should be maintained or improved.

[0032] 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 1.16% 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.

[0033] Surprisingly, the inventors were able to formulate a single-phase hydroalcoholic gel with permeation properties very similar to those of an emulgel.

[0034] Therefore, the inventors sought to improve the user's sensory experience and convenience while maintaining similar skin permeation characteristics to Voltaren 1% or Voltaren 1.16% Emulgel. This approach was adopted to maintain the advantageous properties of Voltaren 1% or 1.16% 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 that of 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 standard of "well-established use" by relying on published literature data for Voltaren 1% Emulgel or Voltaren 1.16% Emulgel.

[0035] composition Hydroalcoholic single-phase composition The compositions disclosed herein are compositions for topical delivery of diclofenac. This means that the compositions contain diclofenac as the active pharmaceutical ingredient (API). The compositions are intended to be applied to the skin of a patient in need of treatment with the API. The compositions are effective vehicles 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 may 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 hereinafter. The skin is a complex structure containing several tissue layers. Therefore, the skin constitutes a significant barrier for the API. For the avoidance of doubt, the compositions disclosed herein are not intended for the treatment of dermal conditions. In one embodiment, the compositions are not for the treatment of dermal conditions.

[0036] 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.

[0037] 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).

[0038] 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.

[0039] 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 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.

[0040] 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 and Voltaren 1.16% Emulgel contain a lipophilic dispersed phase, e.g., liquid paraffin as a lipophilic hydrophobic component. 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. 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 especially difficult to formulate a single-phase hydroalcoholic gel in which the diclofenac or diclofenac salt is completely solubilized over an extended period of time, over shelf life, and / or during storage.

[0041] 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 a specific concentration of a hydrophilic nonionic emulsifier 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.

[0042] One aspect of conventional multiphase systems is that they typically contain globules of a certain globule size. Most multiphase systems contain a dispersed phase with a globule size that scatters light and makes 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 an aqueous-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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] Preferably, the compositions disclosed herein are substantially free of lipophilic excipients. In this 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 this 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 certain compounds, 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.

[0047] 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.

[0048] 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.

[0049] The present inventors have surprisingly found that in the hydroalcoholic compositions of the present disclosure, hydrophilic nonionic emulsifiers can reduce the cumulative permeation of diclofenac. Thus, in one aspect, such hydrophilic nonionic emulsifiers can have a permeation retarding effect on diclofenac or its salts in the hydroalcoholic compositions of the present disclosure. This is particularly surprising in view of the teachings in the art (Iti Som et al., referenced above) regarding the permeation enhancing effect of nonionic emulsifiers.

[0050] As 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 products Voltaren 1% Emulgel or Voltaren 1.16% Emulgel and that can rely on their extensive drug safety experience. Thus, in one aspect, the inventors sought to provide a composition having a permeation profile similar to that of Voltaren 1% Emulgel or Voltaren 1.16% Emulgel. Surprisingly, it has been found that the cumulative permeation of diclofenac from hydroalcoholic gels can be adjusted by incorporating a hydrophilic nonionic emulsifier. Furthermore, nonionic emulsifiers do not contain ionizable groups and are relatively insensitive to changes in pH. Therefore, nonionic emulsifiers can stabilize the compositions.

[0051] In one embodiment, the composition comprises at least one hydrophilic nonionic emulsifier. In one embodiment, the composition comprises a single class of hydrophilic nonionic emulsifier. In one embodiment, the composition comprises a single hydrophilic nonionic emulsifier. In one embodiment, the composition comprises only one hydrophilic nonionic emulsifier.

[0052] In one embodiment, the composition includes a hydrophilic nonionic emulsifier having an HLB of about 13 to about 17, about 14 to about 16, or about 15. In one particular embodiment, the composition includes a hydrophilic nonionic emulsifier having an HLB of about 15. In one embodiment, the composition includes one hydrophilic nonionic emulsifier, and the one hydrophilic nonionic emulsifier has an HLB of about 13 to about 17, about 14 to about 16, or about 15.

[0053] In one embodiment, the composition comprises a hydrophilic nonionic emulsifier that is an ethoxylated C16-C18 alcohol. In another embodiment, the hydrophilic nonionic emulsifier is 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.

[0054] In one particular embodiment, the composition comprises macrogol cetostearyl ether. In another particular 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.

[0055] In one embodiment, the composition comprises a total concentration of hydrophilic nonionic emulsifiers of about 0.5% w / w to about 4% w / w, about 0.8% w / w to about 3% w / w, or about 1% w / w to about 2% w / w. In one embodiment, the composition comprises a total concentration of nonionic emulsifiers of about 1% w / w. In another embodiment, the composition comprises a total concentration of nonionic emulsifiers of about 2% w / w.

[0056] Solvent System The compositions disclosed herein comprise a solvent system comprising 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, greater than about 70% w / w, or greater than about 80% w / w water. In one particular embodiment, the composition comprises about 65% w / w to about 75% w / w water. In another embodiment, the composition comprises about 70% w / w to about 80% w / w water. In one embodiment, the composition is water-based. In one embodiment, the composition is an aqueous composition. Advantageously, water provides a cooling effect to the skin. Water is also a readily available ingredient with a 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 composition comprises water as the base of the composition. Being part of the solvent system, water also plays a role in solubilizing the diclofenac or diclofenac salt.

[0057] 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.

[0058] 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 required visual transparency.

[0059] In some embodiments, the composition includes isopropanol as the only aliphatic C2-C4 monoalcohol. In some embodiments, the composition includes a continuous phase including water and isopropanol, and does not include ethanol. Advantageously, by using isopropanol as the only aliphatic C2-C4 monoalcohol, the number of different ingredients can be kept low, which facilitates production and supply logistics for the topical composition. 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, as ethanol is restricted in many countries for tax or ethical reasons. Thus, in some embodiments, the composition does not include ethanol.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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% or 1.16% Emulgel products, which are described in more detail in another section below.

[0065] In some embodiments, the aliphatic C2-C4 monoalcohol(s) are present in the composition at a concentration of about 5% w / w to about 20% w / w. Preferably, the aliphatic C2-C4 monoalcohol(s) are present at a concentration of about 8% w / w to about 18% w / w. In one embodiment, the aliphatic C2-C4 monoalcohol(s) are present at a concentration of about 10% w / w to about 15% w / w. In certain embodiments, the aliphatic C2-C4 monoalcohol(s) are present at a concentration of about 10% w / w, about 11% w / w, about 12.5% ​​w / w, about 15% w / w, or about 20% w / w. In certain of any of the above embodiments, the aliphatic C2-C4 monoalcohol(s) is isopropanol or ethanol, or a combination of both.

[0066] 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 18% w / w, or about 10% w / w to about 15% w / w. In certain embodiments, the composition comprises isopropanol at a concentration of about 10% w / w, about 11% w / w, about 12.5% ​​w / w, about 15% w / w, or about 20% w / w. In one embodiment, the composition of the present disclosure comprises isopropanol at a concentration of about 5% w / w to about 20% w / w, about 8% w / w to about 18% w / w, or about 10% w / w to about 15% w / w, and does not contain other aliphatic C2-C4 monoalcohol(s).

[0067] These concentration ranges of aliphatic C2-C4 monoalcohol(s) are balanced. On the one hand, high concentrations of aliphatic C2-C4 monoalcohol(s) may be beneficial for API solubilization, antimicrobial, and / or cooling effects. 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 strict labeling, storage, and handling, or 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 described concentration range for the C2-C4 monoalcohol(s) can sufficiently solubilize the API in combination with the water and aliphatic diol of the solvent system. Therefore, the composition may have a reduced risk of API crystallization during storage and after application. The composition may have a reduced risk of leaving API residue or precipitate on the skin. Furthermore, the described concentrations may 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 provides physiological benefit to the patient by providing rapid pain relief. In particular, the cooling sensation may be perceived as immediate onset, noticeable or strong, and long-lasting. The aliphatic C2-C4 monoalcohol(s) further possess 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 that contain high concentrations of water, such as greater than about 60% w / w, greater than about 70% w / w, or greater than about 80% w / w water.

[0068] 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.

[0069] 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 aliphatic C2-C4 monoalcohols at suitable concentrations and further contain a cosolvent that is an aliphatic diol.

[0070] The cosolvent aliphatic diol or C2-C4 polyalcohol may be present in the composition at a concentration of about 2% w / w to about 10% w / w. Preferably, the aliphatic diol or C2-C4 polyalcohol may be present in the composition at a concentration of about 3% w / w to about 8% w / w, or about 3% w / w to about 5% w / w. In one embodiment, the aliphatic diol or C2-C4 polyalcohol is present at a concentration of about 5% w / w. In one embodiment, the aliphatic diol or C2-C4 polyalcohol is present at a concentration of about 3% w / w. In one particular embodiment, the composition comprises about 3% w / w to about 5% w / w of propylene glycol.

[0071] The benefits of including a specific concentration of an aliphatic diol or C2-C4 polyhydric alcohol are described above. The inventors have found that the specific concentration ranges of the aliphatic diol or C2-C4 polyhydric alcohol described are particularly useful. The aliphatic diol or C2-C4 polyhydric alcohol described in the concentration ranges results in compositions with a reduced risk of skin irritation. In another aspect, the described ranges result in compositions with acceptable dry times. In yet another aspect, the resulting compositions have very pleasant skin application characteristics. For example, the resulting compositions are not perceived as sticky or greasy. Furthermore, the resulting compositions are clear, transparent, or sheer. In some embodiments, the compositions can be opalescent. Furthermore, the aliphatic diol concentration also affects the transmission characteristics of the composition.

[0072] In one embodiment, the composition comprises an aliphatic C2-C4 monoalcohol that is isopropanol and an aliphatic diol that is propylene glycol.

[0073] The combined total concentration of the aliphatic C2-C4 monoalcohol and the aliphatic diol is preferably greater than about 10% w / w. The combined total concentration of the aliphatic C2-C4 monoalcohol and the C2-C4 polyalcohol is preferably less than about 30% w / w. Expressed as a range, the combined total concentration of the aliphatic C2-C4 monoalcohol and the aliphatic diol can be from about 10% w / w to about 30% w / w, preferably from about 12% w / w to about 25% w / w. In certain embodiments, the combined total concentration of the aliphatic C2-C4 monoalcohol and the C2-C4 polyalcohol 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.

[0074] 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.

[0075] In some embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:2 to 1:4.5. In some embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:2 to 1:4.2, 1:4, 1:3.7, 1:3, or 1:2.5. In certain embodiments, the ratio of aliphatic diol to aliphatic C2-C4 monoalcohol is 1:2, 1:2.5, 1:3, 1:3.7, 1:4, or 1:4.2. In certain of the above embodiments, the aliphatic C2-C4 monoalcohol is isopropanol and the aliphatic diol is propylene glycol.

[0076] In other specific embodiments, the composition comprises about 10%, about 11%, or about 12.5% ​​isopropanol and about 3% or about 5% propylene glycol, hi certain embodiments, the composition comprises about 12.5% ​​isopropanol and about 5% propylene glycol.

[0077] 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 are replaced with deuterium atoms (i.e., deuterated diclofenac). In one embodiment, the composition includes diclofenac, diclofenac ammonium, diclofenac sodium, diclofenac potassium, or a combination thereof. 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.

[0078] 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.

[0079] 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.

[0080] 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. Generally, in this disclosure, unless otherwise specified, diclofenac salt concentrations are expressed as diclofenac sodium equivalents. 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 compositions contain diclofenac sodium at a concentration of about 0.5% w / w to about 1.5% w / w. Preferably, the compositions contain 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 alternative embodiments, the composition comprises about 1.16% w / w of diclofenac diethylammonium salt. In some other embodiments, the composition comprises about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, or about 1.5% w / w of diclofenac sodium.

[0081] 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.

[0082] The compositions disclosed herein include a gelling agent. The compositions include a gelled hydroalcoholic continuous phase. In other words, the compositions are gels that include an aqueous continuous phase and a three-dimensional network formed by the gelling agent.

[0083] In some embodiments, the compositions of the present disclosure may include a carbomer gelling agent. Carbomer gelling agents provide clear, transparent gels. Carbomer gelling agents also provide gels with superior spreading properties, which are preferred by many consumers over other gels, such as hydroxypropyl methylcellulose gels. For example, carbomer 974P or carbomer 980 can be used.

[0084] 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 at a concentration of about 1% w / w to about 3% w / w, about 1.5% w / w to about 2.5% w / w, or about 2% w / w. In one particular embodiment, the carbomer gelling agent is present at a concentration of about 1.6% 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 2,000 cP to about 16,000 cP. In one particular embodiment, the viscosity of the composition is about 6,000 cP to about 12,000 cP.

[0085] 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 can be present at a concentration suitable to adjust the pH to about 6 to about 8.5, about 7.3 to about 8.2, or about 7 to about 8. The basic agent can be an aliphatic amine, such as a primary, secondary, or tertiary alkanolamine, as well as a primary, secondary, or tertiary alkylamine. For example, monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, dimethylamine, diethylamine, trimethylamine, or triethylamine can 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 can be, for example, a 10% or 30% ammonia solution.

[0086] The compositions may optionally contain additional ingredients such as fragrances, chelating agents, preservatives, stabilizers, antioxidants, colorants, and the like.

[0087] In some embodiments, the compositions disclosed herein are substantially free of permeation enhancers. Typically, permeation enhancers are included in the composition to increase the cumulative permeation and / or flux of the API. However, permeation enhancers can be irritating to the skin. Furthermore, some permeation enhancers require special emphasis on the package label. Specifically, the composition 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 composition preferably does not contain fatty alcohols, fatty acids, isopropyl myristate, isopropyl palmitate, or diethyl sebacate.

[0088] 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.

[0089] 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 cloudiness or physical instability of the formulation. They may also cause irritation. Furthermore, they may affect the permeation of the composition.

[0090] stability As discussed above, it is important that the API is completely solubilized. This can be indicated 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.

[0091] 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, Voltaren Emulgel (diclofenac diethylammonium topical gel, 1.16% (NSAID)). 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 mean of the composition and the comparator product, Voltaren Emulgel (diclofenac diethylammonium topical gel, 1.16%), is within an acceptance interval of 80.00 to 125.00%.

[0092] In certain embodiments, the composition has a 24-hour accumulation 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 a 24-hour accumulation 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, Voltaren Emulgel (diclofenac diethylammonium topical gel, 1.16%), 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.

[0093] In some embodiments, the composition has a cumulative permeation in an in vitro skin permeation test that allows bridging to literature data of Voltaren Arthritis Pain (Diclofenac Sodium Topical Gel, 1% (NSAID) - Arthritis Pain Reliever) or Voltaren Diclofenac Diethylamine 1.16% Gel for registration under well-established criteria for use pursuant to Annex I of Directive 2001 / 83 / EC.

[0094] 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.

[0095] Preferably, the compositions disclosed herein are substantially free of anionic emulsifiers. In some embodiments, the compositions are substantially free of anionic emulsifiers and substantially free of cationic emulsifiers.

[0096] Specific Embodiments In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - aliphatic C2-C4 monoalcohols, aliphatic diols, - hydrophilic non-ionic emulsifiers, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0097] In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - aliphatic C2-C4 monoalcohols, aliphatic diols, - a hydrophilic nonionic emulsifier having an HLB of about 14 to about 16, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0098] In one embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - aliphatic C2-C4 monoalcohols, aliphatic diols, - Macrogol cetostearyl ether 20, and - water A hydroalcoholic single-phase gel composition is provided, comprising:

[0099] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - aliphatic C2-C4 monoalcohols, aliphatic diols, - hydrophilic non-ionic emulsifiers, and - water The present invention provides a hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

[0100] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - aliphatic C2-C4 monoalcohols, aliphatic diols, a hydrophilic non-ionic emulsifier at a concentration of about 0.5% w / w to about 4% w / w, and - water A hydroalcoholic single-phase composition for topical delivery of diclofenac is provided, comprising:

[0101] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - aliphatic C2-C4 monoalcohols, - glycol, a hydrophilic non-ionic emulsifier at a concentration of about 1% w / w to about 2% w / w, and - water A hydroalcoholic single-phase composition for topical delivery of diclofenac is provided, comprising:

[0102] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, isopropanol, ethanol, or a combination thereof; - propylene glycol, - hydrophilic non-ionic emulsifiers, and - water A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0103] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac in a concentration equivalent to about 0.5% w / w to about 1.5% 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 7.5% w / w, a hydrophilic non-ionic emulsifier at a concentration of about 0.5% w / w to about 4% w / w, - Water, and a basic agent in a concentration suitable to adjust the pH of the entire composition to a pH of about 6.5 to about 8.5; A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0104] In another embodiment, diclofenac sodium or diclofenac potassium in a concentration equivalent to about 1% w / w of diclofenac sodium, isopropanol at a concentration of about 5% w / w to about 20% w / w, propylene glycol in a concentration of about 2.5% w / w to about 7.5% w / w; Ethoxylated C at a concentration of about 1% w / w to about 2% w / w 16 ~C 18 a hydrophilic nonionic emulsifier which is an alcohol; - a carbomer gelling agent in a concentration of about 1% w / w to about 2% w / w, a basic agent in a concentration suitable to adjust the pH of the overall composition to a pH of about 6.5 to about 8.5; and - Water with a concentration of approximately 60% w / w to approximately 80% w / w A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, comprising:

[0105] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - aliphatic C2-C4 monoalcohols, aliphatic diols, - hydrophilic nonionic emulsifiers, - Water, and - basic drugs, and optionally flavorings, chelating agents, preservatives, stabilizers, antioxidants, and / or colorants. A hydroalcoholic single-phase gel composition for topical delivery of diclofenac is provided, consisting essentially of: wherein the entire composition has a pH of about 6.5 to about 8.5.

[0106] In another embodiment, - diclofenac or a pharmaceutically acceptable salt of diclofenac, - gelling agents, - aliphatic C2-C4 monoalcohols, aliphatic diols, a nonionic emulsifier having an HLB of about 14 to about 16, - Water, and - basic drugs, and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants, and / or coloring agents. The present invention provides a composition consisting essentially of the above, wherein the entire composition has a pH of about 6.5 to about 8.5.

[0107] In another embodiment, - diclofenac sodium, - carbomer gelling agent, - isopropanol, - propylene glycol, - Macrogol cetostearyl ether, - Water, and - basic drugs, and optionally flavoring agents, chelating agents, preservatives, stabilizers, antioxidants, and / or coloring agents. A composition consisting essentially of:

[0108] 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.

[0109] 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 neutralization of the gelling agent to obtain a gel; - combining in a second container a second portion of water, an aliphatic monoalcohol, an aliphatic diol and a non-ionic emulsifier; - dissolving diclofenac or a pharmaceutically acceptable salt of diclofenac in the mixture in a second container to obtain an API solution; - Combine the gelling agent dispersion and API solution under homogenization / mixing.

[0110] Purpose The compositions disclosed herein are suitable for use in relieving pain, inflammation, and swelling in soft tissue injuries, localized forms of soft tissue rheumatism, and in relieving mild arthritic pain in the knees or fingers.

[0111] Pharmaceutical Composition / Route of Administration / Dosage The composition can be administered to a mammal suffering from pain, inflammation, and swelling in soft tissue injury, localized forms of soft tissue rheumatism, and pain from mild arthritis of the knee or finger. Preferably, the composition is for the treatment of humans. The composition is useful for relieving pain, inflammation, and swelling in soft tissue injury, localized forms of soft tissue rheumatism, and pain from mild arthritis of the knee or finger.

[0112] The composition can be applied to the affected area. The composition may be rubbed in until the skin feels dry. The composition may be applied 3 to 4 times per day. A typical dose of the composition contains about 20 mg to about 40 mg of diclofenac sodium (equivalent amount) per application. 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 affected by or causes one or more of the following: soft tissue injury, pain, inflammation, and swelling in localized forms of soft tissue rheumatism, and non-severe arthritic pain in the knees or fingers.

[0113] The composition can be provided in a package that includes a means for administration. The composition can be provided in a container that includes an applicator for application directly onto the skin.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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).

[0118] Unless otherwise indicated, concentrations are given in % (w / w).

[0119] 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%.

[0120] pH, viscosity and HLB are typically measured at 25°C. [Example]

[0121] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0122] Example 1: Comparison of Cumulative Skin Permeation in Emulgel and Hydroalcoholic Gel over 24 Hours

[0123] In this example, the commercially available product Voltaren Emulgel 1.16% (m / m) diclofenac diethylammonium was reformulated without a lipophilic phase (Tests 1-5) and the cumulative permeation of the compositions was compared.

[0124] In vitro skin permeation studies were conducted in a preclinical laboratory. Skin permeation studies can be used, for example, to determine 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. The cumulative permeation of diclofenac from a hydroalcoholic test formulation was compared to the cumulative permeation from a reference product, Emulgel. Five test formulations and the reference product were each applied to the abdominal skin of human donors at a dose of 10 mg / cm2 at time 0. Each formulation was tested against five skin samples from different donors in 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:

[0125] [Table 1]

[0126] 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.

[0127] The results of the study are given in Table 2.

[0128] [Table 2]

[0129] 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 higher cumulative permeation at 24 hours.

[0130] Example 2: Comparison of Cumulative Skin Permeation Over 24 Hours in Emulgels and Hydroalcoholic Gels Containing 1% w / w Diclofenac Sodium and Various Concentrations of Nonionic Emulsifiers A hydroalcoholic single-phase composition containing 1% w / w diclofenac sodium and varying levels of nonionic emulsifier was studied. Concurrently, the concentrations of isopropanol and propylene glycol were varied to study the effect of these components on cumulative permeation. The reference product was Voltaren. Cumulative skin permeation studies were performed in 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 and 24 hours after dose application. If the cumulative permeation at 4 hours was below the measurement threshold, it was not reported. All formulations were applied in 10 μl doses onto skin samples of a defined surface area.

[0131] [Table 3]

[0132] The results are summarized in the table above and visualized in Figure 2. Tests on 1% diclofenac sodium hydroalcoholic gel compositions compared to the emulgel comparator (Example 1) showed the following trends: in hydroalcoholic gels without a lipophilic phase and without emulsifiers, the permeation rate increases compared to the emulgel compositions (compare cumulative permeation at 24 hours between Tests 2 and 3 and the comparator). In the absence of a dispersed lipophilic phase, diclofenac sodium permeates more rapidly. Including a hydrophilic nonionic emulsifier in the hydroalcoholic single-phase gel (as in Test 1) unexpectedly has a permeation retarding effect (compare cumulative permeation at 24 hours between Tests 2 and 3 and Test 1).

[0133] Example 3: Comparison of Cumulative Skin Permeation Over 24 Hours in Emulgel and Hydroalcoholic Gel Containing 1% w / w Diclofenac Epolamine To test the hypothesis that nonionic emulsifiers have a permeation-retarding effect in hydroalcoholic compositions containing various salts of diclofenac, such as diclofenac salts containing organic counterions, cumulative skin permeation studies were conducted in 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 and 24 hours after application of the dose. If the cumulative permeation at 4 hours was below the measurement threshold, it was not reported. All formulations were applied at a dose of 10 microliters onto skin samples of a specified surface area.

[0134] The formulation tested in this Example 3 was a hydroalcoholic composition containing 1% w / w diclofenac epolamine. At the same time, the concentrations of isopropanol and propylene glycol were varied to study the effects of these components on cumulative permeation. Table 4 shows the compositions of the reference product (Voltaren Arthritis Pain) and test formulations (Test 1, Test 2, Test 3) in Example 3, along with the results of the cumulative permeation experiments.

[0135] [Table 4]

[0136] The results are summarized in Table 4 and visualized in Figure 3.

[0137] Test 1 and Test 2 were very similar in composition, except that Test 2 contained no nonionic emulsifier and Test 1 contained 1.5% w / w Corifol CS 20. Comparing the cumulative permeation at 24 hours for Test 1 and Test 2, the nonionic emulsifier delayed permeation even in a composition containing 1% w / w diclofenac epolamine. Tests 2, 3, and the comparator had comparable cumulative permeation at 24 hours. Tests 2 and 3 contained no lipophilic phase or emulsifier, but contained different concentrations of isopropanol and propylene glycol than the comparator: 18% w / w for Test 2 and 20% w / w for Test 3. The difference in cumulative permeation at 24 hours between Test 2 and Test 3 was not significant. Tests 2 and 3 did not exhibit significantly higher cumulative permeation at 24 hours than the comparator. Although significantly higher permeation was expected due to the absence of a fatty phase and emulsifier, this trend toward higher permeation rates in the hydroalcoholic gels appeared to be balanced or negated by the use of organic counterion diclofenac salts and higher concentrations of propylene glycol.

[0138] Example 4: Comparison of in vitro cumulative skin permeation over 24 hours of emulgels and hydroalcoholic gels containing 1% w / w diclofenac sodium and various concentrations of non-ionic emulsifiers in a non-GLP comparative skin permeation study Hydroalcoholic compositions containing 1% w / w diclofenac sodium and various levels of non-ionic emulsifiers were studied. At the same time, the concentrations of isopropanol and propylene glycol were varied to study the effects of these components on cumulative permeation. The reference products were the same as those in Examples 2 and 3.

[0139] Full-thickness human skin samples (abdominal) were obtained from six female donors aged 43–69 years. Skin samples were stored in a freezer set to maintain a temperature of -20°C. Split-thickness skin samples were prepared from the samples by cutting the skin to a depth of 200–400 μm using an electrodermatoscope. Split-thickness skin samples (200–400 μm) with transepithelial electrical resistance (TEER) values ​​>7.7 kΩ were mounted in static diffusion cells (nominal volume 5 ml, exposed area = 0.64 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., a total of 12 skin samples per formulation). The receptor fluid was phosphate-buffered saline with 5% w / v bovine serum albumin. The receptor fluid was degassed by sonication and stored at a temperature of approximately +4°C before use. Receptor fluid samples were collected at 0, 2, 4, 8, 16, and 24 hours 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.

[0140] The test and comparator drugs were administered to humans using a positive displacement pipette. The formulation was applied to the stratum corneum surface of the skin samples. The formulation was applied uniformly to the stratum corneum surface of the skin at an application rate of 10 (mg / cm2) at time 0. Table 5 shows the compositions of the reference product (Voltaren Arthritis Pain Reliever) and the test formulations (F3 and F5) in Example 4, and Table 6 shows the results.

[0141] [Table 5]

[0142] [Table 6]

[0143] In Example 4, no statistically significant difference was observed in the cumulative permeation at 24 hours between formulation F3 and the reference product. This indicates that the incorporation of an emulsifier had a permeation-retarding effect in hydroalcoholic compositions. Although F3 was a hydrophilic composition, while the reference product was an emulgel, this permeation-retarding effect was so pronounced that the cumulative permeation at 24 hours for F3 was similar to that of the reference product. A higher cumulative permeation was expected from a hydrophilic composition (see Example 1). Surprisingly, the nonionic emulsifier did not further enhance the cumulative permeation. Conversely, the inclusion of a nonionic emulsifier seemed to balance the permeation-enhancing effect of the absence of a dispersed lipophilic phase. Interestingly, the cumulative permeation at 24 hours for formulation F5, which contained a total emulsifier concentration of 3% w / w, was significantly lower than that of the reference product. Therefore, we concluded that the permeation-retarding effect of nonionic emulsifiers in hydrophilic compositions is dose-dependent. The inclusion of more non-ionic surfactant results in a more pronounced permeation retardation effect.

Claims

1. - diclofenac or a pharmaceutically acceptable diclofenac salt in a concentration equivalent to about 0.5% w / w to about 1.5% w / w of diclofenac sodium, - gelling agents, - Aliphatic C at a concentration of about 5% w / w to about 20% w / w 2 ~C 4 Monoalcohol, - an aliphatic diol at a concentration of about 2% w / w to about 10% w / w, a hydrophilic non-ionic emulsifier at a concentration of about 1% w / w to about 2% w / w, and - water 1. A hydroalcoholic single-phase gel composition for topical delivery of diclofenac, comprising:

2. The composition of claim 1 comprising diclofenac sodium.

3. 3. The composition of claim 1, comprising diclofenac sodium in a concentration of about 1% w / w.

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

5. Nonionic emulsifier is ethoxylated C 16 ~C 18 The composition according to any one of claims 1 to 4, which is an alcohol.

6. 5. The composition of claim 1, wherein the nonionic emulsifier is 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.

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

8. The composition of any one of claims 1 to 7, wherein the non-ionic emulsifier retards the permeation of diclofenac.

9. The composition of any one of claims 1 to 8, which is substantially free of one or more of fats, oils, waxes, occlusive agents, or carbohydrate-based ointment bases.

10. The composition of any one of claims 1 to 9, wherein the gel is transparent.

11. The composition of any one of claims 1 to 10, wherein the composition has a pH of about 6.5 to about 8.

5.

12. Aliphatic C at a concentration of about 8% w / w to about 18% w / w or about 10% w / w to about 15% w / w 2 ~C 4 The composition according to any one of claims 1 to 11, comprising a monoalcohol.

13. 13. The composition of any one of claims 1 to 12, comprising an aliphatic diol in a concentration of about 3% w / w to about 8% w / w or about 3% w / w to about 5% w / w.

14. Only aliphatic C 2 ~C 4 14. The composition according to any one of claims 1 to 13, comprising isopropanol as the monoalcohol and propylene glycol as the only aliphatic diol.

15. 15. The composition of any one of claims 1 to 14, having a cumulative permeation in an in vitro skin permeation test that allows relying on literature data for Voltaren Arthritis Pain (Diclofenac Sodium Topical Gel, 1% (NSAID) - Arthritis Pain Reliever) or Voltaren Diclofenac Diethylamine 1.16% Gel for registration under well-established criteria of use according to Annex I of Directive 2001 / 83 / EC.

16. 16. A composition according to any one of claims 1 to 15 for use in a method for relieving pain, inflammation and swelling in soft tissue injuries, localised forms of soft tissue rheumatism and for relieving pain in non-severe arthritis of the knees or fingers.

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