New Formulations and Uses

Abstract

A pharmaceutical composition is provided comprising the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for use in treating pain by topical administration of the composition to a body surface.

Description

[Technical field]

[0001] The present invention relates to topical compositions and their use in the treatment of pain. [Background technology]

[0002] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0003] Pain sensation can have many underlying causes, mainly damage or risk of damage to tissue or nerve. Nociceptive pain is caused by activation of sensory nerve fibers as a result of harmful stimuli (such as heat or cold) or tissue damage due to trauma or inflammation, and neuropathic pain refers to pain caused by injury or disease that affects the nervous system. Neuropathic pain is divided into central neuropathic pain and peripheral neuropathic pain, depending on the location of the damaged or diseased nerve. Pain can also be experienced without the basis of disease or damage to tissue or nervous system. Such pain is called nociplastic pain or hyperesthesia.

[0004] Pain can be acute or chronic (persistent pain that occurs for a long period of time despite medication and / or treatment).Chronic pain is often inadequately treated and is a debilitating condition that leads to poor quality of life, and especially neuropathic pain is often inadequately treated.Therefore, there is a great need to develop effective treatments.

[0005] The transient receptor potential cation channel subfamily V member 1 (TrpV1), also called capsaicin receptor and vanilloid receptor 1, is located primarily in neurons of the peripheral nervous system, but is also found in many other tissues, including the central nervous system. TRPV1 receptors are involved in the transmission and modulation of pain signals, and are also involved in the detection and maintenance of body temperature. The receptor has been the focus of much research into the development of new analgesics, including projects focused on both agonists (e.g., capsaicin) and antagonists of the receptor.

[0006] The oral use of TRPV1 antagonists as potential analgesics has been widely explored, but so far no products based on this mechanism have been approved.

[0007] TRPV1 antagonists including N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide were disclosed in WO2007 / 073303, and the use of this compound (later identified by the development drug code AZD1386) as an oral analgesic for pain associated with osteoarthritis and surgical tooth extraction was later explored in clinical trials. However, the development of the compound as an oral drug was terminated due to the observed elevation of liver enzymes (Quiding et al. PAIN, 154 (2013) 808-812).

[0008] The topical use of TRPV1 antagonists for the treatment of various types of pain, including in particular wounds and tissue injuries, is described in WO2018 / 048779, which describes a study showing that the salivary peptides opiorphin and AMG9810 reduced capsaicin-induced wound licking in mice.Topical use of TRPV1 antagonists has also been recommended for the treatment of hot flashes (WO2019 / 010293).

[0009] It has now been found that topically administered N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is surprisingly effective in the treatment of pain, having a potent and long-lasting analgesic effect when administered topically to the skin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In a first aspect of the invention there is provided a pharmaceutical composition comprising the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for use in the treatment of pain, [ka] Pharmaceutical compositions are provided where treatment comprises topical administration of the composition to a body surface.

[0011] In an alternative first aspect of the present invention, there is provided a method of treating pain comprising locally administering to a body surface of a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof.

[0012] In a further alternative first aspect of the present invention there is provided the use of a pharmaceutical composition comprising the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain by local administration of the composition to a body surface.

[0013] In a further aspect of the present invention there is provided a pharmaceutical composition comprising the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, wherein the composition is formulated for topical use.

[0014] Compositions and compositions for use according to the invention (including compositions for use in methods of treatment and compositions for use in the manufacture of medicaments as described herein) (hereinafter "compositions of the invention") are suitable for, adapted for, and / or packaged and presented for topical administration. In particular, "formulated for topical administration" may be understood to indicate that the composition is packaged or presented for topical administration. Compositions may also be understood to include the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in admixture with one or more pharma- ceutically acceptable topical excipients (such as adjuvants, diluents, and / or carriers) (such as the specific excipients described below).

[0015] The stated preferences, options, and specific embodiments for a given aspect, feature, or parameter of the invention should be considered as disclosed in combination with all preferences and options for all other aspects, features, and parameters of the invention, unless the context dictates otherwise. In particular, the preferences and specific embodiments relating to compositions comprising N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, according to the first aspect of the invention, may be understood to apply to the composition itself, and to compositions used in medical treatment.

[0016] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization or filtration). Salts may also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion using a suitable ion exchange resin.

[0017] Particular acid addition salts which may be mentioned are those formed by reaction with the corresponding acid, thus protonating the compounds of the invention to form carboxylates (e.g. formates, acetates, trifluoroacetates, propionates, isobutyrates, heptanoates, decanoates, caprates, caprylates, stearates, acrylates, caproates, propiolates, ascorbates, citrates, glucuronates, glutamates, glycolates, α-hydroxybutyrates, lactates, tartrates, phenylacetates, mandelates, phenylpropionates, phenylbutyrates, benzoates, chlorobenzoates, methylbenzoates, hydroxybenzoates, methoxybenzoates, dinitrobenzoates, o-acetoxy-benzoates, salicylates, nicotinates, isonicotinates, cinnamates, salts such as oxalates, malonates, succinates, suberates, sebacates, fumarates, malates, maleates, hydroxymaleates, hippurates, phthalates, or terephthalates), halides (e.g., chlorides, bromides, or iodides), sulfonates (e.g., benzenesulfonates, methyl-, bromo-, or chloro-benzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxy-ethanesulfonates, 1- or 2-naphthalenesulfonates, or 1,5-naphthalenesulfonates), or sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, or nitrates.

[0018] More particular salts that may be mentioned include the hydrogen chlorides and especially the hydrogen sulfates.

[0019] In certain embodiments, the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is added to and / or present in the composition in free (non-salt) form.

[0020] Pharmaceutically acceptable excipients that can be used in the compositions of the present invention include vehicles, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents, etc. In particular, such excipients can include adjuvants, diluents, or carriers.

[0021] In certain embodiments, the compositions of the present invention contain the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide in an amount of about 0.05% (w / w) to about 10% (w / w) (calculated as the free (non-salt) compound). In a more specific embodiment, the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is present in an amount of from about 0.05% (w / w) to about 5% (w / w), for example, from about 0.5% (w / w) to about 3% (w / w), or from about 0.5% (w / w) to about 3% (w / w), or from about 0.5% (w / w) to about 2.5% (w / w) (e.g., from about 0.5% (w / w) to about It is present in an amount of about 0.05% (w / w) to about 7% (w / w), such as 2% (w / w), or about (0.5% (w / w) to about 1.5% (w / w)). In a further embodiment, the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is present in an amount of about 0.05% (w / w) to about 2% (w / w), such as about 1% (w / w) to about 2% (w / w).

[0022] When used herein in connection with a particular value (such as an amount, duration, or percentage), the term "about" (or similar terms such as "approximately") may be understood as indicating that such value may vary by up to 10% (particularly up to 5%, e.g., up to 1%) of the defined value. In each case, it is contemplated that such terms may be replaced with a notation such as "±10%" (or by indicating a variation of a particular amount calculated based on the relevant value). It is also contemplated that in each case, such terms may be omitted.

[0023] In certain embodiments, the composition of the present invention further comprises a penetration enhancer component. The penetration enhancer component may be understood to refer to a component that penetrates and / or otherwise interacts with a body surface to facilitate the flux of the active ingredient to the body surface (e.g., skin) to which it is applied. Specific penetration enhancers that may be mentioned include 2-(2-ethoxyethoxy)ethanol (also known as diethylene glycol monoethyl ether, Transcutol®), dimethyl isosorbide, glycerol, ethanol, and combinations thereof. More specifically, the penetration enhancer component is selected from 2-(2-ethoxyethoxy)ethanol, dimethyl isosorbide, and mixtures thereof. Even more specifically, the penetration enhancer component is 2-(2-ethoxyethoxy)ethanol.

[0024] The penetration enhancer component may be present in the composition in an amount of about 10% (w / w) to about 50% (w / w). More specifically, the penetration enhancer component is present in an amount of about 10% (w / w) to about 40% (w / w), such as about 20% (w / w) to about 40% (w / w), such as about 25% (w / w) to about 35% (w / w). In certain embodiments, the penetration enhancer component (e.g., 2-(2-ethoxyethoxy)ethanol) is present in an amount of 30% (w / w).

[0025] The composition of the present invention may also further comprise a solubility enhancer component. In particular, in embodiments, the solubility enhancer is a diol, such as pentanediol, butanediol, propane-1,3-diol, propane-1,2-diol (propylene glycol), and mixtures thereof. In particular, in embodiments, the solubility enhancer is a diol, such as pentanediol, butanediol, propane-1,3-diol, and propane-1,2-diol (propylene glycol). Preferably, the diol component is propylene glycol.

[0026] Other solubility enhancers that may be mentioned include polyethylene glycol, ethanol, isopropyl alcohol, glycerol, and combinations thereof, some of which (including ethanol and glycerol) may also act as penetration enhancers.

[0027] Preferably, the solubility enhancer component is propylene glycol.

[0028] The solubility enhancer component may be present in the composition in an amount of about 10% (w / w) to about 50% (w / w). More specifically, the solubility enhancer component is present in an amount of about 10% (w / w) to about 40% (w / w), such as about 20% (w / w) to about 40% (w / w) (e.g., about 25% (w / w) to about 35% (w / w)). In certain embodiments, the solubility enhancer component (e.g., propylene glycol) is present in an amount of 30% (w / w).

[0029] In certain embodiments, the ratio of the amount of the penetration enhancer component (e.g., 2-(2-ethoxyethoxy)ethanol) to the solubility enhancer component (e.g., propylene glycol) (penetration enhancer component:solubility enhancer component) is from about 3:1 to about 1:3, more specifically, a ratio of from about 2:1 to about 1:2 (e.g., about 1:1).

[0030] In a particular embodiment that may be mentioned, the penetration enhancer component (e.g., 2-(2-ethoxyethoxy)ethanol) and the solubility enhancer component (e.g., propylene glycol) are both present in an amount of 30% (w / w).

[0031] In certain embodiments, the compositions of the present invention also include a gel-forming polymer component. In particular, the gel-forming polymer component is selected from cellulose polymers (e.g., hydroxypropyl methylcellulose), cross-linked polyacrylic acid polymers, and mixtures thereof. More particularly, the gel-forming polymer component is hydroxypropyl methylcellulose.

[0032] The gel-forming polymer component (e.g., hydroxypropyl methylcellulose) may be present in an amount of about 0.05% (w / w) to about 3% (w / w), e.g., about 1% (w / w) to about 3% (w / w) (e.g., about 1% (w / w) to about 2% (w / w)).

[0033] The composition of the present invention may contain water, which is preferred.For gel-based compositions, those skilled in the art will understand that the composition requires the presence of water to form a gel with a gel-forming polymer component (e.g., HPMC).The appropriate amount of water and gel-forming polymer (and other components of the composition) to form a gel of suitable viscosity for topical application to relevant body surface (e.g., skin) can be routinely determined by those skilled in the art using techniques known in the art.

[0034] In certain embodiments, the compositions of the present invention are in the form of a gel. Such embodiments include a gel-forming polymer component (e.g., HPMC) as defined herein, and water to form a gel. In certain embodiments, the gel composition is a gel of 10 -1 and a temperature of about 34°C (e.g., 34°C), 1.5 Pa s to about 2.5 Pa s, e.g., 10 -1 and a temperature of about 34°C (e.g., 34°C), such as 1.8 Pa·s to about 2.2 Pa·s -1 and a temperature of about 34° C. (e.g., 34° C.).

[0035] Thus, in certain embodiments, water is 10 -1 and a temperature of about 34°C (e.g., 34°C), 1.5 Pa s to about 2.5 Pa s, e.g., 10 -1 and a temperature of about 34°C (e.g., 34°C), such as 1.8 Pa·s to about 2.2 Pa·s -1 and a temperature of about 34° C. (e.g., 34° C.).

[0036] The viscosity of the composition can be determined by standard methods known to those skilled in the art, in particular using a shear rheometer (e.g., a Kinexus Pro rheometer). More specifically, the shear rheometer has a measurement geometry CP4 / 40, stainless steel cone:plate geometry, diameter 40 mm with a 4° cone.

[0037] In certain embodiments, the composition of the present invention further comprises a lower alcohol as an additional solubilizing agent. The lower alcohol may be selected from ethanol, isopropanol, propanol, and mixtures thereof. Preferably, the lower alcohol is isopropanol. In certain embodiments, the lower alcohol is present in an amount of about 0.5% (w / w) to about 10% (w / w), more specifically, about 0.5% (w / w) to about 4% (w / w), such as about 0.5% (w / w) to about 3.5% (w / w), such as about 0.5% (w / w) to about 2.5% (w / w).

[0038] In further embodiments, the composition contains as an additional solubilizing agent an alcohol (e.g., isopropanol) selected from the group consisting of benzyl alcohol and lower alcohols (such as ethanol, isopropanol, propanol, and mixtures thereof. In certain embodiments, the alcohol is present in an amount of about 0.5% (w / w) to about 10% (w / w), more specifically, about 0.5% (w / w) to about 4% (w / w), such as about 0.5% (w / w) to about 3.5% (w / w), such as about 0.5% (w / w) to about 2.5% (w / w).

[0039] In certain embodiments, the additional alcohol is benzyl alcohol.

[0040] The compositions of the present invention may also contain other polymeric components as thickeners. Examples of such polymers include PEG 1500, PEG 6000, and PEG 35000.

[0041] The pH of the composition may also be adjusted to an appropriate value ranging from pH 3 to pH 6, which may vary depending on the salt form of N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide used in the composition. In certain embodiments, the pH of the composition may be in the range of about pH 2 to about pH 6, such as about pH 3 to about pH 5, for example, about pH 3 to about pH 4 (e.g., about pH 3).

[0042] The composition of the present invention may also contain a pH adjuster, which may be an organic or inorganic acid or base. Examples of pH adjusters include sodium hydroxide, hydrochloric acid, and citric acid. In particular, the pH adjuster may be sodium hydroxide.

[0043] It has also been found that the inclusion of an aminopolycarboxylic acid sequestering agent, such as EDTA, improves the stability of the active ingredients in the compositions of the invention. Thus, in certain embodiments, the compositions of the invention further comprise an aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.001% (w / w) to about 0.5% (w / w), more particularly about 0.001% (w / w) to about 0.1% (w / w), or about 0.005% (w / w) to about 0.5% (w / w), such as about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.01% (w / w)). Particular aminopolycarboxylic acid sequestering agents that may be mentioned include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA; pentetic acid), and nitrilotriacetic acid (NTA) (and their pharma- ceutically acceptable salts). More particularly, the aminopolycarboxylic acid sequestering agent is EDTA, or a pharma- ceutically acceptable salt thereof, such as the sodium salt (disodium or tetrasodium) or the sodium and calcium salts (calcium disodium edetate), which may be present in an amount of, in particular, about 0.001% (w / w) to about 0.1% (w / w), e.g., about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.005% (w / w) to about 0.05% (w / w), such as about 0.01% (w / w)).

[0044] Particular compositions of the invention that may be mentioned are pharmaceutical compositions (formulated / packaged and presented for topical use) comprising: i) the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (optionally in the form of a pharma- ceutically acceptable salt), in an amount of about 0.05% (w / w) to about 10% (w / w) (e.g., about 0.5% (w / w) to about 2.5% (w / w) (e.g., about 0.5% (w / w) to about 1.5% (w / w)); ii) a penetration enhancer (e.g., 2-(2-ethoxyethoxy)ethanol) in an amount of about 10% (w / w) to about 40% (w / w) (e.g., about 20% (w / w) to about 40% (w / w), e.g., about 30% (w / w)); and iii) a solubility enhancer (e.g., propylene glycol) in an amount of about 10% (w / w) to about 40% (w / w) (e.g., about 20% (w / w) to about 40% (w / w), e.g., about 30% (w / w)).

[0045] Such compositions may optionally further comprise a gel-forming component (e.g., hydroxypropylmethylcellulose) and / or a lower alcohol (e.g., isopropyl alcohol) in an amount of about 0.05% (w / w) to about 5% (w / w) (about 0.05% (w / w) to about 3% (w / w), such as about 1% (w / w)) as an additional solubilizing agent. Such lower alcohols are preferably present in an amount of about 0.5% (w / w) to about 10% (w / w), more specifically about 0.5% (w / w) to about 4% (w / w), such as about 0.5% (w / w) to about 3.5% (w / w), such as about 0.5% (w / w) to about 2.5% (w / w).

[0046] Such compositions may further comprise water (e.g., an amount necessary to form a gel), and / or an aminopolycarboxylic acid sequestering agent such as ethylenediaminetetraacetic acid, or a pharma- ceutically acceptable salt thereof (such as the sodium salt (disodium or tetrasodium) or the sodium and calcium salts (calcium disodium edetate), or a pharma- ceutically acceptable salt thereof, which may be present in an amount of about 0.001% (w / w) to about 0.1% (w / w), more particularly about 0.005% (w / w) to about 0.05% (w / w), such as about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.01% (w / w)).

[0047] Further compositions of the invention that may be mentioned include pharmaceutical compositions formulated (and / or packaged or presented) for topical use (e.g. in the form of a gel), the composition comprising: i) N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05% (w / w) to about 10% (w / w) (e.g., about 0.5% (w / w) to about 2.5% (w / w) (e.g., about 0.5% (w / w) to about 5% (w / w), such as about 0.5% (w / w) to about 1.5% (w / w)); ii) a penetration enhancer component (e.g., 2-(2-ethoxyethoxy)ethanol) selected from the list consisting of 2-(2-ethoxyethoxy)ethanol, dimethyl isosorbide, glycerol, ethanol, and combinations thereof, in an amount of about 10% (w / w) to about 50% (w / w) (e.g., about 20% (w / w) to about 40% (w / w), e.g., about 30% (w / w)); and iii) a solubility enhancer component (e.g., propylene glycol) selected from the group consisting of pentanediol, butanediol, propane-1,3-diol, propylene glycol, and mixtures thereof, in an amount of about 10% (w / w) to about 50% (w / w) (e.g., about 20% (w / w) to about 40% (w / w), e.g., about 30% (w / w)); The ratio of penetration enhancer component to solubility enhancer component is from about 3:1 to about 1:3.

[0048] In certain embodiments, the penetration enhancer component is selected from the group consisting of 2-(2-ethoxyethoxy)ethanol, dimethylisosorbide, and mixtures thereof, and optionally, the penetration enhancer component is 2-(2-ethoxyethoxy)ethanol.

[0049] In a further particular embodiment, the solubility enhancer component is propylene glycol.

[0050] In further specific embodiments, the penetration enhancer component and the solubility enhancer component are each present in an amount of about 25% (w / w) to about 35% (w / w).

[0051] In further specific embodiments, the composition further comprises a gel-forming polymer component selected from the group consisting of a cellulose polymer (e.g., hydroxypropyl methylcellulose), a cross-linked polyacrylic acid polymer, and mixtures thereof, in an amount of about 1% (w / w) to about 3% (w / w), and / or the composition further comprises a lower alcohol selected from ethanol, isopropanol, propanol, and mixtures thereof (e.g., isopropanol), the lower alcohol optionally being present at about 0.5% (w / w) to about 10% (w / w), more particularly, about 0.5% (w / w) to about 4% (w / w), such as about 0.5% (w / w) to about 3.5% (w / w), such as about 0.5% (w / w) to about 2.5% (w / w).

[0052] Such compositions may further comprise an aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.001% (w / w) to about 0.5% (w / w), more particularly about 0.001% (w / w) to about 0.1% (w / w), or about 0.005% (w / w) to about 0.5% (w / w), for example about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.01% (w / w)). Particular aminopolycarboxylic acid sequestering agents that may be mentioned include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA; pentetic acid), and nitrilotriacetic acid (NTA) (and pharma- ceutically acceptable salts thereof). More specifically, the aminopolycarboxylic acid sequestering agent is EDTA, or a pharma- ceutically acceptable salt thereof, such as the sodium salt (disodium or tetrasodium) or the sodium and calcium salt (calcium disodium edetate), which may be present in an amount of, inter alia, about 0.001% (w / w) to about 0.1% (w / w), more specifically, about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.005% (w / w) to about 0.05% (w / w), such as about 0.01% (w / w)).

[0053] Such a composition may in particular be in the form of a gel (and therefore also contain water).

[0054] Further particular compositions of the invention that may be mentioned include compositions formulated (and / or packaged or presented) for topical use (e.g. in the form of a gel), i) N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.5% (w / w) to about 3% (w / w)) (such as about 0.5% (w / w) to about 2.5% (w / w) (e.g., about 0.5% (w / w) to about 1.5% (w / w)); ii) 2-(2-ethoxyethoxy)ethanol in an amount of about 25% (w / w) to about 35% (w / w); iii) propylene glycol in an amount of about 25% (w / w) to about 35% (w / w); iv) isopropyl alcohol in an amount of about 0.5% (w / w) to about 3.5% (w / w); v) hydroxypropyl methylcellulose in an amount of about 1% (w / w) to about 3% (w / w) vi) Water (eg, a sufficient amount to form a gel with hydroxypropyl methylcellulose).

[0055] Such compositions may further comprise an aminopolycarboxylic acid sequestering agent, such as ethylenediaminetetraacetic acid, or a pharma- ceutically acceptable salt thereof (such as the sodium salt (disodium or tetrasodium) or the sodium and calcium salts (calcium disodium edetate), or a pharma- ceutically acceptable salt thereof, which may be present in an amount of about 0.001% (w / w) to about 0.1% (w / w), more particularly about 0.005% (w / w) to about 0.05% (w / w), such as about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.01% (w / w)).

[0056] Further compositions of the invention that may be mentioned include compositions formulated (and / or packaged or presented) for topical use (for example in the form of a gel), i) N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.5% (w / w) to about 3% (w / w)) (such as about 0.5% (w / w) to about 2.5% (w / w) (e.g., about 0.5% (w / w) to about 1.5% (w / w)); ii) 2-(2-ethoxyethoxy)ethanol in an amount of about 25% (w / w) to about 35% (w / w); iii) propylene glycol in an amount of about 25% (w / w) to about 35% (w / w); iv) hydroxypropyl methylcellulose in an amount of about 1% (w / w) to about 3% (w / w) v) containing water (eg, a sufficient amount to form a gel with hyroxypropyl methyl cellulose).

[0057] Such compositions may further comprise an aminopolycarboxylic acid sequestering agent, such as ethylenediaminetetraacetic acid, or a pharma- ceutically acceptable salt thereof (such as the sodium salt (disodium or tetrasodium) or the sodium and calcium salts (calcium disodium edetate), or a pharma- ceutically acceptable salt thereof, which may be present in an amount of about 0.001% (w / w) to about 0.1% (w / w), more particularly about 0.005% (w / w) to about 0.05% (w / w), such as about 0.005% (w / w) to about 0.02% (w / w) (e.g., about 0.01% (w / w)).

[0058] medical use According to a first aspect of the invention, the composition of the invention is used for the treatment of pain.

[0059] Those skilled in the art will understand that reference to treating pain (or, similarly, treating pain) takes its usual meaning in the medical field. Specifically, these terms may refer to achieving a reduction in the severity and / or frequency of occurrence of pain, as determined by a physician who treats a patient who has pain or is susceptible to pain. For example, in the case of pain, this term may refer to a reduction in the severity of the pain experienced by a patient, as determined / described by reference to an appropriate scale (e.g., a numerical rating scale or a visual analog scale).

[0060] For the avoidance of doubt, treatment of pain includes treatment of commonly recognised pain categories (e.g. nociceptive pain or neuropathic pain), in particular pain that is amenable to localized treatment, and also pain associated with particular disorders (such as those listed herein) in which pain is a symptom.

[0061] As used herein, reference to a patient (or patients) shall refer to the living subject being treated, including mammalian (e.g., human) patients. Specifically, reference to a patient shall refer to a human patient.

[0062] For the avoidance of doubt, a person skilled in the art will understand that such treatment or prophylaxis is carried out in a patient (or subject) in need thereof. The need of a patient (or subject) for such treatment can be assessed by one skilled in the art using routine techniques.

[0063] As used herein, the terms disease and disorder (and similarly, terms such as "condition," "disease," "medical problem," etc.) may be used interchangeably.

[0064] As used herein, the term effective amount will refer to an amount of a compound that provides a therapeutic effect to a treated patient. The effect can be observed in an objective manner (i.e., measurable by some test or marker) or subjective manner (i.e., the subject shows and / or feels the effect). In particular, the effect can be observed (e.g., measured) in an objective manner using a suitable test known to those skilled in the art.

[0065] The composition of the present invention is used to treat pain by topical administration.The pain to be treated can therefore be generally defined as pain that is suitable for topical treatment.Because the composition is applied topically, the active compounding ingredients do not enter the systemic circulation.

[0066] The compositions of the present invention may be applied topically to different body surfaces in the treatment of pain. In particular, the compositions may be applied to mucosal surfaces, the eye, or the skin.

[0067] In a preferred embodiment, the body surface to which the composition is topically applied is the skin (more specifically, intact skin).

[0068] In certain embodiments, the composition is applied to intact skin, which can be beneficial as it limits systemic exposure: applying a topical composition to broken or damaged skin can lead to systemic exposure, which in some circumstances may be undesirable (e.g., as it may lead to undesirable side effects).

[0069] In certain embodiments, the pain that is locally treated with the compositions of the invention is nociceptive pain, particularly acute nociceptive pain.

[0070] In a further particular embodiment, the pain is associated with a dermatological pain condition. Examples of such conditions include radiation therapy-induced pain, pyoderma, gangrene, hidradenitis suppurativa, calciphylaxis, vascular disease, burns, shingles, scleroderma, and dermatomyositis. Such conditions are considered suitable for treatment by topical application of the composition of the present invention to the skin.

[0071] In a further embodiment, the pain is associated with an enthesopathy. Examples of enthesopathy include tendinitis (e.g., Achilles tendinitis), tennis elbow, and mouse arm.

[0072] In a further embodiment, the pain is inflammatory pain, including pain associated with rheumatoid arthritis.

[0073] In a further embodiment, the pain is neuropathic pain, in particular peripheral neuropathic pain, which is preferred.

[0074] In certain embodiments, the peripheral neuropathic pain is selected from the group consisting of post-herpetic neuropathy, post-traumatic neuropathy, post-operative neuropathic pain, painful diabetic polyneuropathy, HIV neuropathy, chemotherapy-induced neuropathic pain, leprosy neuropathic pain, post-amputation pain.

[0075] In certain embodiments, the peripheral neuropathic pain is post-herpetic neuropathy.

[0076] In certain embodiments, the peripheral neuropathic pain is post-traumatic neuropathy.

[0077] In certain embodiments, the peripheral neuropathic pain is post-operative neuropathic pain.

[0078] In certain embodiments, the peripheral neuropathic pain is painful diabetic polyneuropathy.

[0079] In certain embodiments, the peripheral neuropathic pain is HIV neuropathy.

[0080] In certain embodiments, the peripheral neuropathic pain is chemotherapy-induced neuropathic pain.

[0081] In certain embodiments, the peripheral neuropathic pain is leprosy neuropathic pain.

[0082] In certain embodiments, the peripheral neuropathic pain is post-amputation pain.

[0083] Dosage Forms and Dosages In a particular embodiment, the composition of the present invention is in a dosage form selected from the list consisting of a cream, a (topical) (e.g., liquid) spray, a (topical) patch, a gel, an ointment, a lotion, and a paste. More particularly, the dosage form is a cream, a (topical) (e.g., liquid) spray, a (topical) patch, or a gel.

[0084] In certain embodiments, the pharmaceutical composition is in the form of a cream.

[0085] In certain embodiments, the pharmaceutical composition is in the form of a (topical) (eg, liquid) spray.

[0086] In certain embodiments, the pharmaceutical composition is in the form of a (topical) patch.

[0087] In certain embodiments, the pharmaceutical composition is in the form of a gel.

[0088] In addition to the specific excipients mentioned above, the different dosage forms may contain specific excipients appropriate to each form, as follows:

[0089] Suitable excipients for gel formulations include matrix materials including cellulose derivatives, carbomers and alginates, gummi tragacanthae, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulosic polysaccharides, sugars such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and especially hyaluronic acid; Suitable excipients for pastes and ointments include glycerin, petrolatum, paraffin, polyethylene glycols of different molecular weights, etc.); Suitable excipients for creams include hydroxypropyl methylcellulose, gelatin, polyethylene glycols of different molecular weights, sodium dodecyl sulfate, sodium fatty alcohol polyoxyethylene ether sulfonate, corn gluten powder, and acrylamide); Suitable excipients for liquids, e.g. water (aerosol) sprays include viscosity modifiers such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohol, water, preservatives, sweeteners, flavors, etc.); Further pharma- ceutically acceptable excipients, such as humectants such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic / caprylic triglyceride, and / or antioxidants such as vitamins and glutathione, and / or pH adjusters such as acids, bases, and pH buffers, may also be included in such formulations, as needed. Further, hexadecanol (cetyl alcohol), fatty acids (e.g., stearic acid), sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (e.g., glyceryl monostearate, etc.), polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, polyoxylglycerides, lauryl dimethylamine oxide. , bile salts (e.g., sodium deoxycholate, sodium cholate), lipids (e.g., fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, glycolipids, polyketides), phospholipids, surfactants / emulsifiers such as N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamers, lecithins, sterols (e.g., cholesterol), sugar esters, polysorbates, preservatives such as phenoxyethanol, ethylhexylglycerin, and thickeners such as acryloyldimethyltaurate / VP copolymer. In particular, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, octanoic / capric glycerides, and the like, may be included in cream formulations, among others.

[0090] The composition of the present invention can further be combined with a suitable matrix material to prepare a dressing or therapeutic patch for application on a biological surface, such as skin or mucosal surface (especially skin).Accordingly, such formulations can be adopted to impregnate a matrix material, such as gauze, nonwoven fabric, or silk paper.Alternatively, the therapeutic patch can be, for example, a band-aid, a facial mask, an eye mask, a hand mask, a foot mask, etc.

[0091] In certain embodiments, the compositions of the invention contain the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (calculated as the free (non-salt compound)) in an amount of about 5 mg / mL to about 100 mg / mL. More specifically, the compound may be present in an amount of about 5 mg / mL to about 50 mg / mL, such as about 5 mg / mL to about 30 mg / mL, such as about 5 mg / mL to about 30 mg / mL or about 5 mg / mL to about 25 mg / mL (e.g., about 5 mg / mL to about 15 mg / mL). In a further embodiment, the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is present in an amount of from about 5 mg / mL to about 20 mg / mL, such as from about 10 mg / mL to about 20 mg / mL.

[0092] According to the present invention, the composition is administered at a concentration of about 0.01 mL / cm 2 ~Approx. 2.0mL / cm 2 More specifically, the composition may be applied to a body surface (e.g., skin) in an amount of about 0.02 mL / cm. 2 ~About 0.2 mL / cm2 (e.g., about 0.02 mL / cm 2 ~about 0.1mL / cm 2 ) at approximately 0.02 mL / cm 2 ~Approx. 1mL / cm 2 Even more specifically, the composition is applied in an amount of about 0.01 mL / cm 2 ~about 0.05mL / cm 2 (For example, about 0.01 to about 0.03 mL / cm2 ) at approximately 0.01 mL / cm 2 ~about 0.06mL / cm 2 In certain embodiments, the composition is applied to a body surface in an amount of 0.05 mL / cm 2 is applied in an amount of

[0093] In a further embodiment, the treatment is about 50 μg / cm 2 ~Approx. 1000μg / cm 2 The method includes applying an amount of the composition to provide a dose of the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (calculated as the free (non-salt) compound) of about 300 μg / cm. More specifically, the dose of the compound is about 300 μg / cm. 2 ~Approx. 900μg / cm 2 (For example, about 500 μg / cm 2 ~Approx. 900μg / cm 2 etc., about 100 μg / cm 2 ~900μg / cm 2 Approximately 200μg / cm 2 ~Approx. 900μg / cm 2 In certain embodiments, the composition is about 700 μg / cm 2 In a further embodiment, the composition is administered in an amount sufficient to provide a dose of about 100 μg / cm 2 ~Approx. 700μg / cm 2 The dosage is administered in an amount sufficient to provide a dose of the active compound.

[0094] In a further embodiment, the composition is about 100 μg / cm 2 ~about 600μg / cm 2 , for example, about 100 μg / cm 2 ~Approx. 500μg / cm 2 (For example, about 100 μg / cm 2 ~about 400μg / cm 2 , or about 100 μg / cm 2 ~Approx. 300μg / cm 2 , or about 50 μg / cm 2 ~about 400μg / cm 2 , or about 50 μg / cm 2~Approx. 300μg / cm 2 ) at approximately 50 μg / cm 2 ~about 600μg / cm 2 is applied in an amount sufficient to give a dose of the compound (free (non-salt) form).

[0095] In certain embodiments, the total amount of the composition applied to the body surface is from about 50 mg to about 700, e.g., from about 50 mg to about 500 mg (e.g., from about 100 mg to about 500 mg or from about 200 mg to about 500 mg), from about 50 mg to about 1 g (per application).

[0096] The composition of the present invention has been shown to have a long-lasting analgesic effect.Therefore, treatment with the composition of the present invention may require administering the composition less frequently than other analgesics.Therefore, in a further embodiment of the present invention, the treatment comprises administering the composition once or preferably twice a day.

[0097] The compositions may also be administered from 1 to 4 times daily.

[0098] Combinations and kits of parts Those skilled in the art will understand that treatment with the composition of the present invention may further include (i.e., may be combined with) additional treatment(s) for the treatment of pain. Specifically, treatment with the compound of the present invention may be combined with measures for the treatment of pain (such as peripheral neuropathic pain as described herein), such as treatment with one or more other therapeutic agents that are useful for the treatment of pain.

[0099] As described herein, the compositions of the invention may be combined with one or more other (i.e., different) therapeutic agents that are useful in the treatment of pain. Such combination products provide for local administration of the compositions of the invention in conjunction with treatment with one or more other therapeutic agents, and may be presented either as separate compositions, at least one of which is a composition of the invention and at least one of which includes another therapeutic agent, or may be presented (i.e., formulated) as a combined formulation.

[0100] Thus, in a further embodiment, a composition of the invention, including for use according to the invention, further comprises a second therapeutic agent for the treatment of pain.

[0101] In a further aspect of the invention there is provided a combination product comprising: (I) a composition of the present invention; (II) one or more other therapeutic agents useful in the treatment of pain.

[0102] wherein each of components (I) and (II) is optionally formulated in admixture with one or more pharma- ceutically acceptable excipients.

[0103] In a further aspect of the invention there is provided a kit-of-parts comprising: (a) a composition of the present invention; (b) one or more other therapeutic agents useful in the treatment of pain (such as peripheral neuropathic pain as described herein), optionally in admixture with one or more pharma- ceutically acceptable excipients; A kit-of-parts is provided in which components (A) and (B) are each provided in a form suitable for administration in conjunction with one another.

[0104] With respect to the kit of parts as described herein, by "administration in conjunction with" (and similarly "administered in conjunction with") we include administration of each formulation sequentially, separately or simultaneously as part of a medical intervention directed to the treatment of the relevant condition.

[0105] Thus, in the context of the present invention, the term "administration in conjunction with" (and similarly, "administered in conjunction with") includes administration of two active combination ingredients (i.e., a compound of the present invention and an additional agent for the treatment of pain, or a composition comprising same) together or sufficiently close in time to allow a more beneficial effect for the patient over the course of treatment of pain than if either agent were administered alone over the same course of treatment in the absence of the other ingredient. The determination of whether a combination provides a greater beneficial effect with respect to and over the course of treatment of a particular condition will depend on the condition being treated, but can be routinely accomplished by one of ordinary skill in the art.

[0106] Furthermore, in the context of the present invention, the term "in conjunction with" includes that one or the other of the two formulations may be administered (optionally repeatedly) before, after and / or simultaneously with the administration of the other component. As used in this context, the terms "administered simultaneously" and "administered simultaneously with" include cases where the individual doses of the compound of the present invention and the additional compound for the treatment of pain, or a pharma- ceutically acceptable salt thereof, are administered within 48 hours (e.g., within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes) of each other.

[0107] As used herein, references to other therapeutic agents that are "useful" in the treatment of pain will refer to agents known to be suitable for use in that manner (e.g., agents commonly used for that purpose). Such references may thus be replaced with references to agents that are "suitable" for the relevant purpose.

[0108] In further embodiments of the compositions, methods and uses for use described herein, the treatment of pain further comprises treatment with a composition of the invention in combination with another agent suitable for the treatment of pain, such as, in particular, an orally administered analgesic.

[0109] Examples of additional therapeutic agents suitable for use in combination with treatment with the compositions of the present invention include opioids, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants, NMDA antagonists, and cannabinoids.

[0110] Preparation of the Composition In a further aspect of the invention, there is provided a process for the preparation of a pharmaceutical composition as defined above, which process comprises bringing into association the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, with one or more pharma- ceutically acceptable excipients.

[0111] In certain embodiments, a process for the preparation of a gel-based formulation as described herein, comprising: i) hydration of a gel-forming polymer (e.g., hydroxypropyl methylcellulose) in water; ii) dissolving N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an organic phase containing a permeation enhancer component (e.g., 2-(2-ethoxyethoxy)ethanol) and a solubility enhancer component (e.g., propylene glycol); iii) mixing the aqueous gel component with an organic phase; and iv) optionally, adjusting the pH to an appropriate value (e.g., about pH 3), for example by addition of a suitable base (e.g., sodium hydroxide solution).

[0112] Without wishing to be bound by theory, it is believed that the compositions, compositions for use, methods and uses described herein provide improved localized treatment for pain.Specifically, localized treatment with the compositions described herein has been shown to be highly effective in treating pain when compared with previous oral use of the same active ingredients, and also when compared with oral treatment with a series of established analgesics.Local administration of the composition has also been found to be associated with significantly longer-lasting analgesic effects than oral administration of the same active ingredients.

[0113] Treatment according to the methods described herein has the advantage over similar treatments known in the prior art that it is, and may be, effective, cause fewer side effects (including increases in body core temperature and / or disturbances in thermosensation), and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or may have other beneficial properties. [Brief description of the drawings]

[0114] [Figure 1] FIG. 1 shows the flux of active ingredients through Franz cell membranes for a series of compositions containing N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide and other excipients including propylene glycol and Transcutol® (2-(2-ethoxyethoxy)ethanol). Two values ​​are shown for formulation 1. The figure shows that high levels of flux were achieved for all formulations tested. EXAMPLES

[0115] Example 1 - Franz Cell Flow Experiments The Franz Cell is a model for the percutaneous absorption of active ingredients from topical formulations. The appropriate receptor solution is added to the Franz Cell apparatus, which is then fitted with a permeable membrane. The test formulation is applied on top of the membrane and the diffusion rate through the membrane is measured over time.

[0116] 1.1 Comparative Fluid-Gel Formulations and Solutions The permeability measurement was taken at 0.64 cm 2 The measurements were taken using a Permeagear vertical jacketed diffusion cell fitted with a silicone membrane (Silatos silicone sheeting reference number 7458) with an area of ​​1.5 μm. 5 mL of 5% hydroxypropyl-beta-cyclodextrin (HPCD) in 0.1 M HCl was used as the receptor solution, which was kept at a temperature of 32 °C. Approximately 0.5-0.7 g of formulation was added to each well and 0.2 mL samples were taken at 0.25, 0.5, 1, 2, 3, 4, 14.5, and 24 hours.

[0117] Comparative flux through Franz cell membranes was assessed for the gel formulation N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (Compound 1) compared to a solution of the compound.

[0118] Details of the gel formulation are given below: The flux of the active ingredient through the membrane of the Franz cell was compared to that achieved by a 5 mg / mL solution of Compound 1 (free base (non-salt)) in Transcutol® and dimethyl isosorbide. [Table 1]

[0119] The results are shown in the table below. [Table 2]

[0120] The gel formulation was found to provide significantly higher permeability than the pure solution, indicating that the level of improvement cannot be attributed solely to increased concentrations of the active ingredients. The presence of propylene glycol in the formulation may also contribute to increased flux.

[0121] 1.2 Further permeability experiments The flux of the active ingredient (Compound 1) from a series of additional gel formulations containing Transcutol® and propylene glycol was measured at 0.64 cm 2 The assay was evaluated using a Permeagear vertical jacketed diffusion cell fitted with a PDMS membrane SSP-M823-005 with an area of ​​1.5 μm. 5 mL of 5% hydroxypropyl-beta-cyclodextrin (HPCD) in 0.1 M HCl was used as the receptor solution, which was kept at a temperature of 32 °C. Approximately 0.5-0.7 g of formulation was added to each well and 0.2 mL samples were taken at 0.25, 0.5, 1, 2, 3, 4, 18.5 / 20, and 24 h.

[0122] The formulations tested are listed in the table below: Formulation 2 contained the active ingredient as the parent compound, all other formulations contained the active ingredient in the form of the hydrogen sulfate salt (the amount quoted refers to the amount of active ingredient (parent compound) present). [Table 3]

[0123] The flux of the active ingredient through the membrane was very similar for all formulations tested, and the results are summarized in Table 1.

[0124] Example 1.3 Preparation of Clinical Study Formulation The following compositions were selected for use in the clinical study described in Example 2. [Table 4]

[0125] The compositions were prepared according to the following process. i) The HPMC polymer was hydrated in water (4.0% w / w HPMC polymer in water) by dispersing the polymer powder in water with vigorous stirring at 80° C. and cooling the dispersion to form a clear viscous gel. ii) The active ingredient was dissolved in a mixture of organic excipients propylene glycol, Transcutol® (2-(2-ethoxyethoxy)ethanol), and isopropyl alcohol to obtain an organic phase. iii) Mixing the pre-hydrated polymer gel and the organic phase by slowly adding the organic phase to the polymer gel with vigorous stirring and shaking. iv) Adjusting the pH of the composition by the addition of sodium hydroxide solution.

[0126] The viscosity of the composition was measured using a Kinexus Pro Rheometer with measurement geometry CP4 / 40, stainless steel cone:plate geometry, 40 mm diameter, 4° cone, 10 -1 and 100 -1 The viscosity was determined at a shear rate of 10 -1 At a shear rate of 100 -1 The shear rate was 0.51 Pa.s.

[0127] Example 2 - Clinical Study The efficacy of a gel formulation of N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (as hydrogen sulfate salt) (hereinafter "Compound 1 gel") was evaluated in a double-blind, randomized, placebo-controlled study on normal skin, skin optimized for penetration, and skin exposed to ultraviolet B radiation in 24 healthy volunteers. Details of the formulation used are shown in the table below. [Table 5]

[0128] Healthy volunteers were screened for eligibility 28 to 2 days prior to their first treatment. A training session (without study drug) was also conducted during screening to introduce subjects to the testing and grading procedures. An individual laser pain threshold (LPT) was determined for each volunteer prior to testing laser-evoked potentials (LEP) from healthy skin.

[0129] On day 1, subjects who signed informed consent and qualified for the study were exposed to increasing doses of UVR to determine their individual minimal erythema dose (MED) in a nevus-free test area. On day 2, a reading to determine the MED will be taken.

[0130] 20cm 2 Six treatment areas with a size of 100 mm were defined on day 1. Areas 1 and 2 were defined for treatment on normal skin. Areas 3 and 4 were defined to examine maximized application conditions using skin peeling to remove a portion of the stratum corneum using a standardized peeling protocol with adhesive tape and occlusive application. Areas 5 and 6 were prepared for exposure to UVR. Areas 1-6 were randomized to treatment with either Compound 1 gel or placebo (3 areas each). The placebo formulation was the same as Compound 1 gel with the active ingredients removed and citric acid and hydrochloric acid added as pH adjusters.

[0131] Treatments were administered once daily for five consecutive days, three times during the pre-UVR portion of the study, one time before UVR on the fourth day, and one time 24 hours after UVR on the fifth day.

[0132] On day 1, areas 1-4 were treated with Compound 1 gel (0.05 ml / cm 2Patients were treated with 1 mL of IMP or placebo and examined for changes in LEP amplitude, and visual analog scale ratings of pain (VAS-P). Assessments were performed before and after IMP application. On days 2 and 3, LEP and VAS-P assessments will also be performed at the same time (± 1 hour) as day 1, before and 1 hour after the second and third application of IMP. On study day 4, LEP and VAS-P were assessed for areas 1-4 at 1, 6, and 9 hours after the fourth IMP application.

[0133] At 2 hours on day 4, skin areas 5 and 6 will be irradiated with UVR at 2 MED.

[0134] LEP, VAS-P, erythema (by skin reflectance spectroscopy (SRS)), and pinprick hyperalgesia (by weighted pinprick threshold (WNT)) were assessed before and 1, 2, 3, 6, and 9 hours after UVR. At the same time points, the anti-inflammatory effect on the area of ​​UVR will be assessed by SRS, where the a value is a measure of "redness."

[0135] Subjects returned for the fifth IMP application on day 5. One hour after IMP application and 24±1 hours after UVR, LEP and VAS-pain were assessed for areas 1-6. In addition, erythema (SRS) and pinprick hyperalgesia (WNT) were assessed in areas 5 and 6.

[0136] Subjects returned for a follow-up visit on day 9 (± 1 day).

[0137] Methods for assessing efficacy Efficacy was assessed by the following methods: (i) Laser algesimetry Laser algometry is the experimental induction of pain by a non-contact thermal nociceptive laser beam with a fixed short duration (ms) and an individually adjusted intensity above the pain threshold (determined at screening). Objective and quantitative measurement of nociception is realized by analysis of contingent vertex EEG event-related potentials (somatosensory / radiant heat ERPs). Analgesic and antihyperalgesic properties of drugs can be objectively and quantitatively demonstrated by modification of LEP parameters, mainly by reducing the amplitude of the main LEP components (N2 and P2) relative to placebo, using peak-to-peak amplitude (PtP).

[0138] The efficacy of the study drugs (Compound 1 gel and placebo) was measured as a reduction in PtP amplitude.

[0139] (ii) VAS-Pain The VAS-Pain is a subjective assessment of pain and was used for all skin conditions. Electronic nociceptive scoring with an electronic 100 mm visual analogue scale (VAS) for post-laser pain (VAS-P) was assessed on a tablet PC, allowing the subject to differentiate pain severity between no pain and severe pain using a 0-100 mm scale. Measurements were taken after each laser session and summarised as an overall impression of "pain" throughout the session.

[0140] (iii) WNT measurement (mechanical hyperalgesia) WNT investigations of mechanical hyperalgesia were performed on the UVB-irradiated treatment areas using fixed weight steps at the same session time points as performed in the LEP+VAS-P (always after these sessions). Skin contact was achieved by positioning a rounded / blunt needle tip (with a defined weight ranging from 1 to 512 mN) on the skin. The WNT set was provided in a calibrated state by the Institute of Physiology and Pathophysiology of University Erlangen-Nuremberg [Rolke et al 2006]). Subjects had to indicate at what weight they felt pain (threshold) for pressure on the respective treatment area.

[0141] (iv) Skin reflectance spectroscopy Quantitative measurements of UV erythema intensity were performed by a CE-labeled colorimeter CR-400 (Konica-Minolta Optics, Inc. Munich), looking for a spectral shift for changes in colorimetric parameters according to the CIE-Lab system (CIE=Commission Internationale l'Eclairage, Lab=color dimensions for SRS, L=luminance, a=red / green dimension, b=blue / yellow dimension), respectively. A "cold" polychromatic light was guided to the skin against a photomultiplier. The output variable is the colorimetric parameter according to this CIE Lab system, in this case the a-value ("reddening"), a parameter without any dimension. The anti-inflammatory effect of a drug results in a decrease in the a-value (=less reddening) of the Lab measurement system.

[0142] Methods of skin UVB exposure The UVB model is used as a standard for the investigation of anti-inflammatory and analgesic compounds.

[0143] UV light consists primarily of UVB radiation (with an invisible spectral range of 280-320 nm, narrow band radiation at 311 nm), which is known to cause significantly more skin reddening (erythema) than UVA radiation, which is primarily responsible for skin tanning properties.

[0144] For screening, UVB was applied once at different doses to six small areas (each 1×1 cm2=6 cm2) of skin on the subject's back to determine the minimal erythema dose (MED), the individual's smallest dose that produces a clearly discernible erythema. UV radiation was provided using a Dermalight® 80 narrowband UVB source (311 nm, invisible range) with a Philips TL 9W / 01 UVB tube to generate UV light. The first area with a regular and clearly defined rectangular erythema (after at least 6-8 hours of appearance time) will be defined as the individual's MED.

[0145] On the morning of the UVR day, 2x individual MED was applied using a Dermalight 180 narrowband UVB source (310-315 nm, with a mean spectrum at 311 nm, invisible range) manufactured by ALTLichttherapietechnik GmbH, Zorbig, Germany, and distributed by Dr. K. Honle Medizintechnik GmbH, Kaufering, Germany. UVB exposure was performed on two skin areas on the back (two areas of 5x4 cm = 20 cm2 each) to generate uniform areas of skin erythema and hyperalgesia large enough to perform repeated laser measurements.

[0146] Sequence of validity testing Treatment areas were tested in numerical order (1, 2, 3, 4, 5, 6).

[0147] For each treatment area, efficacy parameters were determined in the following order: 1. SRS (UVR area only) 2. WNT (UVR region only) 3. LEP 4.VAS pain

[0148] Efficacy variables Laser-evoked potentials N2-P2 peak-to-peak (PtP) amplitude (μV) pain ·VAS pain (mm) Mechanical hyperalgesia Weighted needle test (mN) erythema ·Skin reflectance spectroscopy Endpoint Analysis

[0149] Statistical analysis was based on determination of treatment-related differences at individual time points and comparison of AUC (area under the curve) parameters derived from efficacy endpoints.

[0150] The time points included in the calculation of AUC depend on the objective. 1. Two AUC calculations were used to determine objectives a) and b) (therapeutic regions 1-4) a. All assessments 1 hour after IMP application on days 1-5, with the predose assessment on day 1 serving as baseline. b. All time points on day 4 and before IMP application on day 5 2. To assess objectives c) and d), all time points on day 4 and the assessment before IMP application on day 5 will be included in the calculation of the AUC associated with the treatment regions (treatment regions 5 and 6).

[0151] These parameters were analyzed using a linear mixed regression model, which included the categorical variables treatment (A1, A2, B1 and B2, respectively A3 and B3) and the corresponding baseline values ​​(pre-dose measurements on normal skin) as fixed effects, and the intercept for subject as a random effect.

[0152] All treatment differences with 95% confidence intervals were estimated from this model. The null hypothesis that these differences were equal to zero (no difference between active treatment and placebo) was tested at the 5% level against the two-sided alternative.

[0153] Efficacy analyses were performed using the FAS ("full analysis set").

[0154] All analyses will be performed with the statistical software package SAS (SAS™, SAS Institute, Cary, NC, USA). Statistical models will be fitted with the SAS procedure MIXED.

[0155] Dataset In total, 24 patients were treated in this study and represented the largest analysis population.

[0156] Efficacy Results Effects on normal skin [Table 6] [Table 7] [Table 8]

[0157] Skin Effects Optimized for Penetration [Table 9] [Table 10] [Table 11]

[0158] Effects of UVB on skin [Table 12] [Table 13] [Table 14]

[0159] SRS Because there was no apparent effect, only the AUC on day 4 was determined and individual time points were not analyzed. [Table 15]

[0160] The data show that the analgesic effect of topical treatment with Compound 1 was significantly better than placebo. As expected, the best results were achieved when the product was applied on skin optimized for penetration. However, these effects were also very pronounced when applied on normal and inflamed skin (UVR-induced inflammation). These results also show a long-lasting analgesic effect as a result of topical treatment. The product was well tolerated on both normal skin, skin with compromised barrier function (caused by procedures to optimize penetration), and inflamed skin.

[0161] Comparative effectiveness with approved drugs The following table shows the efficacy of topical treatment with Compound 1 (difference from placebo) observed in this study on normal and optimized skin, compared to the efficacy observed for oral administration of a series of approved drugs using the same methodology. Compound 1 data is based on the results (AUC) on day 4. Data for established products is taken from Schaffler K, et al., Br.J.Clin.Pharmacol.2013;75(2):404-414 and K.Schaffler, Br.J.Clin.Pharmacol.2017;83(7):1424-1435. [Table 16]

[0162] Example 3 - Comparative analysis with previous studies As discussed in Example 2, the kinetics of the analgesic effect of 1 ml of Compound 1 gel (approximating approximately 14 mg of active ingredient) as described in Example 2 was compared with legacy data from previous oral use of the same compound, previously identified as AZD1386 (at a dose of 95 mg).

[0163] Legacy Data Capsaicin Research Source: Clinical Study Report (A double-blind, randomized, single-center, placebo-controlled, crossover study to investigate the effects of a single oral dose of AZD1386 on intradermal capsaicin-induced pain symptoms and heat sensitivity in healthy volunteers) 1st edition, September 8, 2008.

[0164] design This was a phase I, double-blind, randomized, single-centre, placebo-controlled, crossover study conducted at AstraZeneca's CPU Huddinge Hospital, Sweden, to investigate the effects of AZD1386 on intradermal capsaicin-induced pain symptoms and heat sensitivity in healthy volunteers. Subjects received placebo or a single 95mg dose of AZD1386 by oral solution at the treatment visit.

[0165] Two different pain challenges used topical capsaicin cream (Capsina 0.075%®) and intradermal capsaicin (0.3 μg dose in 20% cyclodextrin, 10 μL injection volume), respectively.

[0166] Intradermal injections of capsaicin into the volar surface of both forearms were administered for a total of six times at each treatment visit; one before and five after IP administration. Topical capsaicin was applied onto the ventral mid-portion of the lower leg, measuring 5*3 cm. 2 An area of ​​100 cm was covered. In both challenges, a unique site was applied each time. Pain intensity after capsaicin injection was assessed by a continuous electronic VAS (deriving the variables VAS maximum pain and VAS AUC).

[0167] Results used for comparison End point pain induced by intradermal injection of capsaicin as assessed by eVAS (eVAS pain AUC 0~5分 The methodology associated with determining LEP-induced VAS pain in Study D8000CI-001 was deemed to be the most compatible with the methodology associated with LEP-induced VAS pain determination in Study D8000CI-001. For comparison purposes, Cohen's D was calculated using the mean, n, and SD for placebo and AZD1386 (Table 9 in the study report).

[0168] Molar Extraction Study (D5090C00009) design This is a single-dose, randomized, double-blind, double-dummy, placebo- and naproxen-controlled study to investigate the analgesic efficacy of AZD1386 95mg in patients undergoing surgical extraction of partially or completely impacted mandibular third molars where bone extraction was deemed necessary. Naproxen 500mg was included as a treatment arm for assay sensitivity only.

[0169] Patients requesting pain relief due to pain from the dental surgery area within 6 hours of the end of local anesthetic administration (last anesthetic dose) were randomized to one of three treatment groups: 40 patients received AZD1386 95 mg oral solution and naproxen placebo capsules, 40 patients received AZD1386 placebo oral solution and naproxen placebo capsules, and 23 patients received AZD1386 placebo oral solution and naproxen 500 mg (for assay sensitivity only). A visual analog scale (VAS) was used for the assessment of pain intensity and pain on jaw movement. The VAS consists of a 100 mm horizontal line with no scale, with the left end (0 mm) marked "no pain" and the right end (100 mm) marked "worst pain imaginable." Patients indicated his / her current pain intensity and pain on jaw movement by drawing a vertical line that intersects with the scale on the paper CRF page. Pain intensity was rated by the patient immediately prior to administration of study drug, with subsequent assessments performed at 15 minutes, 30 minutes, 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, 1 hour 45 minutes, 2 hours, 2 hours 30 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours after the start of study drug administration.

[0170] Results used for comparison For Study D5090C00009, the assessment of pain intensity by time point after molar extraction using VAS on a paper CRF (Table 30 of CSR) was deemed to be the closest match to the methodology associated with the determination of LEP-induced VAS pain in Study D8000CI-001. Cohen's D was calculated using the mean, n, and SD for the change from baseline for placebo and AZD1386. The following time points were included in the analysis: 1 hour, 1 hour 30 minutes, 2 hours 30 minutes, 3 hours, 4 hours, 5 hours, 6 hours.

[0171] Data used from the study described in Example 2 The data used to calculate Cohen's D from the study described in Example 2 were taken at 1, 6, and 9 hours on day 4 of the study and are shown in the table below. Given the sample size of n=24, standard deviations (SD) were derived from standard errors (SE). [Table 17]

[0172] Comparative analysis using Cohen's d Cohen's d (Cohen J. Statistical power analysis for the behavioural sciences (2nd ed) Lawrence Erlbaum Associate Publishers: Hillsdale, NJ (1988)) is a measure of effect size used to indicate the standardized difference between two means. As indicated by the term effect size, effect size allows the determination of the magnitude of an effect, for example, a treatment effect. It is also useful in comparing effect sizes reported in different experimental settings (e.g., clinical studies). It is therefore also widely used in meta-analyses.

[0173] Cohen's d can be calculated as the difference between means divided by the pooled standard deviation (SD).

[0174] The table below lists the levels of Cohen's d and their associated effect size interpretations. [Table 18]

[0175] Comparison results Comparison of the results from the clinical study described in Example 2 with legacy data for AZD1386 showed the following: AZD1386 has a short-term significant analgesic effect, approximately 1 to 1.5 hours after oral administration. This was consistent across two studies with different pain conditions and using different outcome measures The effect sizes for these short-lasting effects were at best moderate (d=0.3 and 0.66, respectively). In topical studies, the compound demonstrated significant analgesic effects even at the first observation time point at 1:00 h (p=0.0050 when applied on normal skin and p=0.0007 when applied on skin optimized for penetration). This effect was most pronounced at 6:00 hours (p=0.0005 for normal skin and p<0.0001 for penetration-optimized skin) The effect decreased at 9:00 but was still statistically significant (p=0.0045 when applied to normal skin and p=0.0006 when applied to skin optimized for penetration) In general, the calculated effect sizes for the analgesic effect of topical use were substantially larger than the effect of AZD1386 after oral use As expected, the effect was more pronounced when applied to skin optimized for penetration (d: 0.92, 1.26, and 0.75; this corresponds to the definition of a large or very large effect size compared to application on normal skin). However, the effect sizes reported for use on normal skin were also medium to large (d: 0.75, 0.85, and 0.61). The analgesic effect was unexpectedly long-lasting, with effects observed for over 9 hours after 1 hour of topical exposure.

[0176] The results are summarized in the table below. [Table 19]

[0177] Example 4 - Stability Studies The long-term stability of three batches of compositions containing N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (in the form of the hydrogen sulfate salt) (Composition A (Batches 1 and 2) and Composition B) was evaluated according to the principles of ICH Q1A.

[0178] Composition B differed from composition A only by the addition of 0.1 mg / g disodium edetate (disodium EDTA). Two batches of composition A taken from different manufacturing batches were tested. Full details of the compositions used in this study are provided in the table below.

[0179] Compositions for stability studies [Table 20]

[0180] The stability of Compositions A and B was evaluated according to the principles of ICH Q1A using long-term conditions (temperature 25±2°C and relative humidity 60±5%) and accelerated aging conditions (temperature 40±2°C and relative humidity 75±5%).

[0181] 20 g samples of the compositions were placed in 50 mL polyethylene terephthalate (PET) bottles (Veral, amber) closed with high density polyethylene caps and stored in a temperature and humidity controlled climate chamber under either long-term storage conditions (25±2°C, 60±5% RH) or accelerated aging conditions (40±2°C, 75±5% RH) for the duration of the study.

[0182] The organic impurity profile of the samples was analyzed by liquid chromatography at the start of the experiment and then at fixed time points specified in the table below to establish baseline impurity levels. Impurities present in amounts greater than 0.05 area % were recorded (identified by their relative retention time (RRT)).

[0183] Analysis method The organic impurity profile was analyzed by reversed-phase UHPLC using a C18 stationary phase, UV detection at 247 nm, and a diluent consisting of water / acetonitrile 50 / 50 (v / v). Organic impurities were determined by normalization. A correction factor was determined for the impurity RRT of 0.35. The analytical method details are shown in the table below.

[0184] Details of the analysis method [Table 21]

[0185] result long term conditions Composition A (Batch 1) - Impurity profile over time during storage at 25±2°C and 60±5% RH [Table 22] Composition A (Batch 2) - Impurity profile over time during storage at 25±2°C and 60±5% RH [Table 23] Composition B - Impurity profile over time when stored at 25±2°C and 60±5% RH [Table 24] Accelerated aging conditions Composition A (Batch 1) - Impurity profile over time during storage at 40±2°C and 75±5% RH [Table 25] Composition A (Batch 1) - Impurity Profile over Time During Storage at 40±2°C and 75±5% RH (continued) [Table 26] Composition A (Batch 2) - Impurity profile over time during storage at 40±2°C and 75±5% RH [Table 27] Composition A (Batch 2) - Impurity Profile over Time During Storage at 40±2°C and 75±5% RH (continued) [Table 28] Composition B - Impurity profile over time when stored at 40±2°C and 75±5% RH [Table 29] Composition B - Impurity Profile over Time During Storage at 40±2°C and 75±5% RH (continued) [Table 30]

[0186] These results suggest that composition A is chemically stable for up to six months when stored at room temperature (15-25°C) in a tamper-evident PET bottle sealed with an HDPE closure. However, impurity levels increased significantly under accelerated conditions.

[0187] The inclusion of 0.1 mg / g edetate disodium in composition B led to a clear reduction in organic impurities under accelerated conditions, therefore a shelf life of at least 12 months is likely appropriate based on the appropriate specification limits for each impurity.

[0188] Thus, the inclusion of an aminopolycarboxylic acid sequestering agent such as EDTA in the composition appears to have a positive effect on the stability of the active ingredient leading to a longer shelf life of the composition.

Claims

1. A pharmaceutical composition comprising the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for use in treating pain by topical administration of the composition to a body surface.

2. the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is present in the composition in an amount of about 0.05% (w / w) to about 10% (w / w); Optionally, the compound N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is present in the composition in an amount of about 0.5% (w / w) to about 2.5% (w / w); The composition of claim 1.

3. The composition according to claim 1 or 2, wherein the composition is in the form of a cream, spray, gel, or patch.

4. 3. The composition of claim 1 or 2, wherein the body surface is skin, or the body surface is a mucosal surface or an eye.

5. the composition further comprises a penetration enhancer component; Optionally, (i) the penetration enhancer component is 2-(2-ethoxyethoxy)ethanol; and / or (ii) the penetration enhancer component is present in an amount of about 10% (w / w) to about 50% (w / w); The composition according to claim 1 or 2.

6. the composition further comprises a solubility enhancer component; Optionally, (i) the solubility enhancer component is a diol, such as propylene glycol; and / or (ii) the solubility enhancer component is present in an amount of about 10% (w / w) to about 50% (w / w); The composition according to claim 1 or 2.

7. the composition further comprises a penetration enhancer component and a solubility enhancer component; the ratio of the amount of the penetration enhancer component to the solubility enhancer component is from about 3:1 to about 1:3, optionally the ratio is about 1:1; The composition according to claim 1 or 2.

8. the composition further comprises a gel-forming polymer component; Optionally, the gel-forming polymer component is selected from cellulose polymers, cross-linked polyacrylic acid polymers, and mixtures thereof; and optionally, the gel-forming polymer component is hydroxypropyl methylcellulose; The composition according to claim 1 or 2.

9. the composition further comprises an aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.001% (w / w) to about 0.5% (w / w), optionally wherein the aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, and pharma- ceutically acceptable salts thereof; Optionally, The aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, is ethylenediaminetetraacetic acid, or a pharma- ceutically acceptable salt thereof; The composition according to claim 1 or 2.

10. 3. The composition of claim 1 or 2, formulated for topical use.

11. The composition, (i) N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05% (w / w) to about 10% (w / w); (ii) a penetration enhancer component in an amount of about 10% (w / w) to about 50% (w / w); (iii) a solubility enhancer component in an amount of about 10% (w / w) to about 50% (w / w); The composition of claim 10.

12. 1. A composition formulated for topical use, said composition comprising: (i) N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05% (w / w) to about 10% (w / w); (ii) a penetration enhancer component selected from the list consisting of 2-(2-ethoxyethoxy)ethanol, dimethyl isosorbide, glycerol, ethanol, and combinations thereof, in an amount of about 10% (w / w) to about 50% (w / w); (iii) a solubility enhancer component selected from the group consisting of pentanediol, butanediol, propane-1,3-diol, propylene glycol, and mixtures thereof, in an amount of about 10% (w / w) to about 50% (w / w); A composition wherein the ratio of said penetration enhancer component to said solubility enhancer component is from about 3:1 to about 1:

3.

13. (i) the penetration enhancer component is selected from the group consisting of 2-(2-ethoxyethoxy)ethanol, dimethylisosorbide, and mixtures thereof, optionally wherein the penetration enhancer is 2-(2-ethoxyethoxy)ethanol; and / or (ii) the solubility enhancer component is propylene glycol; and / or (iii) the penetration enhancer component and the solubility enhancer component are each present in an amount of about 25% (w / w) to about 35% (w / w); The composition of claim 12.

14. 14. The composition of claim 12 or 13, wherein the composition further comprises a gel-forming polymer component selected from the group consisting of cellulose polymers (e.g., hydroxypropyl methylcellulose), cross-linked polyacrylic acid polymers, and mixtures thereof, in an amount of about 1% (w / w) to about 3% (w / w).

15. 14. The composition of claim 12 or 13, wherein the composition further comprises a lower alcohol selected from ethanol, isopropanol, propanol, and mixtures thereof.

16. The composition, i) N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof, in an amount from about 0.5% (w / w) to about 3% (w / w); ii) 2-(2-ethoxyethoxy)ethanol in an amount from about 25% (w / w) to about 35% (w / w); iii) propylene glycol in an amount of about 25% (w / w) to about 35% (w / w); iv) isopropyl alcohol in an amount from about 0.5% (w / w) to about 3.5% (w / w); v) hydroxypropyl methylcellulose in an amount of about 1% (w / w) to about 3% (w / w); The composition of claim 12 comprising: vi) water.

17. the composition further comprises an aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.001% (w / w) to about 0.5% (w / w); Optionally, The aminopolycarboxylic acid sequestering agent, or a pharma- ceutically acceptable salt thereof, is ethylenediaminetetraacetic acid, or a pharma- ceutically acceptable salt thereof; 14. The composition according to claim 12 or 13.

18. The composition according to claim 12 or 13, wherein the composition is in the form of a gel.

19. 13. The composition of claim 12, for use in treating pain by topical administration of the composition to a body surface, optionally wherein the body surface is skin.

20. 20. The composition of any one of claims 1, 2, and 19, wherein the pain is nociceptive pain.

21. The pain is selected from the group consisting of radiation therapy induced pain and pain associated with a condition selected from pyoderma, gangrene, hidradenitis suppurativa, calciphylaxis, vascular disease, burns, shingles, scleroderma, and dermatomyositis; or The pain is pain associated with enthesopathy.

20. The composition of any one of claims 1, 2, and 19.

22. the pain is peripheral neuropathic pain, Optionally, The peripheral neuropathic pain is selected from the group consisting of post-herpetic neuropathy, post-traumatic neuropathy, post-operative neuropathic pain, painful diabetic polyneuropathy, HIV neuropathy, chemotherapy-induced neuropathic pain, leprosy neuropathic pain, and post-amputation pain; 20. The composition of any one of claims 1, 2, and 19.

23. The treatment is at about 0.01 mL / cm ２ ~Approx. 2.0mL / cm ２ and optionally, the composition comprises applying the composition to the body surface in an amount of about 0.05 mL / cm ２ and / or The treatment is about 50 μg / cm ２ ~Approx. 1000μg / cm ２ and optionally, the dose is greater than 100 μg / cm ２ ~Approx. 900μg / cm ２ and / or the treatment comprising topically applying the composition once or twice daily; 20. The composition of any one of claims 1, 2, and 19.

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