Treatment of cutaneous lupus erythematosus

Abstract

The present invention relates to the treatment of cutaneous lupus erythematosus. The problem to be solved by the present invention is to provide a new pharmaceutical use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile. A therapeutic or preventive agent for cutaneous lupus erythematosus and a pharmaceutical formulation thereof contain 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile as an active ingredient.

Description

[Technical Field]

[0001] The present invention relates to new pharmaceutical uses of delgocitinib (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile). In another aspect, the present invention relates to the treatment of cutaneous lupus erythematosus. In yet another aspect, the present invention relates to new topical pharmaceutical formulations comprising delgocitinib. [Background technology]

[0002] Lupus erythematosus is an inflammatory autoimmune disease that can involve only the skin (cutaneous lupus erythematosus (CLE)) or can include severe systemic organ involvement (systemic lupus erythematosus (SLE)). CLE can be acute, subacute, or chronic. Discoid lupus erythematosus (DLE) is the most common form of chronic CLE, accounting for 80% of all cases.

[0003] Discoid lupus erythematosus (DLE) is an autoimmune disease that affects the skin by producing scaly, erythematous, localized lesions. Over time, these lesions can lead to scarring, atrophy, pigmentation abnormalities, and hair loss. DLE lesions generally range in size from a few millimeters to 15 cm in diameter and are found primarily in UV-exposed areas (e.g., the head and neck) and, to a lesser extent, on the trunk and extremities. This physical appearance impairs the quality of life of DLE patients and is associated with an increased risk of depression and unemployment.

[0004] DLE is classified as either localized (lesions found only above the neck) or generalized (lesions found both above and below the neck), of which the localized form is by far the most common.

[0005] Currently, there is no cure for DLE, and no approved treatments exist for this condition. The current standard of care is off-label and has limited efficacy. Recommended first-line treatments include sun avoidance, UV protection, and potent topical corticosteroids.

[0006] Several JAK inhibitors are in clinical development or are already on the market. Ruxolitinib (the first FDA-approved inhibitor of JAK1 and JAK2) is an oral agent approved in several countries / regions for the treatment of patients with myelofibrosis. Tofacitinib is currently approved in the United States as an oral agent for the treatment of rheumatoid arthritis and is also being developed for the treatment of psoriasis and atopic dermatitis.

[0007] WO2011 / 013785 describes nitrogen-containing spirocyclic compounds and their pharmaceutical uses. These compounds are said to be JAK inhibitors useful for the prevention or treatment of, for example, autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis, and atopic dermatitis.

[0008] EP2813228A1 describes the pharmaceutical use of JAK inhibitors, more particularly pharmaceutical compositions for treating skin diseases such as senile xerosis, asteatosis, eczema, and contact dermatitis.

[0009] Therefore, there is an unmet medical need for new, highly effective treatments for cutaneous lupus erythematosus that also have an attractive safety profile.

[0010] Currently, an ointment formulation exists, which is a paraffin-based formulation containing delgocitinib in suspended solid form.

[0011] Surprisingly, a stable cream formulation has been obtained that contains delgocitinib dissolved in the aqueous phase. Summary of the Invention

[0012] The present invention relates to the treatment of cutaneous lupus erythematosus, in which treatment, a compound of formula (I) [ka] (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile) or a pharmaceutically acceptable salt thereof is used.

[0013] In one aspect, the present invention relates to the use of a compound of formula (I) for use in the treatment of cutaneous lupus erythematosus.

[0014] In another aspect, the present invention relates to the use of a compound of formula (I) for use in the treatment of discoid lupus erythematosus.

[0015] In another aspect, the present invention relates to a compound of formula (I) for use in the treatment of cutaneous lupus erythematosus. In yet another aspect, the present invention relates to a compound of formula (I) for use in the treatment of discoid lupus erythematosus. In yet another aspect, the present invention relates to a compound of formula (I) for use in the topical treatment of cutaneous lupus erythematosus (e.g., discoid lupus erythematosus). In yet another aspect, the topical formulation is a cream. In yet another aspect, the present invention relates to the use of a compound of formula (I), wherein the compound of formula (I) is administered once daily or twice daily. In yet another aspect, the present invention relates to the use of a compound of formula (I), wherein the compound of formula (I) is administered twice daily for 6 weeks. In another aspect, the present invention relates to a compound of formula (I), wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0016] In another aspect, the invention relates to the use of a compound of formula (I) in the manufacture of a pharmaceutical composition for treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus). In yet another aspect, the pharmaceutical composition is a topical formulation. In yet another aspect, the topical formulation is a cream.

[0017] In another aspect, the present invention relates to a pharmaceutical composition for treating cutaneous lupus erythematosus, the pharmaceutical composition comprising a compound of formula (I): [ka] (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile) or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the present invention relates to a pharmaceutical composition for treating discoid lupus erythematosus.

[0019] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), wherein the treatment is topical (e.g., treatment with a cream).

[0020] In another embodiment, the present invention relates to a pharmaceutical composition, wherein the compound of formula (I) is administered at concentrations of 1 mg / g, 3 mg / g, 8 mg / g, and 20 mg / g. In another embodiment, the compound of formula (I) is administered at a concentration of 20 mg / g. In another embodiment, the compound of formula (I) is administered by once-daily or twice-daily application. In another embodiment, the compound of formula (I) is administered by twice-daily application for 6 weeks.

[0021] In another aspect, the present invention relates to a method of treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0022] In another aspect, the invention relates to a method of treating cutaneous lupus erythematosus (eg, discoid lupus erythematosus) in a subject in need thereof, wherein administration is topical.

[0023] In another aspect, the present invention relates to a method of treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) in a subject in need thereof, wherein the topical formulation is a cream.

[0024] In another aspect, the present invention relates to a method for treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) in a subject in need thereof, wherein the compound of formula (I) is administered at concentrations of 1 mg / g, 3 mg / g, 8 mg / g, and 20 mg / g. In another aspect, the compound of formula (I) is administered at a concentration of 20 mg / g.

[0025] The present invention also provides the use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro-[3,4]octan-1-yl]-3-oxopropanenitrile in the treatment of cutaneous lupus erythematosus.

[0026] The present invention further provides the above uses administered in a once-daily or twice-daily application.

[0027] The present invention further provides the above uses administered at concentrations of 1 mg / g, 3 mg / g, 8 mg / g, and 20 mg / g. The present invention further provides the above uses administered at a concentration of 20 mg / g. Detailed Description of the Invention

[0028] Compounds of formula (I) [ka] The compound 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile is described in WO 2011 / 013785 as a JAK inhibitor for the treatment of autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis, atopic dermatitis, etc., and in EP 2813228 A1 for the treatment of skin diseases such as senile xerosis, asteatosis, eczema, and contact dermatitis.

[0029] The compound of formula (I) can be prepared according to the method described in Preparation 6 of WO2011 / 013785.

[0030] The term "pharmaceutically acceptable salt" refers to any non-toxic salt of the compound of formula (I), including salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and salts with amino acids.

[0031] Salts with inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc. Salts with organic acids include oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid monohydrate, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Salts with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, etc. Salts with organic bases include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, etc. Salts with amino acids include lysine, arginine, aspartic acid, glutamic acid, etc.

[0032] According to known methods, the respective salts can be obtained by reacting the compounds of formula (I) with inorganic bases, organic bases, inorganic acids, organic acids or amino acids.

[0033] The compound of formula (I) may be isotope-labeled with 3H, 14C, 35S, and the like.

[0034] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a substantially purified compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is 80% or greater pure.

[0035] A "pharmaceutical composition" includes oral formulations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions, etc., or parenteral formulations such as topical formulations, suppositories, injections, eye drops, nasal drops, and pulmonary agents. In another aspect, the pharmaceutical composition is a topical formulation such as an ointment or cream. In yet another aspect, the pharmaceutical composition is a cream.

[0036] The pharmaceutical compositions of the present invention are prepared by mixing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients or carriers in appropriate amounts according to methods well known in the art of pharmaceutical preparation. The content of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies depending on the dosage form and administration amount, and may be, for example, 0.1% to 100% by weight of the total composition. For example, the content may be 0.10, 0.20, 0.25, 0.30, 0.50, 0.75, 1.0, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, or 4.00% by weight of the total composition. In another embodiment, the content of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 2% by weight of the total composition.

[0037] As used herein, the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate, or partially arrest the clinical symptoms of a given disease and its complications. An amount sufficient to accomplish this is defined as a "therapeutically effective amount." Amounts effective for each purpose will vary depending on the severity of the disease or injury, the weight and general condition of the subject.

[0038] "Pharmaceutically acceptable pharmaceutical additives" or "pharmaceutically acceptable carriers" include various conventional organic or inorganic pharmaceutical additives or carrier substances that become pharmaceutical materials, such as disintegrants, binders, fluidizing agents, lubricants, solvents, solubilizing agents, suspending agents, isotonicity adjusting agents, buffers, emollients for liquid preparations, bases, emulsifiers, surfactants, wetting agents, stabilizers, stabilizing agents, dispersing agents, plasticizers, pH adjusting agents, absorption enhancers, gelling agents, preservatives, fillers, resolubilizing agents, etc. Furthermore, additives including preservatives, preservatives, antioxidants, and coloring agents may be used as appropriate.

[0039] Disintegrants include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, and the like.

[0040] Binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.

[0041] The flow agents include light anhydrous silicic acid, magnesium stearate, and the like.

[0042] Lubricants include magnesium stearate, calcium stearate, talc, and the like.

[0043] Solvents include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, medium-chain triglycerides, etc.

[0044] Solubilizers include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.

[0045] Suspending agents include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate, and the like.

[0046] Tonicity agents include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like.

[0047] Buffers or pH adjusters include phosphate or citrate salts, sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, sodium citrate dihydrate, citric acid monohydrate, hydrochloric acid, sodium hydroxide, and the like.

[0048] Bases include water, animal and vegetable oils (such as olive oil, corn oil, peanut oil, sesame oil, castor oil, and safflower oil), lower alcohols (such as ethanol, propanol, propylene glycol, 1,3-butylene glycol, and phenol), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (such as white soft paraffin, liquid paraffin, paraffin, and hard paraffin), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, polydimethylsiloxane, isopropyl myristate, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methyl cellulose and carboxyl cellulose), hydroxyethyl esters (such as carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, and polyvinylpyrrolidone), propylene glycol, macrogols (such as macrogol 200 to 600), and combinations of two or more of the foregoing. In one embodiment, the base is liquid paraffin.

[0049] Emulsifiers or surfactants include mixtures of fatty acids, especially cetyl alcohol, stearyl alcohol, and cetostearyl alcohol, macrogol cetostearyl ether, sorbitan esters, sucrose esters, and the like.

[0050] Stabilizers include sucrose esters, other sorbitan esters and polysorbates, glycerol, propylene glycol, ethanol, cetostearyl alcohol, and the like.

[0051] Acidifying agents include strong acids selected from hydrochloric acid and citric acid.

[0052] Chelating agents include ethylenediaminetetraacetic acid (EDTA), edetate disodium, ethylene glycol tetraacetic acid (EGTA), ethylenediamine, phosphoric acid, and the like.

[0053] Preservatives include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, chlorocresol, dichlorobenzyl alcohol, glycerol, ethanol, propylene glycol, benzoic acid / sodium benzoate, diazolidine urea, benzalkonium chloride, and the like.

[0054] Antioxidants include sodium sulfite, ascorbic acid, edetate disodium, edetate trisodium, alpha tocopherol, butylhydroxyanisole, and the like.

[0055] Coloring agents include food dyes, beta-carotene, and the like.

[0056] The pharmaceutical composition of the present invention can be administered to mammals such as humans. The dosage varies depending on the subject, disease, symptoms, dosage form, administration route, etc., and can range from about 0.01 mg to about 1 g. For example, the amount of the compound of formula (I) as an active ingredient can range from about 0.01 mg to about 600 mg per day. This dosage can be administered once or in divided doses.

[0057] The topical preparation can be applied externally, as an ointment, or as a spray, depending on the dosage form. The amount of the topical preparation applied to the affected area can be selected depending on the content of the active ingredient. For example, the topical preparation can be applied once a day or in divided doses. The preferred application method is once a day or twice a day.

[0058] The term "JAK" refers to one or more of the enzymes JAK1, JAK2, JAK3, and TYK2 that belong to the JAK family.

[0059] The phrase "inhibiting JAK" refers to inhibiting the function of JAK to eliminate or attenuate its activity, and to inhibiting one or more enzymes in the JAK family. In one embodiment, the phrase "inhibiting JAK" refers to "inhibiting human JAK." Inhibition of function or elimination or attenuation of activity is, in one embodiment, carried out in the context of a human clinical application.

[0060] A "JAK inhibitor" can be any substance that inhibits JAK, including small molecule compounds, nucleic acids, polypeptides, proteins, antibodies, vaccines, etc. In one embodiment, the "JAK inhibitor" is a "human JAK inhibitor." In another embodiment, the JAK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the JAK inhibitor is a compound of formula (I).

[0061] The term "treatment" as used herein includes improvement of symptoms, prevention of worsening, maintenance of remission, prevention of exacerbation, prevention of recurrence, etc. Furthermore, the term "prevention" means suppressing the occurrence of symptoms.

[0062] The term "treatment" can also include slowing the progression of the disease, disorder or condition, ameliorating, alleviating or reducing symptoms and complications, and / or curing or eliminating the disease, disorder or condition. The term "treatment" can also mean the management and care of a patient for the purpose of addressing the disease, condition or disorder.

[0063] As used herein, the terms "disease," "disorder," and "condition" are used interchangeably to identify a condition in a patient that is not within the normal physiological state of a human.

[0064] The term "cutaneous lupus erythematosus (CLE)" can include acute cutaneous lupus erythematosus, such as butterfly rash, photosensitivity, and mucosal ulcers. CLE can also include subacute cutaneous lupus erythematosus (SCLE), such as papular scaling (psoriasiform) SCLE, annular variant SCLE, and Rowell's syndrome. CLE can also include chronic cutaneous lupus erythematosus (CCLE), such as discoid lupus erythematosus (DLE), neoplastic lupus erythematosus, profundus lupus erythematosus, hypertrophic lupus erythematosus, and chilblain lupus erythematosus.

[0065] One embodiment of the present invention includes a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile and a pharmaceutically acceptable excipient or carrier.

[0066] One embodiment of the present invention includes the use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile for the treatment or prevention of cutaneous lupus erythematosus (e.g., discoid lupus erythematosus).

[0067] One embodiment of the present invention includes a method of treating or preventing cutaneous lupus erythematosus (e.g., discoid lupus erythematosus), comprising administering to a mammal a therapeutically effective amount of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile.

[0068] In one embodiment, the mammal is a human.

[0069] In another embodiment, the human is one suffering from a disease for which medical care is required.

[0070] In another embodiment, the disease is cutaneous lupus erythematosus. In another embodiment, the disease is acute cutaneous lupus erythematosus, such as butterfly erythema, photosensitivity, and mucosal ulcers. In another embodiment, the disease is subacute cutaneous lupus erythematosus (SCLE), such as papular-scaling SCLE, annular SCLE, and Rowell's syndrome. In another embodiment, the disease is chronic cutaneous lupus erythematosus, such as discoid lupus erythematosus (DLE), neoplastic lupus erythematosus, profundus lupus erythematosus, hypertrophic lupus erythematosus, and chilblain-like lupus erythematosus. In another embodiment, the disease is discoid lupus erythematosus (DLE).

[0071] In another aspect, the present invention relates to a therapeutic or prophylactic agent for cutaneous lupus erythematosus (eg, discoid lupus erythematosus), comprising a compound of formula (I).

[0072] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients or carriers.

[0073] In another aspect, the present invention relates to a pharmaceutical formulation for topical administration comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0074] In another aspect, the present invention relates to a pharmaceutical formulation which is a cream comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0075] In another embodiment, the pharmaceutically acceptable excipient can be one or more of a base selected from medium chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof. For example, the base can be liquid paraffin.

[0076] Liquid paraffin may be present in the base in various amounts from about 50 mg / g to about 500 mg / g (eg, about 75 mg / g to about 300 mg / g, 100 mg / g, etc.).

[0077] In another embodiment, the pharmaceutically acceptable surfactant, emulsifier, or stabilizer can be one or more selected from cetyl alcohol, stearyl alcohol, cetostearyl alcohol, or mixtures thereof. For example, the surfactant, emulsifier, or stabilizer can be cetostearyl alcohol.

[0078] Cetostearyl alcohol can be present in the surfactant, emulsifier, or stabilizer in various amounts from about 20 mg / g to about 100 mg / g (eg, from about 40 mg / g to about 80 mg / g, 72 mg / g, etc.).

[0079] In another embodiment, the pharmaceutically acceptable surfactant, emulsifier, or stabilizer can be one or more selected from sorbitan esters, sucrose esters, macrogolcetostearyl ether, or mixtures thereof. For example, the surfactant or emulsifier can be macrogolcetostearyl ether.

[0080] The surfactant, emulsifier, or stabilizer may contain macrogolcetostearyl ether in an amount ranging from about 9 mg / g to about 25 mg / g (eg, from about 15 mg / g to about 20 mg / g, 18 mg / g, etc.).

[0081] In another embodiment, the pharmaceutically acceptable buffer or pH adjuster can be one or more of phosphate, citrate, sodium acetate, sodium carbonate, sodium citrate dihydrate, hydrochloric acid, or mixtures thereof. For example, the buffer or pH adjuster can be one or more of citric acid monohydrate and sodium citrate dihydrate.

[0082] The buffer or pH adjuster can be present in various amounts from about 0.5 mg / g to about 4 mg / g (eg, about 0.7 mg / g to about 2 mg / g, 1 mg / g, etc.) of citric acid monohydrate.

[0083] The buffer or pH adjuster can be present in various amounts, from 0 mg / g to about 1 mg / g sodium citrate dihydrate (eg, 0 mg / g to about 0.5 mg / g, none, etc.).

[0084] In another embodiment, the pharmaceutically acceptable preservative can be one or more selected from benzyl alcohol, sodium dehydroacetate, sorbic acid / salt, or mixtures thereof. For example, the preservative can be benzyl alcohol.

[0085] The preservative may be benzyl alcohol present in various amounts from about 7 mg / g to about 13 mg / g (eg, about 9 mg / g to about 11 mg / g, 10 mg / g, etc.).

[0086] In another embodiment, the pharmaceutically acceptable antioxidant can be one or more selected from sodium sulfite, edetate disodium, edetate trisodium, butylhydroxyanisole, or mixtures thereof. For example, the antioxidant can be butylhydroxyanisole.

[0087] The antioxidant can be butylhydroxyanisole present in various amounts from about 0.05 mg / g to about 0.3 mg / g (eg, from about 0.1 mg / g to about 0.25 mg / g, 0.2 mg / g, etc.).

[0088] In another embodiment, the pharmaceutically acceptable chelating agent can be one or more of EDTA, edetate disodium, EGTA, or ethylenediamine. For example, the chelating agent can be edetate disodium.

[0089] The chelating agent can be present in an amount ranging from about 0.05 mg / g to about 1.5 mg / g (eg, about 0.5 mg / g to about 1 mg / g, 0.6 mg / g, etc.).

[0090] In another embodiment, the pharmaceutically acceptable acidifying agent can be one or more strong acids (e.g., hydrochloric acid or citric acid). For example, the acidifying agent can be hydrochloric acid.

[0091] The acidifying agent can have hydrochloric acid present in various amounts from 0 mg / g to about 25 mg / g (eg, from about 10 mg / g to about 20 mg / g, 17.7 mg / g, etc.).

[0092] In another embodiment, the pharmaceutically acceptable solvent can be purified water, which can be present in amounts varying from about 500 mg / g to about 900 mg / g (eg, 760 mg / g).

[0093] In another aspect, the present invention relates to a method for preparing the pharmaceutical formulation of the present invention.

[0094] Water phase: Purified water, pH adjuster, buffer, acidifier, preservative, and chelating agent were mixed. The drug substance was added to the aqueous phase and dissolved at a temperature of about 15 to 25°C. The pH was adjusted to 4.0-4.4. The aqueous phase was heated to about 65-75°C.

[0095] Oil phase: Liquid paraffin, surfactant, emulsifier, stabilizer, and antioxidant were mixed. The oil phase was heated to about 65-75°C.

[0096] The oil phase was added to the water phase and mixed. The mixture was homogenized for about 20 minutes and then cooled to about 30° C. The cream was then filled into containers.

[0097] Exemplary pharmaceutical formulations of the present invention:

[0098] Ingredient amounts (mg / g): delgocitinib 1, liquid paraffin 100, cetostearyl alcohol 72, macrogol cetostearyl ether 18, benzyl alcohol 10, citric acid monohydrate 0.78, butylhydroxyanisole 0.2, edetate disodium 0.6, sodium citrate dihydrate 0.31, and purified water 797.

[0099] Ingredient amounts (mg / g): delgocitinib 3, liquid paraffin 100, cetostearyl alcohol 72, macrogol cetostearyl ether 18, benzyl alcohol 10, citric acid monohydrate 1.0, butylhydroxyanisole 0.2, edetate disodium 0.6, 3M hydrochloric acid 1.08, and purified water 794.

[0100] Ingredient amounts (mg / g): delgocitinib 8, liquid paraffin 100, cetostearyl alcohol 72, macrogol cetostearyl ether 18, benzyl alcohol 10, citric acid monohydrate 1.0, butylhydroxyanisole 0.2, edetate disodium 0.6, 3M hydrochloric acid 6.43, and purified water 784.

[0101] Ingredient amounts (mg / g): delgocitinib 20, liquid paraffin 100, cetostearyl alcohol 72, macrogol cetostearyl ether 18, benzyl alcohol 10, citric acid monohydrate 1.0, butylhydroxyanisole 0.2, edetate disodium 0.6, 3M hydrochloric acid 17.7, and purified water 760.

[0102] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutical excipient as disclosed in the test drug (IP-1).

[0103] In another aspect, the present invention relates to a pharmaceutical formulation for topical administration comprising a compound of formula (I) and excipients as disclosed in Test Product (IP-2).

[0104] The present invention describes the efficacy of topical treatment for cutaneous lupus erythematosus.In another aspect, the present invention describes the efficacy of topical treatment for discoid lupus erythematosus.

[0105] The present invention provides a clinical trial comparing the efficacy and safety of twice-daily topical application of a cream containing 20 mg / g of the compound of Formula (I) and a cream vehicle in the treatment of adult subjects with cutaneous lupus erythematosus, more specifically discoid lupus erythematosus, for a period of 6 weeks. All subjects will receive active treatment at one DLE target lesion and vehicle treatment at another DLE target lesion.

[0106] The following are defined as efficacy and safety indicators:

[0107] Efficacy was assessed by investigator global assessment (IGA) severity for each target lesion (score of 0 (clear) or 1 (almost clear) at Week 6) and skin activity and damage scores for each target lesion (erythema, scaling / dyskeratosis, edema / infiltration, dyspigmentation, scarring / atrophy) based on the Revised Cutaneous Lupus Erythematos Disease Area and Severity Index (RCLASI). For more information on IGA and RCLASI, see below.

[0108] Subject assessment of efficacy and health-related quality of life was based on the Patient's Global Assessment (PaGA) and Dermatology Life Quality Index (DLQI) of the severity of each target lesion. [Example]

[0109] Clinical trials This is a multicenter, double-blind, randomized, vehicle-controlled, early Phase 2 study in adult subjects with DLE. Subjects will receive topical application of 20 mg / g of the compound of Formula (I) formulated into a cream and a vehicle cream twice daily for 6 weeks. Each subject must have at least two DLE target lesions with active disease. These two target lesions will be randomly assigned 1:1 to active treatment or vehicle treatment.

[0110] Treatment duration At baseline (Day 1), subjects will be randomly assigned (1:1) to receive the drug cream 20 mg / g or vehicle on the two target lesions. Treatment will be administered twice daily for 6 weeks. The first application of the investigational medicinal product (IMP) will be administered at the investigational site on Day 1, when all baseline assessments will be performed. Subsequent applications of the IMP will be administered by the subject at home.

[0111] During the 6-week treatment period, subjects will visit the investigational site according to the schedule at weeks 2, 4, and 6. The final application of the IMP will occur the evening before the subject's scheduled week 6 visit.

[0112] Key selection criteria -Age 18-70 years old. - Histopathological findings (current or previous) consistent with a clinical diagnosis of DLE. - A definite clinical diagnosis of two active DLE target lesions that are less than 6 months old and clinically evaluable. Target lesions may include lesions on the scalp if all lesion-specific eligibility criteria are met. - IGA scores of target lesions at screening and baseline are at least moderate (IGA ≥ 3). - A difference of ≤1 point in IGA scores at screening and baseline between the two target lesions. - Target lesion erythema score ≥ 2 at screening and baseline.

[0113] Main exclusion criteria - Target Lesion Dyspigmentation Score of 2 at screening or baseline. - Target lesion scar / atrophy score of 2 at screening or baseline. - Target Lesion Cicatricial Alopecia Score >0 at screening or baseline in scalp lesions. - History of SLE with clinically significant organ involvement, including SLE-associated pleurisy or pericarditis, and neurological, renal, and / or other major SLE-associated organ system involvement. SLE joint involvement is permitted. - Subjects with unstable or significant SLE disease activity, in the investigator's experience. - Have any other skin condition at screening or baseline that would interfere with the assessment of DLE. Immunosuppressive / immunomodulatory therapy (e.g., methotrexate, cyclosporine, azathioprine, retinoids, dapsone) within 4 weeks prior to baseline. - Systemic prednisolone at >7.5 mg / day or modified doses within 4 weeks prior to baseline (nasal and inhaled corticosteroids are acceptable). -Medication treatment with: Oral antimalarial treatment with hydroxychloroquine >6.5 mg / kg body weight / day or modified dose, or chloroquine >4 mg / kg body weight / day or modified dose within 12 weeks prior to baseline. - Concomitant administration of quinacrine with either hydroxychloroquine or chloroquine within 12 weeks prior to baseline. - Medications known to interact with antimalarials (e.g., digoxin, cimetidine) within 12 weeks prior to baseline. Treatment with topical corticosteroids, calcineurin inhibitors, and phosphodiesterase-4 (PDE-4) inhibitors within 2 weeks prior to baseline. - Use of systemic or cutaneous antibiotics on target lesions within 2 weeks prior to baseline. - UV therapy within 2 weeks prior to baseline. - Any procedure that compromises the skin barrier (e.g., incision) within 2 cm of any border of a target lesion within 4 weeks prior to baseline. - Receipt of live (attenuated) vaccine within 4 weeks prior to baseline. - Consumption of Hypericum perforatum (St. John's wort)-containing products within 4 weeks prior to baseline. Treatment with any commercially available or investigational biologic therapy, including: Any cytodepleting agent, including but not limited to rituximab: Prior to baseline, within 6 months or until lymphocyte counts return to normal, whichever is longer. -Other biologics: Within 3 months or 5 half-lives prior to baseline, whichever is longer. - History of any active skin infection within 1 week prior to baseline. - Clinically significant infection within 4 weeks prior to baseline that, in the opinion of the investigator, may compromise the subject's safety in this study. - Subjects with tuberculosis requiring treatment within 12 months prior to screening and / or a positive blood test for tuberculosis at screening.

[0114] Investigator's Global Assessment (IGA) for Discoid Lupus Erythematosus (DLE) The IGA is used to grade the subject's overall disease severity and is based on a 5-point scale ranging from 0 (none) to 4 (severe). The investigator will grade the severity of DLE separately for each of the two target lesions using the IGA as a lesion-specific assessment.

[0115] Investigator Global Assessment (IGA) for Discoid Lupus Erythematosus (DLE) [Table 1]

[0116] Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) The RCLASI is a validated scoring system that assesses disease activity and damage in patients with CLE, taking into account both anatomical region and morphologic appearance.

[0117] RCLASI skin lesion activity and damage sign scores are applied only to target lesions. Individual sign scores and the sum provide a quantitative assessment of treatment efficacy. Higher RCLASI scores indicate more severe disease. A complete RCLASI assessment will also be performed at baseline to account for the overall CLE disease burden in the study population.

[0118] The total skin disease activity score is defined as the sum of the scores for erythema, scaling / hyperkeratosis, and edema / infiltration. Erythema: 0 = none; 1 = pink, faint; 2 = red; 3 = dark red, crimson / purple / crusted / hemorrhagic Desquamation / hyperkeratosis: 0 = none; 1 = focally adherent desquamation / keratinized pores; 2 = warty hyperkeratosis Edema / infiltration: 0 = none; 1 = slight, barely palpable; 2 = palpable and visible

[0119] The total skin lesion score is defined as the sum of the dyspigmentation and scar / atrophy scores. Dyspigmentation: 0 = none; 1a = hypopigmentation; 1b = hyperpigmentation; 2 = hypo- and hyperpigmentation Scarring / atrophy: 0=none; 1=early scarring; 2=very firm / atrophic / wormlike scarring

[0120] Patient Global Assessment of Disease Severity (PaGA) PaGA is a subject's self-assessment of disease severity according to their perception.

[0121] Subjects will rate the disease severity of each target lesion using the PaGA, which will be assessed using a 5-point scale. 0 = none; 1 = almost none; 2 = mild; 3 = moderate; 4 = severe

[0122] Dermatology Life Quality Index (DLQI) The DLQI is a validated questionnaire with content specific to individuals with skin conditions. It consists of 10 items that assess the subject's perception of the impact of their skin condition over the past week on various aspects of their quality of life (e.g., skin condition-related symptoms and feelings, daily activities, leisure time, work or school, relationships, and medical treatment). Each item is scored on a 4-point Leaket scale (0 = "not at all / not relevant," 1 = "somewhat relevant," 2 = "very relevant," 3 = "very relevant"). The total score is the sum of the 10 items (0-30), with higher scores indicating poorer quality of life.

[0123] Investigational drug (IP-1) [Table 2]

[0124] Investigational drug (IP-2) [Table 3]

[0125] Terms In consideration of the above explanation, the present invention specifically provides the following. 1. A compound of general formula (I) for use in the treatment of cutaneous lupus erythematosus [ka] (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile) or a pharmaceutically acceptable salt thereof.

[0126] 2. The compound for use according to clause 1, wherein said treatment is for discoid lupus erythematosus.

[0127] 3. The compound for use according to clause 1 or 2, wherein said treatment is a topical treatment.

[0128] 4. A compound for use according to any one of the preceding clauses, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a cream.

[0129] 5. The compound for use according to any one of the preceding clauses, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

[0130] 6. The compound for use according to any one of the preceding clauses, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a twice-daily application.

[0131] 7. A pharmaceutical composition for use in the treatment of cutaneous lupus erythematosus, comprising a compound of formula (I) [ka] (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0132] 8. The pharmaceutical composition for use according to clause 7, wherein said treatment is for discoid lupus erythematosus.

[0133] 9. The pharmaceutical composition for use in treatment according to clause 7 or 8, wherein said pharmaceutical composition is topical.

[0134] 10. The pharmaceutical composition for use in treatment according to any one of clauses 7 to 9, wherein said pharmaceutical composition is a cream.

[0135] 11. The pharmaceutical composition for use in therapy according to any one of clauses 7 to 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a concentration of 20 mg / g.

[0136] 12. A pharmaceutical composition for use in therapy according to any one of clauses 7 to 11, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a twice-daily application.

[0137] 13. A method of use in treating cutaneous lupus erythematosus in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) [ka] (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile) or a pharmaceutically acceptable salt thereof to the subject.

[0138] 14. The use according to clause 13, wherein the treatment is for discoid lupus erythematosus.

[0139] 15. The use in therapy according to clause 13 or 14, wherein said administration is topical.

[0140] 16. The method for use in treatment according to any one of the preceding clauses 13 to 15, wherein the topical administration is a cream.

[0141] 17. The use in therapy according to any one of the preceding clauses 13 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

[0142] 18. A therapeutic or preventive agent for cutaneous lupus erythematosus, comprising a compound represented by the formula (I): [ka] (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0143] 19. A therapeutic or prophylactic agent according to clause 18 for the treatment or prevention of discoid lupus erythematosus.

[0144] 20. The therapeutic or prophylactic agent for discoid lupus erythematosus according to clause 18 or 19, wherein the therapeutic or prophylactic agent is a topical agent.

[0145] 21. The treatment or prevention agent according to any one of the preceding clauses 18 to 20, wherein the treatment or prevention agent is a cream.

[0146] 22. The therapeutic or prophylactic agent according to any one of the preceding clauses 18 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

[0147] 23. The therapeutic or prophylactic agent according to any one of the preceding clauses 18 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day.

[0148] 24. A compound of formula (I), A pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients selected from the following: -Base (liquid paraffin, etc.), - surfactants, emulsifiers, stabilizers (such as cetostearyl alcohol and macrogol cetostearyl ether), pH adjusters, buffers (such as phosphates or citrates, and hydrochloric acid), -preservatives, -antioxidants, chelating agents, acidifying agents, as well as -Purified water.

[0149] 25. The pharmaceutical formulation of clause 24, wherein the base is liquid paraffin and is present in an amount of about 50 mg / g to about 500 mg / g.

[0150] 26. The pharmaceutical formulation according to clause 25, wherein the liquid paraffin is present in an amount of about 75 mg / g to about 300 mg / g, in particular 100 mg / g.

[0151] 27. A pharmaceutical formulation according to any one of clauses 24 to 26, wherein the surfactant, emulsifier, stabilizer is one or more of cetostearyl alcohol and macrogol cetostearyl ether.

[0152] 28. The pharmaceutical formulation of clause 27, wherein the cetostearyl alcohol is present in an amount of about 20 mg / g to about 100 mg / g.

[0153] 29. The pharmaceutical formulation according to clause 28, wherein the cetostearyl alcohol is present in an amount of about 40 mg / g to about 80 mg / g, in particular 72 mg / g.

[0154] 30. The pharmaceutical formulation of clause 27, wherein the macrogolcetostearyl ether is present in an amount of about 9 mg / g to about 25 mg / g.

[0155] 31. The pharmaceutical formulation according to clause 30, wherein the macrogolcetostearyl ether is present in an amount of about 15 mg / g to about 20 mg / g, in particular 18 mg / g.

[0156] 32. A pharmaceutical formulation according to any one of the preceding clauses 24 to 31, wherein the buffering agent, pH adjusting agent is selected from phosphates or citrates.

[0157] 33. The pharmaceutical formulation of clause 32, wherein the buffering agent, pH adjusting agent is citric acid monohydrate and is present in an amount of about 0.5 mg / g to about 4 mg / g.

[0158] 34. The pharmaceutical formulation according to clause 33, wherein the citric acid monohydrate is present in an amount of about 0.7 mg / g to about 2 mg / g, in particular 1 mg / g.

[0159] 35. The pharmaceutical formulation of clause 32, wherein the buffering agent, pH adjusting agent, is sodium citrate dihydrate and is present in an amount of 0 mg / g to about 1 mg / g.

[0160] 36. The pharmaceutical formulation according to clause 35, wherein said sodium citrate dihydrate is absent.

[0161] 37. The pharmaceutical formulation of any one of clauses 24 to 36, wherein the preservative is benzyl alcohol.

[0162] 38. The pharmaceutical formulation of clause 37, wherein the benzyl alcohol is present in an amount of about 7 mg / g to about 13 mg / g.

[0163] 39. The pharmaceutical formulation according to clause 38, wherein the benzyl alcohol is present in an amount of about 9 mg / g to about 11 mg / g, in particular 10 mg / g.

[0164] 40. The pharmaceutical formulation of any one of clauses 24 to 39, wherein the antioxidant is butylhydroxyanisole.

[0165] 41. The pharmaceutical formulation of clause 40, wherein the butylhydroxyanisole is present in an amount of about 0.05 mg / g to about 0.3 mg / g.

[0166] 42. The pharmaceutical formulation according to clause 41, wherein the butylhydroxyanisole is present in an amount of from about 0.1 mg / g to about 0.25 mg / g, in particular 0.2 mg / g.

[0167] 43. The pharmaceutical formulation of any one of clauses 24 to 42, wherein the chelating agent is EDTA.

[0168] 44. The pharmaceutical formulation according to clause 43, wherein the chelating agent is edetate disodium.

[0169] 45. The pharmaceutical formulation of clause 44, wherein the edetate disodium is present in an amount of about 0.05 mg / g to about 1.5 mg / g.

[0170] 46. ​​The pharmaceutical formulation according to clause 45, wherein the edetate disodium is present in an amount of 0.5 mg / g to about 1 mg / g, in particular 0.6 mg / g.

[0171] 47. The pharmaceutical formulation according to any one of clauses 24 to 46, wherein the acidifying agent is hydrochloric acid.

[0172] 48. The pharmaceutical formulation of clause 47, wherein the hydrochloric acid is present in an amount of from 0 mg / g to about 25 mg / g.

[0173] 49. The pharmaceutical formulation according to clause 48, wherein the hydrochloric acid is present in an amount of about 10 mg / g to about 20 mg / g, in particular 17.7 mg / g.

[0174] 50. The pharmaceutical formulation of any one of clauses 24 to 49, wherein the purified water is present in an amount of from about 500 mg / g to about 900 mg / g.

[0175] 51. The pharmaceutical formulation of clause 50, wherein the purified water is present in an amount of 760 mg / g.

[0176] 52. The pharmaceutical formulation according to any one of clauses 24 to 51, wherein the compound of formula (I) is present in an amount of 1 mg / g, 3 mg / g, 8 mg / g, or 20 mg / g.

[0177] 53. A pharmaceutical preparation for topical administration, comprising: 1 mg / g of a compound of formula (I), Liquid paraffin, 100 mg / g; Cetostearyl alcohol, 72 mg / g, Macrogol cetostearyl ether, 18 mg / g, benzyl alcohol, 10 mg / g; citric acid monohydrate, 0.78 mg / g; Butylhydroxyanisole, 0.2mg / g, edetate disodium, 0.6 mg / g; sodium citrate dihydrate, 0.31 mg / g, and Purified water, 797mg / g The pharmaceutical formulation comprising:

[0178] 54. A pharmaceutical preparation for topical administration, comprising: 3 mg / g of the compound of formula (I), Liquid paraffin, 100 mg / g; Cetostearyl alcohol, 72 mg / g, Macrogol cetostearyl ether, 18 mg / g, benzyl alcohol, 10 mg / g; Citric acid monohydrate, 1.0 mg / g; Butylhydroxyanisole, 0.2 mg / g; edetate disodium, 0.6 mg / g; 3M hydrochloric acid, 1.08 mg / g, and Purified water, 794mg / g The pharmaceutical formulation comprising:

[0179] 55. A pharmaceutical preparation for topical administration, comprising: Compound of formula (I), 8 mg / g; Liquid paraffin, 100 mg / g; Cetostearyl alcohol, 72 mg / g, Macrogol cetostearyl ether, 18 mg / g, benzyl alcohol, 10 mg / g; Citric acid monohydrate, 1.0 mg / g; Butylhydroxyanisole, 0.2 mg / g; edetate disodium, 0.6 mg / g; 3M hydrochloric acid, 6.43 mg / g, and Purified water, 784mg / g The pharmaceutical formulation comprising:

[0180] 56. A pharmaceutical preparation for topical administration, comprising: 20 mg / g of the compound of formula (I), Liquid paraffin, 100 mg / g; Cetostearyl alcohol, 72 mg / g, Macrogol cetostearyl ether, 18 mg / g, benzyl alcohol, 10 mg / g; Citric acid monohydrate, 1 mg / g; Butylhydroxyanisole, 0.2 mg / g; edetate disodium, 0.6 mg / g; 3M hydrochloric acid, 17.7 mg / g, and Purified water, 760mg / g The pharmaceutical formulation comprising:

[0181] 57. A pharmaceutical formulation according to any one of clauses 24 to 56, wherein the formulation is a cream.

Claims

1. Formula (I): 【Chemical 1】 and a compound of one or more acidifying agents; one or more pharmaceutically acceptable excipients selected from the following: An aqueous pharmaceutical formulation for topical administration comprising: - base, surfactants, emulsifiers or stabilizers, pH adjusters or buffers, - preservatives, - antioxidants, chelating agents, and -Purified water And, (a) a pharmaceutical formulation comprising 20 mg / g of the compound of formula (I), 17.7 mg / g of 3 M hydrochloric acid as the acidifying agent, 100 mg / g of liquid paraffin as the base, 72 mg / g of cetostearyl alcohol and 18 mg / g of macrogol cetostearyl ether as the surfactant, emulsifier, or stabilizer, 1 mg / g of citric acid monohydrate as the pH adjuster or buffer, 10 mg / g of benzyl alcohol as the preservative, 0.2 mg / g of butylhydroxyanisole as the antioxidant, 0.6 mg / g of edetate disodium as the chelating agent, and 760 mg / g of purified water; or (b) A pharmaceutical formulation comprising 8 mg / g of the compound of formula (I), 6.43 mg / g of 3 M hydrochloric acid as the acidifying agent, 100 mg / g of liquid paraffin as the base, 72 mg / g of cetostearyl alcohol and 18 mg / g of macrogol cetostearyl ether as the surfactant, emulsifier, or stabilizer, 1.0 mg / g of citric acid monohydrate as the pH adjuster or buffer, 10 mg / g of benzyl alcohol as the preservative, 0.2 mg / g of butylhydroxyanisole as the antioxidant, 0.6 mg / g of edetate disodium as the chelating agent, and 784 mg / g of purified water.

2. 2. The pharmaceutical formulation of claim 1, wherein the pH of the aqueous phase is 4.0 to 4.

4.

3. 3. The pharmaceutical formulation according to claim 1 or 2, wherein the formulation is a cream.

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