Geftinib formulations in cream form

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 medical 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 prophylactic agent for cutaneous lupus erythematosus containing 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, and a pharmaceutical preparation thereof.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080035580.1, filed on May 14, 2020, with a priority date of May 15, 2019, entitled “Treatment of Cutaneous Lupus Erythematosus”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to novel pharmaceutical uses of digotinib (3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile). In another aspect, this invention relates to the treatment of cutaneous lupus erythematosus. In yet another aspect, this invention relates to novel topical pharmaceutical formulations comprising digotinib. Background Technology

[0003] Lupus is an inflammatory autoimmune disease that may affect only the skin (cutaneous lupus erythematosus, CLE) or may 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.

[0004] Discoid lupus erythematosus (DLE) is an autoimmune disease that affects the skin and is characterized by erythema, scaling, and localized lesions. Over time, these lesions can lead to scarring, atrophy, pigmentation abnormalities, and hair loss. DLE lesions typically range in size from a few millimeters to 15 cm and are primarily found in areas exposed to ultraviolet radiation, such as the head and neck, with less pronounced involvement on the trunk and limbs. Appearance affects the quality of life for DLE patients and is associated with an increased risk of depression and unemployment.

[0005] DLE can be classified as localized (lesions only above the neck) or systemic (lesions both above and below the neck), with the localized form being far more common.

[0006] Currently, there is no cure for DLE, nor is it approved for treatment of this condition. Current standard of care is off-label use and has limited effectiveness. First-line treatment recommendations include sun protection, UV protection, and potent topical corticosteroids.

[0007] Several JAK inhibitors are in clinical development or already on the market. Ruxolitinib, the first JAK1 and JAK2 inhibitor approved by the FDA, is an oral medication and is approved in several countries for the treatment of myelofibrosis. Tofacitinib is currently approved in the United States as an oral medication for the treatment of rheumatoid arthritis and is currently under development for the treatment of psoriasis and atopic dermatitis.

[0008] WO2011 / 013785 describes nitrogen-containing spirocyclic compounds and their pharmaceutical uses. These compounds are claimed to be JAK inhibitors and may be used to prevent or treat conditions such as autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis, and atopic dermatitis.

[0009] EP 2813228 A1 describes the pharmaceutical use of JAK inhibitors and, more specifically, pharmaceutical compositions for the treatment of skin conditions such as xerosis senile, hypospermia, eczema, and contact dermatitis.

[0010] Therefore, there is an unmet medical need for new treatments for cutaneous lupus erythematosus that are highly effective and have an attractive safety profile.

[0011] There is currently an ointment formulation that is a paraffin-based formulation containing digotinib in a suspended solid form.

[0012] Surprisingly, a stable cream formulation containing digotinib dissolved in the aqueous phase has been obtained. Summary of the Invention

[0013] This invention relates to the treatment of cutaneous lupus erythematosus, comprising compounds of formula (I). (I), 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, the present invention relates to the use of compounds of formula (I) for the treatment of cutaneous lupus erythematosus.

[0015] In another respect, the present invention relates to the use of compounds of formula (I) for the treatment of discoid lupus erythematosus.

[0016] In another aspect, the present invention relates to compounds of formula (I) for the treatment of cutaneous lupus erythematosus. In yet another aspect, the present invention relates to compounds of formula (I) for the treatment of discoid lupus erythematosus. In yet another aspect, the present invention relates to compounds of formula (I) for the topical treatment of cutaneous lupus erythematosus (e.g., discoid lupus erythematosus). In yet another aspect, the topical preparation is a cream. In yet another aspect, the present invention relates to the use of compounds of formula (I) for administration once or twice daily. In yet another aspect, the present invention relates to the use of compounds of formula (I) for administration twice daily for 6 weeks. In yet another aspect, the present invention relates to compounds of formula (I) at an administration concentration of 20 mg / g.

[0017] In another aspect, the present invention relates to the use of compounds of formula (I) in the production of pharmaceutical compositions for the treatment of cutaneous lupus erythematosus, such as discoid lupus erythematosus. In yet another aspect, the pharmaceutical composition is a topical preparation. In still another aspect, the topical preparation is a cream.

[0018] In another aspect, the present invention relates to pharmaceutical compositions for treating cutaneous lupus erythematosus, comprising compounds of formula (I). (I), 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the present invention relates to pharmaceutical compositions for treating discoid lupus erythematosus.

[0020] In another aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I), wherein the treatment is localized, for example, with a cream.

[0021] In another aspect, the present invention relates to pharmaceutical compositions 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. In another aspect, the compound of formula (I) is administered once or twice daily. In another aspect, the compound of formula (I) is administered twice daily for 6 weeks.

[0022] 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, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) to the subject.

[0023] In another aspect, the present invention relates to a method of treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) in subjects in need, wherein the administration is by topical application.

[0024] In another aspect, the present invention relates to a method for treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) in subjects in need, wherein the topical preparation is a cream.

[0025] In another aspect, the present invention relates to a method of treating cutaneous lupus erythematosus (e.g., discoid lupus erythematosus) in subjects in need, 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.

[0026] 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]octane-1-yl]-3-oxopropionitrile in the treatment of cutaneous lupus erythematosus.

[0027] The present invention further provides the above-described use, which is applied once or twice a day.

[0028] The present invention further provides the above-described uses, which are administered at concentrations of 1 mg / g, 3 mg / g, 8 mg / g, and 20 mg / g. The present invention further provides the above-described uses, which are administered at a concentration of 20 mg / g. Detailed Implementation

[0029] Compound of formula (I) (I), 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile, previously described in WO2011 / 013785 as a JAK inhibitor for the treatment of autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis and atopic dermatitis, and in EP 2813228 A1 for the treatment of skin diseases such as senile xerosis, hyposlipidemia, eczema and contact dermatitis.

[0030] The compound of formula (I) can be produced according to the method described in Preparation 6 of WO2011 / 013785.

[0031] "Pharmaceutical acceptable salt" can be any non-toxic salt of a compound of formula (I), and includes salts formed with inorganic acids, salts formed with organic acids, salts formed with inorganic bases, salts formed with organic bases, and salts formed with amino acids.

[0032] Salts formed with inorganic acids include those with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts formed with organic acids include those with 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, and p-toluenesulfonic acid. Salts formed with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Salts formed with organic bases include those with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tri(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, methylpyridine, choline, cincorine, and meglumine. Salts formed with amino acids include those with lysine, arginine, aspartic acid, and glutamic acid.

[0033] According to well-known methods, each salt can be obtained by reacting a compound of formula (I) with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid.

[0034] Compounds of formula (I) can be labeled with isotopes such as 3H, 14C, and 35S.

[0035] In one respect, 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 respect, the compound of formula (I) or a pharmaceutically acceptable salt thereof has a purity of 80% or higher.

[0036] "Pharmaceutical composition" includes oral preparations (such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions) or parenteral preparations (such as topical preparations, suppositories, injections, eye drops, nasal drops, lung medications). On the other hand, a pharmaceutical composition is a topical preparation, such as an ointment or cream. In yet another aspect, a pharmaceutical composition is a cream.

[0037] The pharmaceutical composition of the present invention is produced by means of a method known in the field of pharmaceutical formulation technology, by appropriately mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient or carrier in an appropriate amount. The content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition depends on its dosage form, dosage, etc., and is, for example, from 0.1% to 100% of the total weight of the composition. For example, the content is 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% of the total weight of the composition. Alternatively, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 2% of the total weight of the composition.

[0038] As used herein, the term "therapeutic effective amount" of a compound means an amount sufficient to cure, alleviate, or partially prevent the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this goal is defined as a "therapeutic effective amount." The effective amount for each purpose will depend on the severity of the disease or injury, as well as the subject's weight and general condition.

[0039] "Pharmaceutically acceptable excipients" or "pharmaceutically acceptable carriers" include a variety of conventional organic or inorganic excipients or carrier substances used in pharmaceutical materials, such as disintegrants, binders, fluidizing agents, lubricants, solvents, solubilizers, suspending agents, tensioning agents, buffers, and analgesics for liquid formulations, as well as bases, emulsifiers, surfactants, humectants, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, and solubilizers. Additionally, additives, including preserving agents, preservatives, antioxidants, and colorants, may be used if necessary.

[0040] Disintegrants include carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium carboxymethyl cellulose, croscarmellose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, etc.

[0041] Adhesives include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, gummy candy, dextrin, starch, gelatin, sodium carboxymethyl cellulose, gum arabic, etc.

[0042] Fluidizing agents include light anhydrous silicate, magnesium stearate, etc.

[0043] Lubricants include magnesium stearate, calcium stearate, talc, etc.

[0044] Solvents include purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, medium-chain triglycerides, etc.

[0045] Solubilizers include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.

[0046] Suspension agents include benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glyceryl monostearate, etc.

[0047] Tenosynovitis suppressants include glucose, D-sorbitol, sodium chloride, D-mannitol, etc.

[0048] Buffers or pH adjusters include phosphates or citrates, sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, sodium citrate dihydrate, citric acid monohydrate, hydrochloric acid, sodium hydroxide, etc.

[0049] The base materials include water, animal and vegetable oils (e.g., olive oil, corn oil, peanut oil, sesame oil, castor oil, safflower oil, etc.), lower alcohols (e.g., ethanol, propanol, propylene glycol, 1,3-butanediol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (e.g., white soft paraffin, liquid paraffin, paraffin, hard paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointments, hydrophilic lanolin, starch, amylopectin, dimethicone, isopropyl myristate, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethyl (e.g., carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, polyethylene glycol (e.g., polyethylene glycol 200-600, etc.), and combinations of two or more of these substances. In one aspect, the base material is liquid paraffin.

[0050] Emulsifiers or surfactants include mixtures of fatty acids, especially cetyl alcohol, stearyl alcohol and cetearyl alcohol, polyethylene glycol cetearyl alcohol ether, sorbitol esters, sucrose esters, etc.

[0051] Stabilizers include sucrose esters, other dehydrated sorbitol esters and polysorbates, glycerol, propylene glycol, ethanol, cetearyl alcohol, etc.

[0052] Acidifying agents include strong acids selected from, for example, hydrochloric acid or citric acid.

[0053] Chelating agents include ethylenediaminetetraacetic acid (EDTA), disodium edetate, ethylene glycol tetraacetic acid (EGTA), ethylenediamine, phosphoric acid, etc.

[0054] Preservatives include ethylparaben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, chlorocresol, dichlorobenzyl alcohol, glycerin, ethanol, propylene glycol, benzoic acid / sodium benzoate, diazourea, benzalkonium chloride, etc.

[0055] Antioxidants include sodium sulfite, ascorbic acid, disodium edetate, trisodium edetate, α-tocopherol, butylated hydroxyanisole, etc.

[0056] Coloring agents include food colorings, beta-carotene, etc.

[0057] The pharmaceutical compositions of the present invention can be administered to mammals, such as humans. The dosage depends on the subject, disease, symptoms, dosage form, route of administration, etc., and can range from about 0.01 mg to about 1 g per day, for example from about 0.01 mg to about 600 mg, depending on the amount of the compound of formula (I) as the active ingredient. The dosage can be administered once or in several divided doses.

[0058] Topical preparations can be applied by methods such as smearing, rubbing, or spraying, depending on the dosage form. The amount of topical preparation applied to the affected area can be selected based on the content of the active ingredient, and the preparation can be applied, for example, once daily or in several divided doses. Preferred application is once or twice daily.

[0059] The phrase “JAK” refers to one or more enzymes belonging to the JAK family, namely JAK1, JAK2, JAK3, and TYK2.

[0060] The phrase "inhibit JAK" refers to inhibiting the function of JAK, causing it to lose or weaken its activity, and inhibiting one or more enzymes belonging to the JAK family. In one context, "inhibit JAK" specifically refers to "inhibit human JAK." Furthermore, the inhibition of function or the loss or weakening of activity is carried out under clinical application conditions in humans.

[0061] "JAK inhibitor" can be any substance that inhibits JAK, and can be, for example, a low molecular weight compound, nucleic acid, peptide, protein, antibody, vaccine, etc. In one respect, "JAK inhibitor" is "human JAK inhibitor." In another respect, a JAK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; in yet another respect, a JAK inhibitor is a compound of formula (I).

[0062] As used in this article, the term "treatment" includes improving symptoms, preventing exacerbations, maintaining remission, preventing worsening, and preventing both worsening and relapse. The term "prevention" refers to suppressing the occurrence of symptoms.

[0063] The term “treatment” may also include delaying the progression of a disease, disorder or condition, improving, reducing or alleviating symptoms and complications, and / or curing or eliminating a disease, disorder or condition.

[0064] The term “treatment” can also refer to the management and care of a patient in order to combat a disease, condition, or disorder.

[0065] As used in this article, the terms “disease,” “disorder,” and “condition” are used interchangeably to describe a patient’s condition that is not a normal physiological state in humans.

[0066] The term "cutaneous lupus erythematosus (CLE)" can also include acute cutaneous lupus erythematosus, such as ecchymosis, photosensitivity reactions, and mucosal lupus erosions. CLE may also include subacute cutaneous lupus erythematosus (SCLE), such as papulosquamous SCLE (also known as psoriasis), annular variant of SCLE, and Rowell syndrome. Furthermore, CLE can also include chronic cutaneous lupus erythematosus (CCLE), such as discoid lupus erythematosus (DLE), edematous lupus, deep lupus, hypertrophic deep lupus, and chilblain-like lupus.

[0067] Embodiments of the present invention include pharmaceutical compositions for treating or preventing cutaneous lupus erythematosus, such as discoid lupus erythematosus, comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile and pharmaceutically acceptable excipients or carriers.

[0068] Embodiments of the present invention include the use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile for the treatment or prevention of cutaneous lupus erythematosus, such as discoid lupus erythematosus.

[0069] Embodiments of the present invention include a method for treating or preventing cutaneous lupus erythematosus, such as discoid lupus erythematosus, characterized by administering a therapeutically effective amount of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile to a mammal.

[0070] On one hand, mammals are humans.

[0071] On the other hand, humans are people suffering from diseases that require medical care.

[0072] On the other hand, the disease is cutaneous lupus. On another hand, the disease is acute cutaneous lupus, such as ecchymosis, photosensitivity reactions, and mucosal lupus erosions. On another hand, the disease is subacute cutaneous lupus (SCLE), such as papulosquamous SCLE (also known as psoriasis), annular variants of SCLE, and Rowell syndrome. On another hand, the disease is chronic cutaneous lupus, such as discoid lupus erythematosus (DLE), edematous lupus, deep lupus, hypertrophic deep lupus, and chilblain-like lupus. On another hand, the disease is discoid lupus erythematosus (DLE).

[0073] In another aspect, the present invention relates to a therapeutic or preventive agent for cutaneous lupus erythematosus, such as discoid lupus erythematosus, comprising a compound of formula (I).

[0074] 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.

[0075] In another respect, the present invention relates to a topically applied pharmaceutical formulation comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0076] In another aspect, the present invention relates to pharmaceutical formulations, which are creams comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0077] On the other hand, pharmaceutically acceptable excipients can be one or more base materials selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof. For example, the base material can be liquid paraffin.

[0078] The base material may be present in different amounts of liquid paraffin, ranging from about 50 mg / g to about 500 mg / g, for example from about 75 mg / g to about 300 mg / g, and for example 100 mg / g.

[0079] On the other hand, pharmaceutically acceptable surfactants, emulsifiers, or stabilizers may be one or more selected from cetearyl alcohol, stearyl alcohol, cetearyl alcohol, or mixtures thereof. For example, the surfactant, emulsifier, or stabilizer may be cetearyl alcohol.

[0080] Surfactants, emulsifiers, or stabilizers may be present in varying amounts of cetearyl alcohol, from about 20 mg / g to about 100 mg / g, for example from about 40 mg / g to about 80 mg / g, and for example 72 mg / g.

[0081] On the other hand, pharmaceutically acceptable surfactants, emulsifiers, or stabilizers may be one or more selected from sorbitan esters, sucrose esters, polyethylene glycol cetearyl ether, or mixtures thereof. For example, a surfactant or emulsifier may be polyethylene glycol cetearyl ether.

[0082] Surfactants, emulsifiers, or stabilizers may be present in varying amounts of polyethylene glycol cetearyl alcohol ether, ranging from about 9 mg / g to about 25 mg / g, for example from about 15 mg / g to about 20 mg / g, and for example 18 mg / g.

[0083] On the other hand, pharmaceutically acceptable buffers or pH adjusters may be one or more of phosphates or citrates, sodium acetate, sodium carbonate, sodium citrate dihydrate, hydrochloric acid, or mixtures thereof. For example, a buffer or pH adjuster may be one or more of citrate monohydrate and sodium citrate dihydrate.

[0084] The buffer or pH adjuster may be present in varying amounts of citrate monohydrate, from about 0.5 mg / g to about 4 mg / g, for example from about 0.7 mg / g to about 2 mg / g, and for example 1 mg / g.

[0085] The buffer or pH adjuster may be present in varying amounts of sodium citrate dihydrate, from 0 mg / g to about 1 mg / g, for example from 0 mg / g to about 0.5 mg / g, and for example, not present.

[0086] On the other hand, pharmaceutically acceptable preservatives may be one or more selected from benzyl alcohol, sodium dehydroacetate, sorbic acid / salt, or mixtures thereof. For example, the preservative may be benzyl alcohol.

[0087] The preservative may be present in varying amounts of benzyl alcohol, ranging from about 7 mg / g to about 13 mg / g, for example from about 9 mg / g to about 11 mg / g, and for example 10 mg / g.

[0088] On the other hand, pharmaceutically acceptable antioxidants may be one or more selected from sodium sulfite, disodium edetate, trisodium edetate, butylated hydroxyanisole, or mixtures thereof. For example, an antioxidant may be butylated hydroxyanisole.

[0089] The antioxidant may be present in varying amounts of butylated hydroxyanisole, ranging from about 0.05 mg / g to about 0.3 mg / g, for example from about 0.1 mg / g to about 0.25 mg / g, and for example 0.2 mg / g.

[0090] On the other hand, pharmaceutically acceptable chelating agents may be one or more of EDTA, disodium edetate, EGTA, or ethylenediamine. For example, disodium edetate may be a chelating agent.

[0091] The chelating agent may be present in varying amounts of disodium edetate, ranging from about 0.05 mg / g to about 1.5 mg / g, for example from about 0.5 mg / g to about 1 mg / g, and for example 0.6 mg / g.

[0092] On the other hand, pharmaceutically acceptable acidifiers can be one or more strong acids, such as hydrochloric acid or citric acid. For example, hydrochloric acid can be an acidifier.

[0093] The chelating agent may be present in varying amounts of hydrochloric acid, from 0 mg / g to about 25 mg / g, for example from about 10 mg / g to about 20 mg / g, and for example 17.7 mg / g.

[0094] On the other hand, a pharmaceutically acceptable solvent may be purified water, which may be present in different amounts from about 500 mg / g to about 900 mg / g, and for example 760 mg / g.

[0095] In another aspect, the present invention relates to a method for preparing the pharmaceutical formulation, wherein...

[0096] Aqueous phase: Mix purified water, pH adjuster, buffer, acidifier, preservative, and chelating agent.

[0097] The active pharmaceutical ingredient is added and dissolved in the aqueous phase at a temperature of approximately 15-25°C.

[0098] Adjust the pH value to 4.0 - 4.4.

[0099] Heat the aqueous phase to approximately 65-75°C.

[0100] Oil phase: Mix liquid paraffin, surfactant, emulsifier, stabilizer, and antioxidant.

[0101] Heat the oil phase to approximately 65-75°C.

[0102] The oil phase is added to the aqueous phase and mixed.

[0103] Homogenize the mixture for about 20 minutes, then cool it to about 30°C. Then fill the cream into the container closure.

[0104] Exemplary pharmaceutical formulations of the present invention: Ingredients (mg / g): Digotinib 1; Liquid paraffin 100; Cetearyl alcohol 72; Polyethylene glycol cetearyl ether 18; Benzyl alcohol 10; Citric acid monohydrate 0.78; Butyl hydroxyanisole 0.2; Disodium edetate 0.6; Sodium citrate dihydrate 0.31 and purified water 797.

[0105] Ingredients (mg / g): Digotinib 3; Liquid paraffin 100; Cetearyl alcohol 72; Polyethylene glycol cetearyl ether 18; Benzyl alcohol 10; Citric acid monohydrate 1.0; Butyl hydroxyanisole 0.2; Disodium edetate 0.6; 3M hydrochloric acid 1.08; and purified water 794.

[0106] Ingredients (mg / g): Digotinib 8; Liquid paraffin 100; Cetearyl alcohol 72; Polyethylene glycol cetearyl ether 18; Benzyl alcohol 10; Citric acid monohydrate 1.0; Butyl hydroxyanisole 0.2; Disodium edetate 0.6; 3M hydrochloric acid 6.43; and purified water 784.

[0107] Ingredients (mg / g): Digotinib 20; Liquid paraffin 100; Cetearyl alcohol 72; Polyethylene glycol cetearyl ether 18; Benzyl alcohol 10; Citric acid monohydrate 1.0; Butyl hydroxyanisole 0.2; Disodium edetate 0.6; 3M hydrochloric acid 17.7 and purified water 760.

[0108] In another aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) and excipients disclosed in the test product (IP-1).

[0109] In another aspect, the present invention relates to a pharmaceutical preparation for topical application, comprising a compound of formula (I) and an experimental product. (IP-2) The excipients disclosed in the paper.

[0110] This invention describes its role in the topical treatment of cutaneous lupus erythematosus. In another aspect, this invention describes its role in the topical treatment of discoid lupus erythematosus.

[0111] This invention provides a clinical trial to compare the efficacy and safety of twice-daily topical application of a cream (20 mg / g of compound (I)) versus a cream carrier for 6 weeks in adult subjects with cutaneous lupus erythematosus (more specifically, discoid lupus erythematosus). All subjects will receive the active ingredient at one DLE target lesion and the excipient at another DLE target lesion.

[0112] As a measure of effectiveness and safety, the following are defined: Efficacy assessment was an investigator's overall assessment of the severity of each target lesion (a score of 0 (cleared) or 1 (nearly cleared) at week 6) and the skin lesion activity and damage score for each target lesion (erythema, scaling / hyperkeratosis, edema / infiltration, pigmentation abnormalities, scarring / atrophy (based on the Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI)). See below for details on the IGA and RCLASI.

[0113] The efficacy and health-related quality of life assessments of the participants were based on the Patient Overall Assessment (PaGA) for each target lesion severity and the Dermatology Quality of Life Index (DLQI).

[0114] Example

[0115] clinical trials

[0116] This clinical trial is a multicenter, double-blind, randomized, carrier-controlled phase 2a trial in adult subjects with DLE, involving twice-daily topical application of compound (I) at 20 mg / g and a carrier cream for 6 weeks. Each subject must have at least two DLE target lesions with active disease. The two target lesions will be randomized 1:1 to either the active ingredient treatment or the carrier treatment.

[0117] Treatment period

[0118] At baseline (Day 1), treatment allocation for the two target lesions will be randomized (1:1) to either the drug cream 20 mg / g or the carrier. Treatment will be administered twice daily for 6 weeks. The first administration of the investigational drug (IMP) will be performed at the trial site on Day 1, after all baseline assessments have been completed. Subsequent IMP administrations will be performed at the participant's home.

[0119] During the 6-week treatment period, subjects will return to the trial site for scheduled visits in weeks 2, 4, and 6. The final IMP administration will be performed the night before the subject's scheduled week 6 visit.

[0120] Key inclusion criteria: - Age 18-70 years old.

[0121] - Histopathological findings (current or past) are consistent with the clinical diagnosis of DLE.

[0122] - A clear clinical diagnosis of two active DLE target lesions in infants under 6 months of age that are clinically evaluable. This includes lesions located on the scalp if the lesions meet all lesion-specific eligibility criteria.

[0123] - The target lesion IGA score at screening and baseline was at least moderate (IGA ≥3).

[0124] - The difference in IGA score between the two target lesions at screening and baseline is ≤1 point.

[0125] - Target lesion erythema score ≥2 at screening and baseline.

[0126] Main exclusion criteria: - The target lesion pigmentary abnormality score was 2 at screening or baseline.

[0127] - The target lesion scarring / atrophy score was 2 at screening or baseline.

[0128] - At screening or baseline, the target lesion scarring alopecia score in scalp lesions is >0.

[0129] - A clinically significant history of SLE involving organs, including SLE-related pleurisy or pericarditis, and involvement of the nervous system, kidneys, and / or other major SLE-related organ systems. Joint involvement in SLE is acceptable.

[0130] - Subjects with unstable or significant SLE disease activity based on the investigator's experience.

[0131] - Other skin conditions at screening or baseline can interfere with the evaluation of DLE.

[0132] - Immunosuppressive / immunomodulatory therapy within 4 weeks prior to baseline, such as methotrexate, cyclosporine, azathioprine, retinoids, and dapsone.

[0133] - Systemic prednisolone >7.5 mg / day or changes in dose within 4 weeks prior to baseline (nasal and inhaled corticosteroids are permitted).

[0134] - Treat with the following medications: - Oral antimalarial treatment with hydroxychloroquine >6.5 mg / kg / day or chloroquine >4 mg / kg / day or a modified dose was administered within 12 weeks prior to baseline.

[0135] - Quinacrine in combination with hydroxychloroquine or chloroquine for 12 weeks prior to baseline.

[0136] - Drugs known to interact with antimalarial drugs (e.g., digoxin, cimetidine) within 12 weeks prior to baseline.

[0137] - Use of topical corticosteroids, calmodulin inhibitors, and phosphodiesterase 4 (PDE-4) inhibitors within 2 weeks prior to baseline.

[0138] - Use of systemic or dermal antibiotics on the target lesion within 2 weeks prior to baseline.

[0139] - UV therapy within 2 weeks prior to baseline.

[0140] - Any surgical procedure (e.g., incision) that damages the skin barrier within 2 cm of the boundary of any target lesion within 4 weeks prior to baseline.

[0141] - Receive a live (attenuated) vaccine within 4 weeks prior to baseline.

[0142] - Products containing St. John's Wort within the 4 weeks prior to baseline.

[0143] - Treatment with any marketed biological therapy or investigational biologic: - Any cell-depleting agent, including but not limited to rituximab: within 6 months prior to baseline or until lymphocyte counts return to normal, whichever is longer.

[0144] - Other biological agents: within 3 months or 5 half-lives prior to baseline, whichever is longer.

[0145] - History of any active skin infection within 1 week prior to baseline.

[0146] - Clinically significant infections occurring within 4 weeks prior to baseline may, from the investigator's perspective, jeopardize the safety of participants during the trial.

[0147] - Subjects who have developed tuberculosis requiring treatment within the 12 months prior to screening and / or whose blood test for tuberculosis is positive at the time of screening.

[0148] Investigator Global Assessment (IGA) for Discoid Lupus Erythematosus (DLE)

[0149] IGA is used to assess the severity of systemic disease in subjects, based on a 5-point scale from 0 (clearance) to 4 (severe). Researchers will use IGA as a lesion-specific assessment to evaluate the severity of DLE in each of the two target lesions separately.

[0150] Investigator Global Assessment (IGA) for Discoid Lupus Erythematosus (DLE)

[0151] Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI)

[0152] RCLASI is a validated scoring system for assessing disease activity and lesions in CLE patients, taking into account anatomical regions and morphological aspects.

[0153] The RCLASI skin lesion activity and lesion sign scores apply only to target lesions. Individual sign scores and sums provide a quantitative assessment of treatment efficacy. High RCLASI scores indicate more severe disease. Furthermore, a comprehensive RCLASI assessment will be performed at baseline to characterize the overall CLE disease burden in the trial population.

[0154] The total skin activity score is defined as the sum of the scores for erythema, scaling / hyperkeratosis, and edema / infiltration: Erythema: 0 = absent; 1 = pink; 2 = red; 3 = dark red, purple / violet / scab / bleeding.

[0155] Scaling / Hyperkeratosis: 0 = Not present; 1 = Well-defined, adherent scaling / follicular blockage; 2 = Verrucous hyperkeratosis.

[0156] Edema / infiltration: 0 = absent; 1 = slight, just palpable; 2 = palpable and visible.

[0157] The total skin lesion score is defined as the sum of the scores for pigmentation abnormalities and scarring / atrophy: Pigmentation abnormalities: 0 = absent; 1a = insufficient pigmentation; 1b = excessive pigmentation; 2 = both insufficient and excessive pigmentation.

[0158] Scar formation / atrophy: 0 = absent; 1 = initial scar formation; 2 = severe hard / atrophic / worm-like scar formation.

[0159] Patient Overall Assessment (PaGA) of Disease Severity

[0160] PaGA is a self-assessment of the subject's perceived disease severity.

[0161] Participants will use the PaGA to assess the disease severity of each target lesion. The assessment will be conducted using a 5-point scale: 0 = Clear; 1 = Almost clear; 2 = Mild; 3 = Moderate; 4 = Severe.

[0162] Dermatology Quality of Life Index (DLQI)

[0163] The DLQI is a validated questionnaire for those with skin conditions. It consists of 10 items that describe how participants perceive the impact of their skin condition on different aspects of their quality of life over the past week, such as dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal relationships, and treatment. Each item is scored on a 4-point Likert scale (0 = "completely irrelevant / unrelevant", 1 = "somewhat relevant"; 2 = "very relevant"; 3 = "extremely relevant"). The total score is the sum of the 10 items (0-30); a high score indicates a poor quality of life.

[0164] Research Product (IP-1)

[0165] Research Product (IP-2)

[0166] Terms and Conditions

[0167] In view of this description, the present invention specifically provides: 1. A compound of general formula (I): (I), 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof, which is used to treat cutaneous lupus erythematosus.

[0168] 2. The compound used according to Clause 1, wherein the treatment is for discoid lupus erythematosus.

[0169] 3. The compound used according to clause 1 or 2, wherein the treatment is a topical treatment.

[0170] 4. The compound used according to any of the preceding clauses, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is applied in the form of an ointment.

[0171] 5. The compound used according to any of the preceding clauses, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

[0172] 6. The compound used according to any of the preceding clauses, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a form that is applied twice daily.

[0173] 7. A pharmaceutical composition for treating cutaneous lupus erythematosus, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof as the active ingredient.

[0174] 8. The pharmaceutical composition used in accordance with Clause 7, wherein the treatment is discoid lupus erythematosus.

[0175] 9. The pharmaceutical composition used in the treatment according to Clause 7 or 8, wherein the pharmaceutical composition is for external use.

[0176] 10. The pharmaceutical composition used in any of the treatments described in clauses 7-9, wherein the pharmaceutical composition is a cream.

[0177] 11. A pharmaceutical composition used in any of the treatments described in clauses 7-10, wherein the compound of formula (I) or a pharmaceutically acceptable salt is administered at a concentration of 20 mg / g.

[0178] 12. A pharmaceutical composition used in any of the treatments described in clauses 7-11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a form that is applied twice daily.

[0179] 13. A method for treating cutaneous lupus erythematosus in a subject with this need, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) to the subject. (I), 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof.

[0180] 14. The method used according to Clause 13, wherein the treatment is discoid lupus erythematosus.

[0181] 15. The method used in the treatment according to Clause 13 or 14, wherein the application is external.

[0182] 16. The method used in the treatment as described in any of the preceding clauses 13-15, wherein the topical application is a cream.

[0183] 17. The method used in any of the treatments described in clauses 13-16, wherein the compound or pharmaceutically acceptable salt of formula (I) is administered at a concentration of 20 mg / g.

[0184] 18. A therapeutic or preventative agent for cutaneous lupus erythematosus, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof as the active ingredient.

[0185] 19. The therapeutic or preventive agent as described in Clause 18, used for the treatment or prevention of discoid lupus erythematosus.

[0186] 20. The therapeutic or preventive agent as described in Clause 18 or 19, wherein the therapeutic or preventive agent for discoid lupus erythematosus is a topical agent.

[0187] 21. The therapeutic or preventive agent as described in any one of the preceding clauses 18-20, wherein the therapeutic or preventive agent is a cream.

[0188] 22. The therapeutic or preventative agent used in any of the treatments described in any of the preceding clauses 18-21, wherein the compound of formula (I) or a pharmaceutically acceptable salt is administered at a concentration of 20 mg / g.

[0189] 23. The therapeutic or preventative agent used in any of the preceding clauses 18-22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a form that is applied twice daily.

[0190] 24. A pharmaceutical preparation for topical application, comprising:

[0191] - A compound of formula (I), and one or more pharmaceutically acceptable excipients selected from: - Base materials, such as liquid paraffin, - Surfactants, emulsifiers, and stabilizers, such as cetearyl alcohol and polyethylene glycol cetearyl alcohol ether. - pH adjusters and buffers, such as phosphates or citrates and hydrochloric acid. - Preservatives, - Antioxidants - Chelating agents, - Acidifiers, and - Purified water.

[0192] 25. The pharmaceutical formulation according to Clause 24, wherein the base material is liquid paraffin present in an amount from about 50 mg / g to about 500 mg / g.

[0193] 26. The pharmaceutical preparation according to Clause 25, wherein the liquid paraffin is present in an amount from about 75 mg / g to about 300 mg / g, and especially 100 mg / g.

[0194] 27. The pharmaceutical formulation according to any one of clauses 24-26, wherein the surfactant, emulsifier, and stabilizer are one or more of cetearyl alcohol and polyethylene glycol cetearyl alcohol ether.

[0195] 28. The pharmaceutical formulation according to Clause 27, wherein the cetearyl alcohol is present in an amount from about 20 mg / g to about 100 mg / g.

[0196] 29. The pharmaceutical formulation according to Clause 28, wherein the cetearyl alcohol is present in an amount from about 40 mg / g to about 80 mg / g, and especially 72 mg / g.

[0197] 30. The pharmaceutical formulation according to Clause 27, wherein the polyethylene glycol cetearyl ether is present in an amount from about 9 mg / g to about 25 mg / g.

[0198] 31. The pharmaceutical formulation according to Clause 30, wherein the polyethylene glycol cetearyl ether is present in an amount from about 15 mg / g to about 20 mg / g, and especially 18 mg / g.

[0199] 32. The pharmaceutical formulation as described in any one of the preceding clauses 24-31, wherein the buffer or pH adjuster is selected from phosphate or citrate.

[0200] 33. The pharmaceutical formulation according to Clause 32, wherein the buffer or pH adjuster is citric acid monohydrate, present in an amount from about 0.5 mg / g to about 4 mg / g.

[0201] 34. The pharmaceutical preparation according to Clause 33, wherein the citrate monohydrate is present in an amount from about 0.7 mg / g to about 2 mg / g, and especially 1 mg / g.

[0202] 35. The pharmaceutical formulation according to Clause 32, wherein the buffer or pH adjuster is sodium citrate dihydrate, present in an amount from about 0 mg / g to about 1 mg / g.

[0203] 36. The pharmaceutical preparation according to Clause 35, wherein the sodium citrate dihydrate is absent.

[0204] 37. A pharmaceutical preparation according to any one of clauses 24-36, wherein the preservative is benzyl alcohol.

[0205] 38. The pharmaceutical preparation according to Clause 37, wherein the amount of benzyl alcohol present is from about 7 mg / g to about 13 mg / g.

[0206] 39. The pharmaceutical preparation according to Clause 38, wherein the benzyl alcohol is present in an amount from about 9 mg / g to about 11 mg / g, and especially 10 mg / g.

[0207] 40. A pharmaceutical preparation according to any one of clauses 24-39, wherein the antioxidant is butylated hydroxyanisole.

[0208] 41. The pharmaceutical formulation according to Clause 40, wherein the butyl hydroxyanisole is present in an amount from about 0.05 mg / g to about 0.3 mg / g.

[0209] 42. The pharmaceutical formulation according to Clause 41, wherein the butyl hydroxyanisole is present in an amount from about 0.1 mg / g to about 0.25 mg / g, and especially 0.2 mg / g.

[0210] 43. A pharmaceutical preparation according to any one of clauses 24-42, wherein the chelating agent is EDTA.

[0211] 44. The pharmaceutical preparation according to Clause 43, wherein the chelating agent is disodium edetate.

[0212] 45. The pharmaceutical preparation according to Clause 44, wherein the disodium edetate is present in an amount from about 0.05 mg / g to about 1.5 mg / g.

[0213] 46. ​​The pharmaceutical preparation according to Clause 45, wherein the disodium edetate is present in an amount from 0.5 mg / g to about 1 mg / g, and especially 0.6 mg / g.

[0214] 47. A pharmaceutical preparation according to any one of clauses 24-46, wherein the acidifying agent is hydrochloric acid.

[0215] 48. The pharmaceutical preparation according to Clause 47, wherein the amount of hydrochloric acid present is from 0 mg / g to about 25 mg / g.

[0216] 49. The pharmaceutical preparation according to Clause 48, wherein the amount of hydrochloric acid present is from about 10 mg / g to about 20 mg / g, and especially 17.7 mg / g.

[0217] 50. The pharmaceutical preparation according to Clauses 24-49, wherein the purified water is present in an amount from about 500 mg / g to about 900 mg / g.

[0218] 51. The pharmaceutical preparation according to Clause 50, wherein the purified water is present in an amount of 760 mg / g.

[0219] 52. The pharmaceutical preparation according to clauses 24-51, 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.

[0220] 53. The pharmaceutical preparation for topical application, comprising:

[0221] The compound of formula (I), 1 mg / g, Liquid paraffin, 100 mg / g Cetearyl alcohol, 72 mg / g Polyethylene glycol cetearyl ether, 18 mg / g Benzyl alcohol, 10 mg / g Citric acid monohydrate, 0.78 mg / g Butyl hydroxyanisole, 0.2 mg / g Disodium edetate, 0.6 mg / g Sodium citrate dihydrate, 0.31 mg / g, and Purified water, 797 mg / g.

[0222] 54. The pharmaceutical preparation for topical application, comprising:

[0223] The compound of formula (I), 3 mg / g, Liquid paraffin, 100 mg / g Cetearyl alcohol, 72 mg / g Polyethylene glycol cetearyl ether, 18 mg / g Benzyl alcohol, 10 mg / g Citric acid monohydrate, 1.0 mg / g Butyl hydroxyanisole, 0.2 mg / g Disodium edetate, 0.6 mg / g 3M hydrochloric acid, 1.08 mg / g, and Purified water, 794 mg / g.

[0224] 55. The pharmaceutical preparation for topical application, comprising:

[0225] The compound of formula (I), 8 mg / g, Liquid paraffin, 100 mg / g Cetearyl alcohol, 72 mg / g Polyethylene glycol cetearyl ether, 18 mg / g Benzyl alcohol, 10 mg / g Citric acid monohydrate, 1.0 mg / g Butyl hydroxyanisole, 0.2 mg / g Disodium edetate, 0.6 mg / g 3M hydrochloric acid, 6.43 mg / g, and Purified water, 784 mg / g.

[0226] 56. The pharmaceutical preparation for topical application, comprising:

[0227] The compound of formula (I), 20 mg / g, Liquid paraffin, 100 mg / g Cetearyl alcohol, 72 mg / g Polyethylene glycol cetearyl ether, 18 mg / g Benzyl alcohol, 10 mg / g Citric acid monohydrate, 1 mg / g Butyl hydroxyanisole, 0.2 mg / g Disodium edetate, 0.6 mg / g 3M hydrochloric acid, 17.7 mg / g, and Purified water, 760 mg / g.

[0228] 57. A pharmaceutical preparation according to any one of clauses 24-56, wherein the preparation is a cream.

Claims

1. A pharmaceutical formulation for topical application comprising a compound of formula (I) (digotinib) dissolved in an aqueous phase, wherein the formulation is a cream containing... - Compounds of formula (I), and one or more pharmaceutically acceptable excipients selected from the following: - Base material, - Surfactants, emulsifiers, stabilizers, - pH adjusters, buffers - Preservatives, - Antioxidants - Chelating agents, - Acidifiers, and - Purified water.

2. The pharmaceutical formulation according to claim 1, wherein the base material is liquid paraffin, present in an amount from about 50 mg / g to about 500 mg / g.

3. The pharmaceutical formulation according to any one of claims 1-2, wherein the surfactant, emulsifier or stabilizer is cetearyl alcohol, present in an amount from about 20 mg / g to about 100 mg / g.

4. The pharmaceutical formulation according to any one of claims 2-3, wherein the surfactant, emulsifier or stabilizer is polyethylene glycol cetearyl ether and is present in an amount from about 9 mg / g to about 25 mg / g.

5. The pharmaceutical preparation according to claim 1, wherein the buffer or pH adjuster is a phosphate or citrate, sodium acetate, sodium carbonate, sodium citrate dihydrate, hydrochloric acid, or a mixture thereof.

6. The pharmaceutical formulation according to any one of the preceding claims, wherein the buffer or pH adjuster is selected from phosphate or citrate.

7. The pharmaceutical formulation according to claims 5-6, wherein the citrate is citric acid monohydrate and is present in an amount from about 0.5 mg / g to about 4 mg / g.

8. The pharmaceutical formulation according to claims 5-6, wherein the citrate is sodium citrate dihydrate, present in an amount from 0 mg / g to about 1 mg / g.

9. The pharmaceutical preparation according to any one of claims 1-8, wherein the acidifying agent is hydrochloric acid, present in an amount from 0 mg / g to about 25 mg / g.

10. The pharmaceutical preparation according to any one of claims 1-9, 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.

11. The pharmaceutical preparation according to any one of claims 1-10, wherein the amount of compound (I) is 20 mg / g.

12. The pharmaceutical preparation according to any one of claims 1-11, wherein the pH of the aqueous phase is 4.0-4.

4.

13. The pharmaceutical formulation according to claim 1, comprising: compound (I), 20 mg / g; liquid paraffin, 100 mg / g; cetearyl alcohol, 72 mg / g; polyethylene glycol cetearyl ether, 18 mg / g; benzyl alcohol, 10 mg / g; citric acid monohydrate, 1 mg / g; butylated hydroxyanisole, 0.2 mg / g; disodium edetate, 0.6 mg / g; 3M hydrochloric acid, 17.7 mg / g; and purified water, 760 mg / g.

14. The pharmaceutical formulation according to claim 1, comprising: compound (I), 8 mg / g; liquid paraffin, 100 mg / g; cetearyl alcohol, 72 mg / g; polyethylene glycol cetearyl ether, 18 mg / g; benzyl alcohol, 10 mg / g; citric acid monohydrate, 1.0 mg / g; butylated hydroxyanisole, 0.2 mg / g; disodium edetate, 0.6 mg / g; 3M hydrochloric acid, 6.43 mg / g; and purified water, 784 mg / g.

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