Treatment of frontal fibrosing alopecia

Abstract

The present invention relates to the treatment of frontal fibrosing alopecia. 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 preventive agent for frontal fibrosing alopecia, 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 as an active ingredient, and a pharmaceutical preparation thereof.

Description

[Technical field]

[0001] The present invention relates to a novel medical use 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 frontal fibrosing alopecia (FFA). [Background technology]

[0002] Frontal fibrosing alopecia (FFA) was first described in 1994 and is a type of primary lymphocytic cicatricial alopecia. FFA is considered a clinical variant of lichen planopilaris (LPP) because of the shared histopathological features. This variant of LPP is often seen in postmenopausal women and is increasing in prevalence. FFA is characterized by frontal, temporal, or frontotemporal hairline recession and has a distinct clinical pattern that usually includes eyebrow hair loss as well as other associated symptoms. Pruritus, facial papules, eyelash loss, body hair involvement, and trichodynia may also occur in addition to the classical frontotemporal recession and eyebrow hair loss.

[0003] FFAs are also reported in patients with hypothyroidism, contact allergies to fragrances, regular sunscreen use, and autoimmune diseases including lupus erythematosus and rheumatoid arthritis.

[0004] Early diagnosis and prompt treatment are important because FFA is a progressive disorder that can lead to permanent hair loss. However, FFA may progress despite aggressive treatment. There are only a limited number of published guidelines for the treatment of FFA, and there is no consensus or standard treatment regimen for FFA.

[0005] Although intralesional corticosteroids are associated with adverse effects such as pain and skin atrophy, they may achieve disease stabilization, and topical corticosteroids are often ineffective.Furthermore, there are no therapeutic interventions that selectively target the cellular or molecular key components of FFA pathogenesis.

[0006] The etiology and pathogenesis of FFA are not fully understood and remain a subject of research. The inflammatory cell infiltrate around the lesion hair follicle, i.e., the bulge and infundibulum, is characterized by an increase in CD8+ GranzymeB+ cytotoxic T cells and plasmacytoid dendritic cells (pDCs) with elevated levels of the chemokine receptor CXCR3. Available evidence suggests a key role for interferon (IFN)-γ in inducing the bulge disruption of hair follicle immune privilege (HFIP) and subsequent immune-mediated hair follicle epithelial stem cell (eHFSC) destruction observed in FFA. Therapeutically, protection / restoration of bulge immune privilege or neutralization of IFN-γ may help to better manage this treatment-resistant cicatricial alopecia.

[0007] Several JAK inhibitors are in clinical development or are already on the market. Ruxolitinib, the first FDA-approved JAK1 and JAK2 inhibitor, is an oral agent approved in several countries / regions for the treatment of patients with myelofibrosis and various other chronic inflammatory diseases. Other JAK inhibitors, such as tofacitinib and baricitinib, are also approved or in development for the treatment of various chronic inflammatory diseases.

[0008] WO2011 / 013785 describes nitrogen-containing spirocyclic compounds and their pharmaceutical uses. The compounds are described as JAK kinase 3 inhibitors useful for preventing or treating, for example, autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis, and atopic dermatitis.

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

[0010] WO2017 / 050891 describes the use of a pharmaceutical composition for the treatment of alopecia areata.

[0011] Therefore, there is an unmet medical need for novel treatments for FFAs with high efficacy and an attractive safety profile. Summary of the Invention

[0012] The present invention relates to a compound represented by formula (I) [ka] or a pharma- ceutically acceptable salt thereof.

[0013] In one embodiment, the present invention relates to the use of a compound of formula (I) for the treatment of FFA.

[0014] In another embodiment, the invention relates to a compound of formula (I) for use in the treatment of FFA. In yet another embodiment, the invention relates to a compound of formula (I) for use in the topical treatment of FFA. In yet another embodiment, the topical formulation is a cream. In yet another embodiment, the invention relates to the use of a compound of formula (I) administered twice daily. In yet another embodiment, the invention relates to the use of a compound of formula (I) administered twice daily for 12 weeks. In yet another embodiment, the invention relates to a compound of formula (I) administered at a concentration of 20 mg / g.

[0015] In another embodiment, the present invention relates to the use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of FFA. In yet another embodiment, the pharmaceutical composition is a topical formulation. In yet another embodiment, the topical formulation is a cream.

[0016] In another embodiment, the present invention provides a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof for the treatment of FFA.

[0017] In another embodiment the invention relates to a pharmaceutical composition comprising a compound of formula (I), wherein the treatment is a topical treatment, for example a treatment with a cream.

[0018] In another embodiment, the present invention relates to a pharmaceutical composition in which the compound of formula (I) is administered at a concentration of 20 mg / g. In another embodiment, the compound of formula (I) is administered as a twice-daily application. In another embodiment, the compound of formula (I) is administered as a twice-daily application for 12 weeks.

[0019] In another embodiment, the present invention relates to a method of treating FFA in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound of formula (I).

[0020] In another embodiment, the present invention relates to a method for treating FFA in a subject in need of treatment, wherein the administration is topical.In another embodiment, the present invention relates to a method for treating FFA in a subject in need of treatment, wherein the topical formulation is a cream.In another embodiment, the present invention relates to a method for treating FFA in a subject in need of treatment, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0021] 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 FFA.

[0022] The present invention further provides the above use administered as a once-daily application.The present invention further provides the above use administered as a twice-daily application.The present invention further provides the above use administered at a concentration of 20 mg / g. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Formula (I) [ka] The compound 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile has already been described in WO 2011 / 013785 as a JAK3 kinase inhibitor for the treatment of e.g. 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, asteatosis, eczema and contact dermatitis.

[0024] Compounds of formula (I) can be prepared according to the method described in Preparation Example 6 of WO2011 / 013785.

[0025] A "pharmaceutically acceptable salt" may be any non-toxic salt of a 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.

[0026] Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Examples of salts with organic acids include salts 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. Examples of salts with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Examples of salts with organic bases include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, and meglumine. Salts with amino acids include salts with lysine, arginine, aspartic acid, glutamic acid, and the like.

[0027] The respective salts may be obtained by reacting the compounds of formula (I) with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid, according to known methods.

[0028] Compounds of formula (I) may be isotopically corrected, e.g. 3 H, 14 C. 35 It may be labeled with S.

[0029] In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a substantially purified compound of formula (I) or a pharma- ceutically acceptable salt thereof, hi another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 80% or greater pure.

[0030] A "pharmaceutical composition" includes oral formulations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, or parenteral formulations such as topicals, suppositories, injections, eye drops, nasal drops, and pulmonary drops. In another embodiment, the pharmaceutical composition is a topical formulation, such as an ointment or cream. In yet another embodiment, the pharmaceutical composition is a cream.

[0031] The pharmaceutical composition of the present invention is produced by appropriately mixing the compound of formula (I) or a pharma- ceutically acceptable salt thereof with at least one pharma- ceutically acceptable excipient or carrier in an appropriate amount according to a method known in the art of pharmaceutical preparation. The content of the compound of formula (I) or a pharma- ceutical acceptable salt thereof in the pharmaceutical composition depends on its dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the total composition. For example, the content is 0.10, 0.20, 0.25, 0.30, 0.50, 0.75, 0.8, 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.

[0032] In one embodiment, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 0.1% by weight of the total composition.

[0033] In one embodiment, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 0.3% by weight of the total composition.

[0034] In one embodiment, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 0.8% by weight of the total composition.

[0035] In one embodiment, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 2% by weight of the total composition.

[0036] In one embodiment, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 3% by weight of the total composition.

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

[0038] "Pharmaceutically acceptable excipients" or "pharmaceutically acceptable carriers" include various conventional organic or inorganic excipients or carrier substances for pharmaceutical materials, such as disintegrants, binders, flow agents, lubricants, solvents, solubilizers, suspending agents, isotonicity agents, buffers, and emollients for liquid preparations, as well as bases, emulsifiers, surfactants, wetting agents, stabilizers, stabilizing agents, dispersants, plasticizers, pH adjusters, absorption promoters, gelling agents, preservatives, bulking agents, and dissolving agents. In addition, additives such as preservatives, antiseptics, antioxidants, and coloring agents may be used as necessary.

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

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

[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, and the like.

[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] The isotonicity agent includes glucose, D-sorbitol, sodium chloride, D-mannitol and the like.

[0047] 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, and the like.

[0048] Examples of bases include water, animal or 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-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (e.g., white soft paraffin, liquid paraffin, paraffin, solid paraffin, etc.), hydrophilic petrolatum, purified lanolin, water-absorbing ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, polydimethylsiloxane, isopropyl myristate, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethylcellulose), polymers (e.g., carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (e.g., macrogol 200 to 600, etc.), and combinations of two or more of these. 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] The acidifying agent may include a strong acid selected from, for example, hydrochloric acid or 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, diazolidinyl urea, and benzalkonium chloride.

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

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

[0056] The pharmaceutical composition of the present invention may be administered to a mammal such as a human. The dosage varies depending on the subject, disease, symptoms, dosage form, administration route, etc., and may be within the range of about 0.01 mg to about 1 g, for example, about 0.01 mg to about 600 mg per day in terms of the content of the compound of formula (I) as an active ingredient. The dosage may be administered at once or in multiple divided doses.

[0057] The topical agent may be applied, for example, by painting, rubbing, or spraying, depending on the dosage form. The amount of topical agent applied to the affected area may be selected depending on the content of the active ingredient, and the topical agent may be applied, for example, once a day or in multiple doses. More preferably, the topical agent is applied 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 "inhibit JAK" refers to inhibiting the function of JAK to eliminate or reduce its activity, and to inhibit one or more enzymes belonging to the JAK family. In one embodiment, the phrase "inhibit JAK" refers to "inhibit human JAK". In one embodiment, the inhibition of function or the elimination or reduction of activity is carried out in the context of human clinical application.

[0060] A "JAK inhibitor" can be any substance that inhibits JAK, such as a small molecule compound, a nucleic acid, a polypeptide, a protein, an antibody, a vaccine, 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 pharma- ceutically acceptable salt thereof. In yet another embodiment, the JAK inhibitor is a compound of formula (I).

[0061] The term "treatment" as used herein includes amelioration of symptoms, prevention of exacerbation, maintenance of remission, prevention of exacerbation, and prevention of recurrence. The term "prevention" refers to suppressing the onset of symptoms.

[0062] The term "treatment" may also include delaying the progression of a disease, disorder or condition; ameliorating, alleviating, or alleviating symptoms and complications; and / or curing or eliminating a disease, disorder, or condition.

[0063] The term "treatment" can also mean the management and care of a patient for the purpose of combating a disease, condition, or disorder.

[0064] As used herein, the terms "disease," "disorder," and "pathology" are used interchangeably to identify a condition in a patient that is not a normal physiological state in humans.

[0065] An embodiment of the present invention includes a pharmaceutical composition for treating or preventing cicatricial alopecia, 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 pharma- ceutical acceptable excipient or carrier. Another embodiment of the present invention includes a pharmaceutical composition for treating or preventing LPP, 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 pharma- ceutical acceptable excipient or carrier. Another embodiment of the present invention includes a pharmaceutical composition for treating or preventing FFA 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 pharma- ceutically acceptable excipient or carrier.

[0066] An 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 to treat or prevent cicatricial alopecia. Another 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 to treat or prevent LPP. Another 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 to treat or prevent FFA.

[0067] An embodiment of the present invention includes a method for treating or preventing cicatricial alopecia, comprising 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]octan-1-yl]-3-oxopropanenitrile to a mammal. Another embodiment of the present invention includes a method for treating or preventing LPP, comprising 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]octan-1-yl]-3-oxopropanenitrile to a mammal. Another embodiment of the present invention includes a method for treating or preventing FFA, 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 a human suffering from a disease in need of medical care.

[0070] In another embodiment, the disease is cicatricial alopecia. In another embodiment, the disease is LPP. In another embodiment, the disease is FFA.

[0071] In another embodiment, the present invention relates to a therapeutic or preventive agent for cicatricial alopecia, comprising a compound of formula (I). In another embodiment, the present invention relates to a therapeutic or preventive agent for LPP, comprising a compound of formula (I). In another embodiment, the present invention relates to a therapeutic or preventive agent for FFA, comprising a compound of formula (I).

[0072] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and one or more pharma- ceutically acceptable excipients or carriers.

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

[0074] In another embodiment, the present invention relates to a pharmaceutical formulation comprising a compound of formula (I) and one or more pharma- ceutically acceptable excipients, the formulation being a cream.

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

[0076] The base may be present in various amounts of liquid paraffin, from about 50 mg / g to about 500 mg / g, for example from about 75 mg / g to about 300 mg / g, for example 100 mg / g.

[0077] In another embodiment, the pharma- ceutically 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] The surfactant, emulsifier, or stabilizer may be present in various amounts from about 20 mg / g to about 100 mg / g, such as from about 40 mg / g to about 80 mg / g, e.g., 72 mg / g, of cetostearyl alcohol.

[0079] In another embodiment, the pharma- ceutically acceptable surfactant, emulsifier, or stabilizer can be one or more selected from sorbitan esters, sucrose esters, macrogol cetostearyl ethers, or mixtures thereof. For example, the surfactant or emulsifier can be macrogol cetostearyl ether.

[0080] The surfactant, emulsifier, or stabilizer may be present in various amounts of macrogol cetostearyl ether from about 9 mg / g to about 25 mg / g, for example, from about 15 mg / g to about 20 mg / g, for example, 18 mg / g.

[0081] In another embodiment, the pharma- ceutically acceptable buffer or pH adjuster can be one or more of phosphate or 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 may be present in various amounts of citric acid 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, for example, 1 mg / g.

[0083] The buffer or pH adjuster may be present in various amounts, such as from 0 mg / g to about 1 mg / g sodium citrate dihydrate, for example, from 0 mg / g to about 0.5 mg / g, for example, not present.

[0084] In another embodiment, the pharma- ceutically acceptable preservative 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.

[0085] The preservative may be present in various amounts from about 7 mg / g to about 13 mg / g, for example, from about 9 mg / g to about 11 mg / g, for example, 10 mg / g of benzyl alcohol.

[0086] In another embodiment, the pharma- ceutically acceptable antioxidant can be one or more selected from sodium sulfite, disodium edetate, trisodium edetate, butylated hydroxyanisole, or mixtures thereof. For example, the antioxidant can be butylated hydroxyanisole.

[0087] The antioxidant may be present in various amounts 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, for example, 0.2 mg / g butylhydroxyanisole.

[0088] In another embodiment, the pharma- ceutically 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 may be present in various amounts of edetate disodium 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, for example, 0.6 mg / g.

[0090] In another embodiment, the pharma- ceutically acceptable acidifying agent can be one or more strong acids, such as hydrochloric acid or citric acid. For example, the acidifying agent can be hydrochloric acid.

[0091] The acidifying agent may be present in various 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, for example 17.7 mg / g.

[0092] In another embodiment, the pharma- ceutically acceptable solvent can be purified water and can be present in various amounts from about 500 mg / g to about 900 mg / g, for example, 760 mg / g.

[0093] The pharmaceutical formulation of the present application can be prepared according to the method described in WO2020 / 229622.

[0094] Representative specific pharmaceutical formulations of the present invention are as follows: delgocitinib 20mg / g; paraffin liquid 100mg / g; cetostearyl alcohol 72mg / g; macrogol cetostearyl ether 18mg / g; benzyl alcohol 10mg / g; citric acid monohydrate 1.0mg / g; butylated hydroxyanisole 0.2mg / g; edetate disodium 0.6mg / g; 3M hydrochloric acid 17.7mg / g; and purified water up to 1g; Delgocitinib 20mg / g; Paraffinum Liquidum 100mg / g; Cetostearyl Alcohol 72mg / g; Macrogol Cetostearyl Ether 18mg / g; Benzyl Alcohol 10mg / g; Citric Acid Monohydrate 1.0mg / g; Sodium Citrate 1mg / g; Disodium Edetate 1.3mg / g; Hydrochloric Acid 4.99mg / g; Butyl Hydroxyanisole 0.2mg / g; and Purified Water up to 1g.

[0095] The present invention describes the effect of topical treatment of scarring alopecia. In another embodiment, the present invention describes the effect of topical treatment of LPP. In another embodiment, the present invention describes the effect of topical treatment of FFA.

[0096] The present invention provides a clinical trial to evaluate the efficacy and safety of delgocitinib cream 20 mg / g in adult subjects with FFA.

[0097] In this study, the changes in molecular signatures after topical application of delgocitinib cream 20 mg / g in subjects with FFA will be evaluated. The safety and preliminary efficacy of delgocitinib cream in subjects with FFA will also be evaluated.

[0098] Primary objective: To evaluate changes in molecular signatures following topical application of delgocitinib cream 20 mg / g in subjects with FFA.

[0099] Secondary Objective: To evaluate the safety and tolerability of delgocitinib cream 20 mg / g following topical application in subjects with FFA during a vehicle-controlled treatment period.

[0100] Exploratory Objectives: To evaluate the safety and tolerability of delgocitinib cream 20mg / g during the open-label extension.To evaluate the preliminary efficacy of delgocitinib cream 20mg / g after topical application in subjects with FFA. EXAMPLES

[0101] Study design A Phase 2a, Randomized, Double-Blind, Vehicle-Controlled, Single-Center Exploratory Study of Delgocitinib Cream 20mg / g in Subjects with FFA The study will consist of two cohorts: Cohort 1 will include approximately 30 subjects with FFA, and Cohort 2 will include approximately 5 healthy postmenopausal female subjects.

[0102] Cohort 1 All subjects will read and sign an informed consent form before engaging in any study-related activity. Subjects who meet all inclusion criteria and none of the exclusion criteria will be randomized into the study. After a screening period of ≤30 days, eligible subjects will be randomized (1:1) on Day 1 to receive delgocitinib cream 20 mg / g or vehicle cream twice daily for 12 weeks during the vehicle-control treatment period. All subjects who complete the vehicle-control treatment period will then continue into an open-label extension period in which delgocitinib cream 20 mg / g will be applied twice daily for 12 weeks. The open-label extension period will be followed by a 2-week safety follow-up period. Subjects will visit the site 7 times (screening, Day 1, Week 4, Week 8, Week 12, Week 24, and Week 26 / early discontinuation) for scheduled visits. Subjects will also be contacted by phone twice (Weeks 16 and 20).

[0103] On Day 1, identify a lesion target area on the scalp (e.g., forehead, preauricular, or temporal). The lesion target area should be large enough to receive hair count / tricoscopy assessment and all skin sample collection (i.e., skin biopsy, tape stripping, and skin swabs) and should be treated with study drug. If necessary, a second target area may be selected to allow for skin sample collection.

[0104] Cohort 2 All subjects will read and sign an informed consent form before engaging in any study-related activity. Subjects who meet all inclusion criteria and none of the exclusion criteria will be accepted into the study. After a screening period of up to 30 days, eligible subjects will They will be asked to come to the site for skin sample collection. At the investigator's discretion, screening and Day 1 skin sample collection may occur on the same day (if the subject does not have a washout period) or be split across two visits. Cohort 2 will not receive study drug. Subjects will come to the site up to three times (screening, Day 1, and optional follow-up visit) for scheduled visits.

[0105] Inclusion criteria To participate in this study, subjects must meet all of the following criteria at either the Screening and Day 1 visits or only one of the specific visits (Screening or Day 1) listed in the criteria.

[0106] Inclusion Criteria for All Subjects - Subject is willing to participate and able to give informed consent. Note: Consent must be obtained prior to any study-related procedures. -Subject must be willing to comply with all study procedures and must be available for the duration of the study.

[0107] Inclusion criteria for cohort 1 (subjects with FFA) only - Male or female subjects were 18 years of age or older at the time of consent. - Women of childbearing potential have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1. - Subject had a clinically confirmed diagnosis of FFA based on investigator judgment. - Subjects have a target area with a perifollicular erythema score ≥ 2 and a perifollicular scale score ≥ 2 at Screening and Day 1. - For subjects who use makeup, moisturizers, creams, lotions, cleansers, and / or sunscreen on their face, they have used the same product brand / type for a minimum of 4 weeks prior to Day 1 and agree not to change brand / type or frequency of use throughout the duration of the study, agree not to apply such products to areas to be treated during the study, and agree on the day of the visit not to use makeup, moisturizers, creams, lotions, cleansers, and / or sunscreen on their face prior to the visit. -Subjects willing to maintain a consistent hairstyle and hair styling regimen including shampoos and hair products (e.g. hair dye, processes, and timing of salon appointments) and will refrain from weaves or extensions during the study and for 4 weeks prior to Day 1. Note: -Hair dye and shaving are permitted during the study but not within 48 hours prior to the visit. - Female subjects of childbearing potential who engage in sexual intercourse that may lead to pregnancy must agree to use effective contraception for at least 4 weeks prior to Day 1 and until at least 4 weeks after the last study drug application.

[0108] Inclusion criteria for cohort 2 (healthy subjects) only - Female subjects were aged 45 years or older at the time of consent. -Women are postmenopausal, as defined as: -Women who have undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) -Women who have ceased menstruating for at least 12 months prior to the screening visit and have no other medical cause. - Subject is in good overall health as judged by the investigator based on vital signs, medical history, and a brief physical examination.

[0109] Exclusion criteria Subjects who meet any of the following criteria at the Screening and / or Day 1 visit (if applicable) will be denied participation in the study.

[0110] Exclusion criteria for all subjects - Subject is a female who is breastfeeding, pregnant, or planning to become pregnant during the study period. - Subject has received a marketed or investigational biologic within 12 weeks or 5 half-lives (whichever is longer) prior to Day 1. - Subject is currently receiving, or has received within the prior 4 weeks prior to Day 1, a non-biologic investigational drug or device. - Subject has had excessive sun exposure or used a tanning chamber within the 4 weeks prior to Day 1, or is unwilling to minimize exposure to natural and artificial sunlight during the study period. If sun exposure cannot be avoided, the use of sunscreen products (except in areas to be treated for Cohort 1 subjects) and protective clothing is recommended. - Subject has a history of allergic reaction or hypersensitivity to lidocaine or other local anesthetic agents. - Subject has a history of hypertrophic scar or keloid formation at scar or suture sites.

[0111] Exclusion criteria for Cohort 1 (subjects with FFA) only - History of other scalp / hair disorders including discoid lupus erythematosus and central centrifugal cicatricial alopecia. - Presence of active skin disease that may interfere with the diagnosis and / or test evaluation of FFA. -Subjects who have undergone scalp reduction surgery or hair transplantation. - Use of bonded wigs during the study period. - Subject is known to be immunocompromised or is immunocompromised. - Subject has a history of cancer or lymphoproliferative disease within 5 years prior to Day 1. Subjects with successfully treated nonmetastatic cutaneous squamous or basal cell carcinoma and / or carcinoma confined to the cervical epithelium should not be excluded. - Subject has undergone major surgery within 8 weeks prior to Day 1 or is scheduled to undergo major surgery during the study period. - Subject exhibits a clinically significant medical condition or physical / laboratory / ECG / vital sign abnormality that, in the opinion of the investigator, would place the subject at undue risk or interfere with interpretation of the study results. - Subject is positive for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). - Subject has received treatment with any medication that may affect hair growth (including natural products or nutritional supplements such as Viviscal, Nutrafol, and / or Biotin) within the past 4 weeks counting back to Day 1. - Subject has received intralesional scalp corticosteroids or platelet-rich plasma injections within the past 4 weeks counting back to Day 1. - Subject has received systemic therapy with immunosuppressants / modulators or agents that may affect FFA (e.g., corticosteroids, methotrexate, minoxidil, hydroxychloroquine, retinoids, calcineurin inhibitors, tetracyclines, pioglitazone, spironolactone, or 5-alpha reductase inhibitors) within the 4 weeks prior to Day 1. Note: Intranasal and inhaled corticosteroids are permitted. Eye and ear drops containing corticosteroids are also permitted. Note: Systemic administration of standard doses of antihistamines is permitted. - Subject has been treated with topical medications that may affect FFA (including but not limited to topical corticosteroids, calcineurin inhibitors, minoxidil, phosphodiesterase 4 (PDE-4) inhibitors) within the 2 weeks prior to Day 1. - Subject has received treatment with a JAK inhibitor (systemic or topical) within the last 4 weeks prior to Day 1. - Subject has received ultraviolet (UV)-B phototherapy (including tanning beds), excimer laser, or other phototherapy within the last 4 weeks prior to Day 1. - Subject has received psoralen + UVA (PUVA) treatment within the last 4 weeks prior to Day 1. - Subject has a known or suspected allergy to delgocitinib or any component of the investigational drug. - Subject has a history of allergic reaction or hypersensitivity to hypoallergenic ink. - Subject has a known history of clinically significant drug or alcohol abuse within the past year counting back to Day 1.

[0112] Exclusion criteria for cohort 2 (healthy subjects) only - Subject has a history of skin disease or has a skin condition that, in the investigator's opinion, would interfere with study evaluation. - Subject exhibits a clinically significant medical condition or physical / vital sign abnormality that, in the investigator's opinion, would place the subject at undue risk or interfere with interpretation of the study results. - Subject has a known history of chronic infection (e.g., Hepatitis B, Hepatitis C, or HIV). - Subject has received topical medication to treat the targeted skin site within 2 weeks prior to skin sample collection (Day 1).

[0113] Efficacy evaluation (Cohort 1 only) Clinical evaluation of the FFA will be performed by an experienced, qualified dermatologist (board-certified or equivalent) or other appropriately qualified individual. Whenever possible, the same assessor should perform all evaluations on a given subject to ensure consistency and reduce variability.

[0114] Lichen planus pilaris activity index The LPPAI is assessed at each visit. It is a quantitative measure of disease activity. The LPPAI records symptoms (pruritus, pain, burning), signs (erythema, perifollicular erythema and scale), activity measures (anagen traction test), and disease spread. These subjective and objective measures are assigned numerical values ​​to establish a disease activity score. Weighting was given to the presence of symptoms (30%), signs (30%), anagen traction test (25%), and spread (15%), resulting in the following formula: LPPAI (0–10) = (pruritus + pain + burning) / 3 + (scalp erythema + perifollicular erythema + perifollicular scale) / 3 + 2.5 (traction test) + 1.5 (spread / 2). Symptoms and signs are recorded on a 4-point scale: 0 = absent (negative), 1 = mild (+ / -), 2 = moderate (+), and 3 = severe (++,+++). The anagen traction test, when present, is a reliable measure of local disease activity. It involves pinching 10–20 hairs between the thumb, index finger, and middle finger at the scalp end of the hair shaft, pulling it firmly away from the scalp with a vertical force, and sliding the fingers down to the end of the hair. The results are recorded as a binary value (0 = no anagen hair, 1 = anagen hair) and as the total number of anagen hairs / pulled hairs. Finally, an assessment of disease spread is recorded as 0 (no spread) vs. 1 (indeterminate) vs. 2 (spread). In cases where hair loss is difficult to determine, the spread problem is recorded as indeterminate. The detailed procedure for calculating the LPPAI score is shown in Table 1. [Table 1] LPPAI(0~10)=(A+B+C+D+E+F) / 3+2.5(traction test)+1.5(expansion / 2) Scale: 0=Negative 1=+ / - 2=+ 3=++,+++

[0115] Frontal fibrosing alopecia severity score The FFASS is assessed at each visit. The index is based on the assessment of relevant clinical features in the FFA: the extent of frontal and temporal hairline recession (1–5), the extent of eyebrow hair loss (none, partial, or complete), the severity and extent of perifollicular erythema and keratosis, and the severity and frequency of pruritus and pain associated with the FFA. The resulting severity score ranges from 0–25, with higher scores indicating greater severity of FFA. The clinical features included in the FFASS are divided into two categories: extent of alopecia (maximum 21 points) and inflammation (maximum 4 points). The detailed procedure for calculating the FFASS score is shown in Table 2. [Table 2] [Table 3] [Table 4]

[0116] Perifollicle erythema and scale Perifollicle erythema and perifollicular scale of selected lesion target areas will be visually assessed at the visit. Each clinical finding (i.e., perifollicular erythema and perifollicular scale) will be scored using the 4-point severity rating shown in Table 3. To be eligible for the study, subjects must have a lesion target area with a perifollicular erythema score of ≥2 and a perifollicular scale score of ≥2 at screening and day 1. [Table 5]

[0117] Pruritus Numeric Rating Scale The intensity of pruritus caused by FFA is recorded using a numerical rating scale, which is assessed daily starting approximately 7 days before day 1 through day 8, and then at each clinic visit. It is assessed by asking subjects to rate the intensity of their symptoms over the previous 24 hours using a numerical score from 0 to 10 (0 being no symptoms and 10 being the worst symptoms imaginable).

[0118] Burning Sensation Numeric Rating Scale The intensity of the burning sensation caused by FFA is recorded using a numerical rating scale, which is assessed starting approximately 7 days before day 1 and each day through day 8, and then at each clinic visit. It is assessed by asking subjects to indicate the worst symptom they have experienced in the last 24 hours using a numerical score from 0 to 10 (0 being no symptoms and 10 being the worst symptoms imaginable).

[0119] Pain Numeric Rating Scale The intensity of pain caused by FFA will be recorded using a numerical rating scale, which will be assessed starting approximately 7 days before day 1 and each day through day 8, and then at each clinic visit. It will be assessed by asking subjects to rate their most intense symptom over the last 24 hours using a numerical score from 0 to 10 (0 being no symptoms and 10 being the worst symptoms imaginable).

[0120] Hair count / tricoscopy Hair count / tricoscopy assessment will be performed at the visit. Trichoscopy should be performed on the lesion target area several centimeters away from the skin microbiome collection site. Hair count, hair diameter, and hair density will be measured with a fotofinder trichovision.

[0121] Hairline measurement Hairline measurements will be taken at the visit using a disposable paper ruler, measuring from the outer corner of the eye to the hairline (left and right), from the bottom of the brow crease to the hairline, from the top of the frontalis muscle to the hairline, and from the center of the eyebrow to the hairline (left and right).

[0122] Terms In view of the present specification, the present invention provides inter alia:

[0123] [Clause 1] A compound of general formula (I) for use in the treatment of cicatricial alopecia [ka] The compound 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 pharma- ceutically acceptable salt thereof.

[0124] [Clause 2] For use in the treatment of LPP, [ka] The compound 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 pharma- ceutically acceptable salt thereof.

[0125] [Clause 3] For use in the treatment of FAA, [ka] The compound 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 pharma- ceutically acceptable salt thereof.

[0126] [Article 4] The compound according to any one of clauses 1 to 3, wherein said treatment is a topical treatment.

[0127] [Article 5] The compound according to any one of clauses 1 to 4, wherein said compound of formula (I) is administered as a cream.

[0128] [Article 6] 6. The compound according to any one of clauses 1 to 5, wherein said compound of formula (I) is administered at a concentration of 20 mg / g.

[0129] [Article 7] The compound according to any one of clauses 1 to 6, wherein said compound of formula (I) is administered as a twice daily application.

[0130] [Article 8] The compound according to any one of clauses 1 to 7, wherein said compound of formula (I) is administered for 12 weeks.

[0131] [Article 9] 2. Use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of cicatricial alopecia.

[0132] [Article 10] The use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of LPP.

[0133] [Article 11] The use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of FFA.

[0134] [Article 12] 12. The use according to any one of clauses 9 to 11, wherein the treatment is a topical treatment.

[0135] [Article 13] 13. The use according to any one of clauses 9 to 12, wherein the pharmaceutical composition is administered as a cream.

[0136] [Article 14] 14. The use according to any one of clauses 9 to 13, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0137] [Article 15] 15. The use according to any one of clauses 9 to 14, wherein said compound of formula (I) is administered as a twice-daily application.

[0138] [Article 16] 16. The use according to any one of clauses 9 to 15, wherein the compound of formula (I) is administered for 12 weeks.

[0139] [Article 17] Formula (I) [ka] 2. A pharmaceutical composition for treating cicatricial alopecia comprising the compound 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 pharma- ceutically acceptable salt thereof.

[0140] [Article 18] Formula (I) [ka] 2. A pharmaceutical composition for treating LPP comprising the compound 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 pharma- ceutical acceptable salt thereof.

[0141] [Article 19] Formula (I) [ka] 2. A pharmaceutical composition for treating FFA comprising the compound 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 pharma- ceutically acceptable salt thereof.

[0142] [Article 20] 20. The pharmaceutical composition according to any one of clauses 17 to 19, wherein said treatment is a topical treatment.

[0143] [Article 21] 21. The pharmaceutical composition according to any one of clauses 17 to 20, which is a cream.

[0144] [Article 22] 22. The pharmaceutical composition according to any one of clauses 17 to 21, wherein said compound of formula (I) is administered in a concentration of 20 mg / g.

[0145] [Article 23] 23. The pharmaceutical composition according to any one of clauses 17 to 22, wherein said compound of formula (I) is administered as a twice daily application.

[0146] [Article 24] 24. The pharmaceutical composition according to any one of clauses 17 to 23, wherein said compound of formula (I) is administered for 12 weeks.

[0147] [Article 25] Formula (I) [ka] A therapeutic or preventive agent for cicatricial alopecia, comprising the compound 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 pharma- ceutical acceptable salt thereof as an active ingredient.

[0148] [Article 26] 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 pharma- ceutical acceptable salt thereof as an active ingredient.

[0149] [Article 27] 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 pharma- ceutical acceptable salt thereof as an active ingredient.

[0150] [Article 28] 28. The therapeutic or prophylactic agent according to any one of clauses 25 to 27, which is an external medicine.

[0151] [Article 29] 29. The therapeutic or prophylactic agent according to any one of clauses 25 to 28, which is a cream.

[0152] [Article 30] 30. The therapeutic or prophylactic agent according to any one of clauses 25 to 29, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0153] [Article 31] The therapeutic or prophylactic agent according to any one of clauses 25 to 30, wherein said compound of formula (I) is administered as a twice daily application.

[0154] [Article 32] The therapeutic or prophylactic agent according to any one of clauses 25 to 31, wherein the compound of formula (I) is administered for 12 weeks.

[0155] [Article 33] 1. A method for treating cicatricial alopecia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I).

[0156] [Article 34] 1. A method of treating LPP in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I).

[0157] [Article 35] 13. A method of treating FFA in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I).

[0158] [Article 36] 36. The method of any one of clauses 33 to 35, wherein said administering is topical.

[0159] [Article 37] 37. The method according to any one of clauses 33 to 36, wherein said topical preparation is a cream.

[0160] [Article 38] 38. The method according to any one of clauses 33 to 37, wherein said compound of formula (I) is administered at a concentration of 20 mg / g.

[0161] [Article 39] 39. The method according to any one of clauses 33 to 38, wherein said compound of formula (I) is administered as a twice daily application.

[0162] [Article 40] 40. The method according to any one of clauses 33 to 39, wherein said compound of formula (I) is administered for 12 weeks.

[0163] [Article 41] A method for treating frontal fibrosing alopecia (FFA) in a human patient in need of such treatment, comprising administering an external composition comprising the free base form of delgocitinib or a pharma- ceutical acceptable salt thereof.

[0164] [Article 42] The compound delgocitinib or a topical composition comprising delgocitinib for use in a method for treating frontal fibrosing alopecia (FFA) in a human patient in need of treatment, comprising administering a topical composition comprising the free base form of delgocitinib or a pharma- ceutical acceptable salt thereof.

[0165] [Article 43] Use of the compound delgocitinib for the manufacture of an external composition for use in the treatment of frontal fibrosing alopecia (FFA) in a human patient in need of such treatment, the external composition comprising delgocitinib in free base form or a pharma- ceutical acceptable salt thereof.

[0166] [Article 44] The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 43, wherein said patient is clinically diagnosed with FFA.

[0167] [Article 45] 45. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 44, wherein said patient has a target area with a perifollicular erythema score of 2 or more and a perifollicular scale score of 2 or more.

[0168] [Article 46] 46. ​​The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 45, wherein said patient is 45 years of age or older.

[0169] [Article 47] 47. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 46, wherein said patient is female.

[0170] [Article 48] The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 47, wherein said patient is postmenopausal (as defined above).

[0171] [Article 49] 49. The method of treatment, compound or topical preparation, or use of compound according to any one of clauses 41 to 48, wherein the patient has no history of other scalp / hair disorders, including discoid lupus erythematosus and central centrifugal cicatricial alopecia.

[0172] [Article 50] 50. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 49, wherein said patient achieves a reduction from baseline in expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ at week 26.

[0173] [Article 51] 50. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 49, wherein said patient achieves a reduction from baseline in expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ at 24 weeks.

[0174] [Article 52] 50. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 49, wherein said patient achieves a reduction from baseline in expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ at week 12.

[0175] [Article 53] 50. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 49, wherein said patient achieves a reduction from baseline in expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ at week 8.

[0176] [Article 54] 50. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 49, wherein said patient achieves a reduction from baseline in expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ at week 4.

[0177] [Article 55] 55. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 54, wherein said patient achieves an improvement from baseline in LPPAI score at 26 weeks.

[0178] [Article 56] 55. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 54, wherein said patient achieves an improvement from baseline in LPPAI score at 24 weeks.

[0179] [Article 57] 55. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 54, wherein said patient achieves an improvement from baseline in LPPAI score at week 12.

[0180] [Article 58] 55. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 54, wherein said patient achieves an improvement from baseline in LPPAI score at week 8.

[0181] [Article 59] 55. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 54, wherein said patient achieves an improvement from baseline in LPPAI score at week 4.

[0182] [Article 60] 59. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 59, wherein the patient achieves an improvement from baseline in FFASS score at 26 weeks.

[0183] [Article 61] 59. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 59, wherein the patient achieves an improvement from baseline in FFASS score at 24 weeks.

[0184] [Article 62] 59. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 59, wherein the patient achieves an improvement from baseline in FFASS score at week 12.

[0185] [Article 63] 59. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 59, wherein said patient achieves an improvement from baseline in FFASS score at week 8.

[0186] [Article 64] 59. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 59, wherein said patient achieves an improvement from baseline in FFASS score at week 4.

[0187] [Article 65] The method of treatment, compound or topical preparation, or use of compound according to any one of clauses 41 to 64, wherein the patient achieves an improvement from baseline in perifollicular erythema score in the target area at week 26.

[0188] [Article 66] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 64, wherein the patient achieves an improvement from baseline in perifollicular erythema score in the target area at week 24.

[0189] [Article 67] 65. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 64, wherein said patient achieves an improvement from baseline in perifollicular erythema score in the target area at week 12.

[0190] [Article 68] 65. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 64, wherein said patient achieves an improvement from baseline in perifollicular erythema score in the target area at week 8.

[0191] [Article 69] 65. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 64, wherein said patient achieves an improvement from baseline in perifollicular erythema score in the target area at week 4.

[0192] [Article 70] 70. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 69, wherein the patient achieves an improvement from baseline in perifollicular scale score in the target area at week 26.

[0193] [Article 71] 70. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 69, wherein the patient achieves an improvement from baseline in perifollicular scale score in the target area at 24 weeks.

[0194] [Article 72] 70. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 69, wherein the patient achieves an improvement from baseline in perifollicular scale score in the target area at week 12.

[0195] [Article 73] 70. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 69, wherein the patient achieves an improvement from baseline in perifollicular scale score in the target area at week 8.

[0196] [Article 74] 70. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 69, wherein the patient achieves an improvement from baseline in perifollicular scale score in the target area at week 4.

[0197] [Article 75] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at week 26.

[0198] [Article 76] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at 24 weeks.

[0199] [Article 77] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at week 12.

[0200] [Article 78] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at week 8.

[0201] [Article 79] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at week 4.

[0202] [Article 80] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at day 8.

[0203] [Article 81] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at day 7.

[0204] [Article 82] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score on day 6.

[0205] [Article 83] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score at day 5.

[0206] [Article 84] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score on day 4.

[0207] [Article 85] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score on day 3.

[0208] [Article 86] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 74, wherein the patient achieves a reduction from baseline in pruritus NRS score on day 2.

[0209] [Article 87] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score at 26 weeks.

[0210] [Article 88] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score at 24 weeks.

[0211] [Article 89] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein said patient achieves a reduction from baseline in burning sensation NRS score at week 12.

[0212] [Article 90] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein said patient achieves a reduction from baseline in burning sensation NRS score at week 8.

[0213] [Article 91] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein said patient achieves a reduction from baseline in burning sensation NRS score at week 4.

[0214] [Article 92] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein said patient achieves a reduction from baseline in burning sensation NRS score at day 8.

[0215] [Article 93] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score at day 7.

[0216] [Article 94] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score on day 6.

[0217] [Article 95] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score at day 5.

[0218] [Article 96] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score on day 4.

[0219] [Article 97] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score on day 3.

[0220] [Article 98] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 86, wherein the patient achieves a reduction from baseline in burning sensation NRS score on day 2.

[0221] [Article 99] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score at 26 weeks.

[0222] [Article 100] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score at 24 weeks.

[0223] [Article 101] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score at week 12.

[0224] [Article 102] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score at week 8.

[0225] [Article 103] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score at week 4.

[0226] [Article 104] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score on day 8.

[0227] [Article 105] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score at day 7.

[0228] [Article 106] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score on day 6.

[0229] [Article 107] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score on day 5.

[0230] [Article 108] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score on day 4.

[0231] [Article 109] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score on day 3.

[0232] [Article 110] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 98, wherein the patient achieves a reduction from baseline in pain NRS score on day 2.

[0233] [Article 111] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points at week 26.

[0234] [Article 112] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points at week 24.

[0235] [Article 113] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points at week 12.

[0236] [Article 114] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points at week 8.

[0237] [Article 115] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points at week 4.

[0238] [Article 116] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points on day 8.

[0239] [Article 117] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points at day 7.

[0240] [Article 118] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points on day 6.

[0241] [Article 119] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points on day 5.

[0242] [Article 120] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points on day 4.

[0243] [Article 121] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points on day 3.

[0244] [Article 122] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 110, wherein the patient has a baseline pruritus NRS score of 3 or more and achieves a reduction in pruritus NRS score of 3 points on day 2.

[0245] [Article 123] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points at week 26.

[0246] [Article 124] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points at week 24.

[0247] [Article 125] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points at week 12.

[0248] [Article 126] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points at week 8.

[0249] [Article 127] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points at week 4.

[0250] [Article 128] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points on day 8.

[0251] [Article 129] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points at day 7.

[0252] [Article 130] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points on day 6.

[0253] [Article 131] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points on day 5.

[0254] [Article 132] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points on day 4.

[0255] [Article 133] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points on day 4.

[0256] [Article 134] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 122, wherein the patient has a baseline pruritus NRS score of 4 or more and achieves a reduction in pruritus NRS score of 4 points on day 2.

[0257] [Article 135] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points at week 26.

[0258] [Article 136] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points at week 24.

[0259] [Article 137] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points at week 12.

[0260] [Article 138] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points at week 8.

[0261] [Article 139] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points at week 4.

[0262] [Article 140] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points on day 8.

[0263] [Article 141] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points at day 7.

[0264] [Article 142] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points on day 6.

[0265] [Article 143] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points on day 5.

[0266] [Article 144] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points on day 4.

[0267] [Article 145] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points on the third day.

[0268] [Article 146] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 3 or more and achieves a reduction in burning sensation NRS score of 3 points on day 2.

[0269] [Article 147] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points at week 26.

[0270] [Article 148] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a burning sensation NRS score reduction of 4 points at week 24.

[0271] [Article 149] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a burning sensation NRS score reduction of 4 points at week 12.

[0272] [Article 150] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points at week 8.

[0273] [Article 151] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points at week 4.

[0274] [Article 152] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points on day 8.

[0275] [Article 153] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points at day 7.

[0276] [Article 154] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points on day 6.

[0277] [Article 155] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points on day 5.

[0278] [Article 156] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points on day 4.

[0279] [Article 157] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 146, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points on day 3.

[0280] [Article 158] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 134, wherein the patient has a baseline burning sensation NRS score of 4 or more and achieves a reduction in burning sensation NRS score of 4 points on day 2.

[0281] [Article 159] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points at week 26.

[0282] [Article 160] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points at week 24.

[0283] [Article 161] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points at week 12.

[0284] [Article 162] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points at week 8.

[0285] [Article 163] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points at week 4.

[0286] [Article 164] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on day 8.

[0287] [Article 165] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on day 7.

[0288] [Article 166] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on day 6.

[0289] [Article 167] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on the 5th day.

[0290] [Article 168] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on day 4.

[0291] [Article 169] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on the third day.

[0292] [Article 170] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 158, wherein the patient has a baseline pain NRS score of 3 or more and achieves a reduction in pain NRS score of 3 points on the second day.

[0293] [Article 171] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points at week 26.

[0294] [Article 172] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points at week 24.

[0295] [Article 173] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points at week 12.

[0296] [Article 174] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points at week 8.

[0297] [Article 175] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points at week 4.

[0298] [Article 176] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on day 8.

[0299] [Article 177] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on day 7.

[0300] [Article 178] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on day 6.

[0301] [Article 179] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on the 5th day.

[0302] [Article 180] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on the 4th day.

[0303] [Article 181] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on the third day.

[0304] [Article 182] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on the second day.

[0305] [Article 182] The method of treatment, compound or topical preparation, or use of the compound according to any one of clauses 41 to 170, wherein the patient has a baseline pain NRS score of 4 or more and achieves a reduction in pain NRS score of 4 points on the second day.

[0306] [Article 183] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 182, wherein said patient achieves an improvement from baseline to week 26 in hair count / tricoscopy in the target area by fotofinder trichovision.

[0307] [Article 184] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 182, wherein said patient achieves an improvement from baseline to week 24 in hair count / tricoscopy in the target area by fotofinder trichovision.

[0308] [Article 185] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 182, wherein said patient achieves an improvement from baseline to week 12 in hair count / tricoscopy in the target area by fotofinder trichovision.

[0309] [Article 186] 186. The method of treatment, the compound or topical preparation, or the use of a compound according to any one of clauses 41 to 185, wherein administration of said compound or topical preparation is twice daily.

[0310] [Article 187] The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 185, wherein the administration of the topical preparation is twice daily and the topical composition contains 20 mg / g of delgocitinib in free base form or a pharma- ceutically acceptable salt thereof.

[0311] [Article 188] 188. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 187, wherein said topical composition is a water-in-oil emulsion.

[0312] [Article 189] 188. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 187, wherein said topical composition is an acidified water-in-oil emulsion.

[0313] [Article 190] 188. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 41 to 187, wherein the pH of the topical composition is about 3.8 to 4.6.

[0314] [Article 191] 188. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 187, wherein the pH of the topical composition is about 4.4 or less.

[0315] [Article 192] 188. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 187, wherein the pH of the topical composition is about 4.3 or less.

[0316] [Article 193] 188. The method of treatment, compound or topical preparation, or use of a compound according to any one of clauses 41 to 187, wherein the pH of the topical composition is about 4.2 or less.

[0317] [Article 194] 194. The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 188 to 193, wherein the topical composition comprises an oily base.

[0318] [Article 195] The method of treatment, the compound or the topical preparation, or the use of the compound according to any one of clauses 188 to 194, wherein the topical composition comprises an oily base, and the oily base is liquid paraffin.

[0319] [Article 196] The method of treatment, the compound or topical preparation, or the use of a compound according to any one of clauses 41 to 195, wherein said method of treatment is a prophylactic treatment, or said compound or topical preparation is for prophylactic use, or said use of the compound is for prophylactic use.

Claims

1. A compound of general formula (I) for use in the treatment of LPP 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein the treatment is for FFA.

3. 3. The compound of claim 1 or 2, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered as a cream.

4. The compound according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

5. Formula (I) 【Chemistry 2】 2. A pharmaceutical composition for use in treating LPP, comprising the compound 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile of formula (I) or a pharma- ceutical acceptable salt thereof as an active ingredient.

6. The pharmaceutical composition of claim 5, wherein the treatment is FFA.

7. The pharmaceutical composition according to claim 5 or 6, which is a cream.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

Images