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 prophylactic agent for frontal fibrosing alopecia containing 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile as an active ingredient, and a pharmaceutical preparation thereof.

Description

Technical Field

[0001] This invention relates to the use of delgocitinib (decloxitinib), 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, in novel pharmaceutical applications. In another aspect, this invention relates to the treatment of frontal fibrotic alopecia (FFA). Background Technology

[0002] Fibrotic alopecia of the frontal region (FFA) was first reported in 1994 and is a type of primary lymphocytic cicatricial alopecia. Due to its shared histopathological features, FFA is considered a clinical variant of lichen planus of the hairline (LPP). This variant of LPP is common in postmenopausal women and has an increased incidence. FFA is characterized by a receding hairline in the frontal, temporal, or frontotemporal region; it has a distinctive clinical pattern and often includes eyebrow loss, along with other related symptoms. In addition to the typical receding hairline in the frontotemporal region and eyebrow loss, itching, facial papules, eyelash loss, body hair involvement, and hair pain may also occur.

[0003] FFA has been reported in patients with hypothyroidism, fragrance contact allergy, routine sunscreen use, and autoimmune diseases (including lupus and rheumatoid arthritis).

[0004] Early diagnosis and timely treatment are crucial because FFA is a progressive disorder that can lead to permanent hair loss. However, even with aggressive therapy, FFA can still progress. There are limited publicly available guidelines for the treatment of FFA, and there is no consensus or standard treatment for it.

[0005] Intralesional injection of corticosteroids can achieve some degree of stabilization, but is accompanied by associated adverse reactions such as pain and skin atrophy, and topical corticosteroids are generally ineffective. Furthermore, no therapeutic intervention selectively targets the key cellular or molecular elements of the pathogenesis of FFA.

[0006] The etiology and pathogenesis of febrile follicle alopecia (FFA) are not fully understood and remain under investigation. Inflammatory cellular infiltration around the affected hair follicles (i.e., around the bulge and infundibulum) is characterized by an increase in CD8+ granzyme B+ cytotoxic T cells and plasmacytoid dendritic cells (pDCs), with elevated expression levels of the chemokine receptor CXCR3. Available evidence suggests that interferon (IFN)-γ plays a crucial role in inducing the follicular immune privilege (HFIP) bulge collapse and subsequent immune-mediated destruction of epithelial follicular stem cells (eHFSCs) observed in FFA. Therapeuticly, protecting / restoring bulge immune privilege or neutralizing IFN-γ may contribute to better management of this refractory scarring alopecia.

[0007] Several JAK inhibitors are in clinical development or already on the market. Ruxolitinib (the first FDA-approved JAK1 and JAK2 inhibitor) is an oral medication approved in several countries for the treatment of patients with myelofibrosis and a variety of other chronic inflammatory conditions. Other JAK inhibitors, such as tofatinib and baricitinib, have also been approved or are under development for the treatment of various chronic inflammatory conditions.

[0008] WO 2011 / 013785 describes nitrogen-containing spirocyclic compounds and their pharmaceutical uses. These compounds are claimed to be JAK kinase 3 inhibitors for the prevention or treatment of, for example, autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis, and atopic dermatitis.

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

[0010] WO2016 / 179605 relates to the use of JAK inhibitors in methods of promoting hair growth in patients with alopecia areata.

[0011] WO2017 / 050891 describes the use of a pharmaceutical composition for treating alopecia areata.

[0012] A study by Mikhaylov et al. in Arch Dermatol Res. 2023 Mar;315(2):181-189 included the results of a trial of delgotinib ointment for the treatment of alopecia areata (AA). The results showed that delgotinib ointment was ineffective in treating moderate to severe AA.

[0013] Therefore, there is an unmet medical need for new treatments with high FFA efficacy and attractive safety profiles. Summary of the Invention

[0014] This invention relates to the treatment of FFA, comprising compounds of formula (I): (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof.

[0015] In one aspect, the present invention relates to the use of compounds of formula (I) for use in the treatment of FFA.

[0016] In another aspect, the present invention relates to a compound of formula (I) for use in the treatment of FFA. In yet another aspect, the present invention relates to a compound of formula (I) for use in the topical treatment of FFA. In yet another aspect, the topical formulation is a cream. In yet another aspect, the present invention relates to the use of a compound of formula (I) applied twice daily. In yet another aspect, the present invention relates to the use of a compound of formula (I) applied twice daily for 12 weeks. In yet another aspect, the present invention relates to a compound of formula (I) applied at a concentration of 20 mg / g.

[0017] In another aspect, the present invention relates to the use of compounds of formula (I) in the preparation of pharmaceutical compositions for the treatment of FFA. In yet another aspect, the pharmaceutical composition is a topical formulation. In yet another aspect, the topical formulation is a cream.

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

[0019] In another aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I), wherein the treatment is a topical treatment, such as treatment with a cream.

[0020] In another aspect, the present invention relates to a pharmaceutical composition wherein the compound of formula (I) is administered at a concentration of 20 mg / g. In another aspect, the compound of formula (I) is administered as a twice-daily application. In another aspect, the compound of formula (I) is administered as a twice-daily application for 12 weeks.

[0021] In another aspect, the present invention relates to a method for treating FFA in a subject with such need, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) to the subject.

[0022] In another aspect, the present invention relates to a method of treating FFA in a subject with such need, wherein the application is topical. In another aspect, the present invention relates to a method of treating FFA in a subject with such need, wherein the topical preparation is a cream. In another aspect, the present invention relates to a method of treating FFA in a subject with such need, wherein a compound of formula (I) is applied at a concentration of 20 mg / g.

[0023] 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]oct-1-yl]-3-oxopropionitrile in the treatment of FFA.

[0024] The present invention further provides the above-described use as an application once daily. The present invention further provides the above-described use as an application twice daily. The present invention further provides the above-described use at a concentration of 20 mg / g.

[0025] Detailed description of the invention

[0026] Compound of formula (I) (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, previously described in WO2011 / 013785 as a JAK 3 kinase inhibitor for the treatment of, for example, autoimmune diseases, allergic diseases, psoriasis, rheumatoid arthritis and atopic dermatitis, and in EP 2813228A1 for the treatment of skin diseases such as senile xerosis, sebaceous abscess, eczema and contact dermatitis.

[0027] The compound of formula (I) can be produced according to the method described in Preparation 6 of WO 2011 / 013785. Attached Figure Description

[0028] Figure 1 Baseline Demographics

[0029] Figure 2 Baseline Demographics (Continued)

[0030] Figure 3 Changes in LPPAI of Queue 1 relative to baseline

[0031] Figure 4 Changes in FFAS of Queue 1 relative to the baseline

[0032] Figure 5 Hairline measurement

[0033] Figure 6: Hairline measurement (average)

[0034] Figure 7 Total hair loss score

[0035] Figure 8 Results of trichoscopy (number of hairs)

[0036] Figure 9 Results of trichoscopy (number of hair follicles) Detailed Implementation

[0037] "Pharmaceutical acceptable salt" can be any non-toxic salt of a compound of formula (I), and includes salts formed with inorganic acids, salts formed with organic acids, salts formed with inorganic bases, salts formed with organic bases, and salts formed with amino acids.

[0038] Salts formed with inorganic acids include those with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts formed with organic acids include those with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid monohydrate, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Salts formed with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Salts formed with organic bases include those with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, methylpyridine, choline, cincorine, and meglumine. Salts formed with amino acids include those with lysine, arginine, aspartic acid, and glutamic acid.

[0039] According to well-known methods, each salt can be obtained by reacting a compound of formula (I) with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid.

[0040] The compounds of formula (I) can be made using isotopes, for example 3 H, 14 C 35 The S mark.

[0041] In one respect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a substantially purified compound of formula (I) or a pharmaceutically acceptable salt thereof. In another respect, the compound of formula (I) or a pharmaceutically acceptable salt thereof has a purity of 80% or higher.

[0042] "Pharmaceutical composition" includes oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, or parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal medications, and pulmonary medications. In another aspect, pharmaceutical composition is a topical preparation such as ointment and cream. In yet another aspect, pharmaceutical composition is a cream.

[0043] The pharmaceutical compositions of the present invention are produced by appropriately mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with at least one type of pharmaceutically acceptable excipient or carrier in an appropriate amount according to methods known in the field of pharmaceutical formulation technology. The content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition depends on its dosage form, dosage, etc., and is, for example, from 0.1% to 100% by weight of the entire composition. For example, this 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 entire composition.

[0044] In one respect, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.1% by weight of the whole composition.

[0045] In one respect, the amount of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.3% by weight of the whole composition.

[0046] In one respect, the amount of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.8% by weight of the whole composition.

[0047] In one respect, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is 2% by weight of the whole composition.

[0048] In one respect, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is 3% by weight of the whole composition.

[0049] As used herein, the term "therapeutic effective amount" for a compound refers to an amount sufficient to cure, alleviate, or partially prevent the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this is defined as a "therapeutic effective amount." The effective amount for each purpose will depend on the severity of the disease or injury, as well as the subject's weight and general condition.

[0050] "Pharmaceutically acceptable excipients" or "pharmaceutically acceptable carriers" include a variety of conventional organic or inorganic excipients or carrier substances used in pharmaceutical materials, such as disintegrants, binders, fluidizing agents, lubricants, solvents, solubilizers, suspending agents, tonicity agents, buffers, and soothing agents for liquid formulations, as well as matrices, emulsifiers, surfactants, humectants, stabilizers, stabilizing agents, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, antiseptics, fillers, and solvents. Additionally, additives including preserving agents, preservatives, antioxidants, and colorants may be used if necessary.

[0051] Disintegrants include carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, etc.

[0052] Adhesives include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, granulated sugar, dextrin, starch, gelatin, sodium carboxymethyl cellulose, gum arabic, etc.

[0053] Fluidizing agents include light anhydrous silicate, magnesium stearate, etc.

[0054] Lubricants include magnesium stearate, calcium stearate, talc, etc.

[0055] Solvents include purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, medium-chain triglycerides, etc.

[0056] Solubilizers include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.

[0057] Suspension agents include benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate, etc.

[0058] Isotonic regulators include glucose, D-sorbitol, sodium chloride, D-mannitol, etc.

[0059] Buffers or pH adjusters include phosphates or citrates, sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, sodium citrate dihydrate, citrate monohydrate, hydrochloric acid, sodium hydroxide, etc.

[0060] The matrix includes 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-butanediol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (e.g., white soft paraffin, liquid paraffin, paraffin, hard paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrophilic lanolin, 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, polyethylene glycol (e.g., polyethylene glycol 200 to 600, etc.), and combinations of two or more of these. In one aspect, the matrix is ​​liquid paraffin.

[0061] Emulsifiers or surfactants include mixtures of fatty acids (especially cetyl alcohol, stearyl alcohol, and cetearyl alcohol), polyethylene glycol cetearyl alcohol ether, sorbitan ester, sucrose ester, etc.

[0062] Stabilizers include sucrose esters, other sorbitan esters and polysorbates, glycerol, propylene glycol, ethanol, cetearyl alcohol, etc.

[0063] Acidifying agents include strong acids selected from, for example, hydrochloric acid or citric acid.

[0064] Chelating agents include ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid (EGTA), ethylenediamine, phosphoric acid, etc.

[0065] Preservatives include ethylparaben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, chlorocresol, dichlorobenzyl alcohol, glycerin, ethanol, propylene glycol, benzoic acid / sodium benzoate, diazolidinyl urea, benzalkonium chloride, etc.

[0066] Antioxidants include sodium sulfite, ascorbic acid, disodium EDTA, trisodium EDTA, α-tocopherol, butylated hydroxyanisole, etc.

[0067] Coloring agents include food dyes, beta-carotene, etc.

[0068] The pharmaceutical compositions of the present invention can be administered to mammals, such as humans. The dosage depends on the subject, disease, symptoms, dosage form, route of administration, etc., and can be in the range of about 0.01 mg to about 1 g, for example, from about 0.01 mg to about 600 mg / day in terms of the content of the compound of formula (I) as the active ingredient. This dosage can be administered once or in several divided doses.

[0069] Topical formulations can be applied, for example, by application, rubbing, or spraying, depending on the dosage form. The amount of topical formulation applied to the affected area can be selected based on factors such as the content of the active ingredient, and, for example, the topical formulation can be applied once daily or in several fractional doses. Preferred application is once daily or twice daily.

[0070] The phrase “JAK” refers to one or more enzymes belonging to the JAK family, namely JAK1, JAK2, JAK3, and TYK2.

[0071] The phrase “inhibit JAK” refers to inhibiting the function of JAK to eliminate or reduce its activity, as well as inhibiting one or more enzymes belonging to the JAK family. In one respect, the phrase “inhibit JAK” refers to “inhibit human JAK.” In another respect, the inhibition of function or the elimination or reduction of activity is carried out in the context of human clinical applications.

[0072] "JAK inhibitor" can be any substance that inhibits JAK, and can be, for example, low molecular weight compounds, nucleic acids, peptides, proteins, antibodies, vaccines, etc. In one respect, "JAK inhibitor" is "human JAK inhibitor." In another respect, a JAK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet another respect, a JAK inhibitor is a compound of formula (I).

[0073] The term "treatment" as used in this article includes symptom improvement, prevention of exacerbation, maintenance of remission, and prevention of relapse. The term "prevention" refers to suppressing the occurrence of symptoms.

[0074] The term "treatment" can also include delaying the progression of a disease, disorder, or symptom; improving, reducing, or alleviating symptoms and complications; and / or curing or eliminating a disease, disorder, or symptom. The term "treatment" can also refer to the management and care of a patient for the purpose of combating a disease, symptom, or disorder.

[0075] As used herein, the terms “disease,” “abnormality,” and “symptom” are used interchangeably to specify the condition of a patient that is not a normal physiological state in humans.

[0076] Embodiments of the present invention include pharmaceutical compositions for treating or preventing scarring alopecia, the pharmaceutical composition comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile and pharmaceutically acceptable excipients or carriers. Another embodiment of the present invention includes pharmaceutical compositions for treating or preventing LPP, the pharmaceutical composition comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile and pharmaceutically acceptable excipients or carriers. Another embodiment of the invention includes a pharmaceutical composition for treating or preventing FFA, the pharmaceutical composition comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile and a pharmaceutically acceptable excipient or carrier.

[0077] Embodiments of the present invention include the use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile for the treatment or prevention of scarring 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]oct-1-yl]-3-oxopropionitrile for the treatment or prevention of 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]oct-1-yl]-3-oxopropionitrile for the treatment or prevention of FFA.

[0078] Embodiments of the present invention include a method for treating or preventing scarring alopecia, characterized by administering a therapeutically effective amount of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile to a mammal. Another embodiment of the present invention includes a method for treating or preventing LPP, characterized by administering a therapeutically effective amount of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile to a mammal. Another embodiment of the invention includes a method for treating or preventing FFA, characterized by administering a therapeutically effective amount of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile to a mammal.

[0079] In one respect, the mammal is the human.

[0080] On the other hand, this human being is someone suffering from an illness who needs medical care.

[0081] In another aspect, the condition is cicatricial alopecia. In another aspect, the condition is LPP. In yet another aspect, the condition is FFA.

[0082] In another aspect, the present invention relates to a treatment or preventive agent for cicatricial alopecia, the treatment or preventive agent comprising a compound of formula (I). In another aspect, the present invention relates to a treatment or preventive agent for LPP comprising a compound of formula (I). In another aspect, the present invention relates to a treatment or preventive agent for FFA comprising a compound of formula (I).

[0083] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients or carriers.

[0084] In another aspect, the present invention relates to pharmaceutical formulations for topical application, the pharmaceutical formulation comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0085] In another aspect, the present invention relates to a pharmaceutical formulation as a cream comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0086] In another respect, pharmaceutically acceptable excipients may be one or more matrices selected from: medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof. For example, the matrix may be liquid paraffin.

[0087] The matrix 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, and for example, 100 mg / g.

[0088] In another respect, pharmaceutically acceptable surfactants, emulsifiers, or stabilizers may be one or more selected from cetearyl alcohol, stearyl alcohol, cetearyl alcohol, or mixtures thereof. For example, a surfactant, emulsifier, or stabilizer may be cetearyl alcohol.

[0089] Surfactants, emulsifiers, or stabilizers may be present in various amounts of cetearyl alcohol, from about 20 mg / g to about 100 mg / g, for example, from about 40 mg / g to about 80 mg / g, and for example, 72 mg / g.

[0090] In another respect, pharmaceutically acceptable surfactants, emulsifiers, or stabilizers may be one or more selected from sorbitan esters, sucrose esters, polyethylene glycol cetearyl ether, or mixtures thereof. For example, a surfactant or emulsifier may be polyethylene glycol cetearyl ether.

[0091] Surfactants, emulsifiers, or stabilizers may be present in various amounts of polyethylene glycol cetearyl alcohol ether, from about 9 mg / g to about 25 mg / g, for example, from about 15 mg / g to about 20 mg / g, and for example, 18 mg / g.

[0092] In another respect, pharmaceutically acceptable buffers or pH adjusters can be one or more of phosphates or citrates, sodium acetate, sodium carbonate, sodium citrate dihydrate, hydrochloric acid, or mixtures thereof. For example, a buffer or pH adjuster can be one or more of citrate monohydrate and sodium citrate dihydrate.

[0093] The buffer or pH adjuster may be present in varying 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, and for example, 1 mg / g.

[0094] The buffer or pH adjuster may be present in varying amounts of sodium citrate dihydrate, from 0 mg / g to about 1 mg / g, for example, from 0 mg / g to about 0.5 mg / g, and for example, not present.

[0095] In another respect, pharmaceutically acceptable preservatives may be selected from one or more of benzyl alcohol, sodium dehydroacetate, sorbic acid / salt, or mixtures thereof. For example, a preservative may be benzyl alcohol.

[0096] The preservative may be present in various amounts of benzyl alcohol, from about 7 mg / g to about 13 mg / g, for example, from about 9 mg / g to about 11 mg / g, and for example, 10 mg / g.

[0097] In another respect, pharmaceutically acceptable antioxidants may be selected from one or more, or mixtures thereof, of sodium sulfite, disodium EDTA, trisodium EDTA, and butylated hydroxyanisole. For example, an antioxidant may be butylated hydroxyanisole.

[0098] The antioxidant may be present in various amounts of butylated hydroxyanisole, from about 0.05 mg / g to about 0.3 mg / g; for example, from about 0.1 mg / g to about 0.25 mg / g, and for example, 0.2 mg / g.

[0099] On the other hand, pharmaceutically acceptable chelating agents can be one or more of EDTA, disodium ethylenediaminetetraacetate, EGTA, or ethylenediamine. For example, a chelating agent could be disodium ethylenediaminetetraacetate.

[0100] The chelating agent may be present in various amounts of disodium ethylenediaminetetraacetate, such as about 0.05 mg / g to about 1.5 mg / g, for example, about 0.5 mg / g to about 1 mg / g, and for example, 0.6 mg / g.

[0101] On the other hand, a pharmaceutically acceptable acidifier can be one or more strong acids, such as hydrochloric acid or citric acid. For example, the acidifier could be hydrochloric acid.

[0102] The acidifier may be present in different amounts of hydrochloric acid, from 0 mg / g to about 25 mg / g, for example, from about 10 mg / g to about 20 mg / g, and for example, 17.7 mg / g.

[0103] On the other hand, a pharmaceutically acceptable solvent may be purified water, which may be present in various amounts, such as about 500 mg / g to about 900 mg / g, and for example 760 mg / g.

[0104] The pharmaceutical formulation of the present invention can be prepared according to the method described in WO 2020 / 229622.

[0105] An exemplary specific pharmaceutical formulation of the present invention is: Delgotinib 20 mg / g; liquid paraffin 100 mg / g; cetearyl alcohol 72 mg / g; polyethylene glycol cetearyl ether 18 mg / g; benzyl alcohol 10 mg / g; citric acid monohydrate 1.0 mg / g; butylated hydroxyanisole 0.2 mg / g; disodium EDTA 0.6 mg / g; 3 M hydrochloric acid 17.7 mg / g; and purified water to 1 g.

[0106] Delgotinib 20 mg / g; liquid paraffin 100 mg / g; cetearyl alcohol 72 mg / g; polyethylene glycol cetearyl ether 18 mg / g; benzyl alcohol 10 mg / g; citric acid monohydrate 1.0 mg / g; sodium citrate 1 mg / g; disodium EDTA 1.3 mg / g; hydrochloric acid 4.99 mg / g; butylated hydroxyanisole 0.2 mg / g; and purified water to 1 g.

[0107] This invention describes its role in the topical treatment of scarring alopecia. In another aspect, this invention describes its role in the topical treatment of LPP. In yet another aspect, this invention describes its role in the topical treatment of FFA.

[0108] This invention provides a clinical trial evaluating the efficacy and safety of delgotinib cream 20 mg / g in adult subjects with FFA.

[0109] In this trial, changes in molecular characterization following topical application of delgotinib cream at 20 mg / g will be evaluated in subjects with free fibrillary acne (FFA). The safety and preliminary efficacy of delgotinib cream in subjects with FFA will also be assessed.

[0110] Primary objective: To evaluate changes in molecular characterization following topical application of delgotinib cream at 20 mg / g in subjects with free fungal facies (FFA).

[0111] Secondary objective: To evaluate the safety and tolerability of topical application of delgotinib cream 20 mg / g in subjects with FFA during treatment in a mediator-controlled setting.

[0112] Exploratory objective: To evaluate the safety and tolerability of 20 mg / g delgotinib cream during open-label expansion. To assess the preliminary efficacy of topical application of 20 mg / g delgotinib cream in subjects with free facial atrophy (FFA).

[0113] Example

[0114] Experimental Design: A phase 2a, randomized, double-blind, mediator-controlled, single-center exploratory trial of delgotinib cream 20 mg / g in subjects with FFA.

[0115] The trial consists of two cohorts: cohort 1 will include approximately 30 participants with FFA and cohort 2 will include approximately 5 healthy postmenopausal women.

[0116] Queue 1: Before engaging in any trial-related activities, all participants will read and sign an informed consent form. Participants who meet all inclusion criteria and do not meet any exclusion criteria will be randomized to the trial. After a screening period not exceeding 30 days, eligible participants will be randomized (1:1) on day 1 to receive either delgotinib cream 20 mg / g twice daily (delgotinib / delgotinib group) or the mediator cream (placebo / delgotinib group) for 12 weeks during the mediator-controlled treatment period. All participants who complete the mediator-controlled treatment period will then proceed to the open-label extension period and receive delgotinib cream 20 mg / g twice daily for 12 weeks. A 2-week safety follow-up period will follow the open-label extension period. For scheduled trial visits, participants will visit the center on seven occasions: screening, day 1, week 4, week 8, week 12, week 24, and week 26 / early termination. Participants will also be contacted by telephone on two occasions: week 16 and week 20.

[0117] On Day 1, the target lesion area on the scalp will be determined (e.g., the forehead, periauricular region, or temporal region). The target lesion area should be large enough to accommodate hair counting / trigomesis assessment and the collection of all skin samples (i.e., skin biopsy, tape removal, and skin swabs), and should be treated with the clinical trial drug. If necessary, a second target area may be selected to allow for skin sample collection.

[0118] Queue 2: Before engaging in any trial-related activities, all participants will read and sign an informed consent form. Participants who meet all inclusion criteria and do not meet any exclusion criteria will be admitted to the trial. After a screening period not exceeding 30 days, eligible participants will be asked to come to the center for skin sample collection. At the investigator's discretion, Day 1 screening and skin sample collection may be conducted on the same day (if the participant does not have a washout period) or at two separate visits. The study product will not be administered in Cohort 2. For scheduled trial visits, participants will come to the center on up to three occasions: screening, Day 1, and optional follow-up.

[0119] The delgotinib cream used in the trial contained: Delgotinib 20 mg / g; liquid paraffin 100 mg / g; cetearyl alcohol 72 mg / g; polyethylene glycol cetearyl ether 18 mg / g; benzyl alcohol 10 mg / g; citric acid monohydrate 1.0 mg / g; butylated hydroxyanisole 0.2 mg / g; disodium EDTA 0.6 mg / g; 3 M hydrochloric acid 17.7 mg / g; and purified water to 1 g.

[0120] Selection criteria

[0121] To be eligible to participate in this trial, participants must meet all of the following criteria at screening and Day 1 visit, or only at one of the designated visits (screening or Day 1) as specified in the criteria: Inclusion criteria for all participants: - Participants must volunteer and be able to sign an informed consent form. Note: Informed consent must be obtained before any trial-related procedures.

[0122] - Subjects must be willing to comply with all trial procedures and must be available for the duration of the trial.

[0123] Inclusion criteria for Cohort 1 (subjects with FFA only): - Male or female participants who are 18 years of age or older at the time of signing informed consent.

[0124] - Female subjects of childbearing age were negative for serum pregnancy test at screening and negative for urine pregnancy test on day 1.

[0125] - Based on the researcher's judgment, the subject already had a clinically confirmed diagnosis of FFA.

[0126] - Subjects with a perifollicular erythema score ≥ 2 and a perifollicular scaling score ≥ 2 in the target area at screening and on day 1.

[0127] - For subjects who use cosmetics, moisturizers, creams, emollients, cleansers, and / or sunscreens on their face, the subjects have been using the same brand / type of product for at least 4 weeks prior to Day 1, agree not to change the brand / type or frequency of use throughout the trial, agree not to apply those products to the treatment area during the trial, and agree not to use cosmetics, moisturizers, creams, emollients, cleansers, and / or sunscreens on their face on the clinical visit day prior to the visit.

[0128] - Participants are willing to maintain a consistent hairstyle and hair care regimen, including shampoos and conditioners (including hair coloring, perming, and scheduled hair appointments), and are willing to avoid braiding or hair extensions throughout the trial and for four weeks prior to Day 1. Note: Hair coloring and shaving of scalp hair are permitted during the trial, but not within 48 hours prior to the trial visit.

[0129] - For female subjects of reproductive age who have any sexual intercourse that may result in pregnancy: Subjects must agree to use an effective method of contraception from at least 4 weeks before day 1 until at least 4 weeks after the last administration of the study drug.

[0130] Inclusion criteria for Cohort 2 (healthy subjects only): - Female participants aged 45 or older at the time of informed consent.

[0131] - Women are defined as postmenopausal as follows: - Women who have undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy); - Women who have not menstruated for at least 12 months prior to the screening visit without any other medical reason.

[0132] - According to the researchers' judgment, based on vital signs, medical history and brief physical examination, the subjects were in good overall health.

[0133] Exclusion criteria

[0134] Subjects who meet any of the following criteria at screening and / or Day 1 (if applicable) will be excluded from participation in this trial: Exclusion criteria for all subjects: - Women who are breastfeeding, pregnant, or planning to become pregnant during the trial.

[0135] - Subjects received any marketed or investigational biologics within 12 weeks or 5 half-lives (whichever is longer) prior to Day 1.

[0136] - The subject is currently receiving a non-biological research product or device, or has received a non-biological research product or device within 4 weeks prior to Day 1.

[0137] - Subjects who have had excessive sun exposure or used a tanning room in the four weeks prior to Day 1, or who do not wish to minimize exposure to natural and artificial sunlight during the trial. When sun exposure cannot be avoided, the use of sunscreen products (except for the treatment area of ​​subjects in Cohort 1) and protective clothing is recommended.

[0138] - Subjects have a history of allergic reactions or significant sensitivity to lidocaine or other local anesthetics.

[0139] - Subjects have a history of hypertrophic scars or keloid formation at the scar or suture site.

[0140] Exclusion criteria for Cohort 1 (subjects with FFA only): - History of other scalp / hair conditions, including discoid lupus erythematosus and central centrifugal scarring alopecia.

[0141] - The presence of active skin disease that may interfere with FFA diagnosis and / or test assessment.

[0142] - Subjects who have already undergone scalp reduction surgery or hair transplantation.

[0143] - Adhesive wigs were used during the experiment.

[0144] - The subject is known to have immunodeficiency or immunodeficiency.

[0145] - Subjects must have a history of cancer or lymphoproliferative disorders within the 5 years prior to Day 1. Subjects with successfully treated non-metastatic squamous cell carcinoma of the skin or basal cell carcinoma and / or localized carcinoma in situ of the cervix are not excluded.

[0146] - Subjects who have undergone major surgery within 8 weeks prior to Day 1, or who plan to undergo major surgery during the trial.

[0147] - Subjects with any clinically significant medical condition or physical / laboratory / ECG / vital signs abnormalities that, in the investigator's opinion, would put the subject at undue risk or interfere with the interpretation of trial results.

[0148] - The subject's results were positive for hepatitis B surface antigen (HBsAg), hepatitis B core antigen antibody (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).

[0149] - Subjects had been treated with medications that could affect hair regrowth (including natural products or nutritional supplements such as Viviscal, Nutrafol, and / or Biotin) for the last 4 weeks prior to Day 1.

[0150] - During the last 4 weeks prior to Day 1, the subjects had received intralesional scalp corticosteroids or platelet-rich plasma injections.

[0151] - Within 4 weeks prior to Day 1, the subject must have received systemic treatment with immunosuppressive / modulatory drugs or drugs that can affect FFA (e.g., corticosteroids, methotrexate, minoxidil, hydroxychloroquine, retinoic acid, calcineurin inhibitors, tetracycline, pioglitazone, spironolactone, or 5α-reductase inhibitors). Note: Intranasal and inhaled corticosteroids are permitted. Eye drops and ear drops containing corticosteroids are also permitted. Note: Standard doses of systemic antihistamines are permitted.

[0152] - Within 2 weeks prior to Day 1, the subject had used any topical medications that could affect FFA, including but not limited to topical corticosteroids, calcineurin inhibitors, minoxidil, and phosphodiesterase-4 (PDE-4) inhibitors.

[0153] - Subjects had received JAK inhibitor (systemic or local) treatment within 4 weeks prior to Day 1.

[0154] - Within 4 weeks prior to Day 1, the subject had received any ultraviolet (UV)-B phototherapy (including tanning beds), excimer laser, or any other phototherapy.

[0155] - Subjects had received psoralen-UV-A (PUVA) treatment within 4 weeks prior to Day 1.

[0156] - Subjects have a known or suspected allergy to delgotinib or any component of the study product.

[0157] - Subjects have a history of allergic reactions or significant sensitivity to hypoallergenic inks.

[0158] - Subjects had a known clinically significant history of drug or alcohol abuse in the last year prior to Day 1.

[0159] Exclusion criteria for Cohort 2 (healthy subjects only): - Subjects with a history of skin disease or existing skin conditions, according to the researchers, will interfere with trial evaluation.

[0160] - Subjects with any clinically significant medical condition or physical / vital abnormalities that, in the investigator's opinion, would put the subject at undue risk or interfere with the interpretation of trial results.

[0161] - Subjects have a known history of chronic infectious diseases (e.g., hepatitis B, hepatitis C, or HIV).

[0162] - Within 2 weeks prior to skin sample collection (Day 1), the subjects had already received topical medication treatment at the target skin site.

[0163] result

[0164] Thirty patients were randomly assigned to receive the treatment described in Cohort 1 above.

[0165] The baseline characteristics of these 30 patients can be found in Figure 1 and Figure 2 I saw it in the middle.

[0166] Validity assessment (cohort 1 only)

[0167] Clinical assessments of FFAs are conducted by experienced and qualified dermatologists (committee-certified or equivalent) or other appropriately qualified individuals. To ensure consistency and reduce variability, all assessments for a given subject are performed by the same assessor whenever possible.

[0168] Activity index of hairy lichen planus

[0169] The LPPAI was assessed during the visit. It is a quantitative measure of disease activity. The LPPAI records symptoms (itching, pain, burning), signs (erythema, perifolliculitis, and scaling), activity measures (anagen pulltest), and disease extension. These subjective and objective measures were assigned numerical values ​​to establish a disease activity score. Weights were given to symptoms (30%), signs (30%), anagen pulltest (25%), and the presence of extension (15%) to obtain the equation: LPPAI(0-10) = (itching + pain + burning) / 3 + (scalp erythema + perifolliculitis + perifolliculitis scaling) / 3 + 2.5 (pulltest) + 1.5 (extension / 2). Symptoms and signs were recorded on a 4-point scale: 0 = absent (negative), 1 = mild (+ / -), 2 = moderate (+), and 3 = severe (++,+++). The anagen-phase hair traction test (when present) is a reliable measure of localized disease activity. It involves holding 10 to 20 hairs at the scalp end of the hair shaft with the thumb, index, and middle fingers and firmly pulling them away from the scalp with a vertical force so that the fingers slide to the ends of the hairs. The result is recorded as a binary value (0 for no anagen-phase hairs and 1 for anagen-phase hairs) and also as the number of anagen-phase hairs / the total number of hairs pulled. Finally, an assessment of disease extension is given, recorded as 0 (no extension), 1 (uncertain), and 2 (extension). When hair loss is difficult to determine, the extension problem is recorded as uncertain. The detailed process for calculating the LPPAI score is provided in Table 1.

[0170] Table 1: Activity Index of Trichophyton follicle (LPPAI)

[0171] LPPAI(0-10) = (A+B+C+D+E+F) / 3 + 2.5 (tension test) + 1.5 (expansion / 2)

[0172] Scoring: 0 = negative, 1 = + / -, 2 = +, 3 = ++, +++

[0173] The results of the LPPAI test can be found in Figure 3 I saw it in the middle.

[0174] Severity score of frontal fibrotic alopecia

[0175] FFASS is assessed during the visit. This index is based on an assessment of relevant clinical features in FFA. These features include the degree of receding hairline at the forehead and temples (from 1 to 5), the degree of eyebrow loss (none, partial, or complete), the severity and extent of perifollicular erythema and hyperkeratosis, and the severity and frequency of itching and pain associated with FFA. The resulting severity score ranges from 0 to 25, with higher scores indicating greater FFA severity. The clinical features included in FFASS are divided into two categories: extent of hair loss (up to 21 points) and inflammation (up to 4 points). Table 2 provides a detailed process for calculating the FFASS score.

[0176] Table 2: Severity Scoring of Frontal Fibrous Alopecia

[0177] The delgotinib / delgotinib group in this study showed a linear improvement in changes relative to baseline in FFAS.

[0178] The results of the FFA assessment can be seen in Figure 4 .

[0179] Perifollicular erythema and scaling

[0180] During the visit, perifolliculitis and perifolliculitis were visually assessed in the selected target lesion areas. Each clinical finding (i.e., perifolliculitis and perifolliculitis) was scored using a 4-point severity scale presented in Table 3. To be eligible for this trial, subjects must have target lesion areas with a perifolliculitis score ≥ 2 and a perifolliculitis score ≥ 2 at screening and on Day 1.

[0181] Table 3: Severity Scale for Perifofollicular Erythema and Perifofollicular Scaling

[0182] Numerical Rating Scale for Itching

[0183] The severity of itching caused by FFA will be recorded using a numerical rating scale. Assessment will begin approximately 7 days before day 1 and continue daily until day 8. Thereafter, assessment will be conducted during follow-up visits, which will be done by asking subjects to assign numerical scores on a scale from 0 to 10, representing the most severe symptoms in the last 24 hours, with 0 indicating no symptoms and 10 indicating the most severe symptom imaginable.

[0184] Combustion Sensation Numerical Rating Scale

[0185] The severity of the burning sensation caused by FFA will be recorded using a digital rating scale. It will be assessed daily from approximately 7 days prior to day 1 until day 8. Thereafter, it will be assessed during follow-up visits. This will be assessed by asking subjects to assign a numerical score on a scale from 0 to 10, representing the most severe severity of their symptoms in the last 24 hours, with 0 indicating no symptoms and 10 indicating the most severe symptom imaginable.

[0186] Numerical Rating Scale for Pain

[0187] The severity of pain caused by FFA will be recorded using a numerical rating scale. It will be assessed daily from approximately 7 days prior to day 1 until day 8. Thereafter, it will be assessed during follow-up visits. This will be assessed by asking subjects to assign numerical scores on a scale from 0 to 10, representing the most severe severity of their symptoms in the last 24 hours, with 0 indicating no symptoms and 10 indicating the most severe symptom imaginable.

[0188] Hair count / trigonometry

[0189] Hair counting / trichoscopy will be performed during the visit. Trichoscopy should be performed on the target area of ​​the lesion, a few centimeters away from the skin microbiota sampling site. Hair count, hair diameter, and hair density will be measured using a fotofindertrichovision.

[0190] The results of trichoscopy can be seen in Figure 8 and Figure 9 .

[0191] Hairline measurement

[0192] Hairline measurements will be taken during the visit. Disposable paper rulers will be used to measure from the lateral canthus (right and left) to the hairline, from the glabella to the hairline, from the top of the frontalis muscle to the hairline, and from the middle of the eyebrow to the hairline (right and left).

[0193] The results can be found in Figure 5 The dashed line represents the results in the placebo / delgotinib group, and the solid line represents the results in the delgotinib / delgotinib group.

[0194] exist Figure 6A The middle value is the average of all hairline measurements, and... Figure 6B The middle line represents the average of all hairline measurements without eye measurement. The dashed line represents the results in the placebo delgotinib group, and the solid line represents the results in the delgotinib group.

[0195] At week 12, all subjects were at least stable in terms of disease compared to baseline (except for measurements from the right outer canthus to the hairline).

[0196] At week 24, all subjects achieved at least disease stabilization compared to baseline.

[0197] Biomarker measurement

[0198] FFA is a disease driven by IFN-γ. IFN-γ drives the expression of CXCL-9 and CXCL-10.

[0199] The following skin samples were collected during the trial to assess changes in molecular characteristics.

[0200] - Skin biopsies for transcriptomics and immunohistochemical analysis (n = 3): - Day 1: Two skin biopsies (4 mm) were taken before the first administration of the test drug (one from a diseased hair follicle in the target area and one from a non-disease hair follicle (e.g., on the occipital scalp).

[0201] - Week 12: One skin biopsy (4 mm) was taken from a hair follicle in the target area of ​​the lesion (outside the scar from the previous biopsy).

[0202] Changes in the expression of chemokine (CXC motif) ligand 9 (CXCL9), (CXC motif) ligand 10 (CXCL10), and interferon (IFN)-γ in skin biopsies were measured at baseline and week 12.

[0203] In the active treatment group (delgotinib / delgotinib group), at week 12, there were significant changes relative to baseline for CXC9 (p < 0.05) and CXCL-10 (p < 0.05), but no significant changes for IFN-γ.

[0204] In the placebo group (placebo / delgotinib group), there were no significant changes relative to baseline at week 12 for CXCL9, CXCL-10, and IFN-γ.

[0205] It can be concluded that the compound of formula (I) inhibits the process driven by IFN-γ.

[0206] Terms and Conditions

[0207] In view of the specification, the present invention specifically provides: Clause 1. A compound of general formula (I) (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, is used for the treatment of scarring alopecia.

[0208] Clause 2. A compound of general formula (I) (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, is used for the treatment of LPP.

[0209] Clause 3. A compound of general formula (I) (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, is used for the treatment of FFA.

[0210] Clause 4. The compound used under any of the preceding clauses, wherein the treatment is a topical treatment.

[0211] Clause 5. The compound for use under any of the preceding clauses, wherein the compound of formula (I) is applied as a cream.

[0212] Clause 6. The compound used under any of the preceding clauses, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0213] Clause 7. The compound for use under any of the preceding clauses, wherein the compound of formula (I) is applied as a twice-daily application.

[0214] Clause 8. The compound used according to any of the preceding clauses, wherein the compound of formula (I) is applied for 12 weeks.

[0215] Clause 9. Use of a compound of formula (I) in the preparation of a pharmaceutical composition for treating scarring alopecia.

[0216] Clause 10. Use of a compound of formula (I) in the preparation of a pharmaceutical composition for treating LPP.

[0217] Clause 11. Use of a compound of formula (I) in the preparation of a pharmaceutical composition for treating FFA.

[0218] Clause 12. Used in accordance with any of Clauses 9 to 11 above, wherein the treatment is a local treatment.

[0219] Clause 13. The use according to any of the preceding clauses 9-12, wherein the pharmaceutical composition is a cream.

[0220] Clause 14. The use of any of the preceding clauses 9-13, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0221] Clause 15. For any of the preceding clauses 9-14, wherein the compound of formula (I) is applied as a twice-daily application.

[0222] Clause 16. For any of the preceding clauses 9-15, wherein the compound of formula (I) is administered for 12 weeks.

[0223] Clause 17. A pharmaceutical composition for treating scarring alopecia, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof.

[0224] Clause 18. A pharmaceutical composition for treating LPP, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof.

[0225] Clause 19. A pharmaceutical composition for treating FFA, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile or a pharmaceutically acceptable salt thereof.

[0226] Clause 20. A pharmaceutical composition according to any one of Clauses 17-19 above, wherein the treatment is a topical treatment.

[0227] Clause 21. The pharmaceutical composition according to any one of Clauses 17-20 above is a cream.

[0228] Clause 22. A pharmaceutical composition according to any one of the preceding clauses 17-21, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0229] Clause 23. A pharmaceutical composition according to any one of the preceding clauses 17-22, wherein the compound of formula (I) is administered as a twice-daily application.

[0230] Clause 24. A pharmaceutical composition according to any one of Clauses 17-23 above, wherein the compound of formula (I) is administered for 12 weeks.

[0231] Clause 25. A treatment or preventative agent for scarring alopecia, comprising a compound of formula (I) as an active ingredient. (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof.

[0232] Clause 26. A therapeutic or preventative agent for LPP, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, as the active ingredient.

[0233] Clause 27. A treatment or preventative agent for FFA, comprising a compound of formula (I). (I) 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, as the active ingredient.

[0234] Clause 28. A treatment or preventive agent according to any one of Clauses 25-27 above, wherein the agent is a topical preparation.

[0235] Clause 29. A treatment or preventative agent according to any one of Clauses 25-28 above, wherein the agent is a cream.

[0236] Clause 30. A treatment or preventive agent according to any one of Clauses 25-29 above, wherein the compound of formula (I) is administered at a concentration of 20 mg / g.

[0237] Clause 31. A treatment or preventative agent according to any one of Clauses 25-30 above, wherein the compound of formula (I) is applied as a twice-daily application.

[0238] Clause 32. A treatment or preventative agent according to any one of Clauses 25-31 above, wherein the compound of formula (I) is administered for 12 weeks.

[0239] Clause 33. A method for treating scarring alopecia in a subject with such need, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) to said subject.

[0240] Clause 34. A method for treating LPP in a subject who has such need, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) to said subject.

[0241] Clause 35. A method for treating FFA in a subject who has such need, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) to said subject.

[0242] Clause 36. The method according to any one of Clauses 33-35 above, wherein the application is partial.

[0243] Clause 37. The method according to any one of Clauses 33-36 above, wherein the topical preparation is a cream.

[0244] Clause 38. The method according to any one of Clauses 33-37 above, wherein the compound of formula (I) is applied at a concentration of 20 mg / g.

[0245] Clause 39. The method according to any one of Clauses 33-38 above, wherein the compound of formula (I) is applied as a twice-daily application.

[0246] Clause 40. The method according to any one of Clauses 33-39 above, wherein the compound of formula (I) is administered for 12 weeks.

[0247] Clause 41. A method of treating frontal fibrotic alopecia (FFA) in human patients with this need, the method comprising applying a topical composition comprising delgotinib based on a free base or a pharmaceutically acceptable salt thereof.

[0248] Clause 42. The compound delgotinib or a topical composition comprising delgotinib used in a method for treating frontal fibrotic alopecia (FFA) in human patients in need of such treatment, the method comprising administering a topical composition comprising a free base-based delgotinib or a pharmaceutically acceptable salt thereof.

[0249] Clause 43. Use of the compound delgotinib in the preparation of a topical composition for the treatment of frontal fibrotic alopecia (FFA) in human patients in need, including the administration of a topical composition comprising delgotinib based on a free base or a pharmaceutically acceptable salt thereof.

[0250] Clause 44. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-43, wherein the patient has a clinically confirmed FFA.

[0251] Clause 45. The treatment method, compound or topical preparation used, or purpose of the compound according to any one of Clauses 41-44, wherein the patient has a target area with a perifollicular erythema score ≥ 2 and a perifollicular scaling score ≥ 2.

[0252] Clause 46. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-45, wherein the patient is 45 years of age or older.

[0253] Clause 47. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-46, wherein the patient is female.

[0254] Clause 48. The treatment method, compound or topical preparation used, or purpose of the compound according to any one of Clauses 41-47, wherein the patient is postmenopausal (as defined above).

[0255] Clause 49. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-48, wherein the patient has no history of other scalp / hair diseases, including discoid lupus erythematosus and central centrifugal scarring alopecia.

[0256] Clause 50. The treatment method, compound or topical preparation used, or compound used according to any of Clauses 41-49, wherein the patient achieves a reduction in the expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ relative to baseline at week 26.

[0257] Clause 51. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-49, wherein the patient achieves a reduction in the expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ relative to baseline at week 24.

[0258] Clause 52. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-49, wherein the patient achieves a reduction in the expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ relative to baseline at week 12.

[0259] Clause 53. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-49, wherein the patient achieves a reduction in the expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ relative to baseline at week 8.

[0260] Clause 54. The treatment method, compound or topical preparation used, or compound used according to any of Clauses 41-49, wherein the patient achieves a reduction in the expression of one or more of the biomarkers CXCL9, CXCL10, and / or IFN-γ relative to baseline at week 4.

[0261] Clause 55. The patient achieves an improvement in LPPAI score relative to baseline at week 26, based on any of the treatments, compounds or topical preparations, or uses of compounds described in Clauses 41-54.

[0262] Clause 56. The patient achieves an improvement in LPPAI score relative to baseline at week 24, based on any of the treatments, compounds or topical preparations, or uses of compounds described in Clauses 41-54.

[0263] Clause 57. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-54, wherein the patient achieves an improvement in LPPAI score relative to baseline at week 12.

[0264] Clause 58. The patient achieves an improvement in LPPAI score relative to baseline at week 8, pursuant to any of the treatments, compounds or topical preparations used, or the purpose of the compound as described in Clauses 41-54.

[0265] Clause 59. Treatment, use of a compound or topical preparation, or application of a compound according to any of Clauses 41-54, wherein the patient achieves an improvement in LPPAI score relative to baseline at week 4.

[0266] Clause 60. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-59, wherein the patient achieves an improvement in FFASS score relative to baseline at week 26.

[0267] Clause 61. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-59, wherein the patient achieves an improvement in FFASS score relative to baseline at week 24.

[0268] Clause 62. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-59, wherein the patient achieves an improvement in FFASS score relative to baseline at week 12.

[0269] Clause 63. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-59, wherein the patient achieves an improvement in FFASS score relative to baseline at week 8.

[0270] Clause 64. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-59, wherein the patient achieves an improvement in FFASS score relative to baseline at week 4.

[0271] Clause 65. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-64, wherein the patient achieves improvement in the target area perifollic erythema score relative to baseline at week 26.

[0272] Clause 66. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-64, wherein the patient achieves improvement in the target area perifollic erythema score relative to baseline at week 24.

[0273] Clause 67. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-64, wherein the patient achieves improvement in the target area perifollic erythema score relative to baseline at week 12.

[0274] Clause 68. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-64, wherein the patient achieves improvement in the target area perifollic erythema score relative to baseline at week 8.

[0275] Clause 69. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-64, wherein the patient achieves improvement in the target area perifollic erythema score relative to baseline at week 4.

[0276] Clause 70. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-69, wherein the patient achieves improvement in perifollicular scaling in the target area relative to baseline at week 26.

[0277] Clause 71. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-69, wherein the patient achieves an improvement in the target area perifollicular scaling score relative to baseline at week 24.

[0278] Clause 72. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-69, wherein the patient achieves an improvement in the target area perifollicular scaling score relative to baseline at week 12.

[0279] Clause 73. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-69, wherein the patient achieves an improvement in the target area perifollicular scaling score relative to baseline at week 8.

[0280] Clause 74. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-69, wherein the patient achieves an improvement in the target area perifollicular scaling score relative to baseline at week 4.

[0281] Clause 75. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-74, wherein the patient achieves a reduction in the NRS score of pruritus relative to baseline at week 26.

[0282] Clause 76. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the NRS score of pruritus relative to baseline at week 24.

[0283] Clause 77. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the NRS score of pruritus relative to baseline at week 12.

[0284] Clause 78. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the NRS score of pruritus relative to baseline at week 8.

[0285] Clause 79. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the NRS score of pruritus relative to baseline at week 4.

[0286] Clause 80. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the pruritus NRS score relative to baseline on day 8.

[0287] Clause 81. A treatment method, compound or topical preparation, or use of a compound according to any of Clauses 41-74, wherein the patient achieves a reduction in the pruritus NRS score relative to baseline on day 7.

[0288] Clause 82. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-74, wherein the patient achieves a reduction in the pruritus NRS score relative to baseline on day 6.

[0289] Clause 83. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the pruritus NRS score relative to baseline on day 5.

[0290] Clause 84. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-74, wherein the patient achieves a reduction in the pruritus NRS score relative to baseline on day 4.

[0291] Clause 85. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-74, wherein the patient achieves a reduction in the pruritus NRS score relative to baseline on day 3.

[0292] Clause 86. A treatment method, compound or topical preparation, or use of a compound according to any of Clauses 41-74, wherein the patient achieves a reduction in the NRS score of pruritus relative to baseline on day 2.

[0293] Clause 87. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline at week 26.

[0294] Clause 88. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline at week 24.

[0295] Clause 89. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline at week 12.

[0296] Clause 90. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline at week 8.

[0297] Clause 91. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline at week 4.

[0298] Clause 92. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 8.

[0299] Clause 93. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 7.

[0300] Clause 94. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 6.

[0301] Clause 95. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 5.

[0302] Clause 96. A treatment method, compound or topical preparation, or use of a compound according to any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 4.

[0303] Clause 97. A treatment method, compound or topical preparation, or use of a compound according to any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 3.

[0304] Clause 98. A treatment method, compound or topical preparation, or use of a compound according to any of Clauses 41-86, wherein the patient achieves a reduction in the burning NRS score relative to baseline on day 2.

[0305] Clause 99. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in pain NRS score relative to baseline at week 26.

[0306] Clause 100. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in pain NRS score relative to baseline at week 24.

[0307] Clause 101. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline at week 12.

[0308] Clause 102. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in pain NRS score relative to baseline at week 8.

[0309] Clause 103. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in pain NRS score relative to baseline at week 4.

[0310] Clause 104. The treatment method, compound or topical preparation used, or use of a compound according to any of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 8.

[0311] Clause 105. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 7.

[0312] Clause 106. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 6.

[0313] Clause 107. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 5.

[0314] Clause 108. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 4.

[0315] Clause 109. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 3.

[0316] Clause 110. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-98, wherein the patient achieves a reduction in the pain NRS score relative to baseline on day 2.

[0317] Clause 111. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points at week 26.

[0318] Clause 112. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points at week 24.

[0319] Clause 113. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points at week 12.

[0320] Clause 114. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points at week 8.

[0321] Clause 115. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points at week 4.

[0322] Clause 116. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 8.

[0323] Clause 117. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 7.

[0324] Clause 118. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 6.

[0325] Clause 119. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 5.

[0326] Clause 120. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 4.

[0327] Clause 121. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 3.

[0328] Clause 122. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-110, wherein the patient has a baseline pruritus NRS score of ≥ 3 and achieves a pruritus NRS score reduction of 3 points on day 2.

[0329] Clause 123. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points at week 26.

[0330] Clause 124. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points at week 24.

[0331] Clause 125. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points at week 12.

[0332] Clause 126. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points at week 8.

[0333] Clause 127. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points at week 4.

[0334] Clause 128. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 8.

[0335] Clause 129. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 7.

[0336] Clause 130. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 6.

[0337] Clause 131. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 5.

[0338] Clause 132. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 4.

[0339] Clause 133. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 4.

[0340] Clause 134. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-122, wherein the patient has a baseline pruritus NRS score of ≥ 4 and achieves a pruritus NRS score reduction of 4 points on day 2.

[0341] Clause 135. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score at week 26.

[0342] Clause 136. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score at week 24.

[0343] Clause 137. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score at week 12.

[0344] Clause 138. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score at week 8.

[0345] Clause 139. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score at week 4.

[0346] Clause 140. The treatment method, compound or topical preparation used, or purpose of the compound used in any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 8.

[0347] Clause 141. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 7.

[0348] Clause 142. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 6.

[0349] Clause 143. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 5.

[0350] Clause 144. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 4.

[0351] Clause 145. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 3.

[0352] Clause 146. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 3 and achieves a reduction of 3 points in the burning NRS score on day 2.

[0353] Clause 147. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a burning NRS score reduction of 4 points at week 26.

[0354] Clause 148. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score at week 24.

[0355] Clause 149. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a burning NRS score reduction of 4 points at week 12.

[0356] Clause 150. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a burning NRS score reduction of 4 points at week 8.

[0357] Clause 151. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score at week 4.

[0358] Clause 152. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 8.

[0359] Clause 153. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 7.

[0360] Clause 154. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 6.

[0361] Clause 155. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 5.

[0362] Clause 156. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 4.

[0363] Clause 157. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-146, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 3.

[0364] Clause 158. The treatment method, compound or topical preparation or use of a compound according to any of Clauses 41-134, wherein the patient has a baseline burning NRS score of ≥ 4 and achieves a reduction of 4 points in the burning NRS score on day 2.

[0365] Clause 159. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points at week 26.

[0366] Clause 160. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points at week 24.

[0367] Clause 161. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points at week 12.

[0368] Clause 162. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points at week 8.

[0369] Clause 163. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points at week 4.

[0370] Clause 164. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 8.

[0371] Clause 165. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 7.

[0372] Clause 166. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 6.

[0373] Clause 167. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 5.

[0374] Clause 168. A treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 4.

[0375] Clause 169. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 3.

[0376] Clause 170. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-158, wherein the patient has a baseline pain NRS score of ≥ 3 and achieves a pain NRS score reduction of 3 points on day 2.

[0377] Clause 171. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points at week 26.

[0378] Clause 172. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points at week 24.

[0379] Clause 173. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points at week 12.

[0380] Clause 174. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points at week 8.

[0381] Clause 175. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points at week 4.

[0382] Clause 176. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 8.

[0383] Clause 177. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 7.

[0384] Clause 178. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 6.

[0385] Clause 179. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 5.

[0386] Clause 180. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 4.

[0387] Clause 181. A treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 3.

[0388] Clause 182. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 2.

[0389] Clause 182. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-170, wherein the patient has a baseline pain NRS score of ≥ 4 and achieves a pain NRS score reduction of 4 points on day 2.

[0390] Clause 183. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-182, wherein the patient achieves improvement in target area hair counting / trichomoning from baseline to week 26 via fotofinder trichomoning.

[0391] Clause 184. The treatment method, compound or topical preparation or use of a compound according to any one of Clauses 41-182, wherein the patient achieves improvement from baseline to week 24 via target area hair counting / trichoscopy via fotofinder trichovision.

[0392] Clause 185. The treatment, compound or topical preparation or use of any of Clauses 41-182, wherein the patient achieves improvement from baseline to week 12 via target area hair counting / trichoscopy via fotofinder trichovision.

[0393] Clause 186. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-185, wherein the patient achieves an improvement in hairline measurement from baseline to week 4.

[0394] Clause 187. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-185, wherein the patient achieves an improvement in hairline measurement from baseline to week 8.

[0395] Clause 188. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-185, wherein the patient achieves an improvement in hairline measurement from baseline to week 12.

[0396] Clause 189. A treatment method, compound or topical preparation, or use of a compound according to any one of Clauses 41-185, wherein the patient achieves an improvement in hairline measurement from baseline to week 24.

[0397] Clause 190. The treatment method, compound or topical preparation used, or use of a compound according to any one of Clauses 41-185, wherein the patient achieves an improvement in hairline measurement from baseline to week 26.

[0398] Clause 191. The treatment method, the use of a compound or topical preparation, or the application of a compound under any of Clauses 41-190, wherein the compound or topical preparation is applied twice daily.

[0399] Clause 192. The treatment method, the use of a compound or topical preparation or the application of a compound under any of Clauses 41-190, wherein the topical preparation is administered twice daily and the topical composition comprises 20 mg / g of delgotinib based on a free base or a pharmaceutically acceptable salt thereof.

[0400] Clause 193. A treatment method, a compound or topical preparation used, or the use of a compound under any of Clauses 41-192, wherein the topical composition is a water-in-oil emulsion.

[0401] Clause 194. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 41-192, wherein the topical composition is an acidified water-in-oil emulsion.

[0402] Clause 195. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 41-192, wherein the pH of the topical composition is between about 3.8 and 4.6.

[0403] Clause 196. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 41-192, wherein the pH of the topical composition is about 4.4 or lower.

[0404] Clause 197. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 41-192, wherein the pH of the topical composition is about 4.3 or lower.

[0405] Clause 198. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 41-192, wherein the pH of the topical composition is about 4.2 or lower.

[0406] Clause 199. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 188-198, wherein the topical composition comprises an oily matrix.

[0407] Clause 200. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 188-199, wherein the topical composition comprises an oily matrix and the oily matrix is ​​liquid paraffin.

[0408] Article 201. A treatment method, a compound or topical preparation used, or a use of a compound under any of Articles 41-200, wherein the treatment method is a preventive treatment, the compound or topical preparation used is for preventive use, or the use of a compound is for preventive use.

[0409] Clause 202. A compound used in accordance with any one of Clauses 5, 13, 21, 29 and 37 above, wherein the compound of formula (I) is applied as a cream, wherein the pH of the cream is between about 3.8 and 4.6.

[0410] Clause 203. A compound used in accordance with any one of Clauses 5, 13, 21, 29 and 37 above, wherein the compound of formula (I) is applied as a cream, wherein the pH of the cream is about 4.4 or lower.

[0411] Clause 204. A compound used in accordance with any one of Clauses 5, 13, 21, 29 and 37 above, wherein the compound of formula (I) is applied as a cream, wherein the pH of the cream is about 4.3 or lower.

[0412] Clause 205. A compound used in accordance with any one of Clauses 5, 13, 21, 29 and 37 above, wherein the compound of formula (I) is applied as a cream, wherein the pH of the cream is about 4.2 or lower.

[0413] Clause 206. The compound used under any of the preceding clauses 202-205, wherein the cream composition comprises an oily base.

[0414] Clause 207. The compound used under any of Clause 206 above, wherein the cream composition comprises an oily base, and the oily base is liquid paraffin.

[0415] Clause 208. A treatment method, a compound or topical preparation used, or an application of a compound under any of Clauses 41-207, wherein the topical composition is an acidified topical composition comprising: Compound of formula (I) at 20 mg / g, 80-120 mg / g matrix (e.g., selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof). Emulsifiers, surfactants, and / or stabilizers of 60-110 mg / g, Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

[0416] Clause 209. A treatment method, a compound or topical preparation used, or an application of a compound under any of Clauses 41-207, wherein the topical composition is an acidified topical composition comprising: Compound of formula (I) at 20 mg / g, A matrix of 80-120 mg / g (e.g., selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof). 40-140 mg / g of emulsifiers, surfactants, and / or stabilizers. Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

[0417] Clause 210. A treatment method, a compound or topical preparation used, or an application of a compound under any of Clauses 41-207, wherein the topical composition is an acidified topical composition comprising: Compound of formula (I) at 20 mg / g, A matrix of 80-120 mg / g (e.g., selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof). 50-90 mg / g of cetearyl alcohol, 13-22 mg / g of macrogol stearyl ether. Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

[0418] Clause 211. A treatment method, a compound or topical preparation used, or an application of a compound under any of Clauses 41-207, wherein the topical composition is an acidified topical composition comprising: Compound of formula (I) at 20 mg / g, A matrix of 70-130 mg / g (e.g., selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof). Cetearyl alcohol, 30-110 mg / g 8-26 mg / g of polyethylene glycol stearyl ether Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

[0419] Clause 212. A treatment method, a compound or topical preparation used, or the use of a compound under any of Clauses 208-211, wherein the topical composition is an acidifying topical composition comprising a buffer selected from phosphate, citrate, acetate, and / or carbonate buffers.

[0420] Clause 213. A treatment method, a compound or topical preparation used, or a use of a compound under any of Clauses 208-212, wherein the topical composition is an acidified topical composition comprising a preservative selected from benzyl alcohol, sodium dihydroacetate, sorbic acid / salt, and / or mixtures thereof.

[0421] Clause 214. A treatment method, a compound or topical preparation used, or a use of a compound under any of Clauses 208-213, wherein the topical composition is an acidified topical composition comprising an antioxidant selected from the group consisting of sodium sulfite, disodium EDTA, trisodium EDTA, butylated hydroxyanisole, and / or mixtures thereof.

[0422] Clause 215. A treatment method, a compound or topical preparation, or the use of a compound under any of Clauses 208-214, wherein the topical composition is an acidified topical composition comprising a chelating agent selected from: EDTA, disodium ethylenediaminetetraacetate, EGTA, and / or ethylenediamine.

[0423] Clause 216. A treatment method, a compound or topical preparation used, or the use of a compound under any of Clauses 208-211, wherein the topical composition is an acidifying topical composition comprising an acidifier selected from one or more strong acids (e.g., hydrochloric acid or citric acid).

Claims

1. A compound of general formula (I) （I）， 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, is used for the treatment of LPP.

2. The compound for use according to claim 1, wherein, The treatment is for FFA.

3. The compound for use according to any one of the preceding claims, wherein, The compound of formula (I) or its pharmaceutically acceptable salt may be applied as an aqueous acidified cream.

4. The compound for use according to any one of the preceding claims, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is administered at a concentration of 20 mg / g.

5. The compound for use according to claim 3, wherein, Acidified water-based creams contain: Compound of formula (I) at 20 mg / g, 80-120 mg / g matrix, Emulsifiers, surfactants, and / or stabilizers of 60-110 mg / g, Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

6. The compound for use according to claim 5, wherein, The acidified aqueous cream comprises: Compound of formula (I) at 20 mg / g, 80-120 mg / g matrix, 40-140 mg / g of emulsifiers, surfactants, and / or stabilizers. Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

7. The compound for use according to claim 5, wherein, The acidified aqueous cream comprises: Compound of formula (I) at 20 mg / g, 80-120 mg / g matrix, 50-90 mg / g of cetearyl alcohol, 13-22 mg / g of polyethylene glycol stearyl ether, Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

8. The compound for use according to claim 7, wherein, The acidified aqueous cream comprises: Compound of formula (I) at 20 mg / g, 70-130 mg / g matrix, Cetearyl alcohol, 30-110 mg / g 8-26 mg / g of polyethylene glycol stearyl ether Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

9. A pharmaceutical composition for use in the treatment of LPP, said pharmaceutical composition comprising a compound of formula (I). （I） 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]oct-1-yl]-3-oxopropionitrile, or a pharmaceutically acceptable salt thereof, is used as the active ingredient.

10. The pharmaceutical composition for use according to claim 10, wherein, The treatment is for FFA.

11. The pharmaceutical composition for use in treatment according to any one of claims 9-10, wherein, The pharmaceutical composition is an acidified aqueous cream.

12. The pharmaceutical composition for use in treatment according to any one of claims 9-117, wherein, The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a concentration of 20 mg / g.

13. The pharmaceutical composition according to claim 11, wherein, The acidified aqueous cream comprises: 20 mg / g of the compound of formula (I), 80-120 mg / g matrix, Emulsifiers, surfactants, and / or stabilizers of 60-110 mg / g, Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

14. The pharmaceutical composition according to claim 13, wherein, The acidified aqueous cream comprises: 20 mg / g of the compound of formula (I), 80-120 mg / g matrix, 40-140 mg / g of emulsifiers, surfactants, and / or stabilizers. Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

15. The pharmaceutical composition according to claim 13, wherein, The acidified aqueous cream comprises: 20 mg / g of the compound of formula (I), 80-120 mg / g matrix, 50-90 mg / g of cetearyl alcohol, 13-22 mg / g of polyethylene glycol stearyl ether, Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

16. The compound for use according to claim 15, wherein, The acidified aqueous cream comprises: 20 mg / g of the compound of formula (I), 70-130 mg / g matrix, Cetearyl alcohol, 30-110 mg / g 8-26 mg / g of polyethylene glycol stearyl ether Buffer, preservative, Antioxidants Chelating agents Water (to 1 g) and acidifier.

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