Sjögren's syndrome treatment

Abstract

To provide a new treatment agent for Sjogren's syndrome.SOLUTION: A treatment agent for Sjogren's syndrome contains 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octane-1-yl]-3-oxopropanenitrile or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a therapeutic agent for Sjogren's syndrome. [Background technology]

[0002] Sjögren's syndrome is a disease of unknown cause that occurs due to chronic inflammation in exocrine glands such as the lacrimal glands and salivary glands, and causes dryness in mucous membranes such as the inside of the eyes and mouth. However, treatment for Sjögren's syndrome is still centered on symptomatic treatment aimed at alleviating the dryness symptoms, and the development of a fundamental treatment is desired (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] MSD MANUAL Professional Version, Sjogren Syndrome, February 2020, https: / / www.msdmanuals.com / en-jp / professional / musculoskeletal-and-connective-tissue-disorders / autoimmune-rheumatic-disorders / sj%c3%b6gren-syndrome Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a novel therapeutic agent for Sjogren's syndrome. [Means for solving the problem]

[0005] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: delgocitinib), a compound having Janus kinase (JAK) inhibitory activity, suppresses the infiltration of CD4-positive cells, which is considered to be a major symptom of Sjögren's disease (see Non-Patent Document 1). The present invention is based on this finding and provides the following inventions.

[0006] [1] A therapeutic agent for Sjogren's syndrome, comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof. [2] A method for treating Sjogren's syndrome, which comprises administering 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof to a subject. [3] 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 or a salt thereof for the manufacture of a therapeutic agent for Sjogren's syndrome. [4] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof for use in the treatment of Sjogren's syndrome. [Effects of the Invention]

[0007] According to the present invention, a new therapeutic agent for Sjogren's syndrome can be provided. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is a graph showing the inhibitory effect of repeated instillation of delgocitinib on the infiltration of CD4-positive cells into the conjunctiva in CAE model mice in Test Example 1. [Figure 2] 1 is a graph showing the inhibitory effect of repeated instillation of delgocitinib on the infiltration of CD4-positive cells into the conjunctiva in D-LGE model rats in Test Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0009] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0010] The therapeutic agent for Sjogren's syndrome according to this embodiment (hereinafter also referred to as "the agent according to this embodiment") contains 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof.

[0011] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: delgocitinib) has the following formula: [ka] (Hereinafter, this compound will also be referred to as "delgocitinib"). Delgocitinib or a salt thereof can be produced by, for example, the methods described in WO 2017 / 006968 and WO 2018 / 117151.

[0012] The salt of delgocitinib is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, etc.

[0013] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt, etc. Examples of salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.

[0014] The agent according to this embodiment can be used to treat Sjogren's syndrome, more specifically to improve various symptoms (dry eyes, dry mouth, etc.) caused by Sjogren's syndrome.

[0015] The content of delgocitinib or a salt thereof in the agent according to this embodiment is not particularly limited and is set appropriately depending on the type and content of other compounded ingredients, the formulation, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of delgocitinib or a salt thereof may be, for example, 0.001% by mass to 10% by mass, 0.001% by mass to 5% by mass, 0.003% by mass to 3% by mass, 0.005% by mass to 1% by mass, 0.01% by mass to 0.5% by mass, 0.015% by mass to 0.4% by mass, 0.02% by mass to 0.3% by mass, or 0.03% by mass to 0.3% by mass, based on the total amount of the agent according to this embodiment. Furthermore, from the viewpoint of more significantly exhibiting the effects of the present invention, the content of delgocitinib or a salt thereof may be, for example, 0.001 w / v% to 10 w / v%, 0.001 w / v% to 5 w / v%, 0.003 w / v% to 3 w / v%, 0.005 w / v% to 1 w / v%, 0.01 w / v% to 0.5 w / v%, 0.015 w / v% to 0.4 w / v%, 0.02 w / v% to 0.3 w / v%, or 0.03 w / v% to 0.3 w / v%, based on the total amount of the agent according to this embodiment.

[0016] The agent according to this embodiment may contain, in addition to delgocitinib or a salt thereof, excipients, lubricants, binders, disintegrants, coating agents, stabilizers, isotonicity agents, buffers, pH adjusters, solubilizers, thickeners, preservatives, antioxidants, sweeteners, colorants, flavors, etc.

[0017] Examples of the dosage form of the agent according to this embodiment include oral administration preparations such as tablets, capsules, granules, and powders, and parenteral administration preparations such as injections, eye drops, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, patches, inhalants, and transdermal preparations. Such preparations can be prepared appropriately according to the purpose by known methods described, for example, in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition.

[0018] The dosage of the agent according to this embodiment is determined appropriately depending on the route of administration, the age and sex of the patient, the severity of symptoms, etc. For example, when administered to an adult (body weight approximately 60 kg), delgocitinib or a salt thereof can be administered at a dose of 10 μg to 200 mg, preferably 30 μg to 100 mg, more preferably 50 μg to 75 mg per day, once a day or in divided doses several times a day.

[0019] When the agent according to the present embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and have few side effects. For example, for adults (15 years of age or older) and children 7 years of age or older, examples of dosage and administration methods include instilling 1 drop, 2 drops, 3 drops, 1 to 2 drops, 1 to 3 drops, or 2 to 3 drops at a time, once, twice, 3 times, 4 times, 5 times, 6 times, 1 to 2 times, 2 to 3 times, 3 to 4 times, 4 to 5 times, or 5 to 6 times a day.

[0020] As one embodiment of the present invention, there is provided a method for treating Sjogren's syndrome, which comprises administering delgocitinib or a salt thereof to a subject. As another embodiment of the present invention, there is provided a use of delgocitinib or a salt thereof for the manufacture of a therapeutic agent for Sjogren's syndrome. As another embodiment of the present invention, there is provided delgocitinib or a salt thereof for use in the treatment of Sjogren's syndrome. [Example]

[0021] The present invention will be specifically explained below based on test examples, but the present invention is not limited to these. In the test examples below, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100 mL."

[0022] [Test Example 1: Inhibitory effect of repeated instillation of delgocitinib on infiltration of CD4-positive cells into the conjunctiva using CAE model mice] Controlled Adverse Environment (CAE) model mice have been reported to exhibit some of the phenotypes of Sjögren's disease, including infiltration of CD4+ cells into the conjunctiva (J.Immunol., 2006;176:3950-3957). Using this model mouse, we evaluated the inhibitory effect of delgocitinib on conjunctival CD4+ cell infiltration. Delgocitinib was dissolved in borate buffer to prepare a 0.03% delgocitinib ophthalmic solution, and scopolamine hydrobromide trihydrate (Tokyo Chemical Industry Co., Ltd.) was dissolved in PBS (Kohjin Bio Co., Ltd.) to prepare a 0.167% scopolamine solution. Female C57BL / 6J mice (Japan SLC, Inc.) were raised under low humidity and ventilation conditions and subcutaneously administered scopolamine for 7 days to generate CAE model mice. During these 7 days, vehicle (borate buffer) or 0.03% delgocitinib ophthalmic solution was instilled into the eyes at a dose of 3 μL / eye four times daily. The eyeballs from each mouse were then harvested and embedded in OCT compound (Sakura Finetech Japan Co., Ltd.). Frozen sections were prepared and immunostained using anti-mouse CD4 antibody (Becton Dickinson Co., Ltd.) and Simple Stain Mouse MAX-PRO (Nichirei Corporation). Bright-field images of the upper and lower eyelid tissues were taken using a microscope (Keyence Corporation). The total number of stained cells present in the lamina propria of each upper and lower eyelid was counted in the obtained images, and this total was used to calculate the number of CD4-positive cell infiltration per eye. The results are shown in Figure 1.

[0023] As shown in Figure 1, compared with untreated mice, the number of CD4-positive cells in the conjunctiva of CAE model mice administered with the vehicle was significantly increased, whereas the increase in the number of CD4-positive cells in the conjunctiva of CAE model mice administered with 0.03% delgocitinib ophthalmic solution was significantly suppressed (Student T-test).

[0024] [Test Example 2: Inhibitory effect of repeated instillation of delgocitinib on infiltration of CD4-positive cells into the conjunctiva in a rat model with bilateral lacrimal gland excision (D-LGE)] The bilateral lacrimal gland excision (D-LGE) model has been reported to exhibit an ocular surface phenotype similar to that of Sjögren's syndrome (Sci. Rep., 2018;8:1483). Based on this literature, we created a D-LGE model using rats and evaluated the inhibitory effect of delgocitinib on conjunctival CD4+ cell infiltration. Delgocitinib was dissolved in borate buffer to prepare a 0.3% delgocitinib ophthalmic solution. D-LGE model rats were prepared by removing the intraorbital and extraorbital lacrimal glands from male SD rats. Vehicle (borate buffer) or 0.3% delgocitinib ophthalmic solution was administered to the rats at a dose of 5 μL / eye four times daily for 7 days. The eyeballs of each rat were then harvested and embedded in OCT compound (Sakura Finetech Japan Co., Ltd.). Frozen sections were prepared and immunostained using anti-rat CD4 antibody (Becton Dickinson Co., Ltd.) and Simple Stain Rat MAX-PRO (Nichirei Corporation). Bright-field images of the upper eyelid tissue were taken using a microscope (Keyence Corporation). The total number of stained cells present in the conjunctival lamina propria was counted in the obtained images, and this was defined as the number of CD4-positive cell infiltrations per eye. The results are shown in Figure 2.

[0025] As shown in Figure 2, compared with rats that underwent sham surgery (Sham group), the number of CD4-positive cells in the conjunctiva of D-LGE model rats administered with vehicle was significantly increased, whereas the increase in the number of CD4-positive cells in the conjunctiva of D-LGE model rats administered with delgocitinib 0.3% ophthalmic solution was significantly suppressed (Student T-test).

[0026] These results suggest that delgocitinib is effective in treating Sjögren's syndrome.

Claims

[Claim 1] A therapeutic agent for Sjogren's syndrome, comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof.

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