Sjögren's syndrome treatment

Abstract

To provide a new treatment for Sjögren's syndrome. [Solution] A Sjögren's syndrome treatment agent containing 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropannitrile or a salt thereof.

Description

Technical Field

[0005] ,

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

Background Art

[0002] Sjogren's syndrome is a disease of unknown cause that occurs due to chronic inflammation in exocrine glands such as the lacrimal gland and salivary gland, and presents dry symptoms in mucous membranes such as in the eyes and mouth. However, the treatment of Sjogren's syndrome is still mainly symptomatic treatment aimed at improving dry symptoms, and the creation of a fundamental treatment method is desired (Non-Patent Document 1).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the present invention is to provide a new therapeutic agent for Sjogren's syndrome. [[ID=​​​​The present inventors conducted diligent research to solve the above problems and found that 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropannitrile (generic name: delgocitinib), one of the compounds that has Janus kinase (JAK) inhibitory activity, suppresses the infiltration of CD4-positive cells (see Non-Patent Literature 1), which is considered to be the main finding of Sjögren's syndrome. The present invention is based on this finding and provides the following inventions.

[0006] [1] A treatment for Sjögren's syndrome containing 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropannitrile or a salt thereof. [2] A method of treating Sjögren's syndrome, involving the administration of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropannitrile or a salt thereof. [3] Use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof for the manufacture of a treatment for Sjögren's syndrome. [4] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropannitrile or a salt thereof, for use in the treatment of Sjögren's syndrome. [Effects of the Invention]

[0007] According to the present invention, a novel therapeutic agent for Sjögren's syndrome can be provided. [Brief explanation of the drawing]

[0008] [Figure 1] This graph in Test Example 1 shows the inhibitory effect of repeated eye drop administration of delgocitinib on the infiltration of CD4-positive cells in the conjunctiva using CAE model mice. [Figure 2] This graph in Test Example 2 shows the inhibitory effect of repeated administration of delgocitinib as eye drops on the infiltration of CD4-positive cells in the conjunctiva using a D-LGE model rat. [Modes for carrying out the invention]

[0009] The embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[0010] The Sjögren's syndrome treatment agent 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]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropannitrile or a salt thereof.

[0011] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3,4]octan-1-yl]-3-oxopropannitrile (generic name: delgocitinib) is represented by the following formula: [ka] The compound is represented by (hereinafter, this compound is also referred to as "delgocitinib"). Delgocitinib or its salts can be produced by methods described in, for example, International Publication No. 2017 / 006968 and International Publication No. 2018 / 117151.

[0012] The salts of delgocitinib are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), 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, and salts with basic amino acids.

[0013] Salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts with organic acids include, for example, 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, and p-toluenesulfonic acid. Salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts. Salts with organic bases include, for example, salts with diethylamine, diethanolamine, meglumine, and N,N-dibenzylethylenediamine. Salts with acidic amino acids include, for example, salts with aspartic acid and glutamic acid. Salts with basic amino acids include, for example, salts with arginine, lysine, and ornithine.

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

[0015] The content of delgocitinib or its salt in the agent according to this embodiment is not particularly limited and is appropriately set according to the types and contents of other formulation components, the formulation form, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of delgocitinib or its salt is, 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. Also, from the viewpoint of more significantly exhibiting the effects of the present invention, the content of delgocitinib or its salt is, 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] In addition to delgocitinib or its salt, the agent according to this embodiment may contain excipients, lubricants, binders, disintegrants, coating agents, stabilizers, isotonic agents, buffers, pH adjusters, solubilizers, thickeners, preservatives, antioxidants, sweeteners, colorants, fragrances, etc.

[0017] Examples of the formulation form of the agent according to this embodiment include oral administration formulations such as tablets, capsules, granules, and powders; parenteral administration formulations such as injections, eye drops, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, patches, inhalants, and transdermal absorption preparations. The said formulation can be appropriately prepared according to the purpose by a known method described in, for example, the General Rules for Formulations of the 17th Revised Japanese Pharmacopoeia.

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

[0019] When the agent according to this embodiment is an eye drop, its usage and dosage are not particularly limited as long as they exhibit an effect and have few side effects. For example, in the case of adults (15 years old and above) and children 7 years old and above, 1 drop, 2 drops, 3 drops, 1 - 2 drops, 1 - 3 drops, or 2 - 3 drops can be instilled into the eyes once, twice, three times, four times, five times, six times, 1 - 2 times, 2 - 3 times, 3 - 4 times, 4 - 5 times, or 5 - 6 times a day.

[0020] As one embodiment of the present invention, a method for treating Sjögren's syndrome by administering dergositinib or a salt thereof is provided. Also, as another embodiment of the present invention, the use of dergositinib or a salt thereof for the production of a therapeutic agent for Sjögren's syndrome is provided. Further, as another embodiment of the present invention, dergositinib or a salt thereof for use in the treatment of Sjögren's syndrome is provided.

Example

[0021] Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited thereto. In the following test examples, unless otherwise specified, the unit “%” of the content means “w / v%” and is synonymous with “g / 100 mL”.

[0022] 〔Test Example 1: Inhibitory effect of repeated topical administration of dergositinib on infiltration of CD4 - positive cells in the conjunctiva using CAE - model mice〕 Controlled Adverse Environment (CAE) model mice have been reported to exhibit some phenotypes of Sjögren's syndrome, such as infiltration of CD4-positive cells into the conjunctiva (J.Immunol.,2006;176:3950-3957). Using this model mouse, we evaluated the inhibitory effect of delgocitinib on CD4-positive cell infiltration in the conjunctiva. Delgocitinib was dissolved in borate buffer to prepare a 0.03% delgocitinib eye drop solution. Additionally, scopolamine hydrobromide trihydrate (Tokyo Chemical Industries, Ltd.) was dissolved in PBS (Kojin Bio Inc.) to prepare a 0.167% scopolamine administration solution. CAE model mice were created by subcutaneously administering scopolamine solution to female C57BL / 6J mice (Nippon SLC Co., Ltd.) for 7 days while rearing them under low humidity and ventilation conditions. During these 7 days, the mice were repeatedly instilled with either a base (borate buffer) or delgocitinib 0.03% eye drops four times a day at a dose of 3 μL / eye. Subsequently, eyeballs were collected from each mouse and embedded in OCT compound (Sakura FineTech Japan Co., Ltd.). Frozen sections were prepared, and immunostaining was performed using anti-mouse CD4 antibody (Becton Dickinson Corporation) and Simple Stain Mouse MAX-PRO (Nichirei Corporation). Bright-field imaging of the upper and lower eyelid tissues was performed on the prepared immunostained slides using a microscope (Keyence Corporation). The total number of stained cells present in the lamina propria of the conjunctiva of each upper and lower eyelid was measured, and this total number was taken as the number of CD4-positive cell infiltrations per eye. The results are shown in Figure 1.

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

[0024] [Test Example 2: Inhibitory effect of repeated administration of delgocitinib eye drops on conjunctival CD4-positive cell infiltration in bilateral lacrimal gland excision (D-LGE) model rats] The dilatation-long epigastric gland (D-LGE) model has been reported to exhibit ocular surface phenotypes similar to those of the Sjögren's syndrome group (Sci.Rep.,2018;8:1483). Based on this literature, a D-LGE model was created using rats, and the inhibitory effect of delgocitinib on conjunctival CD4-positive cell infiltration was evaluated. Delgocitinib was dissolved in borate buffer to prepare a 0.3% delgocitinib ophthalmic solution. D-LGE model rats were created by excising the intraorbital and extraorbital lacrimal glands from male SD rats. These D-LGE model rats were repeatedly administered either a base (borate buffer) or 0.3% delgocitinib eye drops four times a day at a dose of 5 μL / eye for 7 days. Subsequently, eyeballs were collected from each rat and embedded in OCT compound (Sakura FineTech Japan Co., Ltd.). Frozen sections were prepared, and immunostaining was performed using anti-rat CD4 antibody (Becton Dickinson Corporation) and Simple Stain Rat MAX-PRO (Nichirei Corporation). Bright-field imaging of the upper eyelid tissue was performed on the prepared immunostained slides using a microscope (Keyence Corporation). The total number of stained cells present in the lamina propria of the conjunctiva was measured from the obtained images and expressed as the number of CD4-positive cell infiltrations per eye. The results are shown in Figure 2.

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

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

Claims

[Claim 1] The invention described in the specification.

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