TW201542207A - Therapeutic agent for severe asthma - Google Patents

Abstract

An object of the present invention is to provide a pharmaceutical composition that is effective for treating severe asthma. The present invention relates to a medicament for treating severe asthma.

Description

Severe asthma treatment Field of invention

The present invention relates to a severe asthma therapeutic agent.

Background of the invention

There are about 300 million people in the world, and 250,000 of them die every year. The prevalence rate is now increasing. Therefore, it is considered to be a health problem on the scale of the earth (Non-Patent Document 1).

The purpose of asthma therapy is to control the clinical symptoms associated with the disease and to maintain its state. From this point of view, in GINA, the patient's disease state is classified into five treatment steps based on "whether the drug can be used to control symptoms". Non-patent document 2). According to this classification, although almost all asthmatic patients are classified into a patient subtype that is sufficiently controlled with a beta agonist and a low dose of an anti-inflammatory agent (treatment steps 1-3), on the other hand, there are still the following Other patient subtypes classified as treatment steps 4-5: only a very small number (about 5% of asthmatic patients) (Non-Patent Document 3) requires a high dose of a drug to control clinical symptoms, or even if a high dose of a drug is used Still unable to maintain control of clinical symptoms, asthma symptoms / acute exacerbations or frequent airway obstruction. This subtype differs from the asthma subtype of treatment steps 1-3 in the European Respiratory Society. (European Respiratory Society; ERS) / American Thoracic Society (ATS) treatment guidelines, called severe asthma, is considered to be one of the major unmet needs (Non-Patent Document 4).

In order to develop a treatment method for severe asthma, studies on the use of disease patterns and tissues of patients, and steroid resistance, one of the characteristics of severe asthma, have been reported to indicate IFN-γ, IL-2/IL-4, IL. -17, collagen, or IL-33 acts on respiratory smooth muscle and white blood cells to cause respiratory allergic or pneumonia with low steroid reactivity (Non-Patent Documents 5-9), but the nature of the disease state remains unclear and has not yet been established. Effective treatment. In addition, patients who can only control symptoms with the highest dose of steroids are exposed to the risk of serious side effects caused by steroids. The development of effective new drugs is eagerly affected by severe asthma as an unsolved medical problem. Expectation.

It is generally known that Tetomilast or its salt has an inhibitory effect on active oxygen (O ₂ ^- ) production, inhibition of cytokine production, adhesion inhibition, treatment of chronic obstructive pulmonary disease, and MMP-2 and/or MMP. -9 hindering action (for example, Patent Documents 1 to 4).

However, the efficacy of Tetomilast or its salt in the treatment of severe asthma is completely unknown.

Advanced technical literature Patent literature

[Patent Document 1] Japanese Patent Laid-Open No. Hei 5-51318

[Patent Document 2] Japanese Patent Laid-Open No. Hei 10-152437

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2003-104890

[Patent Document 4] International Publication No. 2009/113736

Non-patent literature

[Non-Patent Document 1] J Allergy Clin Immunol 2010;126(5):926-38.

[Non-Patent Document 2] Global Strategy for Asthma Management and Prevention 2014 (revision)

[Non-Patent Document 3] Am J Respir Crit Care Med 2000; 162(6): 2341-51.

[Non-Patent Document 4] Eur Respir J. 2014; 43(2): 343-73

[Non-Patent Document 5] J Immunol. 2009; 182(8): 5107-5115.

[Non-Patent Document 6] J Immunol. 1993; 151(7): 3460-3466.

[Non-Patent Document 7] Eur Respir J. 2012; 39(2): 439-445.

[Non-Patent Document 8] Eur Respir J. 2011; 37(1): 173-182.

[Non-Patent Document 9] Nat Commun. 2013; 4: 2675.

Summary of invention

The present invention is directed to providing a medicament useful for severe asthma.

As described above, asthma and severe asthma can be clearly distinguished by definition, and patients who are not effective in the treatment of asthma therapy are considered to be patients with severe asthma. Among them, the inventors of the present invention prepare an animal model exhibiting severe asthma symptoms, and use the animal model to repeatedly study As a result, it was surprisingly found that Tetomilast exhibited an extremely high therapeutic effect on severe asthma. The present invention has been completed based on such knowledge.

The present invention provides the severe asthma therapeutic agent according to the following items 1 to 17 (with steroid-dependent or steroid-resistance, for the treatment of an asthmatic patient having an insufficient effect on an existing therapeutic drug, etc. (hereinafter, The total number is referred to as "the drug of the present invention")).

Item 1. A severe asthma treatment containing totemister (Tetomilast) or a pharmaceutically acceptable salt thereof.

Item 2. The therapeutic agent according to the above item 1, wherein the severe asthma therapeutic agent is a respiratory allergic inhibitor with steroid dependence or resistance.

The therapeutic agent according to the above item 1, wherein the severe asthma is asthma with steroid-dependent or resistance.

Item 4. A medicine comprising Tetomilast or a pharmaceutically acceptable salt thereof for use in the treatment of an asthmatic patient having insufficient effect of an existing therapeutic agent.

Item 5. The drug according to the above item 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug.

Item 6. The drug according to the above item 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug, a long-acting β2 stimulating drug, a leukotriene receptor antagonist, and a theophylline sustained-release preparation.

Item 7. The drug according to the above item 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug, a long-acting β2 stimulating drug, and white three An ene receptor antagonist, a theophylline sustained release preparation, and an oral steroid drug.

Item 8. The drug according to the above item 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug, a long-acting β2 stimulating agent, a leukotriene receptor antagonist, a theophylline sustained-release preparation, or a steroid Drugs and anti-IgE antibodies.

Item 9. A medicine comprising Tetomilast or a pharmaceutically acceptable salt thereof, which is a treatment for a patient who is not effective even in the treatment of step 4 of GINA classification.

Item 10. A medicine comprising Tetomilast or a pharmaceutically acceptable salt thereof for use in the treatment of a patient who is not effective even in the treatment of the GINA classification step 5.

Item 11. A method of treating severe asthma, comprising administering to a patient in need of treatment for severe asthma a therapeutically effective amount of Tetomilast or a pharmaceutically acceptable salt thereof.

Item 12. Use of Tetomilast or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment of severe asthma.

Item 13. A Tetomilast or a pharmaceutically acceptable salt thereof for use in the treatment of severe asthma.

Item 14. Use of Tetomilast or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of severe asthma.

Item 15. A severe asthma therapeutic agent comprising 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid and a salt thereof, and a solvate thereof At least one selected from the group consisting of.

Item 16. The severe asthma therapeutic agent according to the above item 15, which comprises a crystal of type A from 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic anhydride, 6 -[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic anhydride Form B crystal, 6-[2-(3,4-diethoxybenzene)thiazole-4 -Based on pyridine-2-carboxylic anhydride Form C crystal, 6-[2-(3,4-diethoxybenzene)thiazol-4-yl]pyridine-2-carboxylic acid hydrate crystals and 6-[2- At least one selected from the group consisting of crystals of (3,4-diethoxybenzene)thiazol-4-yl]pyridine-2-carboxylic acid acetonitrile.

The severe asthma therapeutic agent according to any one of the above items 1 to 3, 15 or 16, wherein the pharmaceutical product according to any one of items 4 to 10, the method described in the above item 11, and the aforementioned item 12 And use of Tetomilast or a pharmaceutically acceptable salt thereof according to Item 13, wherein Tetomilast or a pharmaceutically acceptable salt thereof is Tetomi Tetomilast Anhydrate Form A crystal.

The pharmaceutical of the present invention contains Tetomilast or a pharmaceutically acceptable salt thereof. By Tetomilast is meant 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid, or 2-(3,4-diethyl) A compound represented by the name oxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole. Further, in the following, "Tetomilast or its pharmaceutically acceptable salt" may be referred to as "Tetomilast" or the like.

Tetomilast is a known compound, and can be produced, for example, by the method described in Japanese Laid-Open Patent Publication No. Hei 5-51318.

a pharmaceutically acceptable salt of tetomilast, It is easily obtained by allowing a medically acceptable basic compound to act on Tetomilast. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; calcium hydroxide, barium hydroxide, and hydrogen. An alkaline earth metal hydroxide such as magnesium oxide. Further, the pharmaceutically acceptable salt of Tetomilast can be easily obtained by allowing a medically acceptable acidic compound to act on Tetomilast. Examples of the acidic compound include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, and hydrogen bromide; acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, and fumaric acid; An organic acid such as malic acid, tartaric acid, citric acid, succinic acid or benzoic acid.

Tetomilast or a pharmaceutically acceptable salt thereof may also be a solvate consisting of Tetomilast or a salt thereof and a solvent molecule. Examples of the solvate include a hydrate such as Tetomilast, an alcoholate (methanol compound, an ethanolate, an isopropanol compound, etc.), and an acetonitrile compound. Preferably, the solvate of Tetomilast or the like is a hydrate of Tetomilast, an acetonitrile compound of Tetomilast.

Tetomilast or the like contained in the drug of the present invention may be in a known form, and if it is a solid such as Tetomilast or the like, it is an amorphous or well-known crystal polymorph. As the crystal polymorph, for example, Tetomilast anhydrate type A crystal described in JP-A-2007-277235, and Tetomilast anhydrate type B crystal, Totemilast anhydrate C crystal, Tetomilast monohydrate crystals, Tetomilast monoacetonitrile crystals, and the like.

In the present invention, the term "severe asthma" refers to the use of a long-term action type in addition to a high dose of inhaled steroids in order to prevent the formation of a "poor control" as defined by various treatment guidelines such as GINA and ERS/ATS. Asthma caused by the treatment of long-term management drugs such as β2 stimulating agents and leukotriene receptor antagonists and theophylline sustained-release preparations, or asthma that is "controlled poorly" despite the above treatment.

The "bad control" and "high doses of inhaled steroids" in the above treatment guidelines are indicated in the GINA (Tables 1 and 2) and ERS/ATS (Tables 3 and 4) as follows.

* In the table, CFC indicates a chlorofluorocarbon propellant, HFA indicates a hydrofluorocarbon propellant, and DPI indicates a powder for inhalation (dry powder inhaler).

Therefore, specifically, in GINA, if symptoms are not controlled by performing the treatment steps 4 to 5 shown in Table 5, or even if the treatment is poorly controlled by such treatment, it is defined as "severe asthma".

*In the table, ICS indicates inhaled corticosteroids, SABA indicates short-acting β2-stimulator, LTRA indicates leukotriene receptor antagonist, LABA indicates long-acting β2 stimulant, and anti-IgE indicates anti-immunoglobulin E antibody Treatment, OCS refers to oral corticosteroids.

On the other hand, in ERS/ATS, severe asthma as defined in Table 6 was defined.

In the present invention, as a steroid drug, a corticosteroid is preferred. Examples of corticosteroids include: pincocortisol, penicolone, butixocort propionate, RPR-106541, Flunisolide, becocortisol, tris cortisol, butadiene cortisol, and fluphene Cortisol, Mometasone, Ciclesonide, Rofleponide, ST-126, dexamethasone, 6α, 9α-difluoro-17α-[(2-mentylcarbonyl)oxy]-11β-hydroxyl -16α-methyl-3-oxo-androstene-1,4-diene-17β-carboxythio acid (S)-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α- Benzyl-3-oxo-17α-propoxy-androsten-1,4-diene-17β-carboxythio acid (S)-(2-oxo-tetrahydro-furan-3S-yl) ester Etiprednol dicloacetate (BNP-166), etc., may be such racemates, mirror image isomers or non-image isomers, or may be pharmacologically acceptable salts , derivatives and/or solvates (hydrates, etc.).

In the present invention, as a long-acting β2 stimulant, it can be listed For example: abbutrolol, Bambuterol, Bititolerol, Broxaterol, Carbuterol, Clenbuterol, phenolphthalein ( Fenoterol), Formoterol, Hexoprenaline, Ibuterol, Isoetarine, Isoprenaline, isoproterenol, Mabuterol ), Meluadrine, Metaproterenol, Orciprenaline, Pirbuterol, procaterol, Reproterol , TD3327, Lidazole, Salmeterol, Salmefamol, Soterenol, Sulfonterol, Tiaramide, Tebuterin , Tolubuterol, CHF-4226 (=TA2005, or Carmoterol) HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4) -hydroxy-3-hydroxymethyl-phenyl)-ethylamine]-hexyloxy}-butyl)-benzenesulfonamide, 5-[2-(5,6-diethyl-indoline-2- Alkyl)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy- 7-[2-{[2-{[3-(2-Phenylethoxy)propyl]indenyl}ethyl]-amine}ethyl]-2(3H)-benzothiazolone, 1-(2- Fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamine]ethanol, 1-[3-(4-methoxybenzyl-amine)- 4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamine]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamine]ethanol, 1-[2H-5-hydroxy-3- Oxo-4H-1,4-benzoxazine-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamine]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4 -Triazol-3-yl]-2-methyl-2-butylamine}ethanol, 5-hydroxy-8-(1- Hydroxy-2-isopropylamine butyl)-2H-1,4-benzoxazine-3-(4H)-one, 1-(4-amine-3-chloro-5-trifluoromethylbenzene) -2-t-butylamine)ethanol, 1-(4-ethoxycarbonylamine-3-cyano-5-fluorobenzene)-2-(t-butylamine)ethanol, N-[2-hydroxy- 5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamine)-benzene]-ethylamine}-ethyl)-benzene]-carboxamide, etc. The racemic form, the mirror image isomer, or the non-image isomer may also be a pharmacologically acceptable salt and/or solvate (hydrate or the like).

In the present invention, the short-acting β 2 stimulating agent may, for example, be albuterol, procaterol, fenoterol or the like, which may be a racemate, a mirror image isomer, or a non- The mirror image isomer may also be a pharmacologically acceptable salt and/or solvate (hydrate or the like).

In the present invention, the leukotriene receptor antagonist may, for example, be Prulukast hydrate, Montelukast, Zafirlukast, Segest Special (seratrodast), MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, ONO -4057 and so on.

In the present invention, the anti-immunoglobulin E antibody may, for example, be Omalizumab or the like.

In the present invention, the term "steroid resistance" means a state in which the reactivity with steroids is low, the steroid sensitivity caused by genetic factors or environmental stress factors is low, or the function or amount of steroid receptors is weakened. The use of steroids to improve symptoms is of course included.

Also, the severe asthma in the present invention except for the use of steroid drugs In addition to the above-mentioned steroid resistance which is still poorly controlled, it also includes steroid-dependent conditions such as a decrease in steroid drugs or a deterioration in asthma control caused by withdrawal.

Whether or not the judgment is steroid resistance can be evaluated, for example, by the method of the embodiment of the present invention.

The medicament of the present invention is effective for severe asthma. In particular, it is effective for the inhibition of steroid-resistant respiratory allergies and respiratory inflammation. Further, the medicine of the present invention is effective in the treatment of an asthmatic patient who is insufficiently effective in the presence of the existing therapeutic drug, the treatment of the asthmatic patient which is insufficient in the treatment of the GINA classification step 4, or the treatment of the GINA classification step 5 Treatment of patients with inadequate asthma is also effective. Further, the medicine of the present invention is effective for the treatment of bronchial asthma (limited to patients who are refractory to treatment of asthma symptoms even with existing treatment).

Further, the drug of the present invention is effective in the case where the symptoms of a high-capacity inhaled steroid drug and a plurality of asthma medications are not stable.

The drug of the present invention can be used in the form of a general pharmaceutical preparation. The preparation is prepared using a diluent or excipient which is usually used as a filler, a bulking agent, a binder, a wetting agent, a disintegrating agent, a surfactant, a lubricant or the like.

As the pharmaceutical preparation, various forms can be selected depending on the purpose of treatment, and typical examples thereof include a tablet, a pill, a powder, a liquid, a suspension, an emulsion, a granule, a capsule, a suppository, and an injection (liquid). Agents, suspensions, etc.).

When formed into a tablet form, various articles well known in the art as a carrier can be widely used. For example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid, and the like; water, ethanol, propanol, monosaccharide, etc., may be used. Glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other adhesives; dried starch, sodium alginate, acacia powder, lamin powder, Disintegration agents of sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; collapse of sucrose, hard ester, cocoa butter, hydrogenated oil, etc. Inhibitor; absorption enhancer of grade 4 ammonium base, sodium lauryl sulfate, etc.; wetting agent of glycerin, starch, etc.; adsorbent of starch, lactose, kaolin, bentonite, colloidal cerium oxide, etc.; refined talc, stearin A lubricant such as an acid salt, a boric acid powder or a polyethylene glycol. Further, the tablet may be a tablet of a general coating such as a sugar-coated tablet, a gelatin-coated tablet, an enteric coated tablet, a film-coated tablet or a double ingot, or a multi-layered ingot.

In the form of forming into a pellet, various articles well known in the art as a carrier can be widely used. For the examples, for example, excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, talc, etc., gum arabic powder, gum tragacanth powder, gelatin, ethanol, etc., laminaria, A disintegrating agent such as a seaweed.

When formed into a form of a suppository, various articles well known in the art as a carrier can be widely used. As examples thereof, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like can be used.

The capsule is prepared by mixing a general active ingredient compound with various carriers exemplified above and filling it in a hard capsule, a soft capsule or the like according to a usual method.

When it is prepared into an injection, the liquid, the emulsion and the suspension are preferably sterilized and are isotonic with the blood. When forming into the form, the whole item conventionally used in the field can be used as a diluent, for example, can be used. Water, ethanol, polyglycol (Macrogol), propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Further, in order to prepare an isotonic solution, a sufficient amount of salt, glucose or glycerin may be contained in the pharmaceutical preparation, or a general solubilizing agent, a buffering agent, a soothing agent or the like may be added.

The medicine preparation may further contain other medicines such as a coloring agent, a preservative, a flavor, a flavor, a sweetener, and the like as needed.

When the compound of the active ingredient of the present invention is liquefied, for example, the compound can be dissolved in a liquid carrier. The liquid carrier may, for example, be water, brine, or an organic solvent, and among them, water is particularly preferred. Further, in the case of dissolution, a surfactant such as polyethylene glycol having a molecular weight of 200 to 5,000, a polyoxyethylene (20) sorbitan monooleate, a sodium carboxymethylcellulose, a methylcellulose, or a polycondensation may be suitably added. Vinyl pyrrolidone, polyvinyl alcohol, and the like.

When the active ingredient compound of the present invention is pulverized, it can be pulverized by a usual method. For example, lactose, starch, or the like is preferably made into a fine powder, and the mixture is stirred to form a uniform mixture to prepare a powder.

The amount of the active ingredient (Tetomilast, etc.) to be contained in the therapeutic agent of the present invention can be widely used without limitation. It is suitably selected, but it is usually preferably set to be about 1 to 70% by weight in the composition of the preparation.

The method of administering the pharmaceutical of the present invention is not particularly limited, and can be administered in a manner suitable for various preparation forms, other conditions such as patient age, sex, and the like. For example, in the case of tablets, pills, liquids, suspensions, emulsions, granules and capsules, oral administration can be carried out. Further, in the case of an injection, intravenous administration may be carried out alone or in combination with a general rehydration solution such as glucosamine acid, and further, if necessary, administered intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, it is administered intrarectally.

The dose of the therapeutic agent of the present invention can be appropriately selected depending on the usage, the patient's age, sex, and the like, the degree of the disease, and the like, but usually the amount of the active ingredient compound is about 0.2 to 1 kg per 1 day. About 200 mg is preferred.

According to the present invention, an agent effective for the treatment of severe asthma can be provided. In particular, it provides an agent that is highly effective in inhibiting steroid-resistant respiratory allergies and in treating asthma with steroid resistance.

Further, the present invention has an effect from a low amount, and thus has almost no side effects, and is excellent even at the point of tolerance and safety.

Fig. 1 is a graph showing the results of measurement of respiratory allergic (AHR) in Test Example 1.

The production examples and test examples are disclosed below. However, the invention is not limited by the following examples.

Detailed description of the preferred embodiment

Manufacturing example 1

According to the method described in JP-A-2007-277235, a crystal form of 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic anhydride (hereinafter, Called "Compound A"). Using powder X-ray diffraction spectroscopy, it was confirmed that Compound A was an anhydrous Form A crystal of Tetomilast.

Test example 1

<production of disease mode>

As an antigen, Ovalbumin was sensitized to mice (Charles River, Balb/c, female, 8 weeks old), and a steroid-resistant respiratory allergic mouse asthma pattern was prepared in the following order. . Furthermore, the following reagents are used for the reagents.

OVA: Sigma and/or Hyglos GmbH

Alum: Aluminum hydroxide glue made by LSL

IFN- γ : interferon gamma manufactured by PeproTech

LPS: Sigma's Lipopolysaccharide

Dexamethasone: Sigma

Astragalus gum: made by Bell Powder Pharmaceutical Co., Ltd.

On the base day (day 0) and the seventh day, 200 μL of a solution of OVA/Alum (OVA: 0.5 mg/mL; Alum: 8 mg/mL) was administered intraperitoneally to all mice, and antigen-sensitization treatment was performed. Made the mice on the 21st day, On the 28th, 35th, 42nd, and 49th days for 3 consecutive days (only for the 35th day for 2 consecutive days), 30 minutes/day, inhalation with ultrasonic atomizer (Omron) The 10 mg/mL OVA solution was atomized for antigen exposure. On the 37th day, 50 μL of IFN-γ/LPS solution (IFN-γ: 30 μg/mL; LPS: 1 μg/mL) was administered to the respiratory tract of all animals under anesthesia. The respiratory allergic (AHR) and body weight measured on the 38th day were used as indicators, and the mice were divided into (1) solvent group (n=6) and (2) steroid group by layer non-chemical method (n= 11), (3) Group of tested substances (n = 11) 3 groups.

Determination of respiratory allergic

On day 31, day 38, and day 52, inhaled 0 to 20 mg/mL of methylcholine (MCh) without anesthesia, and specific respiratory resistance was measured using the ventilatory function analysis system/PULMOS-1 (sRaw) ) to investigate AHR. For each individual, the sRaw at the time of inhalation of 5, 10, and 20 mg/mL MCh was calculated as the amount of change from the sRaw value of 0 mg/mL MCh (ΔsRaw value), and the MCh concentration dependence of ΔsRaw To represent AHR.

Administration of compounds

3 days from the 21st, 28th, 35th, 42nd, and 49th days (ie, 3 consecutive days/week for 5 weeks), about 1 hour before the above OVA inhalation exposure The compound was administered orally (only, on the 37th day when the OVA inhalation exposure was not performed, orally administered about 1 hour before administration in the respiratory tract of the IFN-γ/LPS solution). For the 3 weeks from the 21st, 28th, and 35th days (ie, 21st, 22nd, 23rd, 28th, 29th, 30th, 35th, 36th, and 37th days), the steroids were administered to all animals. Dexamethasone 1 mg/kg was administered as a compound. 2 weeks from the 42nd day after the mice were grouped, as a drug a mixture of each of the (1) solvent groups is administered with a solvent of xanthine gum; (2) a steroid group is administered with dexamethasone 1 mg/kg (3) a group of test substances is administered a compound A 1 mg/kg .

<test result>

The test results consisted of two independent test results in order to investigate reproducibility. In the test substance group, there were 1 case in each of the two tests, and the total number of animals in 2 cases died. On the 52nd day, the number of cases became n=9.

The AHR of each group on the 52nd day is shown in Fig. 1. Furthermore, the results of Figure 1 are expressed as mean ± standard error (mean ± SE), and comparison of each AHR is performed using Repeated measures ANOVA (Tukey-Kramer assay). The case where the p value is less than 5% is statistically significant.

Comparing the results of AHR between (1) solvent group and (2) steroid group, from the results of p=0.9832, no difference was observed between the two groups, so this model is a respiratory allergy with steroid resistance. Sexual mouse asthmatic pattern. On the other hand, (3) the result of comparing the AHR of the test substance group with the (1) solvent group or the (2) steroid group, p value is p = 0.0043 (solvent group versus test substance group), p = 0.0033 (The steroid group versus the test substance group) showed a significant low value regardless of which group it was compared with.

From the above test results, it was revealed that Compound A significantly inhibited respiratory hypersensitivity in a mouse asthmatic pattern showing respiratory allergicity in which steroids could not be inhibited.

Comparative example 1

The effect of Roflumilast, a representative PDE4 inhibitor, was reviewed in the same manner as in Test Example 1 above, but was not observed. To significant respiratory allergic inhibition.

Claims (14)

A severe asthma therapeutic comprising tetomilast or a pharmaceutically acceptable salt thereof. The therapeutic agent according to claim 1, wherein the severe asthmatic agent is a respiratory allergic inhibitor with steroid dependence or resistance. The therapeutic agent of claim 1, wherein the severe asthma is asthma with steroid-dependent or resistance. A pharmaceutical product comprising Tetomilast or a pharmaceutically acceptable salt thereof for use in the treatment of an asthmatic patient who is deficient in the effectiveness of an existing therapeutic agent. The drug of claim 4, wherein the existing therapeutic drug is a high dose of inhaled steroid drug. The drug of claim 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug, a long-acting β2 stimulating drug, a leukotriene receptor antagonist, and a theophylline sustained-release preparation. The drug of claim 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug, a long-acting β2 stimulating drug, a leucotriene receptor antagonist, a theophylline sustained-release preparation, and an oral steroid drug. The drug of claim 4, wherein the existing therapeutic drug is a high-dose inhaled steroid drug, a long-acting β2 stimulating agent, a leukotriene receptor antagonist, a theophylline sustained-release preparation, an oral steroid drug, and an anti-IgE antibody. . A drug containing Tetomilast or a pharmaceutically acceptable salt thereof for use in the treatment of step 4 of the GINA classification Treatment of patients with feet. A drug containing Tetomilast or a pharmaceutically acceptable salt thereof is a treatment for a patient who is not effective even in the treatment of step 5 of the GINA classification. One method of treating severe asthma is to administer a therapeutically effective amount of Tetomilast or a pharmaceutically acceptable salt thereof to a patient in need of treatment for severe asthma. A use of Tetomilast or a pharmaceutically acceptable salt thereof as a medicament for the treatment of severe asthma. A Tetomilast or a pharmaceutically acceptable salt thereof for use in the treatment of severe asthma. A use of Tetomilast or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of severe asthma.