JP2020145939A - Allergic rhinitis inhibitory composition - Google Patents

Abstract

To provide an allergic rhinitis inhibitory composition.SOLUTION: An allergic rhinitis inhibitory composition contains 15-hydroxy eicosapentaenoic acid (15-HEPE) or a salt thereof, or a prodrug thereof as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to, for example, a composition for suppressing allergic rhinitis.

In modern society, the number of people suffering from allergic diseases such as pollinosis is increasing rapidly, which has become a social problem. According to an epidemiological survey in 2008, the prevalence of allergic rhinitis was 39.4% and the prevalence of pollinosis was 29.8% among those surveyed (Non-Patent Document 1). The prevalence of Japanese cedar pollinosis was 26.5%, which was reported to have increased by about 10% from a similar survey in 1989 (Non-Patent Document 1). Hay fever causes various problems in daily life such as allergic rhinitis such as sneezing, runny nose, and stuffy nose, and allergic conjunctivitis such as itchy eyes, leading to a decrease in QOL of patients and their families.

On the other hand, it is known that edible oils have different constituent fatty acids depending on the type, and the selection of edible oils has a great influence on the quality of fatty acids taken into the body. Furthermore, it has been reported that ingested fatty acids are transformed into various metabolites by the action of lipid-metabolizing enzymes in the body, and each exerts different physiological activities. In addition, it has been found that fatty acid metabolites produced in vivo contribute to suppression and improvement of allergic symptoms, and clinical use of metabolites leading to improvement of symptoms is expected.

Recent studies have shown that omega-3 fatty acids (α-linolenic acid, eicosapentaenoic acid (hereinafter referred to as "EPA"), docosahexaenoic acid ("DHA"), etc.) ingested through the diet are also contained in the body. It has been found that it undergoes metabolism and changes into various metabolites (Non-Patent Documents 2 and 3), and it is clear that some of the metabolites contribute to the improvement of food allergies and contact dermatitis. (Non-Patent Documents 3 to 5 and Patent Document 1).

Special Table 2015-522535 Japanese Unexamined Patent Publication No. 2014-201577 Special Table 2017-505809 Gazette

Ministry of the Environment Pollinosis Environmental Health Manual January 2014 revised edition Schuchardt JP et al., Prostaglandins Other Lipid Mediat. 2014 Jun; 109-111: 23-31. Kunisawa et al., Sci Rep. 2015 Jun 11; 5: 9750. Nagatake et al., J Allergy Clin Immunol. 2017 Dec 27. pii: S0091-6749 (17) 32949-4. Sawada et al., J Exp Med. 2015 Oct 19; 212 (11): 1921-30. Rangi et al., J Allergy Clin Immunol. 1990 Feb; 85 (2): 484-9

Regarding the improvement of allergic rhinitis using lipid components, it is clear in Non-Patent Document 6 that ingestion of EPA, which is a type of omega-3 fatty acid, suppresses eosinophil infiltration and suppresses inflammatory mediator production. Has been made. However, in this report, improvement of rhinitis symptoms such as sneezing has not been evaluated.

On the other hand, in Patent Document 2, 17,18-epoxyeicosatetraenoic acid (hereinafter referred to as "17,18-EpETE"), which is an omega-3 fatty acid metabolite, is described as a food allergy. It is disclosed that it has a preventive or therapeutic effect on allergic diseases such as allergic diarrhea and allergic rhinitis.

Similarly, regarding the physiological activity of 15-hydroxyeicosapentaenoic acid (hereinafter referred to as "15-HEPE"), which is an omega-3 fatty acid metabolite, the treatment of lung disease by 15-HEPE in Patent Document 3 Is reported to be possible. However, no improvement in diseases targeting allergic diseases by 15-HEPE has been reported.

An object of the present invention is to provide a new composition for suppressing allergic rhinitis in view of the above circumstances.

As a result of diligent research to solve the above problems, it was found that 15-HEPE has an effect of suppressing allergic rhinitis symptoms, and the present invention has been completed.

That is, the present invention includes the following.
(1) A composition for suppressing allergic rhinitis, which contains 15-HEPE or a salt thereof or a prodrug thereof as an active ingredient.
(2) The composition according to (1), which contains 15-HEPE or a salt thereof as an active ingredient.
(3) A food or drink for suppressing allergic rhinitis, which contains the composition according to (1) or (2).
(4) A drug for suppressing allergic rhinitis containing the composition according to (1) or (2).

According to the composition for suppressing allergic rhinitis according to the present invention, allergic rhinitis can be prevented, treated or ameliorated.

It is a graph which shows the suppression (preventive effect) of the nasal inflammation state by nasal administration of 15-HEPE using the allergic rhinitis model mouse. It is a graph which shows the suppression (therapeutic effect) of the nasal inflammation symptom by 15-HEPE nasal administration using the allergic rhinitis model mouse. Shows metabolites produced by EPA. It is a graph which shows the rhinitis suppressing effect by nasal administration of the metabolite produced by EPA using the allergic rhinitis model mouse.

Hereinafter, the present invention will be described in detail.

The composition for suppressing allergic rhinitis according to the present invention (hereinafter, referred to as "composition according to the present invention") contains 15-HEPE or a salt thereof or a prodrug thereof as an active ingredient. According to the composition according to the present invention, allergic rhinitis can be prevented, treated or ameliorated. Therefore, the composition according to the present invention can also be used as a preventive, therapeutic or ameliorating agent for allergic rhinitis.

で示される化合物である。 The active ingredient 15-HEPE in the present invention has the following formula:

It is a compound indicated by.

The salt of 15-HEPE is preferably a pharmaceutically acceptable salt, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitrate, pyrosulfate, metaphosphoric acid, or Citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, sulfonic acid (eg, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid), amino acids (eg, glutamate), etc. Examples thereof include salts with organic acids, alkali metal salts such as sodium salts and potassium salts, lysine salts and arginine salts.

A prodrug of 15-HEPE or a salt thereof is any compound that, when administered to a biological system, produces 15-HEPE or a salt thereof as a result of a spontaneous chemical reaction or by an enzyme or metabolic reaction that catalyzes it. Shown. Examples of the groups constituting the prodrug used in the hydroxyl group include C _2-7 -acyl group, C _1-6 -alkoxy (C _2-7 acyl) group, and C _1-6 -alkoxycarbonyl (C _{2- 7} -acyl) group, C _1-6 -alkoxycarbonyl group, C _1-6 -alkoxy (C _2-7 -alkoxycarbonyl) group, (C _2-7 -acyloxy) methyl group, 1- (C _2-7) -Acyloxy) ethyl group, (C _2-7 -alkoxycarbonyl) oxymethyl group, 1-[(C _2-7 -alkoxycarbonyl) oxy] ethyl group and the like, C _2-7 -acyl group, C _{1 -6-} Acylcarbonyl groups are preferred. Examples of the groups constituting the prodrug used in the carboxyl group include C _1-6 -alkyl group, C _1-6 -alkoxy-C _1-6 -alkyl group, and (C _2-7 -acyloxy) methyl group. , 1- (C _2-7 -acyloxy) ethyl group, (C _2-7 -alkoxycarbonyl) oxymethyl group, 1-[(C _2-7 -alkoxycarbonyl) oxy] ethyl group, etc., C _{1 A -6} -alkyl group and a C _1-6 -alkoxy-C _1-6 -alkyl group are preferred.

The composition according to the present invention can be formulated in any form together with an auxiliary agent to prepare a drug that can be orally or parenterally administered. For example, dosage forms for oral administration include solid dosage forms such as tablets, orally rapidly disintegrating tablets, capsules, granules, fine granules, and liquid dosage forms such as syrups and suspensions. Dosage forms for parenteral administration include, for example, nasal drops, injections, eye drops, patches, suppositories, and external preparations for skin. Pharmaceuticals also include quasi-drugs.

In the case of a solid dosage form, various additives used in the production of general preparations may be contained in appropriate amounts. Examples of such additives include excipients, binders, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, pH adjusters, surfactants and the like. ..

In the case of a liquid dosage form, the drug is formulated by a conventional method in the presence of a pH adjuster, a buffer, a solubilizer, a suspending agent, an isotonic agent, a stabilizer, a preservative, etc., as necessary. can do.

The form of the external preparation for skin is not particularly limited, and for example, a pharmaceutical product such as an ointment, a cream, or an external liquid can be used. In addition to the above ingredients, ingredients usually used for external skin preparations such as pharmaceuticals, such as whitening agents, moisturizing agents, various skin nutritional ingredients, ultraviolet absorbers, antioxidants, oily ingredients, surfactants, thickeners, alcohols. Types, coloring agents, water, preservatives, fragrances and the like can be appropriately blended as needed.

In the present invention, it is preferable to administer the composition according to the present invention nasally as a nasal drop.

The composition according to the present invention is prepared as a functional food, a health food, a food for specified health use, a food with a health function such as a food with a nutritional function, a food for special use (for example, a food for the sick), a health supplement, a supplement and the like. You may. For example, the composition according to the present invention can be used for foods with functional claims labeled as "suppressing allergic rhinitis". As supplements, for example, tablets, rounds, capsules (including hard capsules, soft capsules, microcapsules), powders, granules, fine granules, troches, liquids with various additives used in the manufacture of common supplements. It can be in the form of syrup, milk, suspension, etc.

The composition according to the present invention can be blended in foods and drinks. The foods and drinks that can be blended are not particularly limited, but for example, confectioneries such as candy, gummy, and chewing gum; confectioneries such as cookies, crackers, biscuits, chocolates, puddings, jellies, snacks, cooked rice, buns, and udon noodles. Frozen desserts such as ice cream, ice candy, sherbet, gelato; bakery foods such as donuts, cakes, bread, French bread, croissants; noodles such as udon, buckwheat, Chinese noodles, and kishimen; cooked rice such as white rice, red rice, and pilaf; Sauces such as curry, stew, and dressing; kneaded products such as ham, sausage, kamaboko, chikuwa, and fish sausage; various side dishes such as tempura, croquette, and hamburger; beverages such as juice and tea.

The daily dose (intake) of the composition according to the present invention can be changed depending on factors such as the age, weight, sex, and condition of the patient. For example, the daily dose (intake) of the composition according to the present invention is 0.01 μg to 10000 mg per person (preferably per person) in terms of the active ingredient (15-HEPE or a salt thereof or a prodrug thereof). 1 mg to 4000 mg).

The effect of the composition according to the present invention can be evaluated, for example, in allergic rhinitis model mice in which allergic rhinitis is reproduced by administration of ovalbumin (J Immunol. 2007 Nov 1; 179 (9): 5897-906.). .. For example, the composition according to the present invention is nasally administered to the allergic rhinitis model mouse, and the number of sneezing (symptoms of allergic rhinitis) at a specific time is counted. When the number of sneezing is significantly reduced as compared with the control group in which the composition according to the present invention is not administered, it can be judged that the composition according to the present invention suppresses allergic rhinitis.

On the other hand, in accordance with the above description of the composition according to the present invention, the present invention comprises administering or ingesting the composition according to the present invention to a patient or subject (human) for allergic rhinitis. It also relates to methods of suppression or prevention, treatment or amelioration of allergic rhinitis.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited to these Examples.

[Example 1] Prevention and therapeutic effect of 15-HEPE on allergic rhinitis 1-1. Preparation of allergic rhinitis model mouse
(1) C57BL / 6J mice (female) 7 weeks old were purchased from Japan SLC.
(2) 25 μg of ovalbumin (OVA: Sigma-Aldrich) and 1 mg of aluminum hydroxide (Thermo Fisher Scientific) were suspended in 200 μl of PBS. This suspension was intraperitoneally administered to mice to sensitize them.
(3) OVA was suspended in PBS at a concentration of 250 μg / 20 μl to induce rhinitis. PBS was prepared for the control group.
(4) From 1 week after sensitization, 20 μl of the suspension shown in (3) was administered to the nasal cavity of mice to induce rhinitis, and the number of sneezing for 5 minutes immediately after administration was counted. Rhinitis was triggered every day.

1-2. Test 1 15-HEPE preventive effect on allergic rhinitis
15-HEPE was purchased from Cayman Chemical and dissolved in PBS containing 0.5% ethanol at a concentration of 500 ng / ml. In addition, 17,18-EpETE was purchased from Cayman Chemical and dissolved in PBS containing 0.5% ethanol at a concentration of 500 ng / ml.

For the allergic rhinitis model mouse shown in Section 1-1, 20 μl of the prepared 15-HEPE or 17,18-EpETE solution, and 20 μl of PBS containing 0.5% ethanol in the control group, 5 minutes before the onset of rhinitis. Was administered nasally in advance. A suspension of OVA (antigen) was nasally administered 5 minutes after drug administration to induce rhinitis, and the number of sneezes for 5 minutes immediately after administration was counted. Administration of 15-HEPE or 17,18-EpETE and subsequent induction of rhinitis was performed for 4 consecutive days.

The results are shown in FIG. From the above test, it was found that nasal administration of 15-HEPE solution reduced the number of sneezing in mice (Fig. 1). From this result, it was found that 15-HEPE is effective in preventing allergic rhinitis symptoms. In addition, 15-HEPE was found to be more effective in preventing allergic rhinitis symptoms than 17,18-EpETE.

1-3. Test 2 15-HEPE therapeutic effect on allergic rhinitis
15-HEPE was dissolved in PBS containing 0.5% ethanol at a concentration of 500 ng / ml.

The allergic rhinitis model mice shown in Section 1-1 were nasally administered with a suspension of OVA (antigen) for 4 consecutive days from the first day to induce rhinitis. On the 4th day of administration, the number of sneezing of mice was counted, and the mice were divided into two groups so that the number of sneezing was even. After the 5th day of administration, 20 μl of the prepared 15-HEPE solution and 20 μl of PBS containing 0.5% ethanol were nasally administered to the control group 5 minutes before the onset of rhinitis. A suspension of OVA (antigen) was nasally administered 5 minutes after administration to induce rhinitis, and the number of sneezes for 5 minutes immediately after administration was counted.

The results are shown in FIG. From the above test, even in mice in which the number of sneezes increased due to the induction of rhinitis, the increase in sneeze could be suppressed by nasal administration of the 15-HEPE suspension (Fig. 2). From this result, it was found that 15-HEPE is effective in suppressing symptoms even when administered after the onset of allergic rhinitis.

1-4. Summary From the results of Tests 1 and 2, it was found that 15-HEPE has an action of suppressing allergic rhinitis symptoms. From these results, it is expected that a treatment method for allergic rhinitis using 15-HEPE will be constructed.

[Comparative Example 1] Verification of Rhinitis Suppressive Effect by Nasal Administration of Metabolites Produced by EPA Produced by EPAs other than 15-HEPE in the allergic rhinitis model mice of Section 1-1 of Example 1 The effect of nasal administration of the metabolite (Fig. 3) to suppress rhinitis was verified.

In addition to 15-HEPE, the metabolites used were 18-hydroxyeicosapentaenoic acid (“18-HEPE”) and 12-hydroxyeicosapentaenoic acid (“12-HEPE”). , 17,18-EpETE, and 17,18-dihydroxyeicosatetraenoic acid ("17,18-DiHETE").

20 μl of a solution containing 10 ng of metabolite in PBS containing 0.5% ethanol was instilled into the control group (Mock), and 20 μl of PBS containing 0.5% ethanol was instilled into allergic rhinitis model mice, and 5 minutes later, in PBS. 20 μl of a solution containing 250 μg of OVA was instilled into the nose. This operation was repeated for 4 consecutive days, and the number of sneezing for 5 minutes immediately after the OVA instillation on the 4th day was counted.

The results are shown in FIG. From the above tests, it was found that nasal administration of 15-HEPE solution significantly reduced the number of sneezes in mice compared to other metabolites (Fig. 4). Other metabolites were comparable to 17,18-EpETE (Patent Document 2), which is known to have a preventive or therapeutic effect on allergic diseases such as allergic rhinitis, in terms of reduction in the number of sneezes.

Claims (4)

A composition for suppressing allergic rhinitis, which contains 15-hydroxyeicosapentaenoic acid (15-HEPE) or a salt thereof or a prodrug thereof as an active ingredient. The composition according to claim 1, which contains 15-HEPE or a salt thereof as an active ingredient. A food or drink for suppressing allergic rhinitis containing the composition according to claim 1 or 2. A drug for suppressing allergic rhinitis, which comprises the composition according to claim 1 or 2.

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