JP2011006391A - Medical composition containing cetraxate, for treating or preventing pollinosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new pollinosis-treating or preventing agent having a pollen protease inhibitory activity.SOLUTION: This pollinosistreating or preventing agent is provided by containing cetraxate or its salt used for the pollen protease inhibitory agent.

Description

  The present invention relates to the inactivation of pollen allergen using the pollen protease inhibitory action of cetraxate, and thus to the use for treatment or prevention of hay fever using cetraxate.

  Hay fever is caused by plant pollen coming into contact with mucous membranes such as the nose and eyes, and it is a syndrome characterized by a series of symptoms such as seizure / repetitive sneezing, nasal discharge, nasal congestion, and itchy eyes. It is.

  Japanese cedar pollinosis is the representative in Japan, but Japanese alder tree in January-April, Japanese cedar in February-April, Japanese cypress and birch in March-May, Japanese maple in May-July, Ragweed in August-September, 9- In November, pollen, such as mugwort, scatters, and each has hay fever. Moreover, since about 70% of cypress pollinosis patients are also cedar pollinosis patients, it is also called cedar and cypress pollinosis, and commonality exists in hay fever.

  The conventional hay fever countermeasures can be broadly divided into (1) avoidance of pollen exposure by masks and goggles, (2) suppression of pollen allergic reaction by drug administration, and (3) desensitization therapy and physical therapy. is there.

  On the other hand, studies on immunological inactivation or reduction of immunogenicity of allergens have also been made. For example, (A) a technique in which a specific polymer-containing solution is sprayed onto carpets or futons to physically coat and inactivate house dust allergen (see, for example, Patent Document 1), (B) specific surface activity Technology that destroys pollen with an agent and forcibly elutes allergen to render it harmless (see, for example, Patent Document 2), (C) technology that prevents pollen cleavage and suppresses allergen elution (for example, Patent Document 3) Reference) and the like. However, these are basically techniques for improving the allergen environment, and are not compounds that can be applied to pharmaceuticals.

  On the other hand, it is known that the proteolytic enzyme (protease) activity of mite allergen is closely related to allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. In other words, it is speculated that a specific protease possessed by mites promotes the production of bradykinin, which is involved in the exacerbation of inflammatory reaction and increased vascular permeability, resulting in various allergic diseases. Attempts have been made to search for substances that inhibit proteases and to provide them as mite allergy therapeutic agents (see, for example, Patent Document 4).

  Under the same idea, as an approach for searching for various hay fever therapeutic agents, search for compounds having various pollen protease inhibitory activities has been conducted (see, for example, Patent Document 5).

  Cetraxate hydrochloride, a drug for treating gastritis and ulcers, has the main effects of (a) improving gastric mucosal microcirculation, and also increasing gastric mucosal prostaglandin biosynthesis, maintaining gastric mucosal mucus and promoting synthesis. In addition to the protective action, (i) it also has the action of inhibiting the activation and production of pepsinogen in the mucous membrane and the action of inhibiting gastric secretion due to the anti-kallikrein action, etc. (For example, refer nonpatent literature 1).

  Tranexamic acid is also known as an anti-plasmin drug, and plasmin is a serine protease that degrades fibrin and contributes to the development of gastric mucosal damage. In fact, tranexamic acid can suppress stress ulcers in rats It is known (see Non-Patent Document 2). It is also known that tranexamic acid, an antiplasmin agent, has anti-allergic and anti-inflammatory effects in order to suppress the production of kinin, which is a causative substance of allergies and inflammatory lesions, from plasmin ( For example, refer nonpatent literature 1).

JP 2002-128680 A Japanese Patent Laid-Open No. 9-157152 JP 2001-240547 A JP-A-6-192085 Japanese Patent Laid-Open No. 10-306025

Japan Pharmaceutical Collection Medical Drug 2008 Edition Jiho 2007 Gastroenterology Seminar 52 1993 p. 131-140

  Tranexamic acid was known to have serine protease inhibitory action and anti-allergic / anti-inflammatory action, but pollen protease inhibitory action was not known. On the other hand, pollen protease inhibitory action of cetraxate was not known, and no antiallergic action was reported.

  The present invention provides a medical composition for effective treatment or prevention of hay fever, which is also referred to as national disease, while finding a new pharmacological action of cetraxate, which is an anti-ulcer drug.

  The present inventors have conducted intensive research to search for drugs that significantly inhibit pollen protease. As a result, it was found that cetraxate has an excellent pollen protease inhibitory action. Moreover, the present invention has been completed by finding that the effect is 23 times stronger than the positive control AEBSF.

That is, the present invention provides the following inventions.
(1): Setraxate or a salt thereof for use as a pollen protease inhibitor.
(2): A pollen protease inhibitor containing cetraxate or a salt thereof.
(3): A medical composition for treating or preventing hay fever containing cetraxate or a salt thereof.
(4) The cetraxate or a salt thereof according to (1) or (2), wherein the pollen protease inhibitor is a pollen protease inhibitor of alder, cedar, cypress, birch, camodia, ragweed or mugwort pollen.
(5) The cetraxate or a salt thereof according to (1) or (2), wherein the pollen protease inhibitor is a cedar pollen pollen protease inhibitor.
(6): The medical composition according to (3), wherein the hay fever is hay fever caused by alder, cedar, cypress, birch, camouflage, ragweed or mugwort pollen.
(7) The medical composition according to claim 3, wherein the hay fever is hay fever caused by cedar pollen.
(8): The medical composition is eye drops, nasal drops, cosmetics, masks, cotton swabs, clothes sprays, bedding sprays, air sprays or laundry drugs (3), (6) or (7) A medical composition according to 1.

  The present invention showed an excellent pollen protease inhibitory effect as described in Examples below. Therefore, it is useful as a medical composition for treating or preventing hay fever.

  The “salt” of cetraxate or a salt thereof in the present invention means a pharmacologically acceptable salt. As salts of cetraxate, mineral salts such as hydrochloride, nitrate and sulfate, organic acid salts such as methanesulfonate, alkali metal salts such as sodium salt, potassium salt, calcium salt and magnesium salt, alkaline earth metal Examples thereof include salts, and cetraxate hydrochloride is preferable. Setraxate hydrochloride is listed in the 15th revised Japanese Pharmacopoeia.

  The `` pollen protease inhibitor '' according to the present invention is an enzyme that degrades pollen, preferably an enzyme that degrades alder, cedar, cypress, birch, camodia, ragweed or mugwort pollen, more preferably An enzyme that breaks down cedar pollen.

  The “medical composition” of the present invention is a composition containing cetraxate or a salt thereof as a pollen protease inhibitor, and examples thereof include eye drops, nasal drops, cosmetics, masks, cotton swabs, clothing sprays, Examples include bedding sprays, aerial sprays, and laundry drugs.

  Examples of the preparation for oral administration of the present invention (oral administration preparation) include dosage forms such as tablets, capsules, powders, fine granules, liquids, troches, and jelly. As preparations for parenteral administration (parenteral administration preparations), extracts, plasters, spirits, suppositories, suspensions, tinctures, ointments, poultices, liniments, lotions, aerosols, Examples of the dosage form include eye drops and injections.

  The present invention is also suitable as a preparation for parenteral administration, and is used, for example, as a nasal drop, an eye drop, or a skin external preparation.

  The pharmaceutical preparation of the present invention can be prepared by known preparation techniques, and appropriate preparation additives can be added to the preparation. Formulation additives include excipients, binders, disintegrants, lubricants, fluidizers, suspending agents, emulsifiers, stabilizers, moisturizing (wetting) agents, preservatives, solvents, dissolution aids, Preservatives, corrigents, sweeteners, pH adjusters, tonicity agents, propellants, etc. can be mentioned, and formulation additives can be appropriately selected within a range not impairing the effects of the present invention, and appropriate amounts can be added. That's fine.

  In the present invention, cetraxate or a salt thereof is appropriately examined according to the sex, age, symptom, administration (medication) method, frequency of administration (medication), administration (medication) time, etc. Just decide. For example, in the case of internal use, cetraxate or a salt thereof is preferably administered (taken) at 50 to 1000 mg per day, more preferably 200 to 750 mg (taken), and particularly preferably 600 to 750 mg. In the case of topical administration to the skin, eyes, nasal cavity, etc., the content of cetraxate or a salt thereof is preferably 0.1 to 10 w / v%, more preferably 0.5 to 3 w / v%.

  EXAMPLES The present invention will be further described below with reference to examples, but the present invention is not limited to these examples.

1. Pollen Protease Inhibitory Effect 1.1 Test Substances Cetraxate hydrochloride and tranexamic acid were those from Daiichi Sankyo Co., Ltd. Setraxate was dissolved in DMSO to prepare a 100 mM stock solution, and diluted with Tris-Cl buffer to a predetermined concentration before use.

1.2 Crude enzyme solution The cedar pollen was from Wako Pure Chemical Industries, Ltd. After the pollen washing, pollen cells were crushed with an ultrasonic homogenizer, and the supernatant after centrifugation was used as a crude enzyme solution.

1.3 Measurement of pollen protease inhibitory activity A crude enzyme solution was added to a mixture of a substrate (Bz-Arg-MCA) solution and a test substance solution, mixed, and then reacted in a warm bath for 30 minutes. The reaction solution was measured for fluorescence intensity with a fluorescence spectrophotometer.

1.4 Inhibition rate The inhibition rate was calculated by the following equation, where C was the fluorescence intensity of the control (Tris-Cl buffer), S was the fluorescence intensity of the sample-containing reaction solution, and B was the blank.
Inhibition rate (%) = 100 × [1- (SB) / (CB)]

1.5 Test Results Tranexamic acid, serine protease inhibitor AEBSF [4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride: Wako Pure Chemical Industries, Ltd.] and 50% activity inhibitory concentration of cetraxate hydrochloride against cedar pollen protease The results of (IC50) are shown in Table 1.

(Table 1)
IC50 (mM)
――――――――――――――――――――――
Tranexamic acid 77.0
AEBSF 0.37
Setraxate hydrochloride 0.016
――――――――――――――――――――――

  As is apparent from Table 1, it was found that cetraxate hydrochloride exhibits a cedar pollen protease inhibitory action about 23 times stronger than AEBSF, which is a serine protease inhibitor. This effect was found to be a surprising fact that cannot be explained at all from the serine protease inhibitory action of cetraxate, even from the results of tranexamic acid.

2. Formulation Example 2.1 Tablets Tablets were produced by a conventional method with the following composition (6 tablets per day).
Setraxate hydrochloride 600mg
Crystalline cellulose 200mg
Hydroxypropylcellulose 30mg
Magnesium stearate 25mg
Macrogol 6000 16mg
Titanium oxide 24mg

2.2 Eye drops An eye drop solution was prepared by the following method with the following composition.
Setraxate hydrochloride 1%
Additives Appropriate amount Thickener Appropriate amount pH adjuster Appropriate amount Tonicity agent Appropriate amount Preservative Appropriate amount Purified water balance

2.3 Nasal Drops A nasal drop was prepared by the conventional method with the following composition.
Setraxate hydrochloride 1%
Additives Appropriate amount pH adjuster Appropriate amount Preservative Appropriate amount Purified water balance

Since the medicament of the present invention has an excellent cedar pollen protease inhibitory action, it is useful for the treatment or prevention of hay fever.

Claims (8)

  Setraxate or a salt thereof for use as a pollen protease inhibitor.   A pollen protease inhibitor comprising cetraxate or a salt thereof.   A medical composition for treating or preventing hay fever, comprising cetraxate or a salt thereof.   The cetraxate or a salt thereof according to claim 1 or 2, wherein the pollen protease inhibitor is a pollen protease inhibitor of alder, cedar, cypress, birch, camodia, ragweed or mugwort pollen.   The cetraxate or a salt thereof according to claim 1 or 2, wherein the pollen protease inhibitor is a cedar pollen pollen protease inhibitor.   The medical composition according to claim 3, wherein the hay fever is hay fever caused by alder, cedar, cypress, birch, camouflage, ragweed or mugwort pollen.   The medical composition according to claim 3, wherein the hay fever is hay fever caused by cedar pollen.   The medical composition according to claim 3, 6 or 7, wherein the medical composition is eye drops, nasal drops, cosmetics, masks, cotton swabs, clothing sprays, bedding sprays, air sprays or laundry drugs.