JP2007291072A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pharmaceutical composition for preventing and/or treating influenza virus-infected diseases. <P>SOLUTION: The pharmaceutical composition for preventing and/or treating the influenza virus-infected diseases by using tranexamic acid or its salt together with an expectorant (especially, bromhexine or its salt, ambroxol or its salt, or saponines). Especially, the compounding ratio of tranexamic acid or its salt to the expectorant is preferably 1500:1-10:1 and an oral formulation is preferable. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for preventing and / or treating influenza virus infection.

In recent years, the risk of a global epidemic of infection caused by influenza virus (hereinafter referred to as influenza virus infection) has been pointed out. The epidemic of influenza virus infection in the 20th century includes Spanish influenza (Spanish cold) in 1918, Asian influenza (Asian cold) in 1957, Hong Kong influenza (Hong Kong cold) in 1968, etc. Every year, it became a pandemic and caused many deaths. A pandemic of influenza virus infections such as these has serious health consequences and associated social consequences.
At present, it is said that administration of anti-influenza virus drugs is effective as a treatment method for influenza virus infection. As an anti-influenza virus drug, for example, osentamivir phosphate is known and used in Japan.
On the other hand, tranexamic acid or its salt, particularly tranexamic acid, is known to have antiplasmin action, antiallergic action, anti-inflammatory action, etc., and its efficacy is considered to be a bleeding tendency (leukemia) that is considered to be related to the enhancement of systemic fibrinolysis. , Aplastic anemia, purpura, etc. and abnormal bleeding during and after surgery); abnormal bleeding considered to be associated with increased local fibrinolysis (pulmonary bleeding, nasal bleeding, genital bleeding, renal bleeding, during and after prostate surgery) Abnormal hemorrhage); Symptoms such as erythema, swelling, pruritus in eczema and related symptoms, hives, drug eruption and poisoning rash; Symptoms such as sore throat, sore throat, sore throat, sore throat, sores Mouth pain and mouth mucosa after (see, for example, Non-Patent Document 1).
Tranexamic acid or a salt thereof is also known to be useful as a preventive and / or therapeutic agent for influenza virus infection (see, for example, Patent Document 1). Furthermore, it is also disclosed that ambroxol or a salt thereof has an anti-influenza virus action (see Patent Document 2). Although Patent Document 2 describes that bromohexine also has the same action, data supporting this is not disclosed.
To date, there has been no report that antiviral activity has been enhanced by the combined use of tranexamic acid and expectorants.

Japan Pharmaceutical Information Center, Japan, Japan, Japan, Japan, Japan, Japan, Pharmaceuticals and Medical Products, 2006, pages 1491-1492 International Publication No. 2004/032915 Pamphlet JP 2003-155230 A

  However, osecentamivir phosphate, known as an anti-influenza virus drug, is considered to have problems such as gastrointestinal symptoms such as abdominal pain, diarrhea and vomiting, and side effects such as severe psychiatric and neurological symptoms. Further, although tranexamic acid or a salt thereof has high safety and excellent anti-influenza virus action, there is a need for a therapeutic agent having a more potent anti-influenza virus action. In view of such circumstances, the present invention provides a pharmaceutical composition for prevention and / or treatment of influenza virus infection that is highly safe and more effective.

  As a result of intensive studies, the present inventors have newly found that, when an expectorant is used in combination with tranexamic acid, the anti-influenza virus action of tranexamic acid is enhanced, and the present invention has been completed.

That is, the present invention relates to the following inventions.
(1) A pharmaceutical composition for preventing and / or treating influenza virus infection, comprising tranexamic acid or a salt thereof and an expectorant.
(2) The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to (1) above, wherein the compounding ratio of tranexamic acid or a salt thereof and an expectorant is 1500: 1 to 10: 1.
(3) Prevention of influenza virus infection according to (1) or (2) above, wherein the expectorant is one or more selected from bromhexine or a salt thereof, ambroxol or a salt thereof and saponins / Or therapeutic pharmaceutical composition.
(4) The pharmaceutical composition for preventing and / or treating influenza virus infection according to (1) or (2) above, wherein the expectorant is bromhexine or a salt thereof.
(5) The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to any one of (1) to (4) above, wherein tranexamic acid or a salt thereof is tranexamic acid.
(6) The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to any one of (3) to (5) above, wherein the bromhexine or a salt thereof is bromhexine hydrochloride.
(7) The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to any one of (1) to (6) above, wherein the dosage form is an orally administered preparation.

  As will be apparent from the examples described later, in the present invention, it has been found that expectorants enhance the anti-influenza virus action of tranexamic acid or a salt thereof. Therefore, a pharmaceutical composition containing tranexamic acid or a salt thereof and an expectorant is useful for the prevention and / or treatment of influenza virus infection.

  Tranexamic acid or a salt thereof according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method. Examples of salts of tranexamic acid include mineral salts such as hydrochloride, nitrate and sulfate, organic acid salts such as fumarate and methanesulfonate, alkali metal salts such as sodium, potassium, calcium and magnesium. And alkaline earth metal salts. In the present invention, tranexamic acid or a salt thereof is preferably tranexamic acid.

Examples of expectorants according to the present invention include ambroxol or a salt thereof, bromhexine or a salt thereof, saponins (for example, Senega, Onji, and Kyokyo or an extract thereof). Examples of the salt of ambroxol and the salt of bromohexine include mineral acid salts such as hydrochloride, nitrate, carbonate, and sulfate, and organic acid salts such as fumarate and methanesulfonate. These expectorants are known compounds, commercially available products may be used, and they can be produced based on known methods.
In the present invention, the expectorant is preferably bromhexine or a salt thereof, more preferably bromhexine hydrochloride.

  The pharmaceutical composition for preventing and / or treating influenza virus infection of the present invention (hereinafter referred to as the pharmaceutical composition of the present invention) is administered to a patient infected with influenza virus or a person who is likely to be infected. To do. In general, since an infected patient exhibits symptoms such as sneezing, runny nose, nasal congestion, cough, sputum, chills, fever, headache, sore throat, etc., the pharmaceutical composition of the present invention contains tranexamic acid or a salt thereof, and expectorant In addition, a symptomatic drug may be added. Antipyretic analgesics such as aspirin, aspirin aluminum, sazapiline, etenzamide, salicylamide, ibuprofen, acetaminophen, isopropylantipyrine; caffeine, anhydrous caffeine, benzoic CNS stimulants such as sodium caffeine; sedatives such as bromvalerylurea and allylisopropylacetylurea, chlorpheniramine maleate, diphenhydramine, diphenhydramine salicylate, clemastine fumarate, carbinoxamine maleate, mequitazine, alimemazine tartrate, diphenylpyraline hydrochloride , Antihistamines such as triprolidine hydrochloride; lysozyme chloride, bromelain, serrapeptase, semi-alkaline proteinase, glycyrrhizic acid, glycyl Anti-inflammatory drugs such as dipotassium tinate, ammonium glycyrrhizinate, glycyrrhetinic acid, sodium azulene sulfonate; dihydrocodeine phosphate, codeine phosphate, noscapine hydrochloride, noscapine, dextromethorphan hydrobromide, dextromethorphan phenolphthalate, Antitussives such as dimemorphan phosphate, tipepidine hibenzate, tipepidine citrate, eprazinone hydrochloride, metorephedrine, methylephedrine hydrochloride, methoxyphenamine hydrochloride, trimethquinol hydrochloride, phenylpropanolamine hydrochloride; bronchodilation such as theophylline, aminophylline, diprofylline Drugs; Belladonna (total) alkaloids, Belladonna extract, Isopropamide iodide, Scopolamine hydrobromide, Methylbenactidium bromide, Timepidium bromide Anti-acetylcholine agents such as pirenzepine; bactericidal disinfection such as cetylpyridinium, cetylpyridinium chloride, popidone iodine, chlorhexidine gluconate, benzalkonium chloride, decalinium chloride, thymol, iodine / potassium iodide, phenol, chlorhexidine hydrochloride, creosote, benzethonium chloride Agents: Local anesthetics such as dibucaine hydrochloride, ethyl aminobenzoate, lidocaine, lidocaine hydrochloride, oxesecasein; vitamin A, liver oil, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, calcium ascorbate, vitamin D, vitamin E, vitamins such as tocophenol calcium succinate; pantothenic acid, panthenol, sodium pantothenate, calcium pantothenate, panthetin, nicotinic acid, nico Metabolic components such as cinnamate amide, glucuronic acid, glucuronolactone, aminoethyl sulfonic acid, biotin, γ-oryzanol, etc .; ground yellow, cinnamon, gourd, shrimp, mao, licorice, kyounin, hange, shazenso, psycho, bukkyou, Although herbal medicines such as Shini and extracts thereof (extracts, tinctures, etc.) can be mentioned, it should not be limited to the above. Moreover, such a symptomatic therapeutic agent may be blended with the pharmaceutical composition of the present invention in a single component or in combination of two or more.

  The pharmaceutical composition of the present invention can be administered orally or parenterally. Examples of the preparation to be administered orally include tablets, capsules, powders, fine granules, granules, solutions, troches, jellies and the like. In addition, preparations for parenteral administration include injections, plasters, spirits, extracts, suppositories, suspensions, tinctures, ointments, poultices, nasal drops, inhalants, liniments, A lotion agent, an aerosol agent, etc. can be mentioned. Moreover, you may mix | blend the pharmaceutical composition of this invention with a mouthwash, a throat spray, and a mouthwash. In the present invention, oral preparations are preferable, and solid preparations such as tablets, capsules, powders, fine granules, granules, troches, and jelly are particularly preferable.

These preparations can be produced by conventional production methods known to those skilled in the art, and additives can be blended as desired to prepare pharmaceutical preparations of such various dosage forms. Examples of the additive include an excipient, a binder, a disintegrant, a fluidizer, an emulsifier, and a stabilizer. These formulation additives may be used alone or in combination of two or more.
The mixing ratio of each component in the pharmaceutical composition of the present invention may be appropriately determined. For example, the mixing ratio of tranexamic acid or a salt thereof and expectorant is preferably 1500: 1 to 10: 1, and 100: 1 to 20 : 1 is more preferred.

  The pharmaceutical composition of the present invention is appropriately examined for the dose of tranexamic acid or a salt thereof and an expectorant to the patient according to the sex, age, weight, symptom, administration method, frequency of administration, administration timing, etc. of the patient. The appropriate dose should be determined. Therefore, in the pharmaceutical composition of the present invention containing tranexamic acid or a salt thereof and an expectorant, the amount thereof is 10 to 3000 mg of tranexamic acid or a salt thereof as tranexamic acid per day, and the expectorant is bromhexine or a salt thereof. When it is a salt, it is preferably formulated so that 2 to 24 mg of bromhexine is administered, and 400 to 750 mg of tranexamic acid or a salt thereof per day as tranexamic acid, and when the expectorant is bromhexine or a salt thereof, More preferably, 4 to 12 mg of bromhexine is formulated, and 750 mg of tranexamic acid is administered per day, and if the expectorant is bromhexine hydrochloride, 12 mg of bromhexine hydrochloride is administered. What was being particularly preferred.

  When the pharmaceutical composition of the present invention is administered as a nasal drop, the concentration of tranexamic acid or a salt thereof in the preparation is 0.1 to 5 W / W%, and the expectorant is 0.1 to 5 W / W%, preferably Is prepared by setting the concentration of tranexamic acid or a salt thereof to 1 to 3 W / W% and the expectorant to 1 to 3 W / W%, and nasally drops about 1 to 10 times, more preferably 3 to 6 times a day. Is preferred.

  When the pharmaceutical composition of the present invention is administered as an inhalant, the concentration of tranexamic acid or a salt thereof in the preparation is 0.05 to 5 W / W%, the expectorant is 0.05 to 5 W / W%, preferably Inhalation of tranexamic acid or its salt concentration of 0.5-2W / W% and expectorant 0.5-2W / W%, 1-5 times a day, more preferably several times Is preferred.

  The pharmaceutical composition of the present invention may be prepared as a single preparation containing a plurality of components according to the present invention and administered, or each component according to the present invention may be divided into separate preparations. It is good also as a kit formulation which enabled the formulation to administer simultaneously or sequentially.

  Hereinafter, the present invention will be described with reference to examples. However, the present invention should not be limited to these examples.

1. Test Method An influenza virus A / PR / 8/34 strain virus solution was diluted 5000 times with phosphate buffered saline (PBS) to prepare a virus diluted solution. Forty BALB / c mice were anesthetized by intraperitoneal administration of a pentobarbital sodium solution. Further, the anesthetized mice were infected with the virus by inoculating 10 μL of the virus dilution solution into each nostril on one side, 20 μL in total. The test substance and the control substance were orally administered using a metal intragastric tube according to the following test groups (10 animals per group). The test substance and the control substance were administered 6 times in total, 1 hour before virus inoculation, 6 hours after inoculation, 1 day later, and 2 days later (twice a day after the virus inoculation). On the third day after virus inoculation, the amount of virus in the lungs of each test group of mice was measured.
・ Control group: PBS administered ・ Bromhexine hydrochloride administered group: Bromhexine hydrochloride 6 mg / kg ・ Tranexamic acid administered group: tranexamic acid 300 mg / kg ・ Tranexamic acid + bromhexine hydrochloride combined group: bromhexine hydrochloride 2 mg / kg + tranexamic acid 100 mg / Kg administered

2. Method for quantifying the amount of virus in the lung On the third day after virus inoculation, the mice of each test group were exsanguinated under ether anesthesia and the lungs were collected. The collected lungs were weighed, (Lung weight (g) × 9) mL of virus growth medium (* 1) was added, and homogenized using a glass homogenizer. The sample after homogenization was centrifuged with a centrifuge (3000 rpm, 10 min, 4 ° C.), and the supernatant was filtered to obtain a sample for virus titer measurement.

  The culture solution of Madin-Darby canine kidney (MDCK) cells in which a monolayer was previously formed on a 6-well plate was removed and washed with PBS. After removing the washing solution, the virus titer measurement sample previously diluted 10-fold with the virus growth medium was adsorbed at room temperature (20 to 25 ° C.) for 1 hour. After completion of the adsorption, the inoculum was removed, and the primary overlay agar medium (* 2) was overlaid and cultured at 34 ° C. for 2 days. Further, this was overlaid with a secondary multi-layered agar medium (* 3) and cultured at 34 ° C. overnight. The number of plugs was measured, and the viral load (PFU) per gram of lung was calculated.

(* 1) Virus growth medium
2 x Virus growth medium Composition x 10 MEM (GIBCO) 100 mL
Sterile MilliQ water 331.7mL
7% NaHCO ₃ (Meiron) 32.1mL
L-glutamine (200 mM) 15 mL
Vitamin (1: 100) 1mL
Folic acid (1mg / mL) 1mL
Biotin (1mg / mL) 1mL
Fungisson (0.5mg / mL) 2.5mL
35% albumin (SIGMA) 5.7 mL
100 x PS (GIBCO) 10 mL
Total 500mL

Dilute 2 times with sterile MilliQ water.

(* 2) Primary multi-layered agar medium Composition Sterile MilliQ water 7.8 mL
2x virus growth medium 50mL
10% Glucose 1mL
Ac-Trypsin (5 mg / mL) 0.05 mL
2% Agarose 40mL

(* 3) Secondary multi-layered agar composition 2 × 50 ml culture medium for virus propagation
2% Agarose 50mL
1% Neutral Red 0.5mL

3. Test results Table 1 shows the average value of the amount of virus in the lungs of mice in each test group.

  From the results of Table 1, it was confirmed that the combined use of tranexamic acid and bromhexine hydrochloride further enhanced the anti-influenza virus action as compared with the administration of tranexamic acid alone and bromhexine hydrochloride alone. That is, it has been found that a pharmaceutical composition for preventing and / or treating influenza virus infection containing tranexamic acid or a salt thereof and an expectorant exhibits an excellent anti-influenza virus action.

A pharmaceutical composition containing tranexamic acid or a salt thereof and an expectorant showed an excellent anti-influenza virus action.
Therefore, a pharmaceutical composition containing tranexamic acid or a salt thereof and an expectorant exhibits an excellent effect and is useful for the prevention and / or treatment of influenza virus infection.

Claims (7)

A pharmaceutical composition for preventing and / or treating influenza virus infection, comprising tranexamic acid or a salt thereof and an expectorant. The pharmaceutical composition for preventing and / or treating influenza virus infection according to claim 1, wherein the compounding ratio of tranexamic acid or a salt thereof and an expectorant is 1500: 1 to 10: 1. The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to claim 1 or 2, wherein the expectorant is one or more selected from bromhexine or a salt thereof, ambroxol or a salt thereof and saponins. object. The pharmaceutical composition for preventing and / or treating influenza virus infection according to claim 1 or 2, wherein the expectorant is bromhexine or a salt thereof. 5. The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to any one of claims 1 to 4, wherein tranexamic acid or a salt thereof is tranexamic acid. The pharmaceutical composition for preventing and / or treating influenza virus infection according to any one of claims 3 to 5, wherein bromhexine or a salt thereof is bromhexine hydrochloride. The pharmaceutical composition for prevention and / or treatment of influenza virus infection according to any one of claims 1 to 6, wherein the dosage form is a preparation for oral administration.