JP2010083871A - Medicinal composition containing anti-adenoviral agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new anti-adenoviral agent and a medicinal composition for the prevention and/or treatment of adenoviral infection diseases. <P>SOLUTION: Anti-allergic agents; fexofenadine hydrochloride salt, ebastine or amlexanox, are found to have a surprising effect to exert an excellent anti-adenoviral action. They are useful as medicinal compositions for prevention and/or treatment of adenoviral infection diseases such as summer cold, pool fever or keratoconjunctivitis. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an anti-adenovirus agent and a pharmaceutical composition for prevention and / or treatment of adenovirus infection.

  Fexofenadine hydrochloride (fexofenadine hydrochloride) has (1) histamine H1 receptor antagonistic action, (2) type I allergic reaction inhibitory action, (3) eosinophil, inflammatory cytokine, cell adhesion molecule inhibition, (4) In Japan, it has the effect of suppressing the release of chemical mediators, etc. In Japan, it is effective for pruritus associated with allergic rhinitis, urticaria and skin diseases (eczema / dermatitis, cutaneous pruritus, atopic dermatitis). It recognized.

  Ebastine has (1) antiallergic action, (2) histamine H1 receptor antagonistic action, (3) histamine release inhibitory action, etc. in Japan, urticaria, eczema / dermatitis, rash, pruritus, Efficacy and effects of allergic rhinitis are recognized.

  Amlexanox has (1) histamine release inhibitory action, (2) leukotriene production inhibitory action, and (3) anti-leukotriene action. (For example, see Non-Patent Document 1).

  The above drugs are all classified as antiallergic agents (see, for example, Non-Patent Document 1). However, because of their approved efficacy, they are not prescribed for the purpose of treatment at the cold in the clinical setting. It is considered a thing.

  On the other hand, although the composition for the common cold which mix | blended said antiallergic agent is disclosed (refer patent documents 1-6), these are the objectives which suppress the nasal inflammation state, such as a runny nose and a nasal congestion at the time of a cold, ie, symptom It can be said that it was only formulated as a therapy.

  So far, the antiviral action of fexofenadine hydrochloride, ebastine, or amlexanox has not been known, and the anti-adenovirus action has also been unknown.

JP-A-9-52849 Japanese Patent Laid-Open No. 2002-212067 JP 2002-255816 A JP 2002-338486 A JP 2002-348240 A JP 2008-143807 A

Japan Pharmaceutical Collection Medical Drugs 2007 Edition Jiho (2006)

  The present invention aims to find a new pharmacological action of the antiallergic agents fexofenadine hydrochloride, ebastine, and amlexanox, and more specifically, prevention and / or prevention of various diseases caused by adenovirus. It relates to those radical treatments.

  As a result of diligent research, the present inventor has found a surprising effect that an excellent anti-adenovirus action is exhibited in fexofenadine hydrochloride, ebastine, or amlexanox, which has been conventionally used as an antiallergic agent. . As a result, the present inventors have found that these drugs are useful for the prevention and / or treatment of adenovirus infection which is a causative virus such as summer cold, pool fever or keratoconjunctivitis, and have completed the present invention.

That is, the present invention
1. An anti-adenovirus agent containing an anti-allergic agent,
2. 2. The anti-adenovirus agent according to 1, wherein the antiallergic agent is fexofenadine hydrochloride, ebastine, or amlexanox,
3. A pharmaceutical composition for preventing and / or treating an adenovirus infection, comprising the anti-adenovirus agent according to 1 or 2;
4. A pharmaceutical composition for preventing and / or treating summer cold, pool fever or keratoconjunctivitis, comprising the anti-adenovirus agent according to 1 or 2;
5. Further, one or two selected from the group consisting of antipyretic analgesics, central nervous stimulants, anti-inflammatory drugs, antitussives, expectorants, bronchodilators, anticholinergics, vitamins, herbal medicines and herbal extracts. The pharmaceutical composition according to 3 or 4 containing the above,
It is.

  The pharmaceutical composition containing an antiallergic agent of the present invention, in particular, a pharmaceutical composition containing fexofenadine hydrochloride, ebastine or amlexanox is useful because it has an excellent anti-adenovirus action. Furthermore, since it has an excellent preventive and / or therapeutic action for adenovirus infection, it is useful for the prevention and / or treatment of summer cold, pool fever or keratoconjunctivitis.

It is the graph which described the relationship between the elapsed days from adenovirus infection in fexofenadine hydrochloride administration, and transition of survival rate. It is the graph which described the relationship between the elapsed days from the adenovirus infection in ebastine administration, and transition of survival rate. It is the graph which described the relationship between the elapsed days from adenovirus infection in an amlexanox administration, and transition of survival rate.

  The anti-adenovirus agent or the pharmaceutical composition for prevention and / or treatment of adenovirus infection of the present invention is administered to a patient who is likely to be infected with adenovirus or a patient infected with adenovirus. It is. Examples of diseases caused by adenovirus include summer cold, pool fever and keratoconjunctivitis. Therefore, the anti-adenovirus agent or the pharmaceutical composition for preventing and / or treating adenovirus infection of the present invention is preferably administered to patients with these diseases.

  The antiallergic agent in the present invention is a drug used for preventing or suppressing allergic symptoms. Examples of the antiallergic agent in the present invention include phenoxophenazine hydrochloride, ebastine, and amlexanox.

  Amlexanox is listed in the 15th revision Japanese Pharmacopoeia First Supplement 2008. Other drugs (fexofenadine hydrochloride and ebastine) are also commercially available as drugs and can be easily obtained.

  The single dose of fexofenadine hydrochloride or amlexanox varies depending on the indication and age, but is usually 10 to 100 mg, and this is administered 1 to 3 times a day.

  Although the single dose of ebastine varies depending on the indication and age, it is usually 1 to 50 mg, which is administered once or twice a day.

  When the dosage form of the anti-adenovirus agent of the present invention or the pharmaceutical composition for prevention and / or treatment of adenovirus infection is a solid preparation, fexofenadine hydrochloride contained in a single dose or The content of amlexanox is usually 10 to 100 mg, preferably 20 to 80 mg.

  The content of ebastine is usually 1 to 50 mg, and preferably 2 to 20 mg.

  Further, the content of fexofenadine hydrochloride or amlexanox contained when the dosage form is a liquid is usually 0.5 to 100 mg / mL, and preferably 1 to 80 mg / mL.

  Further, the content of ebastine is usually 0.05 to 50 mg / mL, preferably 0.1 to 20 mg / mL.

  The anti-adenovirus agent of the present invention or the pharmaceutical composition for the prevention and / or treatment of adenovirus infection further comprises (1) antipyretic analgesic, (2) central nervous system in addition to the above-mentioned antiallergic agent. Stimulant, (3) anti-inflammatory, (4) antitussive, (5) expectorant, (6) bronchodilator, (7) anticholinergic, (8) vitamin, (9) herbal and herbal extracts Etc. can be contained in the range which does not impair the effect of this invention.

In particular,
(1) antipyretic analgesics such as aspirin, aspirin aluminum, sazapyrine, etenzamide, salicylamide, ibuprofen, acetaminophen, isopropylantipyrine, loxoprofen,
(2) Central nervous stimulants such as caffeine, anhydrous caffeine, sodium benzoate caffeine, theophylline, aminophylline, diprofylline,
(3) anti-inflammatory drugs such as lysozyme hydrochloride, bromelain, serrapeptase, semi-alkaline proteinase, glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate,
(4) Dihydrocodeine phosphate, codeine phosphate, noscapine hydrochloride, noscapine, dextromethorphan hydrobromide, dextromethorphan phenolphthalein salt, dimemorphan phosphate, tipepidine hibenzate, tipepidine citric acid Antitussives such as salt, eprazinone hydrochloride,
(5) expectorants such as L-ethylcysteine hydrochloride, potassium guaiacol sulfonate, potassium cresolate, guaifenesin, bromhexine hydrochloride, carbocysteine, fudstein, ambroxol hydrochloride,
(6) Bronchodilators such as methylephedrine, methylephedrine hydrochloride, methoxyphenamine hydrochloride, trimethquinol hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine,
(7) anticholinergic agents such as belladonna (total) alkaloids, belladonna extract, isopropamide iodide, scopolamine hydrobromide, funnel extract, butyl scopolamine bromide, methylbenactidium bromide, thimepidium bromide, pirenzepine,
(8) Vitamin agents such as vitamin A, liver oil, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, calcium ascorbate, vitamin D, vitamin E, calcium tocopherol succinate,
(9) Herbal medicines such as ground yellow, Keihi, Gooh, Syoukyo, Kyoukyo, Mao, licorice, Kyonin, Hange, Shazenso, Senega, Psycho, Bukkur, Shinyi and extracts of these herbal medicines (extracts, tinctures, etc.), etc.
Can be mentioned, but should not be limited to the above.

  Specific examples of these dosage forms include tablets, granules, powders (including fine granules), capsules, liquids (including syrups) and the like, and additives suitable for each dosage form. Can be produced according to the usual methods described in the Japanese Pharmacopoeia.

  In the above dosage forms, various commonly used additives can be used depending on the dosage form. For example, excipients, stabilizers, coating agents, lubricants, adsorbents, binders, disintegrants, surfactants, colorants, pH regulators and fragrances are used as appropriate, and described in the Japanese Pharmacopoeia, etc. Can be produced according to the usual methods.

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

Example 1 Tablet (1) Component

(Table 1)
In 1 tablet (mg) (1a) (1b) (1c)
------------------------------------
Fexofenadine hydrochloride 60 − −
Amlexanox-25-
Ebastine − − 10
Lactose 120 120 120
Magnesium stearate 2 2 2
Corn starch 50 50 50
Low-substituted hydroxypropylcellulose Suitable amount Suitable amount Suitable amount ------------------------------------

(2) Manufacturing method Take the above ingredients and the amount, and manufacture tablets according to the section of “General Tablets” “Tablet”.

(Example 2) Fine granule (1) component

(Table 2)
In 1 package (mg) (2a) (2b) (2c)
------------------------------------
Fexofenadine hydrochloride 60 − −
Amlexanox-25-
Ebastine − − 10
Lactose 100 100 100
Magnesium stearate 4 4 4
Low-substituted hydroxypropylcellulose Suitable amount Suitable amount Suitable amount ------------------------------------

(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”.

Example 3 Capsule (1) Component

(Table 3)
In 1 capsule (mg) (3a) (3b) (3c)
------------------------------------
Fexofenadine hydrochloride 60 − −
Amlexanox-25-
Ebastine − − 10
Lactose 25 25 25
Magnesium stearate 3 3 3
Corn starch 40 40 40
Hydroxypropylcellulose Suitable amount Suitable amount Suitable amount ------------------------------------

(2) Manufacturing method After taking the above components and quantities and preparing a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granules”, it is filled into capsules to produce hard capsules.

(Example 4) Syrup (1) Ingredient

(Table 4)
10 mL (mg) (4a) (4b) (4c)
------------------------------------
Fexofenadine hydrochloride 60 − −
Amlexanox-25-
Ebastine − − 10
Sodium benzoate 100 100 100
Polyvinyl alcohol 20 20 20
Sucrose 900 900 900
Purified water remainder remainder remainder ------------------------------------

(2) Manufacturing method Take the above ingredients and quantities, and manufacture a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to manufacture a syrup.

(Test example) Anti-adenovirus effect test (1) Test substance Ebastine manufactured by Estech Pharma was used.
For fexofenadine hydrochloride, sanofi-aventis Allegra (registered trademark) tablets were used, and for amlexanox, Takeda Pharmaceutical Co., Ltd. solfa (registered trademark) tablets were used. Calculated from the content per tablet and used.
The test substance was prepared using Japanese Pharmacopoeia water for injection so that the dose of each test substance / 10 mL / Kg, and was forcibly orally administered using a syringe and a gastric sonde.

(2) Animals A C57BL / 6NCrlCrlj female mouse (made by Charles River Japan) 3 weeks old was purchased at a P3 facility controlled at a temperature of 23 ± 3 ° C., a humidity of 55 ± 10%, and a lighting time of 8:00 to 20:00. The animals were bred by placing them in polycarbonate breeding cages sterilized by autoclaving. The feed was put into a water bottle made of polycarbonate sterilized by autoclaving special solid feed for experimental animals (CRF-1, manufactured by Oriental Yeast Co., Ltd.) and tap water passed through a water filter, and each was freely ingested.

  After the acclimatization, the group was divided into 15 to 16 animals per group based on the latest body weight, and the following two groups were used. Group 1 was a positive control group (adenovirus intake and no test substance administration), and group 2 was a test substance administration group (adenovirus intake and test substance administration). The negative control group (not adenovirus ingested and no test substance administered) was omitted in this study because the survival rate was confirmed to be 100% by the preceding test.

(3) Virus used The type of adenovirus used was Mouse Adenovirus strain FL (MAV FL), which was purchased from American Type Culture Collection (ATCC). It was intraperitoneally administered at 5 weeks of age. Dosage level _{(Tissue Culture Infectious Dose: TCID 50} / 10μL) was 1 × 10 ^4.

  Cells purchased from ATCC were cultured, and after confirming the monolayer state under the microscope, the virus was added and Cytopathic Effect (CPE) was confirmed under the microscope. The culture supernatant was collected and stored at -80 ° C or lower.

(4) Test method From 2 weeks before adenovirus inoculation to the 10th day after inoculation, the test substance was forcibly orally administered once a day for a total of 24 times using a gastric sonde and a syringe.
At the second week after administration of the test substance, the virus was inoculated intraperitoneally at a concentration at which death occurred in the preliminary test. The mice were observed for 10 days after the inoculation, and the survival rate of the mice was calculated by the following formula.
Mouse survival rate after virus infection (%) = 100 × [number of surviving mice / total number of mice]

(5) Test result The result of the obtained survival rate is shown in Table 5 and FIGS.
Table 5 shows the survival rate results on the 10th day after adenovirus infection.

(Table 5)
Group (number of mice) Test substance (mg / Kg) Survival rate (%)
―――――――――――――――――――――――――――――――――――――
Test substance administration group (16) Fexofenadine hydrochloride (20) 93.8
Test substance administration group (16) Ebastine (0.5) 81.3
Test substance administration group (15) Amlexanox (10) 80.0
Positive control group (15) Not administered 60.0
―――――――――――――――――――――――――――――――――――――

From Table 5, it was confirmed that in mice infected with adenovirus, the survival rate of mice was significantly improved by administration of fexofenadine hydrochloride, ebastine, and amlexanox.

1 to 3 are graphs in which the horizontal axis represents the number of days elapsed from virus infection and the vertical axis represents the change in survival rate (%).
From each figure, in mice infected with adenovirus, the administration of fexofenadine hydrochloride, ebastine, and amlexanox significantly improved the survival rate of the mice.

  From the above, it was found that fexofenadine hydrochloride, ebastine, and amlexanox all exhibited an excellent anti-adenovirus action.

  The composition containing fexofenadine hydrochloride, ebastine, or amlexanox of the present invention is useful because it has an excellent anti-adenovirus activity. Furthermore, since it has an excellent preventive and / or therapeutic action for adenovirus infection, it is useful for the prevention and / or treatment of summer cold, pool fever or keratoconjunctivitis.

Claims (5)

  An anti-adenovirus agent containing an antiallergic agent.   The anti-adenovirus agent according to claim 1, wherein the anti-allergic agent is fexofenadine hydrochloride, ebastine, or amlexanox.   A pharmaceutical composition for preventing and / or treating an adenovirus infection, comprising the anti-adenovirus agent according to claim 1 or 2.   A pharmaceutical composition for preventing and / or treating summer cold, pool fever or keratoconjunctivitis, comprising the anti-adenovirus agent according to claim 1 or 2.   In addition, one or more selected from the group consisting of antipyretic analgesics, central nervous stimulants, anti-inflammatory drugs, antitussives, expectorants, bronchodilators, anticholinergics, vitamins, herbal medicines and herbal extracts The pharmaceutical composition according to claim 3 or 4, which is contained.

Images