JP2008285474A - Pharmaceutical composition containing anti-adenovirus agent - Google Patents

Abstract

A novel anti-adenovirus agent and a pharmaceutical composition thereof are provided.
[Solution]
The present invention is a novel discovery of an excellent anti-adenovirus action of an antihistamine, and prevention of diseases caused by adenovirus infection (adenovirus infection), such as summer cold, pool fever and keratoconjunctivitis, and the like. Useful for treatment.
[Selection figure] None

Description

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

  Ketotifen fumarate (ketotifen fumarate) has (i) anti-anaphylaxis, (ii) antihistamine, (iii) inhibition of airway reaction by PAF (platelet activating factor), (iv) eosinophils In Japan, it has effects on eosinophils such as degranulation and accumulation suppression, and (v) suppression of antigen-induced hypersensitivity reactions. In Japan, (1) bronchial asthma, (2) allergic rhinitis, eczema Efficacy and effects of dermatitis, urticaria and pruritus are recognized (see Non-Patent Document 1).

  Azelastine hydrochloride (azelastine hydrochloride) is (i) inhibition of leukotriene production / release, antagonism, (ii) inhibition of histamine release, antihistamine action, (iii) inhibition of migration / invasion of inflammatory cells, inhibition of active oxygen production In Japan, (1) bronchial asthma, (2) allergic rhinitis, (3) eczema / dermatitis, urticaria, atopic dermatitis, pruritus, prurigo (See Non-Patent Document 1). Therefore, both ketotifen fumarate and azelastine hydrochloride can be classified as antihistamines.

  On the other hand, summer cold, pool fever, keratoconjunctivitis, and the like are known as diseases caused by adenovirus infection (adenovirus infection), but there is no cure yet. Therefore, the treatment is mainly symptomatic treatment for symptoms such as sneezing, runny nose, nasal congestion, sore throat, cough, fever, headache, etc., antihistamine or anticholinergic agent for sneezing, runny nose, etc. A neurostimulant, an antitussive for cough, and an NSAID for throat, fever, and headache are prescribed according to symptoms.

Until now, the anti-adenovirus action of antihistamines such as ketotifens and azelastines has not been known.
Japan Pharmaceutical Collection, Medical Drugs, 2007 Edition, Jiho (2006)

  As a result of intensive studies, the present inventor has found a surprising effect that an excellent anti-adenovirus action is exhibited in ketotifens and / or azelastines. As a result, ketotifens and / or azelastine is useful as an anti-adenovirus agent, and a pharmaceutical composition containing ketotifens and / or azelastine is adenovirus infection, as well as a summer cold caused by the infection, pool It has been found that the composition is useful as a pharmaceutical composition for preventing and / or treating fever or keratoconjunctivitis, etc., and has led to the completion of the present invention.

The present invention includes (1) an anti-adenovirus agent containing an antihistamine, and
(2) The anti-adenoviral agent according to (1), wherein the antihistamine is a ketotifen and / or azelastine,
(3) A pharmaceutical composition comprising the anti-adenovirus agent according to (1) or (2) for prevention and / or treatment of adenovirus infection,
(4) A pharmaceutical composition comprising the anti-adenovirus agent according to (1) or (2) for prevention and / or treatment of summer cold, pool fever or keratoconjunctivitis,
(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), which contains more than one species,
(6) The anti-adenovirus agent according to (2), wherein the ketotifen is ketotifen fumarate,
(7) The azelastine is azelastine hydrochloride, the anti-adenovirus agent according to (2), and (8) a combination drug containing ketotifens and azelastine in the same pharmaceutical composition (3) to ( The pharmaceutical composition according to any one of 7).

Furthermore, the present invention provides:
(9) Method of administering ketotifens and azelastine to mammals simultaneously, sequentially or separately, and preventing and / or treating adenovirus infections to mammals simultaneously and sequentially with ketotifens and azelastine Alternatively, a method of separately administering and preventing and / or treating an adenovirus infection is provided.

  The anti-adenovirus agent of the present invention and the pharmaceutical composition for prevention and / or treatment of adenovirus infection are useful because they have excellent anti-adenovirus activity. Furthermore, since it has an effect of preventing and / or treating adenovirus infection, it is also useful for preventing and / or treating summer cold, pool fever or keratoconjunctivitis.

  In the present invention, an “antihistamine” is a drug that is generally used for the purpose of suppressing an excessive reaction involving histamine such as an allergic reaction, which acts antagonistically with histamine on a histamine receptor, such as brompheniramine, Chlorpheniramine, clemastine, diphenhydramine, loratadine, triprolidine, azatazine, cetirizine, cyproheptadine, fexofenadine, hydroxyzine, promethazine, ketotifen, azelastine, mequitazine and pharmacologically acceptable salts thereof, preferably ketotifen Azelastine and pharmacologically acceptable salts thereof, more preferably ketotifen fumarate and azelastine hydrochloride.

  In the present invention, “ketotifens” are ketotifen and pharmacologically acceptable salts thereof, and preferably ketotifen fumarate.

  In the present invention, “azelastine” refers to azelastine and pharmacologically acceptable salts thereof, and preferably azelastine hydrochloride.

  In the present invention, the “pharmacologically acceptable salt” means that the active ingredients of the present invention “ketotifen” and “azelastine” have a basic group, and can be converted to an acid salt by reacting with an acid. So show its salt.

  As the “acid salt”, preferably, hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt and the like; and glycine salt, lysine salt Amino acid salts such as arginine salt, ornithine salt, glutamate salt and aspartate, more preferably inorganic acid salt and organic acid salt, and still more preferably hydrochloride salt and fumarate salt. .

  In the present invention, ketotifens and azelastine can be administered simultaneously, sequentially or separately, but generally it is convenient to administer clinically at the same time. Therefore, ketotifens and azelastine are It is preferable to administer as a combination drug. In addition, when it is not preferable for the preparation technique to physically mix the two compounds, each single agent can be administered simultaneously, sequentially or separately.

  “Simultaneous” administration in the present invention includes administration at exactly the same time as pharmacologically acceptable as well as administration at the same time. The dosage form is not particularly limited as long as it can be administered at approximately the same time, but it is preferably a single composition.

  “Sequentially or separately” administration in the present invention is not particularly limited as long as it is a dosage form that can be administered separately at different times. For example, one component is administered, and then, after a predetermined time, There are methods of administering the ingredients.

  In the present invention, “treat” means to cure or ameliorate a disease or symptom or to suppress a symptom.

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

  Ketotifen fumarate (ketotifen fumarate) is listed in the 15th revision Japanese Pharmacopoeia. In addition, azelastine hydrochloride is commercially available as a pharmaceutical and can be easily obtained (for example, it can be purchased from Sanyo Chemical Laboratory).

  Although the single dose of ketotifen varies depending on the indication and age, it is usually 0.1 mg to 5 mg, and this is administered 1 to 3 times a day.

  The single dose of azelastine varies depending on the indication and age, but is usually 0.1 mg to 10 mg, and this is administered 1 to 3 times a day.

  In the case of a solid preparation, the content of ketotifen contained in a single dose is usually 0.1 mg to 4 mg, preferably 0.5 mg to 2 mg.

  Further, the content of azelastine is usually 0.1 mg to 8 mg, and preferably 0.5 mg to 4 mg.

In the case of a liquid preparation, the content of ketotifen is usually 0.005 mg / mL to 4 mg / mL, preferably 0.05 mg / mL to 2 mg / mL.
The content of azelastine is usually 0.005 mg / mL to 8 mg / mL, and preferably 0.05 mg / mL to 4 mg / mL.

  In addition to the ketotifens and / or azelastines, the anti-adenovirus agent of the present invention and the pharmaceutical composition for the prevention and / or treatment of adenovirus infections may further comprise (1) an antipyretic analgesic, ( 2) central nervous stimulant, (3) anti-inflammatory, (4) antitussive, (5) expectorant, (6) bronchodilator, (7) anticholinergic, (8) vitamin, (9) herbal medicine Moreover, herbal medicine extracts and the like can be contained within a range not impairing the effects of the present 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 chloride, bromelain, serrapeptase, semi-alkaline proteinase, glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate,
(4) Antitussives such as dihydrocodeine phosphate, codeine phosphate, noscapine hydrochloride, noscapine, dextromethorphan hydrobromide, dextromethorphan phenolphthalein salt, dimemorphan phosphate, tipepidine hibenzate, tipepidine citrate, epradinone 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) anti-cholinergic agents such as belladonna (total) alkaloids, belladonna extract, isopropamide iodide, scopolamine hydrobromide, funnel extract, butyl scopolamine bromide, methylbenactidium bromide, timepidium 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, tocopherol calcium succinate,
(9) List herbal medicines such as ground yellow, keihi, gooh, shrimp, kikyo, mao, licorice, kyonin, hange, shazenso, senega, psycho, bukkuri, shinny, and extracts of these herbs (extracts, tinctures, etc.) However, it should not be limited to the above.

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

  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. It can be manufactured according to the usual method.

  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)
------------------------------------
Ketotifen fumarate 1-0.5
Azelastine hydrochloride-1 0.5
Lactose 120 120 120
Magnesium stearate 2 2 2
Corn starch 50 50 50
Low-substituted hydroxypropyl cellulose appropriate amount appropriate amount appropriate 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 granules (1) Ingredients (Table 2)
In 1 package (mg) (2a) (2b) (2c)
------------------------------------
Ketotifen fumarate 1-0.5
Azelastine hydrochloride-1 0.5
Lactose 100 100 100
Magnesium stearate 4 4 4
Low-substituted hydroxypropyl cellulose appropriate amount appropriate amount appropriate 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)
------------------------------------
Ketotifen fumarate 1-0.5
Azelastine hydrochloride-1 0.5
Lactose 25 25 25
Magnesium stearate 3 3 3
Corn starch 40 40 40
Hydroxypropylcellulose appropriate amount appropriate amount appropriate 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)
In 10 mL (mg) (3a) (3b) (3c)
------------------------------------
Ketotifen fumarate 1-0.5
Azelastine hydrochloride-1 0.5
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 Ketotifen fumarate was manufactured by WI Corporation, and azelastine hydrochloride was manufactured by Sanyo Chemical Laboratory. The test substance was prepared to 5 mg / 1.0 mL / Kg using Japanese Pharmacopoeia water for injection, and was forcibly orally administered using a syringe and a gastric sonde.

(2) Animals C57BL / 6NCrlCrlj female mice (made by Charles River Japan) 3 weeks old were 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 allowed to freely ingest.

  After the acclimatization, the group was divided into 16 groups 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) Adenovirus 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, adenovirus 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.

  On the second week after administration of the test substance, adenovirus 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 adenovirus infection (%) = 100 × [number of surviving mice / total number of mice (15)]
(5) Test result The result of the obtained survival rate is shown in Table 5 and FIG.

  Table 5 shows the results of survival rate on day 10 after adenovirus infection.

(Table 5)
Group Test substance (mg / Kg) Survival rate (%)
―――――――――――――――――――――――――――――――――――――
Test substance administration group Ketotifen fumarate (0.25) 93.3
Test substance administration group azelastine hydrochloride (0.25) 80.0
Positive control group Not administered 46.7
―――――――――――――――――――――――――――――――――――――
From Table 5, it was recognized that the survival rate was significantly improved by administration of ketotifen fumarate and azelastine hydrochloride in mice infected with adenovirus.

  FIG. 1 is a graph in which the horizontal axis represents the number of days elapsed since adenovirus infection and the vertical axis represents the change in survival rate (%). As shown in FIG. 1, the survival rate was significantly improved by administration of ketotifen fumarate and azelastine hydrochloride.

  Based on the above, it was found that ketotifen fumarate and azelastine hydrochloride exhibit an excellent anti-adenovirus action.

  The anti-adenovirus agent of the present invention and the pharmaceutical composition for prevention and / or treatment of adenovirus infection are useful because they have excellent anti-adenovirus activity. Furthermore, since it has an effect of preventing and / or treating adenovirus infection, it is also useful for preventing and / or treating summer cold, pool fever or keratoconjunctivitis.

It is the graph which described the relationship between the elapsed days from adenovirus infection, and transition of survival rate.

Claims (9)

Anti-adenovirus agent containing antihistamine The anti-adenovirus agent according to claim 1, wherein the antihistamine is ketotifen and / or azelastine. A pharmaceutical composition comprising the anti-adenovirus agent according to claim 1 or 2 for the prevention and / or treatment of an adenovirus infection. A pharmaceutical composition comprising the anti-adenovirus agent according to claim 1 or 2 for preventing and / or treating summer cold, pool fever or keratoconjunctivitis. 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. The anti-adenovirus agent according to claim 2, wherein the ketotifen is ketotifen fumarate. The anti-adenovirus agent according to claim 2, wherein the azelastine is azelastine hydrochloride. The pharmaceutical composition according to any one of claims 3 to 7, wherein the ketotifens and azelastine are a combination drug contained in the same pharmaceutical composition. A method of preventing and / or treating adenovirus infection by administering ketotifens and azelastine to a mammal simultaneously, sequentially or separately.