Viral respiratory infection preventing or treating agent

Abstract

To provide a viral respiratory infectious disease preventing or treating agent of a novel component.SOLUTION: The present invention is characterized by the followings. 1. Glucosylceramide and / or viral respiratory infectious disease preventing or treating agent having glucosylceramide as an active ingredient. 2.Viral respiratory infectious disease preventing or treating agent having β-sitosterol glycoside as an active ingredient. 3. Viral respiratory infectious disease preventing or treating agent described in 1 or 2 above in which the viral respiratory infectious disease is influenza.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to agents for preventing and treating viral respiratory infections. These are widely used in pharmaceuticals, quasi-drugs, health foods, general goods, and the like.

Background Art

[0002] There are various epidemic acute respiratory infections caused by viral infections, such as influenza, coronavirus infection, etc. Influenza is an epidemic acute respiratory infection caused by infection with influenza virus type A or B. Its clinical manifestations are characterized by sudden high fever and systemic malaise, headache, muscle pain, joint pain, etc. in addition to upper respiratory tract inflammation symptoms, and are accompanied by a severe feeling that requires several days of bed rest. Influenza recurs every winter, and a large number of patients occur on a scale of several million in a concentrated manner in a short period of time. Furthermore, when high-risk groups such as the elderly over 65 years old, infants, pregnant women, and those with various underlying diseases contract influenza, the risks of pneumonia complication, hospitalization, and death are several hundred times higher than those of healthy adults. Therefore, influenza is recognized as an important disease that has a great social and economic impact due to the magnitude of the health damage to patients and the scale of its epidemic.

[0003] Conventionally, influenza vaccines have been used as a method for preventing influenza. However, the vaccine strain may be different from the epidemic strain, or even if the strains match, the ability to induce biological defense may be insufficient, and the preventive effect is not necessarily satisfactory. Furthermore, side effects such as redness, swelling, pain, fever, headache, chills, and malaise may occur in vaccinated individuals. In addition, there is also a possibility of urticaria, rash, oral numbness, anaphylactic shock, etc. in people with egg allergy, and gelatin allergy to gelatin contained as a stabilizer in the vaccine has also been reported. There are also reports of other side effects such as Guillain-Barré syndrome, acute encephalopathy, convulsions, and purpura. Therefore, vaccination is carried out under the management and guidance of a doctor (Patent Document 1). Therefore, there is a demand for an influenza preventive and therapeutic agent that is less likely to cause side effects and can be ingested as food.

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2008-297320 [Disclosure of the Invention] [Problems to be Solved by the Invention]

[0005] Under such circumstances, the present inventor has found that a glucosylceramide-containing rice extract known as a food material and β-sitosterol glucoside have a preventive and therapeutic effect on viral respiratory infections such as influenza, and completed the present invention. That is, an object of the present invention is to provide a novel preventive and therapeutic agent for viral respiratory infections containing a food material with few side effects as an active ingredient. [Means for Solving the Problems]

[0006] The features of the present invention for solving the above problems are as follows. 1. A preventive and therapeutic agent for viral respiratory infections containing glucosylceramide and / or a glucosylceramide-containing rice extract as an active ingredient. 2. A preventive and therapeutic agent for viral respiratory infections containing β-sitosterol glycoside as an active ingredient. 3. The preventive and therapeutic agent for viral respiratory infections according to 1. or 2. above, wherein the viral respiratory infection is influenza. [Brief Description of the Drawings]

[0007]

Figure 1

[0008] Hereinafter, the present invention will be described in detail. The present invention is characterized by using glucosylceramide and / or a rice extract containing glucosylceramide as an active ingredient. Glucosylceramide, which is the active ingredient of the present invention, is a substance in which a sugar (mainly galactose) is glycosyl ether-bonded to ceramide.

[0009] The above glucosylceramide is not particularly limited, but is preferably the one represented by the following chemical formula (1).

Chemical formula

[0010] The rice extract containing glucosylceramide can be extracted in large amounts from rice bran. The raw rice is not limited in variety, but Japanese-type (japonica) rice that exhibits sweetness is suitable. In particular, main food rice varieties represented by Koshihikari, Sasanishiki, etc. are preferred. Usually, the pericarp, seed coat, and aleurone layer on the outermost layer of brown rice are removed by a rice polisher to become bran.

[0011] The method for extracting the rice extract containing glucosylceramide from rice bran is not particularly limited, but it is desirable to use the following steps A to C. A. A step of extracting rice bran with an organic solvent B. A step of adding an acid together with water to the extract and precipitating gum in this acid solution C. A step of extracting the gum with alcohol and purifying sphingolipids from this alcohol extract.

[0012] The above steps A and B can utilize the production process of rice bran oil. Generally, when producing rice bran oil, the raw rice bran is extracted with hexane, and then the oil is separated by phosphoric acid treatment to obtain gum. Therefore, by applying the above step C to the gum generated in such a production process of rice bran oil, glucosylceramide can be efficiently extracted.

[0013] In addition to hexane, the organic solvent can be heptane, petroleum ether, ether, chloroform, acetone, etc. As the acid for treating the extract of the organic solvent, acetic acid, oxalic acid, citric acid, formic acid, etc. can be used as organic acids, and phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, etc. can be used as inorganic acids. Desirably, phosphoric acid is used. This is because phosphoric acid has the following advantages. a. The manufacturing process of rice bran oil can be utilized as it is. b. Since it is not a strong acid, tanks, pipes, etc. are less likely to corrode, and the durability of the manufacturing equipment is improved. c. It has no pungent odor like acetic acid or formic acid. d. Since it is easy to remove phospholipids contained in the extract of the organic solvent, the concentration of glucosylceramide contained in the precipitate (gum) increases.

[0014] As the alcohol, ethanol, methanol, isopropyl alcohol, butanol, and their hydrous alcohols, etc. can be used. When using glucosylceramide in food and drink, it is advisable to use ethanol. As a means for purifying glucosylceramide from the alcohol extract of the gum in Step C, column chromatography or other appropriate purification means can be used.

[0015] Also, a commercially available product may be used as the glucosylceramide-containing rice extract. For example, Orizaceramide (registered trademark) manufactured by Orizayuka Co., Ltd. may be used.

[0016] The present invention is characterized by having β-sitosterol glycoside as an active ingredient. β-sitosterol glycoside is not particularly limited, and examples include β-sitosterol glucoside, β-sitosterol rutinoside, β-sitosterol sambubioside, etc. In particular, β-sitosterol glucoside is preferable. Incidentally, β-sitosterol glucoside is a compound represented by the following chemical formula (2).

[0017]

Chemical formula

[0018] The method for obtaining β-sitosterol glucoside is not particularly limited, and commercially available products may be used, or it may be extracted from plants. As a commercially available product, "Sitosterol-3-O-glucoside, β- (AHP Verified)" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. can be used.

[0019] The plant raw material for obtaining β-sitosterol glucoside is not particularly limited, and examples include rice, wheat, beet, konjac, corn, etc. Among these, rice is preferred. The part used for obtaining β-sitosterol glucoside from rice is not particularly limited, but it is particularly preferable to use rice bran and rice germ.

[0020] The method for obtaining β-sitosterol glucoside from rice bran or rice germ is not particularly limited. For example, rice bran or rice germ can be fermented to obtain a fermented product, and then this fermented product can be extracted with a non-polar solvent to obtain a fermented product extract, and then it can be obtained by partitioning this fermented product extract. Also, it can be extracted from "Orizaceraide" (registered trademark) manufactured by Oryza Oil & Fat Co., Ltd.

[0021] The prophylactic agent for viral respiratory infections of the present invention can be used as a raw material for various foods and beverages. Examples of foods and beverages include general foods such as confectioneries (gums, candies, caramels, chocolates, cookies, snacks, jellies, gummies, tablets, etc.), noodles (buckwheat noodles, udon noodles, ramen noodles, etc.), dairy products (milk, ice cream, yogurt, etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juices, coffee, black tea, tea, carbonated beverages, sports beverages, etc.), as well as health foods (tablets, capsules, etc.) and dietary supplements (nutritional drinks, etc.). The prophylactic agent for viral respiratory infections of the present invention may be appropriately formulated in these foods and beverages.

[0022] These food and drink products can be formulated with various ingredients according to their types. For example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L - ascorbic acid, dl-α - tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, gum arabic, carrageenan, casein, gelatin, pectin, agar, B vitamins, nicotinamide, calcium pantothenate, amino acids, calcium salts, pigments, flavors, and food materials of preservatives can be used.

[0023] As a specific production method, the agent of the present invention can be spray - dried or freeze - dried together with powdered cellulose, and then easily incorporated into food and drink products (such as instant foods) by making it into powder, granules, tablets or solutions. Also, the agent of the present invention can be dissolved in, for example, oils and fats, ethanol, glycerin or a mixture thereof to make it liquid, and then added to beverages or solid foods. If necessary, it can be mixed with binders such as gum arabic and dextrin to make it powdery or granular, and then added to beverages or solid foods.

[0024] When applying the preventive agent for viral respiratory infections of the present invention to food and drink products, the addition amount is preferably such that the total content of the active ingredient is 1 - 20 wt% or less with respect to the food and drink products, since the main purposes are disease prevention and health maintenance.

[0025] The prophylactic agent against viral respiratory infections of the present invention may be used as a material for drugs (including pharmaceuticals and quasi-drugs). The agent of the present invention can be appropriately formulated as a raw material for pharmaceutical preparations. Examples of formulation raw materials that can be incorporated into the agent of the present invention include excipients (such as glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cacao butter, hardened vegetable oil, kaolin, talc, etc.), binders (such as distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrants (such as sodium alginate, agar, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, powdered gum arabic, gelatin, ethanol, etc.), disintegration inhibitors (such as sucrose, stearin, cacao butter, hydrogenated oil, etc.), absorption promoters (such as quaternary ammonium bases, sodium lauryl sulfate, etc.), adsorbents (such as glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (such as purified talc, stearate, polyethylene glycol, etc.).

[0026] The dosage can vary depending on the administration method, medical condition, age of the patient, etc. In adults, usually, 0.5 to 5000 mg of the active ingredient per day can be administered, and in children, usually about 0.5 to 3000 mg can be administered. The mixing ratio of the prophylactic agent against viral respiratory infections of the present invention can be appropriately changed depending on the dosage form. Usually, when administered orally or by mucosal absorption, it is about 0.3 to 15.0 wt%, and when administered parenterally, it is preferably about 0.01 to 10 wt%. Note that since the dosage varies under various conditions, there may be cases where an amount less than the above dosage is sufficient, and there may also be cases where it is necessary to administer beyond the range.

Examples

[0027] Hereinafter, examples of the present invention will be described. The examples shown below are for the purpose of confirming various actions and effects of the agent obtained by the present invention, and the scope of the present invention is not limited to these products and manufacturing methods.

[0028] Test Example: Evaluation of the preventive and therapeutic effects of glucosylceramide-containing rice extract, glucosylceramide, and β-sitosterol glucoside (hereinafter simply referred to as "BSG") against influenza 1. Test substances and preparation methods 1-1 Test substance 1 Name: Orizacera (registered trademark) (rice extract containing 30% glucosylceramide) Source: Orizayuka Co., Ltd. 1-2. Test substance 2 Name: Glucosylceramide represented by the following chemical formula (1) isolated from the above Orizacera

Chemical formula

[0029] 2. Preparation of the virus used and the inoculated virus 2-1. Virus used After purchasing from ATCC, a virus mutated into a highly mouse-sensitive virus by Hamri Co., Ltd. was used. Virus name: Influenza virus Strain name: A / PR / 8 / 34 ATCC No.: VR-1469 BSL: 2 Virus titer: 1.58×10 8 TCID 50 / mL Storage: Stored in a deep freezer (CLN-51UD1, Nippon Freezer Co., Ltd.) 2.2 Preparation of the inoculated virus The frozen virus solution was thawed and prepared using PBS at 2 × 10 5 TCID 50 / mL (1 × 10 4 TCID 50 / 50 μL) for general state observation and 6 × 10 4 TCID 50 / mL (3 × 10 3 TCID 50 / 50 μL) for measuring the amount of virus in the lungs.

[0030] 3. Experimental Animals Animal species: Mouse Strain: BALB / c Source: Charles River Laboratories Japan, Inc. Sex: Female Age: 4 weeks (upon arrival) Number of animals used: 48 (50 upon arrival) Reason for choosing the animal species: Since mouse-susceptible influenza virus was used, mice were considered appropriate as a test system.

[0031] 4. Animal Management Conditions 4-1. Breeding Conditions Room temperature: 22.0 - 25.0% (set at 24 ± 3 °C), humidity: 43.29 - 58.18% (set at 50 ± 20 %), ventilation (10 - 25 times / hour), lighting for 12 hours (8:00 - 20:00) 4-2. Feed MF (Oriental Yeast Co., Ltd., Lot 200617) was available for free intake. 4-3. Drinking Water Autoclaved tap water was available for free intake. 4-4. Cages Autoclaved heat-resistant polysulfone cages (207W × 365D × 140H mm, TECNIPLAST Ltd) were used. The animals were bred at 1 - 5 animals / cage. 4-5. Quarantine and Acclimation The general condition of the animals was observed daily from the day of arrival until the end of quarantine and acclimation. The body weight was measured on the day of arrival and at the end of quarantine and acclimation. 4-6. Grouping Animals were randomly assigned to each group using the body weight stratification random sampling method, based on the body weight at the end of quarantine acclimation.

[0032] 5. Test group composition The test group composition was as shown in Table 1 below.

Table 1

[0033] 6. Virus inoculation Under anesthesia with isoflurane (manufactured by Myrin Pharmaceutical Co., Ltd., Lot 196AR0), 50 μL / head of the inoculation virus solution was inoculated transnasally.

[0034] 7. Administration of the test substance From 7 days before virus inoculation until the day before the end of observation, it was orally administered once a day at 10 mL / kg using a syringe and a sonde. The test substance was administered before virus inoculation on the day of virus inoculation.

[0035] 8. Specimen collection (Groups 5 - 8) After euthanasia by overdose of thiopental sodium (manufactured by Nippon Kayaku Co., Ltd., Lot LU1200, Isothol (registered trademark) for injection 0.5 g), the lungs were collected and weighed. For virus quantification, 50 - 100 mg of the lungs were collected, immersed in RNAlater (Thermo Fisher Scientific, Lot 00874638), left in the refrigerator for 1 day, and then stored in a deep freezer until use. The remaining lungs were also stored in a deep freezer.

[0036] 9. Observation and measurement items 9-1. General condition The general condition was observed at least once a day. 9-2. Body weight measurement At the time of grouping (first administration: Day -7), Day 0, 3, 7, 10, and Day 14

[0037] 10. Statistical analysis For the quantitative data obtained as test data, the mean ± standard deviation was calculated. For the mice used for general condition observation, after calculating the average survival days and survival rate, a Log-Rank test was performed on the solvent group.

[0038] 11. Results The survival rates are shown in Figure 1 and Table 2 below. Table 3 below shows the average survival days and the survival rate at the end of the observation. The average survival days of Group 1 (solvent group), Group 2 (ceramide group), Group 3 (glucosylceramide group), and Group 4 (β-sitosterol glucoside group) were 7.1 days, 8.5 days, 7.8 days, and 8.9 days, respectively. As a result of statistical analysis, the survival days of Group 2 and Group 4 were significantly extended compared to Group 1.

Table 2

Table 3

[0039] 12. Discussion and Effects of Examples For the purpose of confirming the effects of ceramide and its components using an influenza-infected mouse model, the survival rate and average survival days of mice after virus inoculation were evaluated. As a result, the survival days of ceramide and BSG were significantly extended compared to the solvent group. In addition, a tendency for the survival days of the main component of glucosylceramide to be extended was also confirmed. From the above, it was confirmed that glucosylceramide, the rice extract containing it, and BSG are useful as influenza prevention and treatment agents.

[0040] Formulation examples of the agent (rice extract containing glucosylceramide) according to the present invention are shown. Note that the following formulation examples do not limit the present invention. Also, in the following formulation examples, only an example of the rice extract containing glucosylceramide is shown, but BSG and the above glucosylceramide can be formulated in the same way. Formulation Example 1: Chewing Gum Sugar 53.0 wt% Gum base 20.0 Glucose 10.0 Maltose 16.0 Flavor 0.5 Glucosylceramide-containing rice extract 0.5 100.0 wt%

[0041] Formulation Example 2: Gummy Reduced maltose 40.0 wt% Granulated sugar 20.0 Glucose 20.0 Gelatin 4.7 Water 9.68 Yuzu juice 4.0 Yuzu flavor 0.6 Dye 0.02 Glucosylceramide-containing rice extract 1.0 100.0 wt%

[0042] Formulation Example 3: Candy Sugar 50.0 wt% Maltose 33.0 Water 14.4 Organic acid 2.0 Flavor 0.2 Glucosylceramide-containing rice extract 0.4 100.0 wt%

[0043] Formulation Example 4: Yogurt (Hard - Soft) Milk 41.5 wt% Skim milk powder 5.8 Sugar 8.0 Agar 0.15 Gelatin 0.1 Lactic acid bacteria 0.005 Glucosylceramide - containing rice extract 0.4 Flavor Trace Water Remainder 100.0 wt%

[0044] Formulation Example 5: Soft Drink Fructose - glucose liquid sugar 30.0 wt% Emulsifier 0.5 Glucosylceramide - containing rice extract 0.3 Appropriate amount of spice Purified water Remainder 100.0wt%

[0045] Formulation Example 6: Tablet confectionery Sugar 76.4wt% Glucose 19.0 Sucrose fatty acid ester 0.2 Glucosylceramide-containing rice extract 0.5 Purified water 3.9 100.0wt%

[0046] Formulation Example 7: Soft capsule Brown rice germ oil 47.0wt% Yuzu seed oil 40.0 Emulsifier 12.0 Glucosylceramide-containing rice extract 1.0 100.0wt%

[0047] Formulation Example 8: Tablet Lactose 54.0wt% Crystalline cellulose 30.0 Starch decomposition product 10.0 Glycerin fatty acid ester 5.0 Glucosylceramide-containing rice extract 1.0 100.0wt%

Industrial applicability

[0048] As described above, the present invention can provide a novel prophylactic and therapeutic agent for viral respiratory infections.

Claims

1. A preventive and therapeutic agent for viral respiratory infections, containing β-sitosterol glycoside as an active ingredient.

2. 2. The method according to claim 1, wherein the viral respiratory infection is influenza.

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