JPH06199680A - Anti-influenza virus agent - Google Patents

Abstract

PURPOSE:To provide the subject medicine containing a Chinese medicine, KEISINIEPPIITITO as the active component, exhibiting an excellent antiinfluenza virus activity, remarkably excellent in safety and practically useful as an effective and safe medicine. CONSTITUTION:The objective medicine contains KEISINIEPPIITITO as the active component. KEISINIEPPIITITO is generally prepared recommendably by using Cinnamonomi cortex, peony, Glycyrrhizae radix and Ephedrae herba respectively in an amount of 0.75 to 3 and blending 0.5 to 3.5 Zingiberis rhizoma, 1 to 4 Zizyphi fructus and 1 to 5 Gypsum therewith. KEISINIEPPIITITO itself or its extract can be used as the active component and an aqueous extract is preferable in the case of an extract. In addition, the above medicine is administrated preferably in an amount of 3 to 15g/day per an adult on active component base in several times.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anti-influenza virus agent, and more particularly to an anti-influenza virus agent containing Keishinikoshijoichito as an active ingredient.

[0002]

2. Description of the Related Art There are not many excellent medicines against viral diseases as against medicines against bacterial diseases.

The cold epidemic occurs every year in both urban and rural areas. However, the prevention of influenza virus infection, which is the main cause of the common cold, must rely on vaccines, in which case it is difficult to do without understanding the epidemic virus species. In addition, no effective and safe drug is yet provided for colds caused by influenza virus even after the onset of treatment, and only symptomatic treatment with antipyretic and antiphlogistic analgesics and secondary infections with antibiotics are performed. is there.

Therefore, it has been desired to develop a medicine which is effective and safe for the common cold.

[0005]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies on various Kampo prescriptions in order to solve the above-mentioned problems, and as a result, found that Keishi-Nikoshi-Eiichi-to has excellent anti-influenza virus activity. The present invention has been completed and the present invention has been completed.

That is, the present invention is an anti-influenza virus agent containing, as an active ingredient, Keishi-Nii-Koshigei-to (hereinafter referred to as the active ingredient of the present invention).

[0007] The active ingredient of the present invention, Keishi-Nijikoshi-Gouichi-to, is described in the classical Chinese herbal formula (Kinbyo summary, etc.),
Although there are some differences, the compounding range of the crude drug is generally as follows.

[Keishi Nikoshi Joichi hot water] Keishi 0.75-3.0 Ginger 0.5-3.
5 Shakuyaku 0.75-3.0 Ojumu 1.0-4.
0 Licorice 0.75-3.0 Gypsum 1.0-5.
0 mao 0.75-3.0

[0009] It has been hitherto unknown that Keishinikoshigeikoto has anti-influenza virus activity.

The active ingredient of the present invention may be prepared by combining the above-mentioned formulation of Keishinikoshigeiichito as it is or an extract thereof as an active ingredient and combining it with a known pharmaceutical carrier.

Examples of the extract include various aqueous solvent extracts, and it is preferable to use the water extract. As a specific example of adjusting the extract, there is a method of extracting the above-mentioned composition of Keishi-Nikoshigei-to with 10 times the amount of hot water, and filtering the resulting extract. This extract can be dried if necessary and used as a dry powder.

Specific examples of the active ingredients of the present invention will be shown and described in detail.

Specific Example 1 2.5 g of laurel, 1.0 g of ginger, 2.5 g of peony, 3.0 g of large jujuba, 2.5 g of licorice, 3.0 g of gypsum and 2.5 of mahuang
170 g of mixed crude drug (Keieden Nikoshi Joichi-to: 17.0 g)
g of purified water was added, and the mixture was heated and extracted at 100 ° C. for 1 hour.
The extract obtained is filtered and then spray-dried to 4.68.
g of dry extract powder was obtained.

Concrete Example 2 250 g of cabbage, 100 g of ginger, 250 g of peony root, 3 of oju
00g, licorice 250g, gypsum 300g and mahuang 250g
17 liters of purified water was added to the mixed crude drug (1) of Keieda Nikoshi Joichi-to (1.7 kg), and the mixture was heated to 100 ° C and extracted for 1 hour. The obtained extract was centrifuged and the residue was separated to obtain a solution.

This solution was subjected to aseptic clarification filtration with a 0.3 μm membrane filter (manufactured by Toyo Roshi Kaisha, Ltd.). The obtained filtrate was ultrafiltered using a diafilter G-10T (manufactured by Bio Engineering Co., Ltd .: molecular weight cut off 10,000). For this ultrafiltration, a membrane with a diameter of 152 mm was set on the lower surface of a container with an internal volume of 2.0 l and the pressure was 3 kg / cm ^2.
Then, as the liquid in the container was concentrated, about 2 l of purified water was added. As a result, 15 l of ultrafiltrate was obtained.

Next, the fact that the active ingredient of the present invention has anti-influenza virus activity will be described with reference to experimental examples.

The present inventors have investigated the mortality rate due to influenza infection, the intrapulmonary growth of virus, and the previously reported intrapulmonary consolidation most closely related to the death of mice due to influenza infection as indicators of the active ingredient of the present invention. The effect was examined.

Experimental Example 1 Effect on Influenza Infection of Mice Infection was performed using a baponefrine-type glass nebulizer,
Influenza A ₂ virus (H ₂
N ₂ strain) was sprayed for 30 minutes. The virus used was chorioallantoic fluid that was inoculated and grown once in embryonated chicken eggs before use, and 1/50 per mouse under this spraying condition.
0 ml of viral fluid was inhaled into the lungs. The active ingredient of the present invention (70 mg / kg) was orally administered 1 day before infection and 1 day and 4 days after infection using a stomach probe. The antiviral action of the active ingredient of the present invention was evaluated by the survival rate and the average survival time as compared with the control mouse 3 weeks after the infection. Mice orally administered with physiological saline instead of the active ingredient of the present invention were used as a control group. The results are shown in FIGS.

FIG. 1 Influenza A ₂ virus (5 L
D ₅₀ equivalent)

FIG. 2 Influenza A ₂ virus (10
LD ₅₀ equivalent)

FIG. 3 Influenza A ₂ virus (20
LD ₅₀ equivalent)

From the results of FIGS. 1 to 3, it was confirmed that the active ingredient of the present invention has an action of reducing the mortality rate due to influenza infection.

Effect of virus on pulmonary growth The active ingredient of the present invention (70 mg / kg) was orally administered one day before and one and four days after infection using a stomach probe. After influenza infection, the lungs were excised daily, homogenized, suspended in serum-free medium at a concentration of 10%, and
Centrifugation was carried out at 00 revolutions for 10 minutes to obtain a virus test solution. The test solution was serially diluted 10-fold in the same medium, and 0.2 ml of each diluted solution was inoculated into embryonated chicken eggs at 36 ° C and 72 ° C.
After culturing for a time, chorioallantoic fluid was obtained. The virus titer in chorioallantoic fluid is
EID ₅₀ method using similar embryonated chicken eggs [American Joan of Hysenix (American Jo
rnal of Hygienics) 27 493
(1938)], and the effect of the active ingredient of the present invention on virus growth was compared with that of a control group. The results are shown in Fig. 4.

FIG. 4

From the results of FIG. 4, it was confirmed that the active ingredient of the present invention has an action of suppressing the intrapulmonary growth of influenza virus.

Effect on Consolidation of the Lung (Lung Lesion) The active ingredient of the present invention (70 mg / kg) was orally administered 1 day before and 1 and 4 days after infection using a gastric sonde. After the influenza infection, the lungs were removed daily and the method of Horsefar [Journal of Experimental
Medicin (Journal of Experime
ntal Medicine) 95 135 (195
2)], the consolidation was judged by the score described below. [Lung Consolidation] 4: 100% or Death 3: 75-99% 2: 50-74% 1: 25-49% 0: Less than 25% Results are shown in FIG.

FIG. 5

From the results of FIG. 5, it was confirmed that the active ingredient of the present invention suppressed the progress of consolidation in the lung, which is characteristic of influenza infection in mice.

As is clear from the above results, it was confirmed that the active ingredient of the present invention has an excellent anti-influenza virus effect. Therefore, Keishinikoshijokichito, which is the active ingredient of the present invention, is useful as an anti-influenza virus agent.

It should be noted that, since the active ingredient of the present invention, Keishi-Nii-Koshigei-to has a long history as a Chinese medicine and its safety has been confirmed, it can be safely used. For example, for mice and rats, the limit dose is 15 g /
It is extremely safe, as evidenced by the fact that no cases of death were observed after oral administration of kg.

Next, the formulation of the active ingredient of the present invention will be described.

The dosage form of the active ingredient of the present invention is not particularly limited and may be appropriately selected and used as needed. Oral preparations such as tablets, capsules, granules, fine granules and powders, suppositories, It can be used as a parenteral preparation such as an injection.

In order to exert the intended effect, it depends on the age, body weight and degree of disease of the patient, but usually 3 to 15 g as the weight of the active ingredient of the present invention is divided into several times a day in adults. Seems to be appropriate.

The active ingredient of the present invention includes tablets, capsules,
Oral preparations such as granules are produced by a conventional method using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a surfactant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The active ingredient of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

On the other hand, parenteral preparations are manufactured by a conventional method,
Generally, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as the diluent. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Next, the present invention will be described in more detail with reference to Examples of formulations of the active ingredient of the present invention, but the present invention is not limited thereto.

Example 1 Corn starch 21 g Crystalline cellulose 10 g Carboxymethyl cellulose calcium 7 g Light anhydrous silicic acid 1 g Magnesium stearate 1 g Keishi Nikokoshi-Ichiyu 160 g total 200 g According to the above formulation The mixture was mixed and compression-molded with a tableting machine to obtain 200 mg tablets. This tablet contains 160 mg of Shigyakuto obtained in Example 1, and 20 to 80 tablets for adults are to be taken in several divided doses per day.

Example 2 Corn starch 29 g Magnesium stearate 2 g Carboxymethyl cellulose calcium 8 g Light anhydrous silicic acid 1 g Keishi Nikokoshi-Ichiyu 160 g Total 200 g According to the above formulation, After compression molding with a compression molding machine, it was crushed with a crusher and sieved to obtain granules. 1 g of this granule contains 800 mg of Keishikakeito obtained in Example 2, and 4 to 18 times a day for adults.
Take g in several divided doses.

Example 3 Corn starch 19 g Light anhydrous silicic acid 1 g Keishi Nikoshigeichitou obtained in Example 1 180 g Total 200 g According to the above-mentioned recipe, 1 to were uniformly mixed to obtain 200 mg.
Was filled in a No. 2 capsule. One capsule of this capsule contains 20 mg of kanzo-bushito obtained in Example 3, and 20 to 80 capsules per day for adults are to be taken in several divided doses.

Example 4 300 g of alanine (containing no pyrogens) was added to 20 liters of Keishi Nikoshigeiichitou obtained in Example 2, dissolved and lyophilized. This lyophilized product was dispensed into 900 vials to obtain an injection. This injection 1 vial contained 406 mg of the freeze-dried product and was easily dissolved in 10 ml of purified water. The injection solution after dissolution was 92% (550n
It had a permeability of m) and passed the pyrogenic test method of the Japanese Pharmacopoeia.

Claims (1)

[Claims] 1. An anti-influenza virus agent which contains Keishi-Nii-Koshigei-to as an active ingredient.