JPH07118161A - Antiviral agent - Google Patents

Abstract

PURPOSE:To obtain an antiviral agent having low side action by using KAKKONTO (an antifebrile infusion) as an active component. CONSTITUTION:KAKKONTO produced by compounding KAKKON (root of Pueraria lobata), TAISOU (fruit of Zizyphus vulgaris), SHAKUYAKU (root of Paeonia albiflora), MAOU (stalk of Ephedra sinica), KEIHI (bark of Cinnamomum cassia), KANZOU (root of Glycyrrhiza glabra) and SHOUKYOU (rhizome of Zingiber officinale) or the extract of the KAKKONTO is used as an active component of the agent. The agent is administered at a daily rate of 3-15g of the active component in several divided doses. The amount of the active component in the preparation is generally 0.01-5mug/g of the base in the case of an agent for external use. The extraction is carried out by using various aqueous solvents, preferably water. For example, 1 pt. of KAKKONTO is extracted with 10-20 pts. of hot water and the obtained extract liquid is filtered and optionally dried to obtain the agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel antiviral agent.

[0002]

2. Description of the Related Art There are not many excellent medicines against viral diseases as against medicines against bacterial diseases. Although many chemically synthesized substances have antiviral activity, many of them are difficult to use clinically because of insufficient activity or serious side effects.

Most of herpes simplex virus (HSV) infections, which represent viral diseases, were infected in infants and children, but the aging of the initial infection has advanced along with recent changes in hygiene environment and lifestyle. It was Therefore, the first infection in adolescents and middle-aged people becomes a problem, and herpes labialis, corneal herpes, and genital herpes caused by the reactivation are becoming a problem. In addition, an increase in intractable herpesvirus infections in immunodeficient patients and AIDS patients has become a clinical issue with the advancement of medical treatment. As antiviral agents which are said to be effective in the treatment of these HSV infections, there are known a few types of synthetic agents such as acyclovir, which are actually used clinically because of serious side effects. The current situation is that there are still few.

Therefore, it has been desired to develop an antiviral agent with few side effects.

[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, ▲ Katsuneto has excellent antiviral activity. They have found the present invention and completed the present invention.

[0006] That is, the present invention is an antiviral agent containing Katsukonto as an active ingredient (hereinafter referred to as the active ingredient of the present invention).

[0007] Nekoyu, which is the active ingredient of the present invention, is
It is described in the classics of Kampo formulas (Shokan theory, Kimbyo abbreviation, etc.), and although there are some differences, the compounding range of crude drugs is generally as follows.

[▲ Katsuneyu] Kakkon 4.0-9.0 Maoh 3.0-6.0 Taiso 3.0-5.0 Keishi 2.0-6.0 Peony 2.0-6.0 Licorice 2.0-5.0 Ginger 1.0-6.0

Further, it has not been known at all that it is useful for the treatment of viral diseases, especially herpes diseases, because Kakunetou has antiviral activity.

The active ingredient of the present invention has the composition as described above.
The root hot water as it is, or its extract as an active ingredient,
This may be formulated into a combination 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 in which the above-mentioned Kakukonto is extracted with 10 to 20 times the amount of hot water and the obtained extract is filtered. 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 Cuckon 4.0 g, Ephedra 3.0 g, Taiso 3.0
180g of purified water was added to a mixed crude drug (▲ Kakkonto: 18.0g) of g, peony 2.0g, peony 2.0g, licorice 2.0g and ginger 2.0g.
It was extracted by heating at 0 ° C for 1 hour. The obtained extract was filtered and then spray-dried to obtain 3.75 g of dry extract powder.

Concrete Example 2 600 g of Cuckon, 450 g of Ephedra, 450 of Tassoum
g, 300 g of cabbage, 300 g of peony, 3 licorice
A mixed crude drug (00g and 300g of ginger)
27 l of purified water was added to Neto (2.7 kg) and heated,
Extraction was carried out for 1 hour after reaching 100 ° C. 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, purified water was added as the liquid in the container was concentrated. As a result, an ultrafiltrate was obtained.

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

Experimental Example 1 The effect of Kakoneto was examined using mice transdermally infected with the herpes simplex ♦ virus (HSV-1).

Virus: The HSV-1 strain Hayashida strain passaged in Vero cells was used. Mice: Seven-week-old female BALB / c mice were used. Virus inoculation: The epidermis of the mouse, which had been hair-removed using a chemical depilatory (Shiseido Co., Ltd.), was disrupted 20 times with a 26G intradermal needle, and 10 μl (1 × 10 ⁶ PFU) of the virus solution was applied. Administration method: The active ingredient of the present invention (3
3, 66, 200 mg / kg / day) or water (control group)
From 4 hours before virus inoculation, every 12 hours, twice a day, 4
It was orally administered daily. The progress of skin lesions was observed daily and evaluated as a numerical value as follows. 0: No lesion 2: Local eruption (blister formation or erosion formation) 4: Multiple erosion 6: Shingles formation 8: Shingles formation + ulcer formation D (10): Death Statistical treatment: control group and administration of active ingredient of the present invention Group mortality comparisons were performed by Fisher's exact test. A comparison of skin lesions after infection is made by Mann-Whitney.
U) It evaluated by the test.

The results are shown in Tables 1 to 4.

Table 1 Control group

Table 2 ▲ Kota-neto (33 mg / kg /
Day)

Table 3 ▲ Kota-neto (66 mg / kg /
Day)

Table 4 ▲ Katsuneto (200 mg / kg /
Day) As is clear from the above results, the active ingredient of the present invention is
It was confirmed to have excellent antiviral activity.

It should be noted that, since the active ingredient of the present invention, Kakon-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.

Therefore, the active ingredient of the present invention,
Neto is useful as an antiviral agent.

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 and an external preparation.

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 addition to the above-mentioned excipients, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc., may be appropriately used in this type of preparation. 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, calcium carboxymethyl cellulose, 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,
For example, when manufacturing external preparations such as ointments, lotions, and liniments, as a carrier (base), liquid paraffin, isoper, petrolatum, silicone oil, higher aliphatic alcohols (palmityl alcohol, oleyl alcohol) ), Higher fatty acids (myristic acid, stearic acid), fatty acid esters (microcrystalline wax, isopropyl myristate, etc.), lanolin, plastibase (mixture of liquid paraffin and polyethylene), polyethylene glycol, water etc. Is. In addition, if necessary, emulsifiers (fatty acid monoglyceride, sorbitan fatty acid ester, polyoxyethylene lauryl ether, etc.), wetting agents (glycerin, propylene glycol, sorbit, etc.), preservatives (methyl or propyl paraoxybenzoate, etc.), antioxidants Agent (BH
A), pH adjusting agent (citric acid, etc.), suspending agent (CMC)
Etc.) and other drugs (pruritus, analgesics, etc.) can be added. The above-mentioned external medicines include those intended for percutaneous absorption.

The formulation content of the active ingredient of the present invention varies depending on the dosage form, the age of the patient and the condition of the affected part in order to exert the intended effect, but in the case of an external preparation, it is generally 0.01 μm.
~ 5 μg / base g is suitable, 0.1-0.5 μg /
Base g is preferred.

Next, the present invention will be described in more detail by showing Examples of the preparation 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 ▲ Cut root hot water obtained in Example 1 160 g Total 200 g According to the above formulation, Then, compression molding was performed using a tableting machine to obtain 200 mg tablets. This tablet contains 160 mg of Kakkonto 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 silicic acid 1 g ▲ Katsuneto obtained in Example 1 160 g Total 200 g According to the above formulation, After compression molding with a machine, it was crushed with a crusher and sieved to obtain granules. 1 g of this granule contains 800 mg of Kakkonto obtained in Example 1, and 4 to 1 a day for adults
Take 8g in several divided doses.

Example 3 Cornstarch 19 g Light anhydrous silicic acid 1 g Katsuneto obtained in Example 1 180 g Total 200 g
Was filled in a No. 2 capsule. One capsule of this capsule contains 180 mg of Kakkonto obtained in Example 1, and 20 to 80 capsules for an adult are divided into several times and taken.

Example 4 300 g of alanine (containing no heat-generating substance) was added to 20 l of root hot water obtained in Example 2, dissolved and freeze-dried.
This lyophilized product was dispensed into 900 vials to obtain an injection. 1 vial of this injection contains 40 lyophilized products
It contained 6 mg and was easily dissolved in 10 ml of purified water. In addition, the injection solution after dissolution was 92% (550 nm)
It had a permeability of 10%, and passed the test method for pyrogenic substances of the Japanese Pharmacopoeia.

Example 5 Katsuneto obtained in Example 1 0.05 g Nezuto isopropyl myristate 5 g Plastibase 94.95 g The above-mentioned components (1) to (4) were mixed and gradually added to the mixture with stirring to homogenize the oily ointment. And

Example 6 Katsuneto obtained in Example 1 0.05 g isopropyl myristate 5.95 g isopropyl myristate 10 g vaseline 66 g liquid paraffin 5 g microcrystalline wax 13 g The mixed components were added at 45 to 50 ° C, and the mixture was stirred and homogenized until solidified to obtain an oily ointment.

Example 7 Katsukonto obtained in Example 1 0.05 g Polyethylene glycol (400) 11.95 g Polyethylene glycol (400) 12 g Polyethylene glycol (4000) 76 g The above ingredients were dissolved at 70 ° C. Was added to this at 50 ° C., and the mixture was stirred and homogenized until solidified to obtain a hydrophilic ointment. For hydrophilic ointment, add Calbol 9
34 can be blended.

Example 8 Katsuneto obtained in Example 1 0.01 g isopropyl myristate 5.99 g stearic acid 19 g cetyl alcohol 4 g polyoxyethylene lauryl ether 2 g glycerine monostearate 0.5 g propylene glycol 4 g quenque Acid 0.05 g Methyl paraoxybenzoate 0.05 g ◆ Paraoxybenzoic acid 0.05 g The above-is dissolved at 80 ° C., and then- ◆ containing distilled water 64.35 g heated and dissolved at 85 ° C. is added. Heat-dissolved ~ was added at 55 ° C, and the mixture was stirred and homogenized to give a cream.

Example 9 Root hot water obtained in Example 1 0.001 g propylene glycol 12 g polyoxyethylene lauryl ether 1 g isostearic acid 1 g octyldodecanol 4 g glycerin 3 g citric acid 0.075 g The above to 40 ° C. Was dissolved, and 78.924 g of distilled water was added to this with stirring to make a lotion.

Example 10 Rooted root hot water obtained in Example 1, 0.05 g Hydrocortisone acetate 0.5 g Diphenhydramine 0.5 g White Vaseline 4.85 g White Vaseline 95 Mixed into an ointment.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koji Terasawa 463-5 Horikawa-cho, Toyama City, Toyama Prefecture (72) Inventor Kazuhiko Nagasaka 300-127 Kitashiro, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. An antiviral agent containing Katsu root as an active ingredient.