JPH031289B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to antiviral agents. Compared to medicines for bacterial diseases, the development of medicines for viral diseases has lagged significantly.
Although many chemically synthesized substances have antiviral activity, many of them have severe side effects and are therefore difficult to put to practical use. Therefore,
It is hoped that an antiviral agent without side effects will emerge. The inventor focused on the fact that herbal medicines generally have few side effects, and searched for herbal medicine ingredients that had antiviral activity.
root bark, Moutan Cortex), Peony
The present invention was completed based on the discovery that 1,2,3,4,6-pentagalloylglucose, which is contained in herbal medicines such as Paeoniae root and Paeoniae Radix, has excellent antiviral activity. That is, this invention provides 1,2,3,4,6-
It is an antiviral agent whose active ingredient is pentagalloylglucose. 1,2,3,4,6-Pentagaloylglucose is found in Chemical and Pharmaceutical Products [Chem.Pharm.Bull. (Tokyo)] Vol. 28. No. 2850
(1980), and its structural formula is as follows. 1,2,3,4,6-pentagalloylglucose is derived from Botanpi (the original plant Botanpi) as a herbal medicine.
Paeonia suff-ruticosa), peonies (Paeonia albiflora), or their raw counterparts, or gallics (Nutgalls,
Galla halepensis), Chinese Nutgalls,
Galla Rhois), etc. are extracted with a hydrophilic organic solvent such as methanol, ethanol, acetone, or a mixture of these and water, and the extract is extracted using differences in solubility in various solvents, differences in affinity for various adsorbents, etc. It can be obtained by purification. Since the 1,2,3,4,6-pentagalloylglucose thus obtained has antiviral activity, it can be used to treat viral diseases such as herpes, chickenpox, and warts. for example,
The results of testing the antiviral activity of 1,2,3,4,6-pentagalloylglucose against herpes simplex virus are as follows. [Test method] 24 hours before the start of the antiviral test, a monolayer of dispersed FL cells was formed in a Petri dish with a diameter of 35 mm.
At the beginning of the test, the medium was removed from each dish and 1 ml of herpes simplex virus containing medium was added to each dish. Place each dish in a humidified, 5% _CO2 incubator for 36 hours.
After incubating for 1 hour at °C, add 1 ml of medium and 1,
An aqueous solution containing 2,3,4,6-pentagalloylglucose was added. After 24 hours, the number of multinucleated giant cells in each dish was determined, and the minimum concentration at which no multinucleated giant cells appeared was defined as the antiviral activity. The results are as follows.

[Table] Furthermore, as a result of examining the acute toxicity of 1,2,3,4,6-pentagalloylglucose using rats, it was found that the toxicity was extremely low. Although the antiviral agent of the present invention can be used as an orally administered drug or an injectable drug, it is particularly suitable for use as an external drug. External preparations include ointments (oil-based ointments, hydrophilic ointments), lotions,
Includes liniment agents, etc. When manufacturing external preparations, carriers (bases) such as liquid paraffin, Isopar, petrolatum, silicone oil, aliphatic higher alcohols (palmityl alcohol, oleyl alcohol, etc.), higher fatty acids (myristic acid, stearic acid, etc.) are used as carriers (bases). etc.), fatty acid esters (microcrystalline wax, isopropyl myristate, etc.), lanolin, plastibase (a mixture of liquid paraffin and polyethylene), polyethylene glycol, water, etc. are usually used. In addition, emulsifiers (fatty acid monoglycerides,
sorbitan fatty acid ester, polyoxyethylene lauryl ether, etc.), wetting agents (glycerin, propylene glycol, sorbitate, etc.), preservatives (methyl or propyl paraoxybenzoate, etc.),
Antioxidants (BHA, etc.), PH regulators (citric acid, etc.),
Suspension agents (CMC, etc.) and other drugs (antipruritics, analgesics, etc.) can be added. The above-mentioned external drugs also include those intended for transdermal absorption. Drugs for oral administration and drugs for injection are each manufactured by conventional methods. The content of 1,2,3,4,6-pentagalloylglucose, the active ingredient, varies depending on the dosage form, age of the patient, condition of the affected area, etc., but in the case of external drugs, it is generally 0.001 to 0.5%. Appropriate, 0.01~0.1
% is preferred. Next, a production example of 1,2,3,4,6-pentagalloylglucose and an example of the present invention will be shown. In addition, in the Examples, 1,2,3,4,6-pentagalloylglucose was abbreviated as "active ingredient." Production Example 1 50g of Botanpi was immersed in ml of methanol for one week and extracted. The extract was concentrated to dryness, and ether and water were added to the residue. The aqueous layer was separated and extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was lyophilized. This was dissolved in methanol and adsorbed on a Sephadex LH-20 column, then methanol was passed through it at a rate of 30 ml/hour, and the eluate was divided into fractions of 20 ml each. from each fraction
Take 50 μl each and dilute with 2.5 ml of methanol.
The absorption value at 254 nm was measured, and the results shown in FIG. 1 were obtained. The fractions indicated by A in Figure 1 are collected, concentrated and lyophilized to give crude 1, 2,
140 mg of 3,4,6-pentagalloylglucose was obtained. Production Example 2 The crude 1,2,3,4,6-pentagalloylglucose obtained in Production Example 1 above was dissolved in 20 ml of 25% methanol, 5 ml of which was adsorbed on a Licroprep RP-18 column, and then dissolved in 25% methanol. was passed at a rate of 5 ml/min. The adsorption value of the eluent at 254 nm was measured, and the results shown in FIG. 2 were obtained. This column chromatography was repeated four times. The portion indicated by B in FIG. 2 was collected, concentrated and lyophilized to obtain 125 mg of purified 1,2,3,4,6-pentagalloylglucose. This product was identified as the standard product by nuclear magnetic resonance spectrum. Production Example 3 Purified 1,2,3,4,6-pentagalloylglucose was obtained by processing in the same manner as in Production Examples 1 and 2 using 100 g of peonies. The antiviral activity of this product is
It was almost the same as the product of Production Example 2. Example 1 (A) Active ingredient 0.05g Isopropyl myristate 5g (B) Plastibase 94.95g (A) was mixed, and this was gradually added to B while stirring, and the mixture was homogenized to obtain an oily ointment. Example 2 (A) Active ingredient 0.05g Isopropyl myristate 5.95g (B) Isopropyl myristate 10g Vaseline 66g Liquid paraffin 5g Microcrystalline wax 13g B was melted by heating, and A, which had been mixed in advance with this, was mixed with 45 g of A.
The mixture was added at ~50°C and homogenized by stirring until solidified to form an oily ointment. Example 3 (A) Active ingredient 0.05g Polyethylene glycol (400) 11.95g (B) Polyethylene glycol (400) 12g Polyethylene glycol (4000) 76g B was melted at 70°C, and A pre-mixed with it was added.
The mixture was added at 50°C and homogenized by stirring until solidified to obtain a hydrophilic ointment. In addition, Carbopol 934 can be further blended into the hydrophilic ointment. Example 4 (A) Active ingredients 0.01g Isopropyl myristate 5.99g Stearic acid 19g Cetyl alcohol 4g (B) Polyoxyethylene lauryl ether 2g Glycerin monostearate 0.5g Propylene glycol 4g Citric acid 0.05g (C) Distilled water 64.35g Methyl paraoxybenzoate 0.05g Paraoxybenzoic acid 0.05g Melt B at 80°C, add C heated and dissolved at 85°C, further add heated and melted A at 55°C,
The mixture was stirred and homogenized to form a cream. Example 5 (A) Active ingredients 0.001g Propylene glycol 12g Polyoxyethylene lauryl ether 1g Isostearic acid 1g Octyldodecanol 4g Glycerin 3g Citric acid 0.075g (B) Distilled water 78.924g A was dissolved at 40°C and stirred into this. While doing so, B was added to prepare a lotion. Example 6 (A) Active ingredient 0.05g Hydrocortisone acetate 0.5g Diphenhydramine 0.5g White petrolatum 4.85g (B) White petrolatum 95g A was melted by heating and mixed uniformly with B to prepare an ointment.

[Brief explanation of the drawing]

1 and 2 are ultraviolet absorption curves at 25 nm of the fractions obtained in Production Examples 1 and 2, respectively.

Claims (1)

[Claims] 1. An antiviral agent containing 1,2,3,4,6-pentagalloylglucose as an active ingredient.