JPH05255367A - Production of cantharidin derivative composition and anti-viral agents containing it - Google Patents

Abstract

PURPOSE: To obtain cantharidin derivative composition that have oil-solubility, dissolution stability, and superior therapeutic effect and useful for treating viral diseases, by thermal reacting cantharidin with fat and oil, fatty acid or the like.

CONSTITUTION: Cantharidin or its free acid is reacted thermally with fat and oil such as bean oil, fatty acid such as lauric acid and/or aliphatic alcohol such as octylalcohol at a temp. of 80-210°C to obtain the objective composition. Preferably, the composition is contained in an anti-viral agent by 0.00005-0.005 weight % in terms of cantharidin.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a novel cantharidin derivative composition having improved oil solubility.

[0002]

2. Description of the Related Art Cantharidin is contained in an insect, Hanmyo, and a dry powder of the insect has been used as a crude drug Cantharis as a raw material for Cantharis preparations. For example, an ointment prepared by adding beeswax, pine butter, beef tallow, turpentine oil and the like to Cantalis powder has been used as a blistering agent and skin stimulant in Chinese medicine for a long time.

In recent years, cantharidin has been isolated as a pure product having the following formula, various physiological activities have been revealed, and it has been reported that it is effective for viral infections such as antiviral hepatitis.

[0004]

[Chemical 1]

[0005]

Although cantharidin is oil-soluble, it is necessary to further increase solubility and dissolution stability in order to produce various preparations as a medicine. An object of the present invention is to provide a cantharidin derivative composition having higher solubility than cantharidin.

[0006]

In the present invention, by heating and reacting cantharidin or its free acid with fats and oils, fatty acids and / or aliphatic alcohols, the acid anhydride group of cantharidin of the above formula is opened. The generated carboxyl group and / or epoxy group in the ring is reacted with fats and oils, fatty acids and / or aliphatic alcohols to cause various reactions such as esterification reaction, etherification reaction and / or ester conversion reaction. It has been found that a novel composition of matter is obtained, which improves solubility and efficacy.

The heating reaction in the method of the present invention is carried out at 80 to 210 ° C. with stirring under normal pressure. About 105 ℃
Then, cantharidin dissolves rapidly in fats and oils, and the solubility increases with increasing temperature, but the maximum temperature range is 102 ~.
It is 110 degreeC. In this temperature range, dissolution and reaction
Stir continuously to complete within 30 minutes. Although some of the above-mentioned fats and oils react with cantharidin or its free acid,
The rest will be the solvent for the cantharidin derivative produced, so
When the cantharidin derivative is 0.0001 to 0.1% by weight (in terms of cantharidin), and in addition to the above fats and oils, 0-4% by weight of hanmyo oil and 0 to 2% by weight of an antioxidant are added, and the mixture is heated and reacted. A cantharidin derivative composition having improved solubility and stability after dissolution is obtained.

As the fats and oils, for example, soybean oil, corn oil, rapeseed oil, sunflower oil, sesame oil, cocoa butter, myristin and beef tallow are used, and as the fatty acids, for example, lauric acid, palmitic acid, stearic acid and oleic acid are used. . Examples of the aliphatic alcohol include octyl alcohol, nonyl alcohol, propylene glycol,
Glycerin and polyethylene glycol are used.

In order to obtain purified cantharidin from Cantharis, Cantharis (agar powder) is immersed in an organic solvent such as acetone, chloroform, dichloromethane or trichloromethane for extraction. The residue is dried and then re-extracted by immersing it in concentrated hydrochloric acid-acetone solution again to separate concentrated hydrochloric acid and the formed inorganic phase. Recovery of the organic solvent from both organic phases yields a crude mixture of catalidine and algal oil. Petroleum ether is added to this, and the operation of extracting Hanmyo oil is repeated, washed with alcohol, and recrystallized to obtain crystalline cantharidin.

The cantharidin derivative composition obtained by heating and reacting the above crystalline cantharidin or its free acid with fats and oils as described above is an antioxidant such as lecithin, gallic acid ester, vitamin C, and vitamin C, if necessary. E, BHT, and BHA are added, and further various types of ointments are added according to various preparations, and ointments, lotions, tablets, injections, suppositories, aerosols and the like are manufactured by a conventional method.
The content of the cantharidin derivative composition in these preparations is 0.00005 to 0.005% by weight in terms of cantharidin.

[0011]

【Example】

Example 1 To 0.1 g of crystalline cantharidin, 250 g of soybean oil and 1 g of algal oil were added and heated under normal pressure. When the temperature reached 105 ° C., cantharidin was dissolved. Furthermore, the temperature was raised to 210 ° C. and a heating reaction was carried out for 30 minutes. The obtained mixture of cantharidin derivative and fats and oils can be used as it is as a drug substance.

Test Example 1 Therapeutic Effect of Condyloma acuminata The therapeutic effect on Condyloma acuminata was tested using a cream having the following composition. Cantharidin derivative obtained in Example 1 and mixture of fats and oils and alum oil 25 g Emulsified wax (stearyl alcohol 90 g + sodium lauryl sulfate 10 g + purified water 4 ml) 12 g purified water 10 m
l

[0013] A cream was applied daily around the affected area of a patient with Condyloma acuminata who had six red-colored rice grain-like protruding warts on the male foreskin tether. On the first day one disappeared and the others turned white, on the third day all the warts disappeared or shrank, and on the fifth day they recovered normally.

Test Example 2 Therapeutic effect against viral hepatitis The therapeutic effect against acute hepatitis B viral hepatitis was tested using an intravenous injection solution having the following composition. Cantharidin derivative obtained in Example 1 and mixture of fat and oil and erythroid oil 10 g Emulsifier (lecithin) 0.7 g Purified water 100 ml

Prior to treatment, the patient had a low GPT and exhibited severe jaundice. Table 1 shows the therapeutic effects after 4 weeks of intravenous injection of 3 ml twice a day.

[0016]

[Table 1]

[0017]

INDUSTRIAL APPLICABILITY The cantharidin derivative composition produced by the method of the present invention has improved solubility in oils and fats and improved stability of solubility, so that the therapeutic effect on viral diseases is improved.

Claims (10)

[Claims] 1. A process for producing a cantharidin derivative composition, which comprises reacting cantharidin or its free acid with an oil, a fatty acid and / or an aliphatic alcohol by heating. 2. The production method according to claim 1, wherein the heating reaction is carried out by adding ruminal oil to the oil or fat. 3. The method according to claim 1, wherein the heating reaction is carried out in the presence of an antioxidant. 4. The method according to claim 1, wherein the heating reaction is carried out at 80 to 210 ° C. 5. The method according to claim 4, wherein the heating reaction is performed at 102 to 110 ° C. 6. An antiviral agent comprising a cantharidin derivative composition obtained by reacting cantharidin or its free acid with an oil, a fatty acid and / or a fatty alcohol by heating. 7. The content of the cantharidin derivative composition in terms of cantharidin is 0.00005 to 0.005% by weight.
The antiviral agent according to claim 6. 8. A cantharidin derivative in an amount of 0.0001 to 0.1% by weight (in terms of cantharidin), 0 to 4% by weight of kansai oil and 0 to 2% by weight of an antioxidant in an oil, a fatty acid and / or an aliphatic alcohol. The antiviral agent according to claim 6 or 7, which comprises a cantharidin derivative composition containing the same. 9. The antiviral agent according to claim 6, which is an antihepatitis viral agent. 10. An anti-condyloma drug as claimed in claim 6.
The antiviral agent according to any one of 1.