For the treatment of chronic alcoholism

 

(57) Abstract:

The product contains as active principle purified lipophilic extract of Salvia miltiorrhyza Bunge, including Tanshinone IIA and Miltirone (active start). The tool reduces the consumption of alcohol. 3 C. p. F.-ly, 4 Il.

The present invention relates to pharmaceutical compositions for the treatment of chronic alcoholism, characterized in that they contain as active principle purified lipophilic extract of Salvia miltiorrhyza Bunge. The invention also relates to a method of obtaining purified lipophilic extract of Salvia miltiorrhyza Bunge and thus obtained extract. Moreover, the invention relates to the use of pure active principles contained in this extract (Tanshinone IIA and Miltirone) in the treatment of chronic alcoholism, and to pharmaceutical compositions for the specified treatment, which contain as active principles Tanshinone IIA and/or Miltirone.

Alcohol abuse and chronic alcoholism phenomena, which together can be attributed to the term "alcoholism", posing a serious problem of the modern society (Gessa G. L., Bisogno compulsivo di bere e principio del piacere" [The compulsive need to drink and the pleasure principle] in Medicina delle tossicodipenden and more than 1 million people are dependent on alcohol (Calamo-Castro F. P. Epidemiologia Dell alcogolismo in Italia [Epidemiology of alcoholism in Italy] in Atti del VII Congresso Nazionale della S. I. A. [Records of the 7thNational Congress of the S. I. A.] Mediserve, Rome, 295-301 (1991)). These figures are much higher, if we consider countries such as the United States of America, where more than 13 million addicted to alcohol. Alcohol abuse and valid chronic alcoholism lead to huge public expenditure (recently, since 1991, in the United States annually consumes about 200 thousand million dollars) and are a cause of great social and psychological harm addicted persons.

Existing approaches for treating alcoholism in addition to the approaches of psychological nature (group therapy, etc) include the use of drugs such as disulfiram and urea calcium, which act on the metabolism of alcohol by inhibiting (suppressing) aldehyddehydrogenase liver, and, consequently, increasing the levels of acetaldehyde in the blood, together with undesirable phenomena, which are observed every time when taking alcohol.

In accordance with the present state of the prior art the only plant derived which use the koi medicine and is the subject of patent application WO 93/00896.

At present, it was unexpected to find that purified lipophilic extract of the roots of Salvia miltiorrhyza Bunge can be successfully used to reduce the voluntary consumption of alcohol and other drugs that cause a tendency to last. Moreover, it was also proved useful are separate pure products isolated from the extract, such as Tanshinone IIA and Miltirone. The dried roots of Salvia miltiorrhyza Bunge (Danshen, Radix Salviae miltiorrhyzae) are officially listed in the Chinese Pharmacopoeia; they are widely used for the treatment of menstrual disorders, cardiovascular diseases such as angina and disorders of platelets, as well as insomnia (Tang W, Eisenbrand G. Salvia miltiorrhyza Bge., in Chinese drugs of plant origin; Chemistry, Pharmacology, and Use in Traditional Chinese Medicine, p. 891-902 - Springer-Verlag, Berlin (1992); Kee Chang Huang, Antianginal Herbs in The Pharmacology of Chinese Herbs, p. 81-84 - CRC Press, Boca Raton (1993)).

It is also known the use of hydro-alcoholic extracts of Salvia miltiorrhyza for the local treatment of excess fat (patent Italy 1239281).

The extract according to the invention differs from the known; it is lipophilic type and is obtained by solvent extraction of the roots of Salvia miltiorrhyza acetone at temperatures between about 20 and 50oSNO 1:5. After a decrease in the concentration of from about 1/20 to 1/50 of the original volume of water is added and is not miscible with water, the solvent. After dilution, if necessary, 95oethanol, remove the acetone by means of repeated washings with water until the concentrated organic phase containing the active agent.

Lipophilic extract of the present invention is characterized by the presence of the content of Tanshinone IIA from 5 to 30% weight/weight, preferably from 15 to 25%, and Miltirone from 0.5 to 3% weight/weight, preferably from 0.8 to 2%.

Determination of inhibitory effect on alcohol consumption, make use of a line of rats consuming alcohol, called "Sardinian alcohol-preferring" (Sp) (Fadda F., Mosca E., Colombo g, Gessa G. L., Alcohol-preferring rats: Genetic sensitivity to alcohol-induced stimulation of dopamine metabolism, in Physiol. Behav. 47, 727 (1990)).

In the last few years to determine the effect of various substances on a voluntary alcohol consumption was successfully used those animals that had a free choice between alcohol and water and consumed daily from 6 to 7 g of alcohol per 1 kg of body weight (with a ratio of water to alcohol of more than 2:1); see, for example, Balakleevsky A., Colombo, G., Fadda f, Gessa G. L., Ro 19-4603, a benzodiazepine receptor inverse agonist, attenuates voluntary ethanol consumption in rats selectively bred for high ethanol s, in Alcoholism: Clinical and Experimental Research 16(3), 449-452 (1992).

The animals were kept in normal conditions, received a free choice between water (which has always existed) and alcohol (10% solution V/V), which was offered for 4 h per day (i.e. the first 4 h of the dark during the day/night cycle). Consumed amount of water and alcohol write every day at the same time. Food was provided without restrictions. Upon reaching the constant consumption of alcohol and water was administered orally with various doses of purified lipophilic extract of Salvia miltiorrhyza (obtained as above), dissolved in dimethyl sulfoxide in volume 2 ml/kg once daily for 5 consecutive days. As control was used an equal volume of media. At the end of the treatment record water consumption and alcohol up until the recorded values before treatment will not be re-installed. Statistically significant difference from the average values obtained in the group treated only with vehicle (*p<0,05, **p<0,01) estimated using the Dunnet test for multiple comparisons.

In Fig. 1 shows the effect of repeated oral administration of increasing doses of the extract of n is shown in Fig. 3 shows the effect on consumption of alcohol, resulting from repeated doses of both extracts and active principles contained in it (Tanshinone IIA and Miltirone); and, finally, in Fig. 4 shows the effect on the water consumption of the extract and the above-mentioned active principles under repeated doses.

From the analysis of Fig. 1 and 2 it can be concluded that the extract significantly reduces the consumption of alcohol and dependent dose-dependent manner, in some cases, this result is achieved (i.e., in higher doses) after the first day of injection. Reducing alcohol consumption is kept constant until the fifth day and then regresses after stopping treatment. Moreover, it should suddenly be noted that this trend is accompanied by a tendency of gradual increase in water consumption, as if the animal had replaced it instead of alcohol. This last observation is particularly important, because it shows that treatment with the test product is well tolerated, and the animal is returned without any difficulty to a more physiological life cycle, using water instead of alcohol.

Introduction in regular doses, repeated for 5 days, as extra onanti - taking into account doses are the main factors responsible for the action of the extract.

The invention therefore provides pharmaceutical compositions that can be administered orally and which contain as active principle or lipophilic extract of Salvia miltiorrhyza, or purified active principle Tanshinone IIA and/or Miltirone, the latter may be obtained from commercial sources, or by using conventional cleaning lipophilic extract. The composition of the invention in addition to the customary excipients or carriers will contain from about 10 to about 500 mg of the extract or equivalent doses of Tanshinone IIA and Miltirone, taken with regard to their content in the extract.

Example 1

Getting lipophilic extract

1 kg of the pulverized roots of Salvia miltiorrhyza extracted 4 times with 5 l of acetone at 50oC. Re-combined extracts are concentrated under vacuum to 500 ml, the concentrate is diluted with 1 l of methylene chloride and 500 ml of H2O. the Phases are separated, and the organic phase containing the active agent, washed with water until until deleted acetone and unwanted polar substances.

Phase chloromethylene concentrated to small volume; astatke drying over night get 11.3 g of extract, containing 15.2% of Tanshinone IIA and 1.1% Miltirone.

Example 2

The composition in the form of capsules

Each capsule 130 mg contains mg:

The extract of example 1 - 25

Pre gelatinizing starch - 25

Microcrystalline cellulose - 49

Lactose - 15

The colloidal silica - 6

Cross-stitched sodium carboxymethyl cellulose and 6.5

Polyvinylpyrrolidone - 2,5

Magnesium stearate - 1

Example 3

The composition in the form of tablets

Each tablet 400 mg contains mg:

The extract of example 1 - 100

Pre gelatinizing starch - 100

Microcrystalline cellulose - 96

Lactose - 45

The colloidal silica - 25

Cross-stitched sodium carboxymethyl cellulose - 20

Polyvinylpyrrolidone - 10

Magnesium stearate - 4

Miltirone

5,6,7,8-tetrahydro-8,8-dimethyl-2-(1-methylethyl)-3,4-penentration, 9CI. 5,6,7,8-tetrahydro-2-isopropyl-8,8-dimethyl-3,4-phenantroline, 20-Nor-5,7,9,13-abilateral-11,12-dione. Rosmarino.

< / BR>
Tanshinone P

6,7,8,9-tetrahydro-1,6,6-trimethylpentane[1,2-b] furan-10,11-dione, 9CI. 14,16-epoxy-20-nor-S(10),6,8,13,15-abiertamente-11,12-dione, Tanshinone PA.

1. The use of lipophilic extract of the roots of Salvia miltiorrhyza Bunge, containing 5 to 30%/nshinone IIA as a means for the treatment of chronic alcoholism.

3. The use of Miltirone as a means for the treatment of chronic alcoholism.

 

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