The method of obtaining funds with antitumor activity


A61K31/305 -

 

(57) Abstract:

The invention relates to medicine, in particular to the technology of medicines, and can be used to produce mercury-containing drugs with antitumor activity. The merits of the proposals is that the mercuric chloride dissolved in semi-natural white grape wine with a sugar content of 2.7 to 3.3%, or dry white wine, in which pre contribute sucrose in the amount of 27 to 33 g/l, after which the resulting solution is heated without direct access to open fire at 55 5C for 15 to 20 min and incubated the mixture at 5 to 10°C for 6 to 8 days. Studies on human leukocyte tumor cultures of the line L-41 showed cytotoxic activity on tumor cells.

The invention relates to medicine, in particular technology of drugs, and can be used to produce mercury-containing drugs intended for the treatment of various diseases as antitumor and immunomodulating tools.

There are various drugs that have anti-tumor activity, and methods for their preparation.

The known method the OIG way for the proposed drug.

In the patent of India described the process of obtaining a composition for the treatment of cancer soft tissue [1] the Method includes: mixing equal amounts of well crushed, sifted powdered mercury compounds: mercury dichloride (mercuric chloride, Hg2Cl2), mercury chloride (calomel Hg2Cl2), mercury sulfide (HgS), mercury oxide (HgO), mercury sulfate (HgSO4). The mixture is subjected to sublimation (sublimation). Collect the white crystalline desublimate. 1.0 g of the obtained desublimate pound (tracuriroot) with 10.0 g of lactose. This process is repeated 10 times. After the 10th operations take 1.0 g of the obtained product and add to it 10.0 g of absolute alcohol, vigorously shaken. The process of mixing and shaking of the initial components is repeated 100 times. The resulting 100-th operation, the product is mixed with lactose in a ratio of 1:5. Ready the product is Packed in 200 kg

The drug is obtained with this method is intended for internal use.

The method has the following disadvantages:

Used a complex composition that includes 5 mercury-containing compounds. Of them, sublimation (sublimation) when heated can be only two soybean sublimation 580aboutC). Oxide and mercury chloride at temperatures at temperatures above 400aboutTo decompose. Sulphate of mercury undergoes decomposition at temperatures above 500aboutC. These processes proceed according to the following equations:

2HgO __ 2Hg +O2< / BR>
Hg2Cl2___ HgCl2+Hg

HgSO4__ Hg + SO2+O2< / BR>
Thus, for the three mercury-containing compounds mentioned above, the process proceeds with the decomposition to metallic mercury (Hg, so pl. -39aboutWith so Kip. 357aboutC). Last fusible and volatile.

Not clear component part of the product at the final stage of its preparation. In the patent there is no analytical description.

In the process execution method is extremely difficult and laborious sufficient.

In U.S. patent describes the method of preparation of the composition, which is primarily intended for external use in the treatment of skin diseases such as psoriasis, eczema, ichthyosis and other [2]

A method of obtaining a composition is that in ethyl alcohol in a certain ratio dissolve camphor, oil of bitter almonds, oil of juniper berries and other components. Next in order add carbolic acid, in order to enable or to reduce the number.

To obtain the finished product mixture was kept from one day to one week to make it passed the chemical transformations.

It should be noted that ethyl alcohol is used as solvent in the preparation of this composition does not protect ions of mercury from their toxicity on the human body, so how can not contact with the mercury compounds in the coordination and relations.

The closest analogue of proposition is the method of getting cancer means on the basis of the dichloride of mercury (corrosive sublimate), used in folk medicine.

The method consists in dissolving 1.0 g of the dichloride of mercury (corrosive sublimate) in 3.0 liters of distilled or boiled (spring, well) water, followed by keeping the mixture for 6 hours Then 30.0 g of this solution are mixed with 3.0 l of water and the resulting solution was incubated for 12 h

However, obtained in a known manner, the drug is toxic, as in the preparation of the composition in solution do not enter any components that protect the ions of mercury from their toxic effects on the body. Water, which is used as the solvent does not have in its composition complexing compounds, reactivedifusive properties. In addition, when stored in aqueous solution and in contact with the air dichloride of mercury gradually decomposes and the drug loses its pharmacological properties.

The objective of the invention is the creation of an original method, which would allow to obtain a highly toxic drug with a wide spectrum of action.

The task of creating a highly effective and non-toxic drug on the basis of the dichloride of mercury (corrosive sublimate) is solved using the proposed method, which allows for a drug containing dichloride of mercury (mercuric chloride) and a solvent, to eliminate the toxic effects of mercury.

According to the invention can be obtained by different almustapha drugs in liquid dosage form. At the same time as solvent in technology use natural white dry or semi-dry wine.

Method depending on the used solvent can be carried out in the following ways:

1. When used as a solvent of dry white wine method is carried out as follows: first, prepare a solution of sucrose in the dry white grape wine. Next, to the resulting solution add the prepared solution of the dichloride of mercury in a solution of sucrose in the dry white grape wine is heated in a water bath (without access to direct fire) to 555aboutC for 15-20 min and then incubated solution in a dry, dark place for 7 days. (1 day).

The prepared solution of the drug after receiving positive results of the analysis in accordance with the requirements of the project VFS Packed in containers made of dark glass.

2. When using a semi-dry white wines phase dissolution refined sugar or sugar in the semi-dry white grape wine exclude. This is because semi-dry wines contain residual amounts of sugary substances (GOST R 50208-92 E).

The process of preparation of the drug is carried out by dissolving the dichloride of mercury (corrosive sublimate) is selected as the solvent a white, semi-dry grape wine. Subsequent processes: heating (at 555about(C) for 15-20 minutes and extracts (5-10aboutC) for 7 days. (1 day) carried out as described in method 1.

In the proposed invention the technology can be used following varieties of grape wines: Aligote, Riesling, Mtsvane, Ereti, Rkatsiteli, Saperavi, etc.

The choice in favor of a dry or semi-dry white wines was made because wine contains a large complex of substances as acute respiratory infections (mainly potassium), sugar, nitrogenous pectin and tannins, flavonols (quercetin), glycosides, phosphorus, trace elements Mn, Cu, Zn, Fe, Mg, F, Br and other b vitamins: B1B2,.B6B12group P, PP and C. In the grape wine contains enzymes: diphenol and polyphenoloxidase, which causes permanent change of wine (especially young wines). Grape wine its composition is close to the juice of raw materials. The main difference between wine from grape juice is that in the wine during fermentation (fermentation) are formed: ethyl alcohol, glycerin, lactic, succinic acid, and during the exposure, aldehydes, acetals and esters. The alcohol and sugar content of grape wines are divided into: natural dry, dry special, semi-dry and semi-sweet. The volume fraction of ethyl alcohol for dry, semi-dry wines 9-13% Mass concentration of sugars, g/l: for dry wines of not more than 3, no more than semi 5-25. Mass concentration 1 l: titratable acids 3-8 g, iron 3-20 mg of copper should not exceed 5 mg. special Fermentation fermentation fungi yeast (from a kind of Saccharamyces cerevisiae, called Saccharomyces cerevisiae) into alcohol and carbon dioxide. Winemaking is based on the use of wild yeasts present on the skins of the berries. Another is the founders (for example, alcohol, water and others) is its acidity (pH of 3-3 .5). Acidic environment determines its bactericidal properties (cholera and typhoid organisms die in it within 5-30 min). Wine can easily penetrate through intact skin and mucous membranes, which, in turn, facilitates the penetration into the body of the main active substances of the preparation of the dichloride of mercury (mercuric chloride, HgCl2).

The process of preparation of the drug on the basis of the dichloride of mercury (corrosive sublimate)

In dry white grape wine (wine is listed above) at room temperature (18-20about(C) dissolve the sugar, using refined sugar or granulated sugar in concentrations that mass fraction of sucrose in the composition of the drug at the final stage was 27-33 g/L. Introduction sucrose ex tempore in dry white wine as an additional component aims to strengthen the protective properties of wine relative to the main component of the drug to the dichloride of mercury (corrosive sublimate) due to the hydroxyl groups in the molecule of sucrose.

To prepare the drug to 2,7-3,3% sucrose solution in dry white grape wine add dichloride of mercury, mix to obtain a solution. The resulting solution Ni in the sucrose solution in dry white grape wine is left to extract for 7 days. (1 day) at 5-10aboutC.

The process of heating of a solution of the dichloride of mercury in a solution of sucrose in the dry white grape wine is carried out with the purpose to intensify the reaction of interaction of ligand components of wine, namely enzymes, tannins, pectins, organic acids, sugars and other ion mercury (Hg2+).

Ion mercury (Hg2+) has a strong complexing ability with many ligands with only one donor atom, especially a nitrogen atom (N) or sulfur atom (S). A chemical reaction takes place due to the sulfhydryl (SH), hydroxyl (Oh), amino (NH2and a number of other groups contained in the molecules of these components on the coordination ion relations of mercury. As a result of reaction formed stable mercury-containing molecular complexes; high acidity of the drug contributes to the formation of complex compounds of mercury due to the carboxyl C anions of organic acids in grape wine. Strength of binding of mercury cation (Hg2+)with the ligands and the stability of the resulting mercury-containing complexes in a drug depends on pH. In the acidic environment of mercury ions (Hg2+) capable of forming hydroc the BU the drug due to the fact, all available communication ion mercury (Hg2+) coordinating work and no toxicity.

An important feature of the final product is the fact that the main active component of his dichloride contains mercury ion (Hg2+), which is one of the most strongly binding of metal ions is exposed and rapid ligand exchange, which is an important characteristic of mercury toxicology.

In humans, mercury-containing complexes dissociate, free mercury ions (Hg2+), interacting with sulfhydryl groups of protein molecules (for example, it is known that many forms of tumors are accompanied by impaired production of enzymes, proteins and hormones), block their action, create the desired anti-tumor effect, and then excreted through the kidneys, saliva and skin when sweating.

The advantage of the proposed method to obtain the drug known is that the drug is recommended for use in dosage form and physico-chemical characteristics of his subject project at VFS.

In the production of this drug is expensive equipment is not required, the technology princeska weight) of dry white wine "Aligote" add 246,0 g of refined sugar. The mixture was thoroughly stirred with a stick until sugar is dissolved. 0.1 l of the resulting solution is passed to the analytical laboratory for analysis on the content of the mass fraction of sucrose.

Get 8,1 l (by volume) solution of sucrose in the dry white grape wine "Aligote". The output is 98.8% considering the source refined sugar.

Next, in a glass beaker with a capacity of 1 l pour 0.5 liters of the prepared solution of sucrose in the dry white grape wine "Aligote", added 2.7 g of dichloride of mercury (corrosive sublimate) and the mixture was thoroughly stirred with a glass rod to dissolve the component.

10 l bottle, equipped with a plastic funnel, using a measuring cylinder, pour 7 l of a solution of sucrose in the dry white grape wine "Aligote". Added thereto in small portions while stirring the mixed solution of the dichloride of mercury (corrosive sublimate). Then the volume in the bottle was adjusted to 8.1 l by the addition of 0.6 l of sucrose solution in dry white grape wine "Aligote". The resulting solution is stirred with a wooden stick for 5-10 minutes

The bottle with the prepared solution of the dichloride of mercury (corrosive sublimate) is placed in a water bath and heated with stirring wooden Palo is it in natural conditions, the solution is cooled to about 19-20aboutC. After cooling, the bottle of solution is kept for aging in a dry, protected from light place at a temperature not lower than 50aboutWith and not higher than 10aboutWith in 7 days. After a specified period of time take samples of the solution in the amount of 0.3 l and passed to the analysis in the analytical laboratory for compliance of its quality project VFS on the drug.

Get 7,8 l (by volume) solution of dichloride of mercury (corrosive sublimate) in sucrose solution in dry white grape wine "Aligote". The output is 96,3% considering the source dichloride mercury content of the basic substance is not lower than 0.30 mg/ml

Physico-chemical characteristics of the drug.

Slightly opalescent liquid from light yellow to intense yellow color with a smell of wine. When standing, a precipitate may form.

With a solution of potassium iodide forms a red precipitate, soluble in excess of potassium iodide (GF X, S. 746, reaction B, mercury oxide).

With a solution of silver nitrate a white curd-like precipitate, soluble in ammonia solution (GF X, S. 747, chlorides).

With a solution of cobalt nitrate and a solution of caustic soda appears blue staining (sucrose).

Mass fraction of sucrose in the Prem3.

P R I m m e R 2. The method is carried out as described in example 1 with the difference that the solvent of the dichloride of mercury (corrosive sublimate) using semi-dry white grape wine.

Because semi-dry white grape wine contains sweeteners refined sugar in the preparation of the drug is not used. The process of obtaining the drug begin with the dissolution of the dichloride of mercury (corrosive sublimate) in semi-dry white grape wine.

In a glass beaker with a capacity of 1.0 liter pour 0.5 liters of semi-dry white wine "Saperavi", it added 2.7 g of dichloride of mercury (corrosive sublimate) and the mixture was thoroughly stirred with a glass rod to obtain a solution.

Next, the process carried out as described in example 1.

Physico-chemical characteristics of the drug.

Physico-chemical parameters of the preparation obtained according to example 2 are the same.

Toxicological characteristics of the drug.

ED50to 9.9 ág/ml

Antitumor activity of the drug on transplantable tumor cultures.

The study was conducted on human leukocyte tumor cultures of the line L-41.

The cultivation of the cult is as nutrient medium used in equal proportions environment 199 Wednesday Needle with the addition of 10% bovine serum and antibiotics: 100% penicillin, 50 units of streptomycin per 1 ml of medium. Drug separately wine and the dichloride of mercury (mercuric chloride) was diluted in protein-free culture medium and made them in different concentrations of 3-4 culture for contact with the cell monolayer. As applicable early in the drug is the dichloride of mercury (corrosive sublimate), we are in the preliminary experience for comparison found that the ED50corrosive sublimate, inhibiting the growth of tumor cultures L-41 is less than 10 μg/ml On the second day after setting experience produced microscopy microscopic evaluation of drug action on a 4-point system and quantitative determination of the protein content of the cultures by the method of Lowry modification OYAMA and eagle.

Criterion cytotoxic activity of the drug, the percentage of inhibition of growth inhibition of protein synthesis.

The study showed that ED50the drug is 9.9 µg/ml, U50corrosive sublimate approximately 8 μg/ml of Affinity values U50suggests that the active principle in the preparation is to sublimate. Grape wine in the tested concentrations has a slight stimulating effect on the culture to 10%

According to existing standard methods of selection is equal to 100 mcg/ml.

Studies have shown that ED50the drug is 10 µg/ml, which is 10 times higher than the standard and is indicative of his pronounced cytotoxic effect on tumor cultures.

Clinical trials of the drug obtained by the proposed method, confirmed a wide range of therapeutic actions.

Drugs effective in the treatment of various cancers, skin diseases and ulcers.

The METHOD of OBTAINING FUNDS with ANTITUMOR ACTIVITY, including the dissolution of mercuric chloride in a solvent and then curing the mixture, characterized in that the solvent used semi-natural white grape wine with a sugar content of 2.7 to 3.3%, or dry white wine, in which pre contribute sucrose in the amount of 27 to 33 g/l, after which the resulting solution is heated without direct access to open fire at a temperature of 50 60oC for 15 to 20 minutes, and the curing is carried out at 5 to 10oC for 6 to 8 days.

 

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