Radioprotection composition and method for producing the composition

FIELD: medicine.

SUBSTANCE: method involves utilizing bioflavonoid production waste products from larch wood for obtaining preparations possessing antiradiation activity containing 1-3% by volume of 5-dihydroquercitine and 99-97% by volume of Arabinogalactane.

EFFECT: high antiradiation activity; no additional drugs required; increased bioavailability.

5 cl, 2 dwg, 2 tbl

 

The invention relates to medicine and relates to ways to protect the body during irradiation, particularly to compositions with radioprotective properties and the way it is received, and may find application in radiobiological experiment in clinical and agricultural practices in the territories with radioactive contamination.

To solve the tasks previously used traditional media with different action: chelators, Immunostimulants, anti-bacterial and anti-fungal drugs, radioprotectors. The latter include as specific compounds, for example, sulfur-containing (Kuna P. Chemical radiocasete. M, 1989), phosphorus (EN 204969), and nonspecific, particularly vitamins E and C.

This nonspecific radioprotectors are distinguished by the fact that in addition to the radioprotective (expressed significantly weaker than the specific means) action possess immunomodulatory, wound healing, antiviral, or any other activity that contributes to the survival of organisms exposed beam to defeat, not only in the first days after irradiation, but in the later period, when manifested complications and disorders not only because of the "radiation syndrome", but also from various bodies.

Non-specific radioprotectors also carrying the camping bioflavonoids, of quercetin and dihydroquercetin (DQC), which are used in the adjuvant drugs and biological additives, in addition to possessing radioprotective also a tonic effect (RU 2065278; EN 2187319; EN 2043030).

Dry milk products and milk products according to EN 2043030 possess radioprotective properties by adding them from 0.005 to 2% DQC and 0.005-1% ascorbic acid. However, the composition is a food product, i.e. at high nutritional value and has a weak radioprotective effect, and in addition, it is unacceptable for individuals with allergies to dairy products or any other diet.

The aim of the present invention is to provide a drug with a higher radioprotective effect. This effect provides a composition under the trade name "sofular"containing 97-99% of arabinogalactan (AG) and 1-3% of the DQC. Siilar has a pronounced radioprotective action. The preparation can be performed in a standard dosage form suitable for oral administration.

Traditionally, AG was used as a non-toxic filler or polymer carrier when creating medicines (US5912008; US6372194; US6399086), and as a tool for the diagnosis of some bacteria possessing a weak antibacterial effect (EP 13 8784). Identified some immunological activity of AG (Phytochemistry 1988, 27(8), 2511-2517).

The KV (3,5,7,3',4'-pentahydroxyflavanone), as bioflavonoid has a multidirectional action and is more widely used in composition with other flavonoids for the treatment of a wide range of diseases (RU2090205; WO 93/23096; DE 4432947; WO 96/10341; US 5424331; EP 719554 and others). In particular, it is known for its radioprotective action (Iltchenko T.U. and other "Pharmacology and toxicology", 1975, No. 5, s-612).

It has been unexpectedly found that the combination of DQC with hypertension in the claimed ratio has a radioprotective effect is stronger than the effect of the DQC when used alone. In addition, AG as a traditional filler can serve as a necessary component in the creation of a drug without the introduction of other additional excipients: composition in the claimed ratio of ingredients is stable, flexible and allows you to tablet finished dosage form in which the number of DQC determined by the weight of the finished tablet.

As a result of the research it was found that the efficiency of DQC as radioprotector increased in the absence of other bioflavonoids and had more directed action.

Example 1.

Radioprotective properties DQC varying degrees of purity and different compositions

The experiment was conducted on 6 groups of mice CBA average weight 20 g, 10 animals in each group subjected externally the mu gamma irradiation at 3.0 Gy (dose rate - 41,13 rad/min) on the "Gamma Cell"; the exposure time is 7 minutes and distance from the source to 12.5 cm). DQC different purity was administered intragastrically at a rate of 1 mg per mouse in a suspension in 3%starch solution or in the form of a mixture with hypertension for 20 min before irradiation; the control group received a starch suspension.

Was prepared following the preparations for the introduction of groups of animals: DQC with a purity of 93% (additionally included dihydrokaempferol and naringenin) in a starch suspension; DQC with a purity of 98% starch suspension; the mixture DQC (0,05%) and AG (99,5%); a mixture of DQC (1-2%) and AG (99-98%); a mixture of DQC (3%) and AG (97%).

The effectiveness of the treatment was tested on the content of leukocytes in the peripheral blood after 9 days (account conducted using a counting chamber Volume-Goryaeva) and the number of cells in the marrow of the femur within 14 days, respectively, after irradiation. The results of the experiment are shown in tables.

As can be seen from table 1, both of the analyzed indicators cleaner product containing 98% DQC, had a stronger and more pronounced effect than less pure, with content DQC 93%. Thus, the parameters of the control group cellularity of the bone marrow was different from the group with 98% of the DQC in starch in 2.1 times against differences in 1.7 times for groups with 93% of the DQC in starch.

The difference from control was intensified as a result of the introduction instead of a starch composition with hypertension (table 2). the contents of the white blood cell count was significantly higher after the introduction of Sofiero, than after the introduction of the DQC in starch, which shows the advantages of the claimed composition. Indicators cellularity of the bone marrow for Sofiero were also higher, although these differences were not statistically significant. However, reduced to 0.05% content DQC in a mixture with hypertension, although he had a radioprotective effect, but the results were not statistically significant different from the control group of animals.

Thus, the presented results showed that the content of the DQC from 1 to 3% vol. mixed with AG has the most pronounced radioprotective action. It is not excluded that this additional effect may be due not only to the mutual strengthening of the immunomodulating activity of the components, but also prolongation radioprotective effect DQC due to the special molecular structure of the polysaccharide.

It should also be noted the increase of bioavailability of the DQC in the proposed composition, as well as the fact that the above results do not reflect the possible strengthening antibacterial, antifungal, antiviral action, also contribute to the protection damaged by irradiation of the skin. Not identified toxic or any unwanted side effects of the composition when it intragastric administration to rats at a dose of 200 mg/kg

The increase in the content of DK is in the composition up to 5% would not lead to additional strengthen the radioprotective effect and therefore is not appropriate.

This drug can also be used on traditional for DCK purpose: as a source of vitamin e, an antioxidant, hepatoprotector, immunomodulator, anticancer drug and as probiotic fiber.

Another aspect of the present invention is a method of obtaining the specified composition sofular"

Known methods for producing compositions of AG impurities bioflavonoids. So, EN 2040268 describes obtaining AG from sawdust larch wood by extraction with water at ordinary (room) temperature, filtration, evaporation of an aqueous extract, purification from phenol impurities by the addition of acetone, the decantation of the supernatant liquid, washing the obtained precipitate AG acetone and drying. The resulting product contained 2.4% of impurities in the form of a mixture DQC with dihydrokaempferol.

According to EN 2143437 mixture containing up to 98-99% of AG impurities in the form of 0.01% of the mixture DCK with other bioflavonoids, can be obtained from waste DQC by processing the cooled after removing DQC aqueous extract solutions of coagulant and flocculant, deposition acylovir alcohol, washing the precipitate with ethanol and drying.

Instead of deposition is known to use for selection of AG from a solution of polyamide sorbent as described in EN 2002756 (method not found is rasprostraneniya because of the complexity and high cost of working with sorbents on an industrial scale); or ion-exchange column according to EP 138784 (method leads to large losses of AG and sophisticated technology makes it unreasonably expensive).

Proposed in the present invention the method is concerned, as EN 2143437, the use of waste products DQC worked larch sawdust. However, the method is not getting AG high purity, and drug with specific content DQC with radioprotective action. In connection with the intended purpose of the method is distinguished by its use as a solvent instead of acetone or acetonitrile, only ethanol for remaining solvent in the finished product did not lead to unwanted side effects or toxicity.

In addition, the proposed method ensures the absence copilarie of naringenin and quercetin that αform poisonous. Missing in it and other bioflavonoids that reduce, as shown above, its effectiveness for the claimed purpose.

The method consists in the following: spent the selection DCK from larch wood by extraction with ethyl alcohol at room temperature in the periodic system; the extract obtained was evaporated; maintaining a temperature of 60°With over half of the extract was besieged by the resin; put the mother liquor in the refrigerating chamber for crystallization; dropped the s in the sediment DQC and other bioflavonoids were separated by filtration under vacuum; were extracted waste sawdust with water at a temperature of 80°With (strictly) in the periodic system; the extract obtained, depending on what content DQC wanted to get either dried or additionally was extracted with ethanol, and the precipitated product was filtered and dried. To illustrate the method provides the following example.

Example 2.

A method of obtaining a composition with a content of DQC 2-3 vol.%

Sawdust larch wood were processed to highlight the DQC and other bio-flavonoids as described above; then 130 kg of waste sawdust filled in 350 liters of water at a temperature of 80°With (strictly) and was extracted with 2 hours in the periodic system; received 300 l of extract, which was dried by spray drying. Yield (97-98% vol. arabinogalactan and 2-3 vol.% dihydroquercetin) was 16 kg

Example 3.

A method of obtaining a composition with a content of DQC 1-2 vol.%

Sawdust larch wood were processed to highlight the DQC and other bio-flavonoids as described above; then 130 kg of waste sawdust filled in 350 liters of water at a temperature of 80°With (strictly) and was extracted with 2 hours in the periodic system; received 300 l of extract was evaporated to 32 l; added 20 l of ethanol, were extracted for 30 min, the precipitated substance was filtered, dried under vacuum. Output gotovo the product (98-99% vol. arabinogalactan and 1-2% vol. dihydroquercetin) was 16 kg

The purity of the selection DQC in the product obtained claimed process was controlled by the traditional method using HPLC (voskoboynikova IV and other pharmacy, 1992, No. 6, p.74-75). Analysis was performed by GC SP-7850 with a UV detector at a wavelength of 290 nm using column Lichrosorb 150×4.6 mm; mobile phase used a mixture of acetonitrile - 2%acetic acid, 30:70, the sensitivity of the method is 0.1 mg/ml

The following chromatogram (see drawing) shows that the output time of the peak of the DQC was 3 min; no other peaks confirms the absence copilarie other flavonoids: dihydrokaempferol (time out peak was supposed to be 7 min), naringenin (time out peak should be at 15.3 min) and quercetin (time out peak was supposed to be 20 min).

Example 4. Tablets

The product obtained in example No. 3, finely pulverized and then at the rotary teletrauma machine pressed tablets of 0.2,

Example 5. Tablets, mg:

The product obtained in example No. 3100
Microcrystalline cellulose56
Silicon dioxide2
Crosspovidone 2020
Magnesium stearate2
Lactose 120

To the product obtained in example No. 3, add microcrystalline cellulose, crosspovidone, magnesium stearate, lactose in the ratio indicated and 1 mg silicon dioxide are mixed in a diffusion mixer, sift through the mill with a sieve. To the resulting mixture add the remaining silicon dioxide, and prepare the final mixture in a diffusion mixer, and then pressed into tablets using standard hardware.

Example 6. Capsules mg:

The product of example 210
Corn starch60
Lactose120
Magnesium stearate10

The product of example 2 finely pulverized and mixed with a powdered pre-mixed in a diffusive mixer with magnesium stearate and lactose. The mixture is sifted through the mill with a sieve. The ingredients are mixed for about 10 min and placed in a dry gelatin capsules.

Table 1
Indicators radioprotective properties of dihydroquercetin varying degrees of purity in the experiment with irradiation
Groups of miceThe number of leukocytes in 1 ml of bloodQuantity of glue is OK bone marrow (× 106)
Control (starch)6708±12410,35±1,30
DQC 93%purity in starch (dihydrokaempferol and naringenin)8259*±28917,59*±1,11
DQC 98%purity in starch8289*±24621,65*±0,63
* means P< 0.05 with respect to corresponding figure in the control group

Table 2
Indicators radioprotective properties of dihydroquercetin in compositions with arabinogalactan after irradiation
Groups of miceThe number of leukocytes in 1 ml of bloodThe number of bone marrow cells (×106)
Control(starch)6708±12410,35±1,30
0.5% dihydroquercetin + arabinogalactan7556±59911,75±0,94
1-2% of dihydroquercetin + arabinogalactan10556**±44123,98*±1,77
3% dihydroquercetin + arabinogalactan11667**±36525,36*±252
* means P< 0.05 with respect to corresponding figure in the control is the group

** means P< 0.05 with respect to the corresponding figure of dihydroquercetin 98%purity in starch

1. Radioprotective agent, containing dihydroquercetin, characterized in that it further contains arabinogalactan with the following component content,%:

Dihydroquercetin1,0-3,0
Arabinogalactan99,0-97,0

2. The tool according to claim 1, characterized in that it is intended for ingestion.

3. The tool according to claim 2, characterized in that it is a tablet.

4. The method of obtaining radioprotective tools, including extraction of larch wood ethyl alcohol at room temperature, evaporation of the extract, the precipitation of the resins at a temperature of 60°With the removal of a major fraction of bioflavonoids crystallization, re-extraction with water at a temperature of 80°waste sawdust, followed by drying the obtained extract containing dihydroquercetin and arabinogalactan.

5. The method according to claim 4, in which the drying is carried out an additional extraction with ethyl alcohol, filtering the precipitated product.



 

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