Pharmaceutical composition and method effects on the reticuloendothelial system, treatment of cystic fibrosis and chronic pain syndromes accompanying diseases musculoskeletal diseases and cancers

 

(57) Abstract:

Usage: in medicine for effects on the reticuloendothelial system, treatment of cystic fibrosis and chronic pain syndromes accompanying diseases musculoskeletal diseases and cancer. The inventive pharmaceutical composition comprises (g/100 ml aqueous solution) one or more pharmaceutically acceptable, water-soluble boron compounds from 0.01 to 1, fluorine 0,01-1, magnesium 0.2 to 3, vanadium of 0.001 to 0.6, manganese, 0.02 to 2, iron 0,15-6, cobalt 0,002-1, Nickel of 0.01-2, copper, 0.01 to 1, zinc 0.1 to 3, molybdenum 0.001 to 0.8 is not deposited each other and other components of the composition and having a neutral or acidic pH in the aquatic environment, and it also contains glycine 0.1 to 2, glycerol and 0.2-8, L-(+)-ascorbic acid 0.01 to 2, neutral or acidic, water-soluble and pharmaceutically acceptable salt of ethylenediaminetetraacetic acid is 0.01-3, tartrate potassium sodium 0.01 to 10, succinic acid of 0.001-2 and L-(+)-tartaric acid is 0.01-2. Specified pharmaceutical composition used in the daily dosage comprising from 5 drops to 500, preferably from 50 to 150 drops. 2 C. and 20 C.p. f-crystals, 2 tab.

The present invention relates to pharmaceutical compositions, paromov, occurring in dystrophic diseases of the musculoskeletal or related blastomycosis diseases cancer origin, and method of preparation of such compositions.

In patents Hungary N 176202 and the UK N 2022998 described pharmaceutical composition suitable for exposure by the reticuloendothelial system (RES), i.e. tissue system consisting of tissues of different types located in different anatomical areas or organs of humans and animals. This composition contains

I) a mixture of pharmaceutically acceptable water-soluble compounds of boron, fluorine, magnesium, vanadium, manganese, iron, cobalt, Nickel, copper, zinc and molybdenum, not deposited either in the sediment in contact with each other or other components of the composition having a neutral or acidic reaction (pH) in the aquatic environment;

II) glycine;

III) glycerol;

IV) L-(+)-ascorbic acid;

V) neutral or acidic water-soluble salt of 2, 4, 5, 7 tetrachlorofluorescein (according to the current nomenclature 2', 4', 5', 7'-tetrachlorofluorescein);

VI) a neutral or acidic, water-soluble, pharmaceutically acceptable salt of ethylenediaminetetraacetic acid;

the magnesium: connection vanadium:connection manganese: connection iron:connection cobalt:connection Nickel:copper:link zinc:connection molybdenum: glycine:glycerin: L-(+) -ascorbic acid salt of 2, 4, 5, 7 tetrachlorofluorescein:salt ethylenediaminetetraacetic acid:potassium tartrate sodium, components respectively(0,01 1):(0,02 1):(0,4 3): (0,02 0,6): (0,1 2):(1 6):(0,1 1):(0,02 2): (0,05 1):1:(0,1 3):(0,01 0,8):(0,1 2):(2 8): (0,01 2):(0,003 0,5):(0,1 3):(0,7 - 10).

This composition is prepared by dissolving the components in water, mixing with a pharmaceutically acceptable pharmaceutical carriers, solvents and/or fillers, with the subsequent translation of the thus obtained mixture in medicinal form one of the known methods.

According to a preferred variant implementation of the invention, the boron compounds used boric acid; fluoride - sodium fluoride or vanadium TRIFLUORIDE; as compounds of magnesium sulfate or magnesium chloride or hydrates; as vanadium compounds ammonium Vanadate or vanadium TRIFLUORIDE; as compounds of manganese sulfate, chloride or hydrates; as compounds of iron sulfate, iron (II) or iron (III) or hydrates of iron; as compounds of cobalt chloride or sulfate, or a hydrate; as compounds of Nickel chloride sulfate or hydrates; as compounds of copper sulfate copper (II) or its hydrate, zinc compounds, zinc sulfate or g is sustained fashion variant implementation of the invention using the disodium salt of 2', 4', 5', 7'-tetraiodofluorescein as salt tetrachlorofluorescein, the disodium salt of ethylenediaminetetraacetic acid as salts of ethylenediaminetetraacetic acid, and to prepare aqueous environment of use distilled water.

The aim of the present invention to provide pharmaceutical compositions suitable for the treatment of cystic fibrosis and chronic pain syndromes related cancer or arising in degenerative diseases of the musculoskeletal system, and, in addition, expressing the positive qualities of old songs mentioned above.

The invention is based on the finding that the above objective can be achieved with the exception of the above-described composition of salt 2', 4', 5', 7'-tetrachlorofluorescein and replace it with succinic acid and L-(+)-tartaric acid. Thus obtained composition is applicable to the treatment of the above pain syndromes.

Then the invention based on the finding that the composition obtained by the above-mentioned replacement of components that can give the effect of a traditional analgesics, such as morphine, used in the treatment of chronic neblagopryatnye side effects are normal painkillers, good for portability and reduces addiction to medicines.

The invention is based on the establishment of another fact, namely, that positive features described in the above patents Hungary and the UK composition does not change with the reduction of the lower limit of the mass ratios of certain complexes.

Thus, the present invention relates to a pharmaceutical composition suitable for exposure by the reticuloendothelial system and treatment of mucoviscidosis and chronic pain that accompany degenerative diseases of the musculoskeletal system or cancer.

Specified pharmaceutical composition includes

I) one or more pharmaceutically acceptable water-soluble boron compound, fluorine, magnesium, vanadium, manganese, iron, cobalt, Nickel, copper, zinc and molybdenum, not deposited either with each other or other components of the compositions having a neutral or acidic reaction (pH) in the aquatic environment;

II) glycine;

III) glycerol;

IV) L-(+)-ascorbic acid;

V) succinic acid;

VI) a neutral or acidic, water-soluble, pharmaceutical the strong acid,

where the mass ratio of the boron compound: compound of fluorine: the magnesium compound:compound of vanadium:connection manganese:connection iron: connection cobalt:connection Nickel: copper:link zinc:connection molybdenum:glycine: glycerin:L-(+)-ascorbic acid:succinic acid: salt ethylenediaminetetraacetic acid tartrate of potassium-sodium L-(+) -tartaric acid are(0,01 1):(0,01 1):(0,2 - 3):(0,01 0,6): (0,02 2): (0,15 6):(0,002 1):(0,01 2):(0,01 1):(0,1 3): (0,001 0,8):(0,1 2):(0,2 8): (0,01 2):(0,001 2): (0,01 - 10):(0,01 2).

Patented composition obtained by reaction of the above components in the aquatic environment, transferring the mixture into a pharmaceutical composition with one or more pharmaceutically acceptable diluent and/or excipient, as usual.

Claimed in the invention the pharmaceutical composition is similar to that described in the previously mentioned patents Hungary and the UK, prepared with water, i.e., the components can be dissolved and mixed in the aquatic environment.

In addition to the above components of patented pharmaceutical composition may include soljubilizatory, preferably ethanol, buffer to bring the pH to desirable, the pharmaceutically pricely and fillers.

When used as a solvent of distilled water to the concentration of the ingredients I) to (VIII) can vary from about 0.001 to 10% by percentage ratio of mass to volume.

Proposed in the present invention the pharmaceutical composition may be prepared from a variety of complex compounds which, when mixed in an aqueous solution is formed more complex, remaining at the same time, water-soluble. The resulting aqueous solution can be concentrated and the concentrate is absorbed by the filler for the preparation of suppositories or pessaries.

According to the preliminary variant of the invention, the pharmaceutical composition comprises a compound of boron boric acid preferably in an amount of from 0.01 to 1 wt. to the volume; as fluoride, sodium fluoride or vanadium TRIFLUORIDE, preferably in quantities of from 0.01 to 1 wt. to the volume; as compounds of magnesium sulfate, magnesium chloride or its hydrate, preferably in quantities of from 0.2 to 3 wt. to the volume; as vanadium compounds ammonium Vanadate or trichloride vanadium preferably in quantities of from 0.001 to 0.6. to the volume; as manganese compounds hydrate ssto compounds of iron sulfate heptahydrate iron (II) or iron sulfate (III), preferably in amounts of from 0.15 to 6 wt. to the volume; as compounds of cobalt, the uranyl chloride heptahydrate cobalt or cobalt sulfate, preferably in an amount of from 0.002 to 1 wt. to the volume; as compounds of Nickel heptahydrate of Nickel chloride or Nickel sulfate, preferably in an amount of from 0.01 to 2 wt. to the volume; as compounds of copper sulfate copper (II) or its pentahydrate preferably in quantities of from 0.01 to 1 wt. to the volume; as compounds of zinc sulfate or heptahydrate zinc, preferably in quantities of from 0.1 to 3 wt. to the volume; as compounds of molybdenum, ammonium molybdate ((NH4)6Mo7O244H2O) or sodium molybdate (Na2MoO42H2O) preferably in amounts of from 0.001 to 0.8 wt. to the volume.

Upstream and downstream data related to the expression of concentrations in units of wt. to volume, should be understood as the amount of material presented in grams dissolved in 100 ml of solution.

The preferred ranges of concentrations of the other components of the pharmaceutical compositions according to the present invention are:

glycine from 0.1 to 2 wt. to the volume

glycerin is from 0.2 to 8 wt. to the volume

L-(+)-ascorbic acid is from 0.01 to 2 wt. to the amount of 0.01 to 3 wt. to the volume

tartrate potassium sodium from 0.01 to 10 wt. to the volume

L-(+)-tartaric acid from 0.01 to 2 wt. to the volume

The preferred concentration of ethanol (acceptable 96% volume concentration), which is additive to facilitate dissolution, is from 0.05 to 10 wt. to the volume, while the preferred amount of the pharmaceutically acceptable acid (preferably hydrochloric or sulfuric) is from 0.05 to 1 wt. to the volume.

The pH value of patented pharmaceutical composition is preferably in the range from 1.9 to 4. To regulate the pH sulfuric or hydrochloric acid take 1 n concentration.

Pharmaceutical composition, which the present invention is prescribed for admission through the mouth in the form of drops, as well as rectal or intrawaginalno in the form of suppositories or pessaries.

Pharmaceutical composition for rectal or vaginal destination is prepared, pariva aqueous solution to a syrupy consistency, after which they impregnate the mass of the candle. Rectal and vaginal suppositories molded from the resulting mass by methods conventional in the pharmaceutical industry. The basis for candles is composed mostly of oil Kaka is their field of application examples.

Example 1. The pharmaceutical composition in an amount of 100 l was prepared as follows.

1. Preparation of complexing agents (ligands).

a) 300 g of Selectone" B2(Na2EDTA) dissolved when heated in 4 l of distilled water.

b) 200 g of the tartrate of potassium-sodium dissolved in 2 l of distilled water.

c) 50 g of succinic acid and 410 g of the heptahydrate of magnesium sulfate dissolved by heating in 2 l of distilled water.

d) 50 g L-(+)-tartaric acid, and 94 g of monohydrate, manganese sulfate dissolved in 1 l of distilled water.

e) 60 g of boric acid and 600 g of glycerol in a concentration of at least 86,4% (mass. share) is dissolved in the presence of 200 ml of distilled water at low heat.

f) 230 g of glycine is dissolved in 800 ml of distilled water at low heat, then add the copper sulfate and zinc sulfate on recipe p. 4.11.

2. 30 g of L-(+)-ascorbic acid is dissolved by shaking in 500 ml of warmed up to 50-60oC distilled water.

3. If necessary, adjust pH to values in the range of 1.9 to 4, using L-(+)-ascorbic acid.

4. Preparation of the complexes.

Complex I.

Complex II.

100 g of 5-water copper sulfate is dissolved in 500 ml of distilled water. In another flask dissolve 500 g of 7-water zinc sulfate in 1 l of distilled water. First, the copper sulfate solution, then zinc sulfate sequentially injected into a solution of glycine, prepared as described in paragraph 1. The resulting purple solution was poured, with stirring, at present in the tank, the solution of complex I.

Complex III.

To 1 l of the solution "Selector" B2prepared by 1. a) add 10 g of CoCl26H2O, 35 g (NH4)6Mo7O244H2O, 52 g with NISO47H2O 8 g of NH4VO3in 800 ml of distilled water and dissolve the solid components when heated. The resulting solution is added to the tank, which is in solution.

Separately dissolved in 1000 g of iron sulfate heptahydrate (II) in 4 l of distilled water, adding 2 l of a solution "Selectone" B2prepared according to recipe 1. a); the resulting solution was poured into the tank, and then, while stirring, add the remaining solution "Selectone" B2. The result is a bluish-green turbid solution.

the NII in 1 l of distilled water, then, while stirring, poured to the solution in the tank.

Complex V.

94 g of monohydrate, manganese sulfate and 50 g L-(+)-tartaric acid are dissolved while heating in 500 ml of distilled water, then the resulting solution was poured to the solution in the tank.

Complex VI.

60 g of boric acid and 600 g of glycerin are dissolved in 200 ml of distilled water at low heat. Then the resulting solution add to the solution in the tank.

5 a composition.

A solution of tartrate of potassium-sodium prepared according to recipe 1. b), and then a solution of L-(+)-ascorbic acid, prepared in accordance with the note 2. while stirring, pour in the solution present in the tank. The volume of solution was adjusted to 98 l by adding distilled water. Then measure the pH value of the solution, which should be from 1.9 to 4. If the pH value exceeds 4, it is brought to 3 by adding additional L-ascorbic acid. The final volume of the solution lead to 100 HP

The resulting solution was incubated for 12-24 hours During this time the solution enlightened color becomes yellowish green. After checking the quality of the solution can be packaged.

100 ml obtained in that the reed sodium NaF 0.20 g

glycine C2H5NO20,23 g

sulphate of copper (II) CuSO45H2O 0.10 g

zinc sulfate ZnSO45H20.50 g

molybdate of ammonia (NH4)6Mo7O247H2O 0,052 g

chloride cobalt (II) CoCI26H2O 0,010 g

the disodium salt of ethylenediaminetetraacetic acid (Na2ATAN2O) C10H14N2O8Na27H2O 1.0 g

magnesium sulfate (II) MoSO47H2O 0,41 g

succinic acid C4H6O40,050 g

manganese sulfate (II) MnSO4H2O 0,094 g

L-(+)-tartaric acid C4H6O60,050 g

boric acid (H3BO3to 0.060 g

glycerol (87%) C3H8O30,60 g

tartrate potassium sodium C4H4O6KNa4H2O - 0.20 g

Example 2. The composition is prepared according to the method of example 1, but the number of source components are selected so that 100 ml of the prepared solution of ingredients was

the ammonium metavanadate 0,068 g

sodium fluoride 0,30 g

glycine 1,94 g

sulphate of copper (II) 0,012 g

zinc sulfate 2.85 g

molybdate ammonium 0,020 g

sulfate Nickel (II) 0,070 g

chloride cobalt (II) 0,0021 g

the disodium salt of Ethylenediamine,153 g

magnesium sulfate (II) 2,94 g

succinic acid 0,030 g

manganese sulfate (II) of 0.23 g

L-(+)-tartaric acid 1,94 g

boric acid 0,30 g

glycerol (87%) 7,92 g

tartrate potassium sodium 0.10 g

Example 3. The composition is prepared according to the method of example 1, but the number of source components are selected so that 100 ml of the prepared solution of ingredients was

the ammonium metavanadate 0,576 g

sodium fluoride 0.95 g

glycine 0.50 g

sulphate of copper (II) 0,99 g

zinc sulfate 1,00 g

molybdate ammonium 0,768 g

sulfate Nickel (II) 1.92 g

chloride cobalt (II) 0.10 g

the disodium salt of ethylenediaminetetraacetic acid (Na2ATAN2O) 2,97 g

L-(+)-ascorbic acid 1,94 g

sulphate of iron (II) 1.50 g

magnesium sulfate (II) of 0.60 g

succinic acid 1.98 g

manganese sulfate (II) a 1.96 g

L-(+)-tartaric acid 0.10 g

boric acid 0,98 g

glycerol (87%) 1.0 g

tartrate potassium sodium 9,78 g

Example 4. The composition is prepared according to the method of example 1, but the number of source components are selected so that 100 ml of the prepared solution of ingredients was

the ammonium metavanadate 0.0011 g

sodium fluoride 0,012 g

glycine,012 g

chloride cobalt (II) 0.97 g

the disodium salt of ethylenediaminetetraacetic acid (Na2ATAN2O) to 0.011 g

L-(+)-ascorbic acid 0,012 g

sulphate of iron (II) 5,76 g

magnesium sulfate (II) 0,206 g

succinic acid to 0.011 g

manganese sulfate (II) 0,021 g

L-(+)-tartaric acid to 0.011 g

boric acid to 0.011 g

glycerol (87%) 0.21 g

tartrate potassium sodium 0,012 g

The following details the results of tests and observations of the pharmaceutical activity of the composition of this invention.

The audit was conducted in a number of organizations under the supervision of a doctor.

The group of patients selected subjects included men and women of different ages. They received a composition that meets the present invention, in the form of a solution (1 ml corresponds to 18 drops). Patients received drops of tea or a light drink. In addition to the drops of patients received 100 to 300 mg of ascorbic acid per day in the form of tablets or aqueous solution, depending on the dosage in drops. Patients with a high level of acidity acid has been optional.

A) Test painkiller action for chronic pain that accompany degenerative diseases of the supports is ABO control.

The test: Orthopedic clinic of the medical University Semmelweis, Budapest.

The composition of example 1 was administered to adult patients in the following doses:

patients weighing more than 70 kg 3 times 20 drops a day for 1 week, then 2 times 20 drops in 2 weeks and depending on the condition clears 2 times in 10 drops or 1 times 10 drops per day in the next 2 weeks,

patients with body weight less than 70 kg received 2 times 20 drops a day for 1 week, then 2 times 20 drops in 2 weeks and depending on the onset of improvement 1 times 10 drops per day in the next 1-2 weeks.

The tests covered 156 patients, which effectively composition was obtained in 76 patients (group I), and placebo (group II) 86 patients. Perceived improvements in 57 patients (75%) of group I and 26 (32.5 per cent) of group II. In 19 (25%) and 54 (67%) patients from group I and II respectively, the state has not changed.

The results of the tests are grouped by types of diseases listed in table 1.

B) Clinical trials of analgesic action of the drug for pain that accompany cancer.

Method of processing results: sociologicheskoe clinic Budapest.

Tests were conducted on a group of 35 patients, 17 of them received each time the morphine and the composition of example 2 at the rate of 1 drop per kg body weight (group I), while 18 patients received only morphine (group II). In group I, the dose of morphine was reduced by half compared with the dose received by patients from group II.

Complete disappearance of pain was achieved in 12 patients (71%) of group I, while the same effect was obtained in 11 patients (61%) from group II with the introduction of twice as large than in group I, doses of morphine. Reduction, but not complete disappearance of pain was observed in groups I and II in 5 (29%) and 39% of patients, respectively.

C) observing the change in the clinical status of children with cystic fibrosis.

Cystic fibrosis is an inherited disease that occurs when genetic disorders, is still considered incurable. The most notable manifestation is that the secret of the gland has a higher than normal viscosity. So, excessively viscid mucus secreted by the gland, sticks to the surface of the lungs and respiratory tract, covered with mucous membrane, and cannot be removed spontaneously. Accumulating allocation and development on them pathogene serious consequence with the defeat of the digestive system is the lack of enzymes in the duodenum due to thickening of secretions of the pancreas, leading to poor digestion and assimilation of nutrients. As a result, the patients have a rich, containing undigested stool, develops dystrophy.

Received ill treatment usually comes down to liquefy viscous secretion and completion of the missing enzymes and vitamins. However, even with the most careful treatment't go away, not all violations. In addition, these patients more susceptible to infections.

The tests were beaten started in a group of 40 children suffering from cystic fibrosis, 5 of which, however, ceased to take responsible of this invention the composition. Thus, the results of treatment of only 35 children. The age of patients ranged from 3 to 18 years.

Method: the composition according to example 3 was administered for 6 months at a daily dose of 1 drop per 1 kg of body weight.

The tests were carried out at the Children's hospital of Budapest.

As a result of treatment using the compositions conforming to the present invention, improved overall health and increased physical activity is a significant part of the cure kids. Students increased endurance to physical loads. Improved appet the holding of iron and zinc in blood plasma of patients was detected, the level of iron and zinc increased in 91% and 51% of patients from groups I and II respectively, which probably played a significant role in the improvement of the patients. Another favorable aspect was also an increase in the content of ferritin in plasma 25 (71%) patients.

The results of observation of the clinical status of the patients are summarized in table 2.

The above test results conclusively prove that the composition conforming to the present invention, provides a very favorable clinical effects in the treatment of cystic fibrosis and chronic pain in diseases of the musculoskeletal dystrophic or cancer.

The dose of the pharmaceutical composition according to the invention depends on the condition, body weight of the patient and the disease. Daily dosage may vary from 5 to 500 drops, really like 20-150 and preferably 40 to 80 drops per day.

1. Pharmaceutical composition suitable for exposure by the reticuloendothelial system and for the treatment of cystic fibrosis and chronic pain syndromes accompanying diseases musculoskeletal diseases and cancers, the content is manganese, iron, cobalt, Nickel, copper, zinc and molybdenum, not deposited each other and other components of the composition, and having a neutral or acidic pH in the aquatic environment, as well as containing glycine, glycerol, L-(+)-ascorbic acid, neutral or acidic, water-soluble and pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, potassium tartrate sodium and water, characterized in that it further comprises succinic acid and L-(+)-tartaric acid with the following components concentration (g/100 ml solution):< / BR>
The boron compounds 1 0,01

Fluoride 0,01 1

Compounds of magnesium 0,2 3

Vanadium compounds 0,001 0,6

Manganese compounds 0,02 2

Compounds of iron is 0.15 6

Compounds of cobalt 0,02 1

Compounds of Nickel, 0.01 to 2

Copper compounds 1 0,01

Zinc compounds 0,1 3

Molybdenum compounds 0,001 0,8

The glycine 0.1 2

Glycerol and 0.2 8

L-(+)-ascorbic acid 2 0,01

Succinic acid of 0.001 2

The specified salt of ethylenediaminetetraacetic acid 0.01 3

Tartrate potassium sodium 0,01 10

L-(+)-tartaric acid in 0.01 2

2. The composition according to p. 1, characterized in that it contains as compounds of boron boric acid.

3. Pharmaceutical canadia.

4. The composition according to p. 1, characterized in that it contains as compounds of magnesium sulfate or magnesium chloride, or their hydrates.

5. The composition according to p. 1, characterized in that it contains as vanadium compounds ammonium Vanadate or vanadium TRIFLUORIDE.

6. The composition according to p. 1, characterized in that it contains as manganese compounds hydrate sulfate or manganese chloride tetrahydrate of manganese.

7. The composition according to p. 1, characterized in that it contains as compounds of iron sulfate heptahydrate iron (II) or iron sulfate (III).

8. The composition according to p. 1, characterized in that it contains as compounds of cobalt, the uranyl cobalt chloride or sulfate heptahydrate cobalt.

9. The composition according to p. 1, characterized in that it contains as compounds of Nickel chloride Nickel or its heptahydrate.

10. The composition according to p. 1, characterized in that it contains as compounds of copper sulfate copper (II) or its pentahydrate.

11. The composition according to p. 1, characterized in that it contains as zinc compounds, zinc sulfate or its heptahydrate.

12. The composition according to p. 1, characterized in that it contains in Kato it contains as salts of ethylenediaminetetraacetic acid disodium salt ethylenediaminetetraacetic acid, two-water.

14. The composition according to p. 1, characterized in that it further comprises a pharmaceutically acceptable acid in an amount necessary to bring the pH to a value in the range from 1.9 to 4.0.

15. The composition according to p. 14, characterized in that it contains as a pharmaceutically acceptable acid sulfuric or hydrochloric acid.

16. The composition according to p. 15, characterized in that it contains sulfuric or hydrochloric acid 1N concentration.

17. The composition according to p. 1, characterized in that it further comprises a pharmaceutically acceptable additive that facilitates dissolution of the ingredients.

18. The composition according to p. 17, characterized in that it contains an additive that facilitates dissolution of the ingredients ethyl alcohol.

19. The composition according to p. 18, characterized in that it contains ethyl alcohol 96.-Noah concentration.

20. The composition according to p. 1, characterized in that it is prepared in the form of drops for oral administration.

21. The composition according to p. 1, characterized in that it is prepared in a form suitable for rectal or intravaginal use.

22. Effect on the reticuloendothelial system, Leche is that disease and cancer, including the use of pharmaceutical compositions containing one or more water-soluble compounds of boron, fluorine, magnesium, vanadium, manganese, iron, cobalt, Nickel, copper, zinc and molybdenum, wherein the use of the pharmaceutical composition under item 1 in the daily dosage comprising from 5 drops to 500, preferably from 50 to 150 drops.

 

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