Water-soluble iron-carbohydrate complexes, method for their preparing, medicinal agent, using

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes water-soluble iron-carbohydrate complexes containing 10-40 wt.-% of iron. Complexes can be prepared from ferric (III) salt aqueous solution and oxidation product aqueous solution of one or more maltodextrins with hypochlorite aqueous solution at alkaline pH value. In using one maltodextrin its dextrose equivalent is from 5 to 20, and in using mixture of maltodextrins the dextrose equivalent is from 5 to 20 and dextrose equivalent of each maltodextrin as component of mixture is from 2 to 40. Also, invention describes a method for preparing this complex and medicinal agents used in treatment and prophylaxis of states associated with iron deficiency.

EFFECT: improved preparing method, valuable medicinal properties of complexes.

15 cl, 1 tbl, 8 ex

 

The technical field to which the invention relates.

The object of the present invention are water-soluble iron-carbohydrate complexes, which are intended for the treatment of iron deficiency anemia, as well as the way they are received, medicines containing these complexes, and their use in the prevention or treatment of iron deficiency anemia. Drugs are particularly suitable for parenteral administration.

The level of technology

Anemia due to iron deficiency can be treated or prevented by use of iron-containing medications. Known use for these purposes the iron-carbohydrate complexes. The basis of one of the most frequently and successfully used in medical practice drugs is a water-soluble complex of iron hydroxide (III) and sucrose (Danielson, Salmonson, Derendorf, Geisser, Drug Res., Vol.46: 615-621, 1996). In the prior art described intended for parenteral administration of iron-dextranase complexes, and the complexes on the basis of pullulan (WO 02/46241), which is difficult to obtain and for the production of which requires the application of pressure and elevated temperatures, as well as the stage of the hydrogenation. Known and other iron-carbohydrate complexes for admission through the mouth.

The present invention aims at providing a preparation of iron is preferable for p is enteralnogo introduction, which is relatively easy to sterilize, while known for parenterally administered drugs based on sucrose or dextran stable only at temperatures up to 100°in consequence of which their sterilization difficult. In addition, the finished preparation according to the invention should have low toxicity and to prevent the occurrence of hazardous induced by dextran anaphylactic shock. The finished product must also show high stability of the complex, which will assign a higher dosage of the drug or increase the injected dose. The preparation of iron should also be manufactured from readily available raw materials without particularly high costs.

Disclosure of inventions

In accordance with this invention, this goal can be achieved by using iron (III) - carbohydrate complexes on the basis of the oxidation products of maltodextrins. Therefore, the subject invention are water-soluble iron-carbohydrate complexes, which can be obtained from a water solution of salts of iron (III) and an aqueous solution of the oxidation product of one or more maltodextrins with an aqueous solution of hypochlorite under alkaline pH, for example, at pH 8 to 12, and using the one maltodextrine its dextrose equivalent ranging from 5 to 20, using the mixture of multidex is Renov dextrose equivalent of the mixture is from 5 to 20, and the dextrose equivalent of each of maltodextrin, which is included in the composition of the mixture is from 2 to 40.

Another object of the invention is a method of obtaining iron-carbohydrate complexes according to the invention, which involves the oxidation of one or more maltodextrins in aqueous solution at alkaline pH, for example, at pH 8 to 12, with an aqueous solution of hypochlorite and the interaction between the obtained solution and the aqueous solution of salt of iron (III), and using the one maltodextrine its dextrose equivalent ranging from 5 to 20, with the use of a mixture of maltodextrins dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of each of maltodextrin, which is included in the composition of the mixture is from 2 to 40.

Maltodextrins used in the present invention, are readily available raw materials, commercially available.

To obtain ligand complexes according to the invention maltodextrins are oxidized in an aqueous solution with a solution of hypochlorite. Suitable for this purpose, the hypochlorite solution is a solution of a hypochlorite of an alkali metal, e.g. sodium hypochlorite solution. Can be used commercially available solutions. The concentration of the hypochlorite solution is at least 13 wt.%, preferably from 13 to 16 wt.%, in terms of active chlorine. Races the thieves used preferably in such a quantity, to oxidation was subjected to from about 80 to 100%, preferably about 90% of the aldehyde groups on the molecule maltodextrin. Thanks to this, due to the glucose part of the molecule maltodextrin reactivity decreases to about 20% or less, preferably to 10% or less.

The oxidation is carried out in an alkaline solution at a pH of from 8 to 12, for example, from 9 to 11. Oxidation can occur at temperatures from 15 to 40°C, preferably from 25 to 35°C. the Duration of the reaction is from 10 minutes to 4 hours, for example, from 1 to 1.5 hours.

The degree of depolymerization of maltodextrins in the described way is minimized. Not wanting to dwell on theory, the authors suggest that oxidation occurs mainly on the terminal aldehyde group (acetaldol or polyacetylenes group, respectively) molecules of maltodextrins.

The oxidation reaction of maltodextrins can also catalyze. For this purpose entered bromide ions, for example, bromides of alkali metals such as sodium bromide. Add the amount of bromide is not critical. It should be small so as to provide easy-to-clean final product (Fe-complex). Enough catalytically effective amount. As mentioned above, d is the addition of bromide may but not necessarily.

In addition, the oxidation of maltodextrins can be, for example, the famous three-oxidative system - hypochlorite/bromide of an alkali metal/2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Method of oxidation of maltodextrins in the conditions of catalysis bromides of alkali metals or triple TEMRO system is described, for example, Thaburet et al. in Carbohydrate Research 330 (2001) 21-29; described method can be used in the present invention.

To obtain the complexes according to the invention the oxidized maltodextrins are subjected to reaction in an aqueous solution with a salt of iron (III). This oxidized maltodextrins can be distinguished, and then again to dissolve; however, the resulting aqueous solutions of oxidized maltodextrins can also be used directly for subsequent reaction with aqueous solutions of iron (III).

As salts of iron (III) can be used water-soluble salts of organic or inorganic acids or mixtures thereof, for example, halides such as chloride and bromide, or sulfate. Preferably the physiologically acceptable salts. Especially preferable to use an aqueous solution of ferric chloride (III).

It is established that the complexation favorably affected by the presence of chloride ions. The latter can be introduced in the form of water-soluble chlorides, still is how the chlorides of alkali metals, for example, sodium chloride, potassium chloride or ammonium chloride. Preferably, as indicated above, the use of iron (III) in the form of chloride.

For the reaction of aqueous solution of oxidized maltodextrin can be mixed, for example, with an aqueous solution of salt of iron (III). While it is preferable to do so when mixing and after mixing the oxidized maltodextrin, salt of iron (III) pH was very acidic or so low that there was no hydrolysis of salts of iron (III), for example, at level 2 or below, to avoid unwanted precipitation of hydroxides. When using iron chloride (III) do not require the addition of an acid as aqueous solutions of ferric chloride (III) by themselves can be quite acidic. Only after mixing, the pH value can be increased to values equal to or higher than 5, for example, to a pH of 11, 12, 13 or 14. Preferably, the increase in pH was slow or gradual, which can be performed, for example, by pre-adding a weak base to a pH of about 3, and then the subsequent neutralization of the stronger base. As a weak base can be used, for example, carbonates or bicarbonates of alkali or alkaline earth metals, such as carbonate or bicarbonate of sodium or potassium or ammonia. Por the measures strong bases are the hydroxides of alkaline or alkaline earth metals, such as the hydroxide of sodium, potassium, calcium or magnesium.

The reaction can be accelerated by heating. For this purpose can be used, for example, temperatures from 15°C to the boiling point. Preferably, the temperature increase was gradual. For example, can be heated to a temperature from about 15°C to 70°S, and then gradually bring the temperature up to the boiling point.

The duration of the reaction may be, for example, from 15 minutes to several hours, for example, from 20 minutes to 4 hours, preferably from 25 to 70 minutes, for example, from 30 to 60 minutes.

The reaction can occur in the weakly acidic region, for example, at pH 5-6. However, it was determined that it is advisable, though not required, to increase the pH value in the course of complex formation to a higher value, for example about pH 11, 12, 13 or 14. To complete the reaction the pH value can subsequently be reduced by adding an acid, for example, to pH 5-6. As such acids can serve as inorganic or organic acids or their mixtures, mainly halogenation acid such as hydrogen chloride or an aqueous solution of hydrochloric acid.

As mentioned above, in most cases, the heating is favorable for complexation. For example, in a preferred embodiment of the invention, in which ve is hichina pH during the reaction rises to the level of pH, at least 5 to 11 or 14, it is possible to work at low temperatures of the order of from 15 to 70°With, for example, from 40 to 60°With, for example, about 50°and then after the new lowering of pH to levels of at least pH 5, you can gradually increase the temperature above 50°C to the boiling point.

The duration of reaction is from 15 minutes to several hours and may vary depending on the reaction temperature. If the method is carried out at intermediate pH above 5, the duration of the reaction may be, for example, from 15 to 70 minutes, for example, from 30 to 60 minutes at high pH, for example, at temperatures up to 70°C, after which the reaction after lowering the pH to levels of at least pH 5 can be conducted over the next 15-70 minutes, for example, from 30 to 60 minutes, at temperatures up to 70°and, if necessary, over the next 15-70 minutes, for example, from 30 to 60 minutes, at elevated temperatures up to the boiling point.

Upon completion of the reaction, the resulting solution can be cooled, for example, to room temperature, and, if necessary, be diluted and filtered. After cooling, the pH value of the solution can be brought to the point of neutrality or slightly lower than, for example, to pH 5-7 by adding acid or base. You can use the acid and base is, those mentioned for the reaction. The obtained solutions are purified and can be used directly for the production of medicines. But you can also select from a solution complexes of iron (III), for example, by precipitation with an alcohol, such as alkanol, for example, ethyl alcohol. The selection can also be performed by spray drying. Cleaning solutions can be done in the traditional way, which is suitable, in particular, to remove salts. For example, it may be carried out using reverse osmosis, with the specified method can be used, for example, before spray drying or before introduction into drugs.

The resulting iron (III) - carbohydrate complexes contain from 10 to 40% wt./wt. iron, preferably from 20 to 35% wt./wt. iron. They are easily dissolved in water. Of them you can do a neutral aqueous solutions with a content of iron, for example, from 1% wt./about. up to 20% wt./about. These solutions can be subjected to heat sterilization. The weighted average molecular weight (Mw) of the complexes obtained as described above is, for example, from 80 kDa to 400 kDa, preferably from 80 to 350 kDa, more preferably up to 300 kDa (determination by gel permeation chromatography as described, for example, Geisser et al. in Arzneim. Forsch./Drug Res. 42 (II), 12, 1439-1452 (1992), p is ragraph 2.2.5).

As mentioned above, some of the complexes according to the invention it is possible to prepare aqueous solutions. These solutions are especially suitable for parenteral administration. However, it is also possible to enter them orally or topically. Unlike widely used at present, iron preparations for parenteral administration, these solutions can be subjected to sterilization at high temperatures, for example, at 121°and above and brief contact order about 15 minutes before reaching the Fo≥15. At higher temperatures, the duration of exposure, respectively, below. Known up to the present time the drugs were to be sterilized by filtration and mixed with preservatives such as benzyl alcohol or phenol. In the present invention there is no need for supplements of this kind. Solutions of the complexes can, for example, pour into ampoules. For example, solutions of from 1 to 20 wt.%, for example, a 5 wt.%, you can pour in vessels such as vials or bottles, for example, from 2 to 100 ml, for example, to 50 ml. of the Preparation of solutions for parenteral administration can be done in the traditional way, in particular, with conventional parenteral solutions of additives. Solutions can be designed in such a way that they can be introduced in the form of injection or infusion, for example, Phi is biologicheskii solution. For admission through the mouth or the local application of drugs can be produced together with the corresponding conventional excipients and auxiliary agents.

Thus, the next subject of invention are water medicines, which are particularly suitable for parenteral, intravenous, as well as intramuscular injection, as well as to receive through the mouth or for local applications, and are particularly useful in the treatment of iron deficiency anemia. The next subject of invention is the use of iron (III) - carbohydrate complexes according to the invention for the treatment and prevention of anemia associated with iron deficiency, or for the production of medicines, mainly for parenteral administration, for the treatment of anemia associated with iron deficiency. These medicines are intended for use in medicine and veterinary medicine.

The benefits of iron-carbohydrate complexes according to the invention include the above mentioned above the possibility of sterilizing them at high temperatures and their low toxicity and reduced the danger of anaphylactic shock. The toxicity of the complexes according to the invention is very small. Compared with LD50known pullulanase complexes, which is 1400 mg Fe/kg LD 50complexes according to the invention is more than 2000 mg Fe/kg Due to the high stability of the complexes obtained according to the invention, it is possible to increase the injected dose. It is possible medicinal product according to the invention to introduce parenteral as a single dose. Such a single dose may be, for example, from 500 to 1000 mg of iron; it can be introduced through, for example, 1 hour. Another advantage is easy to get used as initial products of maltodextrins, which are, for example, commercially available additives in the food industry.

In the present description and the following examples dextrose equivalents are determined by the gravimetric method. To this end, the maltodextrins in aqueous solution is subjected to reaction with the liquid Fehling's at boiling point. The reaction is carried out quantitatively, i.e. until the cessation of bleaching liquid Fehling. Fallen in sediment copper oxide (I) is dried at 105°C to constant mass and is determined by the gravimetric method. On the basis of the obtained data is calculated glucose (dextrose equivalent) in % wt./wt. dry matter maltodextrin. You can work for example with the following solution: 25 ml of liquid Fehling I mixed with 25 ml of liquid Fehling II; 10 ml of aq is the solution of maltodextrin (10% mol/about.) (liquid Fehling I: 34,6 g of copper sulfate (II) dissolved in 500 ml of water; liquid Fehling II: 173 g of potassium tartrate of sodium and 50 g of sodium hydroxide dissolved in 400 ml of water).

The implementation of the invention

Example 1

100 g of maltodextrin (dextrose equivalent of 9.6; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 30 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./wt. Fe) in the conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After that, the pH of the solution was brought to 11 by adding sodium hydroxide solution, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified by adding hydrochloric acid to pH 5 to 6, stood next 30 minutes at 50°C, after which they were heated to 97-98°and was kept for 30 minutes at this temperature. After cooling the solution to room temperature, the pH of the solution was brought to 6-7 by adding sodium hydroxide solution.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 125 g (corresponding to 87% of eroticheskoe values) brown amorphous powder with iron content of 29.3% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 271 kDa.

Example 2

200 g of maltodextrin (dextrose equivalent of 9.6; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 30 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./.Fe) under conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After that, the pH of the solution was brought to 11 by adding sodium hydroxide solution, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified to pH 5-6 by the addition of hydrochloric acid, stood next 30 minutes at 50°C, after which they were heated to 97-98°and was kept for 30 minutes at the same temperature. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide solution.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 123 g (corresponding to 65% of theoretical value) brown amorphous powder with maintained the eating iron 22,5% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 141 kDa.

Example 3

100 g of maltodextrin (dextrose equivalent of 9.6; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 30 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) and 0.7 g of sodium bromide at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./wt. Fe) in the conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After the addition of caustic soda solution pH was brought to 6.5, the solution was heated to 50°and was kept for 60 minutes at 50°C. Then the solution was acidified to pH 5-6 by the addition of hydrochloric acid, stood next 30 minutes at 50°C, after which they were heated to 97-98°and was kept for 30 minutes at the same temperature. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 139 g (corresponding to 88% of theoretical value) brown amorphous powder with the content of the m iron 26,8% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 140 kDa.

Example 4

A mixture of 45 g of maltodextrin (dextrose equivalent of 6.6; was determined by gravimetric method) and 45 g of maltodextrin (dextrose equivalent 14,0; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 25 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) and 0.6 g of sodium bromide at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./wt. Fe) in the conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After the addition of caustic soda brought the pH of the solution to 11, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified with hydrochloric acid to pH 5-6, stood next 30 minutes at 50°C, after which they were heated to 97-98°and was kept for 30 minutes at the same temperature. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide solution.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. Then the complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

what was alocale 143 g (corresponds to 90% of theoretical value) brown amorphous powder with iron content of 26.5% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 189 kDa.

Example 5

90 g of maltodextrin (dextrose equivalent 14,0; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 35 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) and 0.6 g of sodium bromide at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./.Fe) under conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After the addition of sodium hydroxide the pH of the solution was brought to 11, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified with hydrochloric acid to pH 5-6, stood next 30 minutes at 50°C, after which they were heated to 97-98°and was kept for 30 minutes at the same temperature. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 131 g (corresponding to 93% of theoretical value) brown amorphous powder with iron content of 29.9% of the AC./wt. (it was determined by complexometry).

Molecular weight (Mw) 118 kDa.

Example 6

A mixture of 45 g of maltodextrin (dextrose equivalent of 5.4; was determined by gravimetric method) and 45 g of maltodextrin (dextrose equivalent 18,1; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 31 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) and 0.7 g of sodium bromide at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./.Fe) under conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After the addition of caustic soda brought the pH of the solution to 11, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified with hydrochloric acid to pH 5-6, stood next 30 minutes at 50°C, after which they were heated to 97-98°and was kept for 30 minutes at the same temperature. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide solution.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 34 g (corresponding to 88% of theoretical value) brown amorphous powder with iron content of 27.9% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 178 kDa.

Example 7

100 g of maltodextrin (dextrose equivalent of 9.6; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by the addition of 29 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) and 0.7 g of sodium bromide at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./wt. Fe) in the conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After the addition of caustic soda brought the pH of the solution to 11, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified with hydrochloric acid to pH 5-6, stood next 70 minutes at 50°C. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 155 g (corresponds to 90% of theoretical value) brown amorphous powder with iron content of 24.5% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 137 kDa.

Note the p 8

126 g of maltodextrin (dextrose equivalent of 6.6; was determined by gravimetric method) was dissolved at 25°in terms of mixing 300 ml of water and oxidized by adding 24 g of sodium hypochlorite solution (13 to 16% wt. active chlorine) and 0.7 g of sodium bromide at pH 10.

To 352 g of a solution of ferric chloride (III) (12% wt./.Fe) under conditions of stirring (blade stirrer) was first added at room temperature pre-oxidized solution of maltodextrin, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After the addition of caustic soda brought the pH of the solution to 11, the solution was heated to 50°and was kept for 30 minutes at 50°C. Then the solution was acidified with hydrochloric acid to pH 5-6, stood next 70 minutes at 50°C. After cooling the solution to room temperature, its pH is brought to 6-7 by adding sodium hydroxide.

Then the solution was filtered through a sterilizing filter and analyzed for the presence of sludge. The complex was isolated by precipitation with ethyl alcohol in the ratio of 1:0,85 and dried in vacuum at 50°C.

Received 171 g (corresponds to 86% of theoretical value) brown amorphous powder with iron content 21,35% wt./wt. (it was determined by complexometry).

Molecular weight (Mw) 170 kDa.

Comparative evaluation

During this comparative evaluation was compared their is tion of iron-carbohydrate complexes according to the invention with the properties of standard iron-sucrose complex. Comparative evaluation confirmed the possibility, according to the invention, the increase of iron content, conducting heat treatment at elevated temperatures and reduced toxicity (LD50). (see table 1).

Table 1
The complex according to the inventionThe complex hydroxide of iron/sucrose
The Fe content [%]5,02,0
pH5-710,5-11,0
Mw [kDa]1)80-35034-54
Heat121°C/15'100°/35'
LD50in/in, the weighted average value [mg Fe/kg body mass]>2000>200

1. Water-soluble zheltoplodnoy complex having an iron content of from 10 to 40 wt.%, which can be obtained from a water solution of salts of iron (III) and an aqueous solution of the oxidation product of one or more maltodextrins with an aqueous solution of hypochlorite at pH in the alkaline region, and using the one maltodextrine its dextrose equivalent ranging from 5 to 20, with the use of a mixture of maltodextrins dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of each is maltodextrin, included in the composition of the mixture is from 2 to 40.

2. Water-soluble zheltoplodnoy complex according to claim 1 for the treatment or prevention of iron deficiency.

3. The method of obtaining Zelenoglazoe complex according to claim 1, in which one or more maltodextrins in aqueous solution are oxidized under alkaline pH aqueous hypochlorite solution and the resulting solution was subjected to reaction with an aqueous solution of salt of iron (III), and using the one maltodextrine its dextrose equivalent ranging from 5 to 20, with the use of a mixture of maltodextrins dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of each of maltodextrin, which is included in the composition of the mixture is from 2 to 40.

4. The method according to claim 3, characterized in that the oxidation maltodextrine or maltodextrins carried out in the presence of bromide ions.

5. The method according to claim 3 or 4, characterized in that as salts of iron (III) use ferric chloride (III).

6. The method according to any of PP and 4, characterized in that the oxidized maltodextrin and salt of iron (III) is mixed with the receiving water solution having a low pH value, when the hydrolysis of salts of iron (III), after which the pH was raised to pH from 5 to 12 by adding the base.

7. The method according to claim 5, characterized in that the oxidized malted xtren and salt of iron (III) is mixed with the receiving water solution, with such a low pH, when the hydrolysis of salts of iron (III), after which the pH was raised to pH from 5 to 12 by adding the base.

8. The method according to claim 4, characterized in that the reaction is carried out in the period from 15 min to several hours at temperatures from 15°C to the boiling point.

9. The method according to claim 5, characterized in that the reaction is carried out in the period from 15 min to several hours at temperatures from 15°C to the boiling point.

10. The method according to claim 6, characterized in that the reaction is carried out in the period from 15 min to several hours at temperatures from 15°C to the boiling point.

11. The method according to claim 7, characterized in that the reaction is carried out in the period from 15 min to several hours at temperatures from 15°C to the boiling point.

12. Drug containing aqueous solution Zelenoglazoe complex according to claim 1 or obtained according to any one of p-11.

13. The drug is indicated in paragraph 12, prepared for parenteral administration or reception through the mouth.

14. Application Zelenoglazoe complex according to claim 1 or obtained according to any one of p-11 for the treatment or prevention of iron deficiency.

15. Application Zelenoglazoe complex according to claim 1 or obtained according to any one of p-11 for the manufacture of a medicinal product for the treatment or prevention of W is listeining States.



 

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FIELD: polymerization catalysts.

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4 cl, 1 tbl, 11 ex

FIELD: inorganic synthesis.

SUBSTANCE: invention relates to preparation of salts of transition metals with organic acids, in particular to formic acid ferric salt. Method is accomplished via oxidation of ferrous formate with hydrogen peroxide in presence of formic acid and in absence of any dorm of iron as reducer in order to prevent reduction of ferric salt into original ferrous salt. As reducer, ferrous formate is used preliminarily recrystallized and dried or filtered off from reaction mixture suspension. Process is carried out in upright bead mill in two steps. In the first step, ferrous formate powder or precipitate is combined, stepwise or in one go, with 85% formic acid or mixture of filtrate with wash water formed during isolation of desired product to form pasty slurry ensuring stable functioning of bead mill. Second-step operation is effected in bead mill functioning mode involving forced cooling through side surfaces of reactor and continuous introduction of 12.5-25% hydrogen peroxide solution at a rate of 3.25-4.24 g H2O2 per 1 kg starting charge until degree of Fe(II) salt conversion achieves 85-90%. Supply velocity is then lowered until complete conversion is reached. Resulting product slurry is separated from beads and filtered. Filter cake is washed with 85% formic acid and recrystallized in saturated ferric formate solution containing 20-30% of formic acid. Wash liquid is combined with filtrate and used in the first step as described above.

EFFECT: increased yield of target product and simplified its isolation step.

1 tbl, 8 ex

FIELD: inorganic synthesis.

SUBSTANCE: invention relates to preparation of salts of transition metals with organic acids, in particular to formic acid ferric salt. Method is accomplished in bead mill provided with mechanical blade-type stirrer in aqueous formic acid solution (5-10 mole/kg). Iron is used in the form of steel sidewall across the height of reactor and also as particles of reduced iron stirred with stirrer together with glass beads, and/or as broken steel cuttings, and/or yet as split cast iron in any weight proportions. Method is accomplished by continuously introducing 10-20% hydrogen peroxide solution at a rate of 0.015-0,030 mole peroxide/min per 1 kg liquid phase (salt slurry) in presence of stimulating additive, in particular iodine, bromine, alkali metal or ferrous iodides or bromides in amounts (on conversion to halogens) 0.1-0.15 vole per 1 kg reaction mixture. When 1,2-1,5 mole/kg of ferrous salt is accumulated in reaction mixture, stirring and addition of hydrogen peroxide solution are stopped, product slurry is separated from unreacted iron and/or its alloys as well as from glass beads and filtered. Filtrate is recycled into process and precipitate is recrystallized from saturated iron formate solution of aqueous formic acid solution (1-2 mole/kg).

EFFECT: simplified finished product isolation stage, reduced total process time, and reduced power consumption.

1 tbl, 11 ex

FIELD: chemical industry; methods of production of the salts of iron and the organic acids.

SUBSTANCE: the invention is pertaining to the field of chemical industry, in particular, to the method of production of the salts of iron and the organic acids, in particular, to production of the salt of the ferrous iron and the formic acid. The method is realized by the direct interaction of the acid with the iron, its alloys and the ferric oxides. The crumber with the beads and the backflow condenser is loaded with the organic solvent, the formic acid and the water in the mass ratio of 100:(85÷100): (15÷0). As the organic solvent they use ethylcellosolve, butyl acetate, butyl and amyl alcohols, ethylene glycol. The mass ratio of the beads and the liquid phase is 1:1. Ferric oxideFe2O3 orFe3O4 and the iodine are loaded in the amount of 0.40-0.56 or 0/21-0.42 and 0.03-0.1 mole/kg of the liquid phase accordingly. The iron is introduced in the form of the steel shell along the whole height of the reactor and additionally in form of the reduced iron, the fractions of the broken cast iron with dimensions of up to 5 mm and the steel chips in any ratio among themselves at total amount of 20 % from the mass of the liquid phase. The process is conducted at the temperature of 35-55°С practically till the complete consumption of the ferric oxide. The gained suspension is separated from the beads and the metal particles of the greater dimensions and subjected to centrifuging or sedimentation. The clarified liquid phase is returned to the repeated process, and the solid phase is dissolved at stirring action and warming up to 85-95°С in the water solution of the formic acid saturated by the ferric formiate (II) up to 1-2 mole/kg. The present solid impurities are removed at the hot filtration process and the filtrate is cooled and the salt crystals are separated. The technical result of the invention is simplification of the technology of the production process with utilization of the accessible raw.

EFFECT: the invention ensures simplification of the technology of the production process with utilization of the accessible raw.

3 cl, 17 ex

FIELD: chemical industry; methods of production of the salts of iron and the organic acids.

SUBSTANCE: the invention is pertaining to the field of chemical industry, in particular, to the method of production of the salts of the metals of the organic acids, in particular, to production of the salt of the ferrous iron and the formic acid. The method is realized by the direct interaction of the formic acid water solution with the iron and/or its alloys and the ferric oxidesFe2O3 and Fe3O4 in the bead crumber of the vertical type along the whole its height with the steel shell, with the heat supply and equipped with the mechanical stirrer and the backflow condenser-refrigerator. The apparatus is loaded with 23-46 % water solution of the formic acid as the liquid phase in the mass ratio with the glass beads as 1:1.25 and then introduce the oxide - Fe3O4 orFe2O3 in amount of 0.27-0.49 or 0.48-0.64 mole/kg of the liquid phase accordingly, and besides in amount of 18 % from the mass of the liquid phase they add the powder of the reduced iron and-or the crushed cast iron, and-or the crushed steel chips in any mass ratios. Switch on the mechanical stirring and heating and keep the temperature in the reaction zone within the limits of 55-75°С. The process is terminated, when practically the whole loaded oxide is completely consumed. The suspension of the salt is separated from the non-reacted iron, its alloy and the beads and dilute with the water up to the contents of the formic acid within the limits of 1-2 mole/kg. The gained mass at stirring action is slowly heated up to temperature of 85-95°С, controlling transformation of the solid phase into the solution. The gained solution is subjected to the hot filtration, evaporation, cooling and separation of the salt crystals. The filtrate and the earlier the gained distillate are sent back to the repeated process. The technical result of the invention is simplification of the technology of the production process with utilization of the accessible raw.

EFFECT: the invention ensures simplification of the technology of the production process with utilization of the accessible raw.

10 ex

FIELD: production of salts of organic acids, salt of ferrous iron and formic acid in particular.

SUBSTANCE: proposed method consists in loading preliminarily prepared aqueous solution of formic acid at concentration of 4.5-10 mole/kg into reactor provided with bladed mixer, back-flow condenser-cooler and air bubbler. Then, powder of reduced iron and/or broken iron and/or steel chips at any mass ratio in total amount of 20.0-30.6% of mass of liquid phase and stimulating iodine additive in the amount of 0.016-0.164 mole/kg of liquid phase are introduced. Reactor may be provided with steel or cast iron ferrule over entire height. At mechanical mixing, consumption of air for bubbling is maintained between 1.2 and 2.0 l/(min·kg of liquid phase). Working temperature range is 45-65°C which is maintained by external cooling. Process is discontinued when content of iron salts (II) in reaction mixture reaches 1.8-2.0 mole/kg. Suspension of salt in liquid phase is separated from unreacted iron particles and is filtered afterwards. Filtrate is directed for repeated process and salt sediment is re-crystallized from aqueous solution saturated with iron formate by formic acid at concentration of 1-2 mole/kg at heating to temperature of 95°C followed by natural cooling.

EFFECT: enhanced efficiency.

1 tbl, 9 ex

FIELD: chemical industry; methods of production of the ferric formiate (III).

SUBSTANCE: the invention is pertaining to the field of chemical industry, in particular, to the method of production of the ferric formiate (III). The invention is dealt with the organic salts of the transition metals, in particular to production of the salt of the ferric iron and the formic acid. The method is realized by the direct interaction of the regenerated iron powder with the formic acid at presence of the molecular iodine and oxygen of the air as the oxidizing agents. The process is running in the medium of dimethylformamide as the dissolvent for preparation of the necessary liquid phase with the concentrations of the formic acid and iodine of 4.5-10 and 0.03-0.11 mole/kg accordingly. The mass ratio of the liquid phase and the powder of the regenerated iron is 3:1. The process starts at the room temperature and is conducted in the conditions of the forced cooling at the temperature of 50-80°С at the rate of the air consumption for the bubbling of 0.6-1.2 l\minute per 1 kg of the liquid phase. The process is terminated at accumulation of the ferric formiate (III) in the suspension up to 1-1.2 mole/kg. The suspension is separated from the particles of the non-reacted iron and then filtered. The filtrate is recycled to the repeated process, and the ferric formiate (III) (salt) is dried and either is used as required, or additionally is purified by the recrystallization. The technical result of the invention is simplification of the method with improvement of the economic indicators and the increased purity of the final product.

EFFECT: the invention ensures simplification of the method with improvement of the economic indicators and the increased purity of the final product.

8 ex

FIELD: inorganic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing metal complex compounds, in particular, to iron complex (chelate) as its concentrated solution. Method is carried out by interaction of iron salt in an aqueous medium with a chelate-forming agent wherein N,N,N',N'-ethylenediaminetetraacetic acid is used as a chelating agent and citric acid that are added simultaneously or successively. The process is carried out at temperature 70-90°C and in the process of mixing iron salt or after mixing with chelate-forming agent an aqueous solution of ammonia or ammonium citrate is added for providing pH value of the end product 2.0-2.3. The complex-forming agent can comprise succinic acid additionally. Method provides preparing iron chelate as a concentrated solution with the content of iron 60-100 g/l. Invention can be used in agriculture for root and leaf feeding of plants.

EFFECT: improved preparing method.

4 cl, 6 ex

FIELD: inorganic syntheses.

SUBSTANCE: method consists in that iron powder is oxidized in acetic acid/acetic anhydride (4%) medium with air oxygen bubbled through the medium, while maintaining iron-to-acetic acid molar ratio 5:1 and temperature 17-25°C. Reaction mixture is thoroughly stirred with blade stirrer at speed of rotation 720-1440 rpm until reaction mixture accumulates 0.75-0.96 mol/kg ferric salt. Thereafter, air is replaced by nitrogen and 4% acetic anhydride based on initially charged acetic acid is added, temperature is raised to 35-40°C, and iron is oxidized with ferric salt until full consumption of the latter. Resulting snow-white ferrous acetate suspension is separated from unreacted iron, filtered off, and dried. All above operations are carried out under a nitrogen atmosphere. Filtrate, which is saturated ferric acetate solution in acetic acid/acetic anhydride mixture, is recycled to reactor to be reprocessed or it is used according another destination.

EFFECT: simplified technology and improved economical characteristics of process due to use of inexpensive oxidant.

2 ex

FIELD: inorganic syntheses.

SUBSTANCE: ferric acetate is prepared by interaction of metallic iron with acetic acid in presence of an oxidant. Process is carried out at ambient temperature in acetic acid/acetic anhydride medium (weight ratio 5:1) under nitrogen atmosphere. Molar ratio acetic acid/iron/basic ferric acetate is maintained the following: 10:8:1. Reaction mixture is thoroughly stirred with high-speed blade stirrer or shaken at shaking frequency 2 Hz. When consumption of basic ferric acetate is completed, suspension of ferrous acetate is separated by filtration from unreacted iron powder. Precipitate is dried and filtrate returned into the process.

EFFECT: simplified process due to selection of optimal oxidant.

2 ex

FIELD: medicine, radiation medicine.

SUBSTANCE: it has been suggested to apply lactoferrin as a curative preparation in case of acute radiation disease. Lactoferrin should be applied in the experiment at reproducing madullary form of acute radiation disease. Subcutaneous injection of lactoferrin in physiological solution at the dosage of 300 mcg/kg is accompanied with statistically significant increase of lymphocytes and neutrophils in peripheral blood that provides 100%-survival rate of irradiated animals in experimental group.

EFFECT: higher efficiency of therapy.

1 ex, 2 tbl

FIELD: veterinary science.

SUBSTANCE: it is necessary to inject dexamethasone for animals at the dosage of 0.1 mg/kg twice daily till their recovery. Additionally, transcranial electrostimulation should be carried out. One should affect frontal and occipital cranial parts through electrodes with direct current steadily increasing during 2 min from 0 to 6.5 mA. Then electrodes should be supplied with rectangular impulses in the same polarity at frequency being 70-80 Hz and duration being 3-4 msec. Moreover, The amplitude should be slowly increased up to 3 mA for 2 min that corresponds to 2:1 against the ratio with direct current. Duration of electrostimulation procedure corresponds to 30 min, during 5 d. The innovation enables to treat animals in case of hemolytic anemia efficiently and quickly.

EFFECT: higher efficiency of therapy.

2 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with correcting affected erythropoiesis in case of severe hypoxia. One should fulfill subcutaneous single injection of propranolol for laboratory mice on the 2nd d after hypoxia modeling at the dosage of 5 mg/kg. The innovation enables to improve the dynamics for reconstructing cellularity and qualitative values of erythroid source of blood formation, increase the number of erythrocytes in peripheral blood at decreasing the production of their pathological forms due to preventing the lesion of commitment precursor cells of erythropoiesis in post-hypoxic period.

EFFECT: higher efficiency of correction.

3 ex, 3 tbl

FIELD: veterinary.

SUBSTANCE: claimed preparation contains (mass %): disodium or dipotassium salt of ethylenediamine-N,N'-disuccinic acid 15.0-35.0; iron (III) 0.6-4.0; manganese (II) 0.5-2.5; copper (II) 0.05-0.25; zinc (II) 0.3-2.5; cobalt (II) 0.005-0.05; selenium (IV) 0.01-0.03; iodine (I) 0.03-0.08; vitamins: A 0.006-1.2; D3 0.00006-0.0015; E 0.1-3.5; B1 0.005-0.2; B2 0.01-0.25; B3 0.02-0.03; B4 5.5-20.0; B5 0.04-1.4; B6 0.005-1.2; and balance: water.

EFFECT: improved antianemic and growth stimulating preparation for veterinary.

6 cl, 6 tbl

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