Water-soluble iron carbohydrate derivative complexes, the preparation thereof, and medicaments comprising them

FIELD: medicaments.

SUBSTANCE: present invention provides water-soluble iron-carbohydrate derivative complexes which are suitable for the therapy of iron deficiency states, and the preparation thereof, medicaments comprising them, and the use thereof in the prophylaxis or therapy of iron deficiency states. The medicaments are suitable in particular for parenteral administration. A water-soluble iron-carbohydrate derivative complex obtained from the reaction of an aqueous iron (III) salt solution and (b) an aqueous solution of the product of the oxidation and subsequent derivatization of one or more maltodextrins, wherein the oxidation is carried out with an aqueous hypochlorite solution at a pH value in the alkaline range, wherein when one maltodextrin is used its dextrose equivalent is from 5 to 20 and when a mixture of a plurality of maltodextrins is used the dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of the individual maltodextrins in the mixture is from 2 to 40, and the subsequent derivatization is carried out with a suitable reagent. The process for the preparation of the iron-carbohydrate complex, wherein one or more maltodextrins is oxidized in aqueous solution, at an alkaline pH value, with an aqueous hypochlorite solution, the subsequent derivatization is carried out with a suitable reagent, and the resulting solution is reacted with the aqueous solution of an iron (III) salt, wherein when one maltodextrin is used its dextrose equivalent is from 5 to 20 and when a mixture of a plurality of maltodextrins is used the dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of the individual maltodextrins in the mixture is from 2 to 40.

EFFECT: most derivatised maltodextrin ligands exhibit increased stability towards enzymatic degradation by amylase as compared with underivatised maltodextrin, which can promote retarded and uniform degradation of the iron-maltodextrin derivative complexes according to the invention in the body.

15 cl, 11 tbl, 45 ex

 

The object of the present invention are water-soluble iron complexes derived from carbohydrate, which is suitable for the treatment of iron deficiency, as well as the receipt of such complexes, pharmaceutical preparations containing these complexes, and the use of these drugs for prevention or treatment of iron deficiency. Medicines are suitable in particular for parenteral use.

Treatment or prevention of anemia caused by iron deficiency, can be carried out with the use of iron-containing medications. Known use for these purposes iron complexes with carbohydrate. One of the most successfully used today in clinical practice, drugs is the basis of the 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 also complexes of iron dextran for parenteral administration, as well as the complexes on the basis of hard-to-reach pullulan (WO 02/46241), the production of which requires the application of pressure at high temperatures and holding stages of hydrogenation. Other salesopedia complexes are intended for oral administration.

In WO 2004/037865 the applicant discloses the preparation of iron, designed preferably for parenteral administration, which can against the sory just be subjected to sterilization; formerly known parenteral preparations based on sucrose or dextran are only stable at temperatures up to 100°C, which makes it difficult to sterilization. The drug has low toxicity and reduces the risk of developing life-threatening anaphylactic shock caused by dextran. Due to the high stability of the complex is possible the use of higher doses of the drug or increasing the frequency of its introduction. The preparation of iron is made from an easily accessible source products inexpensively. Disclosed, in particular, water-soluble complexes of iron (III) with a carbohydrate-based oxidation products of maltodextrins, and the way they are received. These complexes of iron (III) with a carbohydrate obtained from an aqueous solution of salt 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, from 8 to 12, and in the case of one maltodextrine its dextrose equivalent ranging from 5 to 20; in the case of using a mixture of several maltodextrins dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of the individual maltodextrins included in the composition of the mixture is from 2 to 40.

.Nakano et al. Nahrung/Food 47 (2002), No.4, S.274-278, describe how phosphorylation, among others, dextrin by dry heating in the presence of the tvii phosphate. Specify the degree of phosphorylation of dextrin with 1.07%, 2,42% and 3.2%, which can be achieved depending on the temperature and moisture content of dextrin. Received phosphorylated product was analyzed for its ability to solubilize phosphate. Discussed the possibility of replacing caseinophosphopeptides as a means of enhancing the absorption of calcium phosphate, phosphorylated dextrin. In the named document called, and other features of the synthesis of phosphorylated dextrin, in particular, drying phosphate-containing solution or dry phosphorylation by orthophosphate when heated in vacuum.

M.Z.Sitohy et al. Starch/blitz chess 53 (2001), 317-322, describes the phosphorylation of starch by mixing with a solution of monolatry and dinatriumfosfaatti, filtering, drying, obtaining powder and final heat treatment. Phosphorylated product was tested for its stability to hydrolysis under the conditions of acid and enzymatic hydrolysis; it is proposed to apply it in a mixture of polyacrylate and urea in biodegradable polymeric materials.

US 4841040 describes obtaining phosphorylated dextrins with a molecular weight of from 1,500 to 40,000 daltons and a degree of substitution of from 0.30 to 0.96 and their use as dispersants for aqueous suspensions of minerals and inorganic pigments with a high proportion of solid particles; as amenities gum Arabic solutions for gammirovanie, in solutions ink for lithography and as an additive to the drilling fluid during drilling. The degree of substitution is defined as the molar ratio derivatizing units anhydroglucose to the total number of units anhydroglucose inside the molecule. Hereinafter it is called the molar degree of substitution (MS). Phosphorylated dextrins obtained by oxidation and depolymerization of starch in the reaction with sodium hypochlorite in an alkaline medium and the subsequent or preceding phosphorylation, for example, phosphoric acid, phosphorochloridate, phosphorylchloride or polymer nutritiondata, in particular, nutritionalstatus.

SN-544 779 describes a method of obtaining phosphorylated dextrins by heating a mixture of starch with a solution of phosphoric acid at pH<5 and reduced oxygen content, the subsequent heating in the second stage at a lower oxygen content to the condensation of phosphorus compounds with krakhmaloproduktam and final cooling at reduced oxygen content. The resulting dextrostat shows very good solubility in water. It also points to the possibility of its use as a surface adhesive for paper, as well as in the manufacture of adhesives.

WO 2006/082043 describes in the introduction a number of methods for obtaining starch and is Opatow, for example, the way Neukom (US 2884412), including the suspension of the starch in an aqueous alkaline solution of phosphate, filtering, drying and tempering (annealing) at temperatures of about 140°C metropolitanarea acid in the presence of tributylamine in dimethylformamide (homogeneous version) (Towle et al. Methods Carbohydr. Chem. 6 (1972), 408-410) or, as in the suspension method, in benzene anhydride of phosphoric acid (heterogeneous variant) (Tomasik et al. Starch/Starke 43 (1991), 66-69). The document proposes a method of obtaining a highly-substituted PCB of krakhmaloproduktov, according to which the starch dissolved in a mixture containing means for phosphating (in particular, phosphate salt or phosphate urea), water, and (in the case where the means for phosphating does not include urea) urea, then the water is removed and finally conduct heat reaction with the formation of krahmalistye. The resulting krahmalistye shows degree of substitution of phosphate groups from 0.01 to 2.0, and a very small content of urethane groups. It is proposed to use the received romalotti as additives to mineral or dispersion associated construction materials, and as an additive in pharmaceuticals and cosmetics, as anionic components for polyelectrolyte complexes, as well as the media.

US 3732207 discloses the production of esters, dextrins with and what hydrides organic dibasic acids, in particular succinic acid anhydride or maleic acid anhydride by thermal processing of starch or dextrin with a residual moisture content of about 3% in the presence of an anhydride of an organic acid in an acidic environment. The method allows to obtain esters of dextrin with a molar degree of substitution of from 0.02 to 0.04.

US 4100342 describes the production of esters, dextrins reaction of dextrin with a nonaromatic anhydrides of carboxylic acids containing from 2 to 4 residues of carboxylic acid, in acetic acid in the presence of a tertiary amine as a catalyst and the use of the obtained esters, dextrins as biodegradable components to enhance the cleansing action of detergents.

WO 2004/064850 and WO 92/04904 reveal the dextrin sulphate and their use either alone or in combination with bacteriostatic agent as an antiviral composition, in particular for the treatment of HIV and other sexually transmitted diseases. Sulfates of dextrin with a degree of substitution up to 2 sulfate groups per glucose unit is produced by hydrolysis of starch and subsequent sulfation. When using trimethylamine complex/sulfur trioxide in aqueous alkaline medium gain, mainly 2-sulfate; when using ciclamino acid in dimethylformamide - 6-sulfate, autem acetylation and subsequent sulfation complex trimethylamine/sulfur trioxide in dimethylformamide and removal of acetyl groups by using aqueous solution of caustic soda receive 3-sulfate. These documents also reveals the effect of dextrin sulphate against HIV, as well as their protivoepidemichesky effect.

However, none of these documents describes the formation of iron complexes obtained with derivatives of dextrin.

Therefore, the present invention is to obtain new iron complexes with carbohydrate suitable for the treatment of iron deficiency anemia.

This problem is solved by using complexes under paragraph 1 of the claims. Preferred forms of the complexes are discussed in paragraphs 2 and 3.

Obtaining complexes of the invention is carried out by the method stated in paragraphs 4-10.

As the initial product is used according to the invention maltodextrins. They are easily available raw materials, which can be purchased on the market.

To obtain ligand complexes of the invention maltodextrins first subjected to oxidation in an aqueous solution with a solution of hypochlorite. This method has already been described in WO 2004/037865 included in the list of references taken into account in the preparation of this application.

From solutions of alkali hypochlorites are suitable for this purpose is, for example, sodium hypochlorite solution. Can use regular marketable solutions. The concentration of hypochlorite solutions may, for example, to make, at me the e, 13 wt.%, preferably from 14 to 16 wt.%, in terms of active chlorine. The solutions are preferably used in such an amount that promotes the oxidation of from about 80 to 100%, preferably about 90%, of the aldehyde group in the molecule maltodextrin. This regenerative ability, due to the proportion of glucose molecules maltodextrin, reduced to about 20% or below, preferably to 10% or below.

The oxidation is carried out in an alkaline solution, for example, at pH values from 8 to 12, preferably from 9 to 11. The oxidation can be carried out, for example, at temperatures from 15 to 40°C, preferably from 20 to 35°C. the Duration of the reaction is, for example, from 10 minutes to 4 hours, preferably from 1 to 1.5 hours.

Carrying out the oxidation in the described modes helps to maintain a slight degree of depolymerization used maltodextrins. Not wanting to dwell on theory, the inventors suggested that the oxidation occurs mainly at the place of the terminal aldehyde group (or Polyacetal-group) molecule maltodextrin. This step of the synthesis hereinafter called "C1-oxidation only in order to simplify without a hint of any connection with this name.

To accelerate oxidation reactions may also be used as catalysts. Suitably the m for this is the addition of bromide ions, for example, in the form of alkali bromides, in particular, sodium bromide. Add the amount of bromide is not a critical value. It must be minor in order to provide easy-to-clean final product (Fe-complex). Enough add catalytic amounts. As mentioned above, the addition of bromide is possible, but not necessary.

Moreover, oxidation of maltodextrins can also be used known triple oxidative system hypochlorite/alkaline bromide/2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). The method of oxidation of maltodextrins with the use of alkali bromide as a catalyst or triple TEMRO system is described, for example, Thaburet et al. in Carbohydrate Research 330 (2001), 21-29; this method is applicable to the present invention.

Subsequent processing and secretion of oxidized maltodextrins are carried out by setting the pH of the reaction solution is approximately neutral level using the corresponding acids or buffers, such as, for example, hydrochloric acid, sulfuric acid or acetic acid.

Then the oxidized reaction product can be precipitated by adding a suitable solvent, in which he mostly insoluble. Under the solvent is meant, for example, ethanol, which is used preferably to the concentrations from 80 to 95 wt.%, more preferably from 90 to 94 wt.%, in a volume ratio ethanol:reaction solution equal to about 1:5 to 1:10, preferably from 1:5 to 1:8. In addition, as a precipitating solvents suitable methanol, propanol or acetone. The precipitate is filtered and dried in the traditional way and manner.

Alternative reaction solution can be purified by dialysis or membrane filtration, and the finished product can be obtained by lyophilization or spray drying.

But With1-oxidized maltodextrin can be used without any preliminary selection right at a later stage derivatization.

Subsequent derivatization received C1-oxidized products is traditional, well-known qualified way derivatization of sugars, for example, by oxidation; by esterification with mono - or polyfunctional inorganic or organic acids or their derivatives; carboxyethylgermanium; the addition of organic isocyanates; through the formation of ethers; amidation; through the formation of anhydrides and other

So, for example, can be used for esterification with organic acids or their derivatives. For the esterification may be used any known qualified carboxylic acid or actionspane derivatives of carboxylic acids, preferably the chlorides, anhydrides or acid bromides. Preferably the esterification apply derivatives of C1-C6-carboxylic acid, more preferably acetic anhydride. The esterification is carried out under conventional reaction conditions, for example in aqueous solution or in a suitable for this purpose, a solvent such as, for example, formamide, dimethylformamide, dimethylsulfoxide or acetic acid. The reaction in aqueous solution can be conducted, for example, at a slightly alkaline pH of from about 7.5 to 10, preferably from 8 to 9.5 (pH can be installed on any grounds and maintained constant during the reaction, for example, by using a hydroxide of alkali or alkaline earth metal, such as sodium hydroxide or potassium, and carbonate of alkali or alkaline earth metal), by adding a reactive carboxylic acid derivative, for example, acetylchloride or acetic anhydride. When using other solvents are used the same reagents and selected the appropriate reaction conditions. The reaction can be carried out in the abovementioned solvents at room temperature, under conditions of cooling or heating. The duration of the reaction may be, for example, from 0.5 to 2 hours, preferably from 0.75 to 1.5 hours. Then the subsequent processing is TKA, as with the description of C1-oxidation, i.e. sedimentation, filtration and drying.

In the same way can be done and etherification with polybasic organic carboxylic acids, for example, with the production of esters of succinic, maleic, fumaric, glutaric, or adipic acids, and the second carboxyl group of ester may be either free or alkilany ether. To obtain a suitable anhydrides, mixed anhydrides, chlorides or bromides or other reactive derivatives of polybasic carboxylic acids, in particular succinic acid anhydride, maleic acid anhydride, glutaric acid anhydride, adipic anhydride acid or fumaric acid dichloride. The reaction and subsequent processing are the same as in the above-described esterification. Especially preferred is the esterification with succinic acid anhydride to obtain succinyl-maltodextrine.

Similarly, C1-oxidized maltodextrins can turn into carboxyethyl-derivatives. As a reagent suitable known

a qualified specialist carboxycellulose, for example, halogenecarbonate acid, such as chlorine or bromocarbons acid or their sodium or potassium salts, for example, halogenated in any position C1-C6here is oil acids, such as, for example, α - or β-bromopropionic acid or particularly preferred chlorine - or brooksyne acid.

The reaction is known qualified way, for example, in aqueous solution or in a suitable solvent, such as, for example, formamide, dimethylformamide, dimethylsulfoxide or acetic acid. In aqueous solution the reaction is carried out, for example, at an alkaline pH (at pH 11 to 14, preferably from about 12.5 to 14; for regulating the pH used any cause, for example, NaOH). When using other solvent uses the same reagents and selected the appropriate reaction conditions. The reaction can be carried out in the abovementioned solvents at room temperature, under conditions of cooling or heating during, for example, from 0.5 to 5 hours, preferably for from about 2.5 to 3.5 hours. Subsequent processing and secretion are the same as described in the case of esterification.

Etherification with reactive derivatives of inorganic acids, e.g., sulfation or phosphating are also known qualified method.

The sulfation is carried out, for example, in aqueous solution or in a suitable solvent, such as, for example, formamide, dimethylformamide, dimethylsulfoxide or Sosna acid, with the use of an appropriate reagent of sulfation, for example, SO3-trimethylamine complex or ciclamino acid, at room temperature, under conditions of cooling or heating, preferably, for example, at 30°C for a suitable period of time, for example, from 15 minutes to 2 hours, more preferably for about 30 minutes. When using water as solvent, pH of the reaction solution is brought to strongly alkaline pH (e.g., to pH 12-13), and the solution is stirred further at an appropriate temperature, for example, at 30°C. After acidification with a suitable acid or a buffer, for example, HCl to a pH of from 9.5 to 11, preferably to a pH of about 10,5, are the precipitation and separation, as described in the case of C1-oxidation.

Phosphating is carried out by any known qualified method. The conditions for the dissolution of dextrin with a phosphating reagent in water and establishing a pH of from 2 to 6, preferably about 3. As the phosphating agent can be used all known reagents, preferably a mixture of sodium dihydrophosphate with intrigolapstation in a molar ratio of from 1:0.5 to 1:2,5, for example, 1:1,8. The precipitation of the reaction solution can be performed, for example, ethanol, methanol or acetone, followed by extraction and drying sieges is a, or the reaction solution may be subjected to evaporation to dryness, for example, in a rotary evaporation apparatus, and then dried, preferably at elevated temperature and in vacuum. After grinding, the product is subjected to dry heat, for example, to a temperature of from 120 to 180°C, preferably from 150 to 170°C, preferably in vacuum, and then re-crushed and dissolved in water or in a suitable solvent, preferably at elevated temperature, for example, at 50°C. Then the insoluble residues separated, for example, by centrifugation or filtration, and the obtained solution was subjected to purification using membrane filtration for removal of free orthophosphate. Filtering may be accompanied by IR (infrared)spectroscopy, or by measuring the conductivity. After removing all of the orthophosphate solution was concentrated in a rotary evaporation apparatus, and then spend the deposition and retrieval, as described in the case of esterification.

C2/C3-oszlanyi derivatives can be obtained well-known qualified by the oxidation of C1-oxidized maltodextrin with a suitable oxidant, such as, for example, NaOCl or NaClO4/NaOCl2. The oxidation is carried out, for example, in aqueous solution or in a suitable solvent, such as dimethylformamide, formamide, dimethylsulfoxide acetic acid, at room temperature, under conditions of heating or cooling. When using water as solvent, the reaction proceeds at a slightly alkaline constant pH of 7.5 to 9.5, preferably from 8.5 to 9.0, supported with sodium hypochlorite, and at about 50°C. Then set to neutral pH, for example, by adding HCl, and the product precipitates and is removed as described in the case of esterification.

Through the use of reagents for derivatization in various quantities can be achieved with different molar degree of substitution. When this molar degree of substitution is defined as the molar ratio derivatizing units anhydroglucose to the total number of units anhydroglucose inside a molecule.

The products are analyzed by means of IR spectroscopy. Thus, qualitative analysis can be installed, entered whether the required functional group in maltodextrin. The introduction of carboxyl groups, for example, acetyl group, succinylcoa group or carboxymethyl group, you can track the increase in the number of bands at 1740 cm-1the IR spectrum (C=O-valence fluctuation in COOR). How did C2/C3-oxidation, can be judged by the increase in the number of bands at 1640 cm-1(C=O-valence fluctuation in soo-). The introduction of sulfate groups can be made by increasing the number of lanes at 120 and 830 cm -1(valence fluctuations in). The inclusion of a phosphate group can also be installed qualitative analysis using the31P-NMR spectroscopy. Associated with the polymer monophosphate manifests itself in the form of broad signals at from about 0 to 2 ppm (parts per million parts), while free monophosphate shows a sharp signal at about 0.7 ppm.

Quantitative determination of the molar degree of substitution possible with1H-NMR spectroscopy or13C-NMR spectroscopy relative signal intensity of one of the introduced functional groups to the signal intensity of maltodextrin, which is the derivatization has no effect. In the case of phosphating quantitative determination of molar degree of substitution can also be carried out by ICP-OES (optical emission spectroscopy source inductively coupled plasma, total phosphorus) and ion chromatography coupled with conductivity measurement (determination of the concentration of free monophosphate).

To obtain the complexes according to the invention the oxidized derivateservlet maltodextrins in aqueous solution are introduced into a reaction with a salt of iron (III). This oxidized derivateservlet maltodextrins are extracted from the solution and re-dissolved; however, the resulting aqueous solutions of olenych derivatizing of maltodextrins can also immediately be subjected to subsequent treatment with aqueous solutions of iron (III).

As salts of iron (III) can be used water-soluble salt or mixture of salts of inorganic or organic acids, such as halides, such as chloride and bromide, or sulfate. Preferably used are physiologically safe salts. Particularly preferred is an aqueous solution of iron chloride (III).

It has been proven that the presence of chloride ions has a positive effect on the complexation. These ions may be added, for example, in the form of water-soluble chlorides, such as chlorides of alkali metals, e.g. sodium chloride, potassium chloride or ammonium chloride. Preferred, as already mentioned, is 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 work so that the pH of the mixture of oxidized maltodextrin and salt of iron (III) in the process of mixing and immediately after it was first strongly acidic or so low, so as not to come hydrolysis of salts of iron (III), for example, to a pH equal to 2 or less, in order to avoid unwanted precipitation of hydroxides. When using iron chloride (III) adding acid in most cases is not required, since aqueous solutions of ferric chloride (III) themselves about yourself can be quite acidic. Upon completion of mixing, the pH value increases, for example, to a pH equal to or higher than 5, for example, to a pH of 11, 12, 13 or 14. The increase in pH is preferably carried out slowly or gradually, which can be achieved, for example, by adding first the weak base to bring the pH to about 3, and then adding more strong base to achieve a neutral pH. Under weak basis mean, for example, carbonates, bicarbonates of alkali or alkaline earth metals, such as carbonate or bicarbonate of sodium or potassium, or ammonia. Strong bases are, for example, hydroxides of alkali or alkaline earth metals, such as hydroxides of sodium, potassium, calcium or magnesium.

A beneficial effect on the reaction may have heat. For example, can be used in temperatures from 15°C to the boiling point. Preferred is a gradual increase in temperature. So, for example, may first be heated to a temperature of from about 15 to 70°C, after which the temperature is gradually raised 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, for example, from 25 to 70 minutes, for example, from 30 to 60 minutes.

The reaction can be carried out in a weakly alkaline region, for example, at pH 5 to 6. But ka is shown, better (even if it is not required to increase the pH during complexation to pH 11, 12, 13 or 14. Then, to complete the reaction, it is possible to reduce the pH by addition of acid, for example, to the above pH values from 5 to 6. As acids can be used inorganic or organic acids or mixtures thereof, in particular, halogenation acid such as hydrogen chloride or aqueous hydrochloric acid.

As mentioned above, the complexation in most cases favors the heat. For example, in a preferred variant embodiment, in which the pH value during the reaction increases c >5 to 11 or 14, first working at low temperatures, for example, from 15 to 70°C, for example, from 40 to 60°C, for example, about 50°C; after the new lower pH, for example at least up to pH 5, the temperature is gradually increased to >50°C up to the boiling point.

The duration of reaction is from 15 minutes to several hours and may vary depending on the reaction temperature. When carrying out the method with intermediate regulation of pH values greater than pH 5, it is possible to work within, for example, from 15 to 70 minutes, for example, from 30 to 60 minutes at higher pH and at temperatures of, for example, to 70°C, and after lowering the pH at least up to pH 5, the reaction may be conducted in ECENA from 15 to 70 minutes, for example, from 30 to 60 minutes at temperatures of, for example, to 70°C and, if necessary, in the course of from 15 to 70 minutes, for example, from 30 to 60 minutes, at elevated temperatures up to the boiling point.

After the successful completion of reaction, the resulting solution can be cooled, for example, to room temperature and, if necessary, be diluted and subjected to filtration. After cooling, the pH of the solution may be adjusted by adding acid or base at the level of neutral pH or slightly lower than, for example, at pH 5 to 7. As acids or bases can be used, for example, mentioned in the description of the reaction of acid or base. The obtained solutions are purified and can be used directly for the manufacture of drugs. But you can extract the complexes of iron (III) from solution, for example, by precipitation with an alcohol, such as alkanol, for example, ethanol. The extraction may also be carried out by spray drying. Cleaning can be carried out in the traditional way, in particular, in order to remove salts. It can be done, for example, reverse osmosis, which can be used, for example, before spray drying or before inclusion complexes in medicinal preparations.

The resulting complexes of iron (III) with pleva the om content of iron, for example, from 10 to 40% wt./wt., in particular, from 20 to 35% wt./wt. They are easily dissolved in water. Of them it is possible to prepare a neutral aqueous solutions with a content of iron, for example, from 1 to 20% wt./about. These solutions can be subjected to sterilization by heating. Average molecular weight Mw of the complexes obtained as described above is, for example, from 80 to 800 kDa, preferably from 80 to 650 kDa, particularly preferably up to 350 kDa (determined by gel chromatography, for example, as described Geisser et al. in Arzneim. Forsch/Drug Res.42 (II), 12, 1439-1452 (1992), paragraph 2.2.5).

As mentioned above, some of the complexes according to the invention can be prepared aqueous solutions, which are suitable in particular for parenteral administration. However, they may also be suitable for oral or topical (local) application. They can be sterilized at high temperatures, for example, at 121°C and higher with short-term exposure for at least 15 minutes at the achievement of the Fo≥15. In this case, Fois the processing time in minutes at a variable temperature, which corresponds to the processing time in minutes at 121°C, in terms of the ideal micro-organisms with temperature coefficient destruction of microbial cells that is equal to 10. The manufacturer is known up to the present time preparations partially requires the existence of the Oia sterile filtration at room temperature and/or preservatives, such as benzyl alcohol or phenol. In the present invention in such operations or supplements is not necessary. Can be packaged solutions of complexes, for example in ampoules. For example, can be packaged solutions with concentration from 1 to 20 wt.%, for example, a 5 wt.%, in containers, such as ampoules or vials with the thump of hands tip displacement, for example, from 2 to 100 ml, for example, to 50 ml of the Preparation is ready for injecting fluids can be the traditional method using in each case the traditional parenteral solutions of additives. Solutions can be designed so they can be let go in ready for injection or infusion for infusion, for example, in the salt solution. Preparations for oral or topical application can be compiled with the appropriate traditional excipients (fillers) and auxiliary substances.

Therefore, the next subject of the invention are pharmaceutical preparations which are suitable in particular for parenteral, intravenous, and intramuscular injection, as well as for oral or local use, and can find application in the treatment of, in particular, iron-deficiency anemia. Therefore, the object of the invention is also the use of complexes of iron (III) with the derived uglev is Yes for the treatment and prevention of iron-deficiency anemia or for the manufacture of pharmaceutical preparations in particular, for parenteral administration in the treatment of iron-deficiency anemia. Drugs intended for use in medicine and veterinary medicine.

According to the invention for the first time it was possible to obtain iron complexes with derivatives of maltodextrins.

In comparison with the known from WO 2004/037865 complexes of iron with maltodextrin iron complexes with derivatives of maltodextrins according to the invention allow targeted and more finely regulate the molecular weight in a wide range up to high values, which is impossible in the case of known complexes.

A large part of the iron complexes with derivatives of maltodextrins shows almost unchanged kinetics of decay (θ=0.5) is compared with complexes of iron with maltodextrin, known from WO 2004/037865.

Most complexes derivatizing maltodextrin shows enhanced stability to enzymatic decomposition under the action of amylase compared to rederivation maltodextrin, which can help slow and even collapse of the iron complexes derived from maltodextrin according to the invention in the body.

The output of iron in the complex derivatives according to the invention is up to 100% (in particular, in the case of sulfated derivatives) against 87-93% famous in the x complexes of iron with maltodextrin, that means an economic advantage they obtain on an industrial scale.

Examples

In the present description and the following examples dextrose equivalents are determined gravimetrically. For this maltodextrins are transferred into an aqueous solution with the use of liquid at boiling Fehling. The reaction proceeds quantitatively, i.e. until complete discoloration of the liquid Fehling. Fallen in sediment copper oxide (I) is dried at 105°C to constant mass and is determined gravimetrically. On the obtained performance is calculated glucose (dextrose equivalent) as a % wt./wt. dry matter maltodextrin. You can work for example with the following solution: 25 ml of Fehling's I in the mixture with 25 ml of liquid Fehling II; 10 ml of an aqueous solution of maltodextrin (10% mol/about.) (liquid Fehling I: 34,6 g of copper sulfate (II) are dissolved in 500 ml of water; the fluid Fehling II: 173 g salinetreated and 50 g of sodium hydroxide dissolved in 400 ml of water).

The following explains what methods and with what instruments were determined in each individual case, the properties derived maltodextrin and iron complexes.

1H-NMR: Bruker Avance-400, 400 MHz, solution in D2O (deuterated water), using as internal standard H2O;

13C-NMR: Bruker Avance-400, 100 MHz, solution in D2O using EQ what whether as an external standard (trimethylsilyl)-tetradecanoylphorbol acid;

31P-NMR: Bruker Avance-400, 162 MHz, solution in D2O using as an external standard of concentrated H3PO4;

IR-spectroscopy: FT-IR (infrared Fourier spectrometer Perkin Elmer 1725x, the KBr tablet;

ICP-OES (see above): Horiba Jobin Yvon Ultima 2, the sample was dissolved in H2O;

Ion chromatography: the separation unit Metrohm 733 IC (includes detector conductivity), the sample was dissolved in H2O;

GPC (helpanimals chromatography: pump eluent with HPLC (high performance liquid chromatography) Waters 515; refractometric detector Waters 2410; the sample was dissolved in H2O standard used pullulan;

The definition of Mwsee GPC;

The definition of Mnsee GPC;

Fe: titrimetric determination using EDTA (for example, Jander Jahr, Mass analysis, 15th edition);

Kinetics of decomposition: P.Geisser, M.Baer, E.Schaub. Structure/Histotoxicity Relationship of Parenteral Iron Preparations (Relationship "structure-histotechnol" parenteral iron preparations). Arzneim. - Forsch/DrugResearch 42 (II), 12,1439-1452 (1992);

Spectrophotometer Analytik Jena Specord 205: study the degree of decomposition of 50% (θ=0,5);

The output of iron: the extracted amount of Fe in grams/put the number of Fe in grams.

Example 1

Getting C1-oxidized maltodextrin

250 g of maltodextrin with dextrose equivalent of 12 was dissolved in 750 m the water. Added 1.4 g NaBr, and then within 30 minutes they dosaged is 78.4 g of NaOCl solution (from 14 to 16 wt.%. active chlorine), while the pH was maintained constant at pH of 9.5 (±0,5) by adding 30 wt.%. NaOH. Then the pH was set at pH 7.0 using HCl (20% wt.), and the product precipitated with addition of ethanol (92% wt.) in volumetric ratio of 1:6 (solution: ethanol). The product was removed by decantation from the solution and dried in the following 24 hours at 50°C and 125 mbar.

Example 2

Getting C1-oxidized maltodextrin

100 g of maltodextrin (dextrose equivalent of 9.6, which was determined gravimetrically) was dissolved at 25°C under conditions of stirring in 300 ml of water and subjected to oxidation by the addition of 30 g of sodium hypochlorite solution (from 14 to 16 wt.%. active chlorine) at pH 10, after which the oxidized product was recovered and dried as in example 1.

Example 3

Getting C1-oxidized maltodextrin

A mixture of 45 g of maltodextrin (dextrose equivalent of 6.6, which was determined gravimetrically) and 45 g of maltodextrin (dextrose equivalent 14,0, which was determined gravimetrically) was dissolved at 25°C under conditions of stirring in 300 ml of water and subjected to oxidation by the addition of 25 g of sodium hypochlorite solution (from 14 to 16 wt.%, active chlorine) and 0.6 g of sodium bromide at pH 10, after which the oxidized product were removed and isusually as in example 1.

Examples 4-7

Acetylation

200 g obtained in example 1 maltodextrin (1,23 mole of anhydroglucose) was dissolved in 660 ml of water at 25°C and the pH of the solution was adjusted at 8.5 by the addition of 30% wt. NaOH. Then at a rate of 1.7 ml/min was added acetic anhydride in different quantities specified in table 1, while the pH was maintained constant at pH of 8.5 (±0,5) by adding 30 wt.%. NaOH. The solution was stirred for one hour at a constant pH of 8.5 (±0.5), and then the pH was set at 7.0 with 20% wt. HCl. The product precipitated with ethanol (92% wt.) in volumetric ratio of 1:6 (solution: ethanol). The product was removed by decantation from the solution and dried in the following 24 hours at 50°C and 125 mbar.

By varying the added amount of acetic anhydride was achieved varying degrees of acetylation. The results are presented in table 1.

Table 1
ExampleEquivalent Ac2O (in terms of anhydroglucose)The molar degree of substitution (1H-NMR)Output (%) (mol extracted product/mol used anhydroglucose)
41 0,8424
50,670,6165
60,330,3169
70,160,1474
1-Without derivatization84

Acetylation improved solubility derived maltodextrin in ethanol, which was manifested in the reduction of the yield with increasing degree of substitution.

The degree of acetylation was determined qualitatively by IR-spectroscopy and quantitatively - NMR spectroscopy.

Infrared spectroscopy allows you to track acetylation on increasing the number of bands at 1740 cm-1(C=O-valence fluctuation in COOR). The molar degree of acetylation was determined1H-NMR spectroscopy relative intensity of CH3signal at 2.0 to 2.3 ppm (acetyl group) to the signal intensity in the 3.0 to 4.5 ppm and 5 to 6 ppm (7 protons anhydroglucose group).

Examples 8-11

Succinylcholine

200 g obtained in example 1, C1-oxidized maltodextrin was dissolved in 655 the l of water. the pH of the solution was adjusted at 8.5 by adding 30 wt.%. NaOH, then at 25°C portions were added in 1 hour anhydride of succinic acid, if the pH is kept constant at pH of 8.5 (±0,5) by adding 30 wt.%. NaOH. Then the pH was set at pH 7.0 with 20% wt. HCl, and the product precipitated with ethanol (92% wt.) in the volume ratio of solution:ethanol = 1:6. The product was removed by decantation from the solution and dried in the following 24 hours at 50°C and 125 mbar.

Due to the variation of the added amount of the anhydride of succinic acid was achieved varying degrees of succinylcholine. The results are presented in table 2.

Table 2
ExampleEquivalents of anhydride of succinic acid (in terms of anhydroglucose)The molar degree of substitution (1H-NMR)Output (%) (mol extracted product/mol used anhydroglucose)
80,170,1574
90,080,0782
100,040,0384
110,020,0270
1-Without derivatization84

Succinylcholine had little effect on the solubility of the oxidized maltodextrin.

IR spectroscopy can accurately track succinylcholine to increase the number of bands at 1740 cm-1(C=O-valence fluctuation in COOR/COOH). The molar degree of succinylcholine was determined1H-NMR spectroscopy relative intensity of both CH2signals in the 2.4-to 2.7 ppm (Coccinella group) to the intensity of the signal at the 3.0 to 4.5 ppm and 5 to 6 ppm (7 protons anhydroglucose group).

Examples 12-16

Karboksimetilirovaniya

200 g obtained in example 1, C1-oxidized maltodextrin was dissolved in 660 ml of water. Then added 118 g of solid NaOH so that the pH of the solution was 13-14. Next, portions were added within 20 minutes Chloroacetic acid, after which the solution was stirred at 25°C in the sequel to 3 hours. Then the pH was set at 7.0 with 20% wt. HCl, and the product precipitated with ethanol (92% wt.) in the volume ratio of liquid:ethanol, is avnon 1:6. The product was removed by decantation from the solution and dried in the following 24 hours at 50°C and 125 mbar.

By varying the added amount of Chloroacetic acid was achieved varying degrees of karboksimetilirovaniya. The results are presented in table 3.

Table 3
ExampleEquivalents Chloroacetic acid (in terms of anhydroglucose)The molar degree of substitution1H-NMR)Output (%) (mol extracted product/mol used anhydroglucose)
120,350,03463
130,230,02463
140,180,01776
150,090,01464
160,050,00863
1 -Without derivatization84

The achieved degree of karboksimetilirovaniya an insignificant effect on the solubility of the oxidized maltodextrin.

IR spectroscopy was unable to track karboksimetilirovaniya in these examples due to the low degree of substitution (there were no clear bands at 1740 cm-1C=O-valence fluctuations). The molar degree of karboksimetilirovaniya was determined1H-NMR spectroscopy by the ratio of the intensity of the anomeric protons at about 5.6 ppm (karboksimetilirovannoj anhydroglucose group) to the signal intensity of the anomeric protons 4.8 to 5.8 ppm (anhydroglucose group without derivatization).

Examples 17-20

The sulfation

200 g obtained in example 1, C1-oxidized maltodextrin was dissolved in 600 ml of water and heated to 30°C. was Added SO3-trimethylpentane, and the mixture was stirred at 30°C for 30 minutes (the suspension turned into a solution). It was further added with a rate of 2.8 ml/min 40% wt. NaOH (1.7 equivalents, calculated on the molar amount of SO3-trimethylaminuria corresponding 18-141 ml depending on the degree of substitution), and the solution was stirred at 30°C continued for 2.5 hours. Then the pH was adjusted at a pH of 10.5 with 20% wt. HCl. Product besieged 92% wt. ethanol in the lines concerning the solution:ethanol equal to from 1:7 to 1:8. The product was recovered by decantation of the solution and within 24 hours was dried at 50°C and 125 mbar.

By varying the added amount of SO3-trimethylaminuria was achieved varying degrees of sulfation. The results are presented in table 4.

Table 4
ExampleEquivalents SO3-reagent (in terms of anhydroglucose)The molar degree of substitution (1H-NMR)Output (%) (mol extracted product/mol used anhydroglucose)
170,670,5698
180,340,2792
190,170,1293
200,080,0586
1-Without derivatization84

Stand the high output oxidized sulfated maltodextrin is explained by the deterioration of the solubility of the product in ethanol.

IR spectroscopy it was possible to qualitatively monitor the degree of sulfation (increase in the number of bands at 1260 and 830 cm-1fluctuations valence). The molar degree of sulfation was determined13C-NMR spectroscopy relative intensity C1signal at 96 ppm (sulfated) to the intensity of C1signal at 103 ppm (desulfation types).

Examples 21-24

Phosphating

300 g obtained in example 1 With1-oxidized maltodextrin, NaH2PO4and Na2HPO4(molar ratio 1:1,8) was dissolved in 1.5 liters of water, and the pH of the solution was set at pH 3.0 with 20% wt. HCl. The solution is evaporated to dryness in a rotary evaporator apparatus at 70°c and 125 mbar. The residue was dried in continuation of 16 hours at 50°C and 125 mbar. The resulting product was ground and for 4 hours at 750 mbar was heated to 160°C. the resulting material was again crushed and dissolved in water in a mass ratio of 1:4,4 (solid:water) at 50°C for 1 hour. The solution was cooled to 25°C, and any insoluble residues were separated by centrifugation (5500 rpm, 1 hour).

The resulting solution to remove free orthophosphate was subjected to membrane filtration through a nanofiltration membrane (Nitto-Denko NTR-7410, NaCl-holding capacity is on average 10%) at 22 bar and with whom oresti flow from 180 to 210 l/h. Removal of orthophosphate was controlled by IR spectroscopy washed fractions. The solution of oxidized phosphated maltodextrin was concentrated to 1 liter in a rotary evaporator apparatus at 60°C and 80-250 mbar, after which the product precipitated with ethanol in the volume ratio 1:6 (solution:ethanol). The product was separated by centrifugation of the suspension (5500 rpm, 1 hour) and in the following 24 hours were dried at 50°C and 125 mbar.

By varying the added amount of the mixture NaH2PO4and Na2HPO4taken in a molar ratio of 1:1,8, was achieved varying degrees of phosphating. The results are presented in table 5.

The molar degree of substitution was determined by ICP-OES (optical emission spectroscopy source inductively coupled plasma; total phosphate content) and ion chromatography in combination with measurements of conductivity (the amount of free monophosphate).

Qualitative determination of free monophosphate was performed31P-NMR-spectroscopy. Associated with the polymer monophosphate manifests itself as a broad signal in the region from approximately 0 to 2 ppm, while free monophosphate shows a sharp peak at about 0,7 ppm. On a broad signal at -10 ppm can identify oligophosphates.

Table 5
ExampleEquivalents PO4(in terms of anhydroglucose)Molar
the degree of substitution (ICP)
Free PO4(ppm)Free oligophosphates*** (ppm)Output (%) (mol extracted product/mol used anhydroglucose)
211,850,2580Not determined22
220,55*0,0812222
230,280,2425513
240,23**0,08585218
1Without derivatization--- 84
* The duration of the reaction at 160°C/740 mbar amounted to 16 hours instead of 4 hours.
** Maltodextrin/phosphate in the solution is precipitated with ethanol instead of evaporating to dryness.
*** Content was determined31P-NMR.

Examples 25-29

C2/C3-oxidation (two-step synthesis)

200 g obtained in example 1, C1-oxidized maltodextrin was dissolved in 600 ml of water, and the solution was heated to 50°C. the pH was adjusted at the range from 8.5 to 9.0 with 20% wt. HCl and immediately added 20 g of NaOCl (from 14 to 16 wt.%, active chlorine). The remaining amount of NaOCl was added with the speed of 5.8 ml/min, while the pH is maintained constant at the level of 8.5 (±0,5) by adding 30 wt.%. NaOH. The solution was stirred 1 hour at 50°C and pH 8.5 (±0,5). Then the pH was set at pH 7.0 with 20% wt. HCl, the Product was besieged by 92% wt. ethanol in the volume ratio of solution:ethanol = 1:6. The product was extracted from the solution by decantation and dried in the following 24 hours at 50°C and 125 mbar.

Example 30

C1/S2/C3-oxidation (single-stage synthesis, derivatization in situ)

200 g of maltodextrin with dextrose equivalent of 12 was dissolved in 660 ml of water, and the solution was heated to 50°C. was Added 1.1 g NaBr and d is zerouali within 30 minutes to 135.2 g of NaOCl solution (from 14 to 16 wt.%. active chlorine), if the pH is kept constant at 9.5 (±0,5) by adding 30 wt.%. NaOH. The solution was stirred 1 hour at 50°C and pH of 9.5 (±0,5). Then the pH was set at pH 7.0 with 20% wt. HCl. Product besieged 92% wt. ethanol in the volume ratio of solution:ethanol = 1:6. The product was extracted from the solution by decantation and dried in the following 24 hours at 50°C and 125 mbar.

By varying the added amount of NaOCl (from 14 to 16 wt.%. active chlorine) has been achieved in various molar degree C2/C3-oxidation. The results are shown in table 6.

Table 6
ExampleEquivalents of NaOClThe molar degree of oxidation (13C-NMR)Output (%) (mol extracted product/mol used anhydroglucose)
250,480,04272
260,240,02271
270,120,01288
280,06Not installed75
290,03Not installed78
300,120,01789
1-Without derivatization84

The output of the recovered products were changed slightly.

IR spectroscopy it was possible to monitor the degree With2/C3-oxidation to increase the number of bands at 1640 cm-1(vibration C=O-valence in soo-).

The molar degree C2/C3-oxidation was determined by the method13C-NMR spectroscopy by the ratio of the intensity of the COOH signal 175 and 176 ppm (C2and C3-oxidized) to the intensity of the signal at 76-84 ppm (unoxidized2).

General procedure 1: Getting iron complexes

Getting iron complexes obtained from oxidized derivatizing of maltodextrins carried out in each case using 100 g maltodextrins derived.

To 352 g of a solution of ferric chloride (III) (12% wt./wt. Fe) was first added in terms of what remesiana (paddle stirrer) at room temperature, 100 g of oxidized derivatizing maltodextrin, dissolved in 300 ml of water, and then 554 g of sodium carbonate solution (17,3% wt./wt.).

After that, the pH of the solution was adjusted at pH 11 by adding sodium hydroxide solution, the solution was heated to 50°C and kept for 30 minutes at 50°C. Next, the pH was acidified to pH 5 to 6 by adding hydrochloric acid, the solution is kept for a further 30 minutes at 50°C, and then heated to 97°C-98°C and held at this temperature for 30 minutes. After cooling the solution to room temperature, the pH value of the solution was adjusted at pH 6 to 7 by adding sodium hydroxide solution. Then the solution was filtered through a sterile filter, the solution was extracted complex by precipitation with ethanol in the ratio of 1:0,85 and dried under vacuum at 50°C.

Examples 31-33

Acetylated iron complexes

General processing instructions 1 derived from maltodextrin examples 5-7 were obtained acetylated iron complexes 31-33, whose properties are summarized in table 7 below, where they are compared with the properties of the standard preparation obtained by the process instructions 1 from C1-oxidized, but noderivatives maltodextrin as in example 1.

Table 7
StandardExample 31
MS=0,14 (from example 7)
Example 32
MS=0,31 (from example 6)
Example 33
MS=0,61 (from example 5)
The content of Fe*27,028,929,730,6
Mw168000234000349000511000
Mn100000139000163000334000
The kinetics of the decomposition θ=0,535414644
* in terms of dry substance

The use of acetylated derivatives of maltodextrin with a molar degree of substitution >0,61 led to unstable products.

Acetylated iron complexes showed a higher iron content compared with the standard and increasing with increasing degree of substitution and molecular weight. The kinetics of dissolution at 50% showed very similar to standard the Ohm values. Fe-output acetylated iron complexes reached up to 97%.

Examples 34-36

Succinylcholine iron complexes

General processing instructions 1 derived from maltodextrin examples 9-11 were obtained succinylcholine iron complexes 34-36, whose properties are summarized in table 8 below, where they are compared with the properties of the standard preparation obtained by the process instructions 1 from1-oxidized, but noderivatives maltodextrin as in example 1.

Table 8
StandardExample 34
MS=0,02 (from example 11)
Example 35
MS=0,03 (from example 10)
Example 36
MS=0,07 (from example 9)
The content of Fe*27,024,326,924,4
Mw168000260000347000773000
Mn100000128000of 145,000 188000
The kinetics of the decomposition θ=0,53528326
* in terms of dry substance

Use succinylcholine derived maltodextrin with a molar degree of substitution >0,07 led to unstable products.

Succinylcholine iron complexes showed several low iron content compared to the standard, and increasing with increasing degree of substitution and molecular weight. The kinetics of dissolution at 50% showed in comparison with standard similar to the standard values, with one exception. Fe-output succinylcholine iron complexes reached 94%.

Examples 37-38

Karboksimetilirovaniya iron complexes

General processing instructions 1 derived from maltodextrin examples 15-16 were obtained karboksimetilirovaniya iron complexes 37 and 38, whose properties are summarized in the following table, where they are compared with the properties of the standard preparation obtained by the process instructions 1 from C1-oxidized, but noderivatives maltodextrin as in example 1.

Table 9
StandardExample 37
MS<0,01 (from example 16)
Example 38
MS<0,014 (from example 15)
The content of Fe*27,023,325,5
Mw168000316000404000
Mn100000148000168000
The kinetics of the decomposition θ=0,5353632
* in terms of dry substance

Use karboksimetilirovaniya derived maltodextrin with a molar degree of substitution >0,01 led to unstable products.

The iron content in karboksimetilirovaniya the iron complexes were slightly reduced compared with the standard, and their molecular weight increased with increasing degree of substitution. The kinetics of dissolution at 50% showed approximately equal to the standard values. Fe-output karboksimetilirovaniya iron complexes has reached the al 97%.

Examples 39-41

C2/C3-oxidized iron complexes

General processing instructions 1 derived from maltodextrin examples 27, 28 and 29 were obtained C2/S3-oxidized iron complexes 39-41, whose properties are summarized in table 10 below, where they are compared with the properties of the standard preparation obtained by the process instructions 1 from C1-oxidized, but noderivatives maltodextrin as in example 1.

Table 10
StandardExample 39
MS<0,01 (from example 29)
Example 40
MS<0,01 (from example 28)
Example 41
MS=0,012 (from example 27)
The content of Fe*27,022,226,123,8
Mw168000275000310000433000
Mn100000138000150000230000
The kinetics of the decomposition θ=0,535333639
* in terms of dry substance

The use of C2/S3-oxidized derivatives of maltodextrin with a molar degree of substitution >0,01 led to unstable products.

Indicators of iron content did not show any common trends, indicators of molecular weight increased with increasing degree of substitution. The kinetics of dissolution at 50% showed approximately equal to the standard values. Fe-output C2/C3-oxidized iron complexes reached 95%.

Examples 42-44

Sulfated iron complexes (multi-step synthesis)

General processing instructions 1 derived from maltodextrin examples 18-20 were obtained sulfated iron complexes 42-44, whose properties are summarized in the following table, where they are compared with the properties of the standard preparation obtained by the process instructions 1 from1-oxidized, but noderivatives maltodextrin as in example 1.

Example 45

Sulfated iron complex (single-stage synthesis, derivatization in situ)

100 g of maltodextrin with d is xtranny equivalent of 12 was dissolved in 300 ml of water. To the solution was added 0.7 g NaBr, and then within 30 minutes they dosaged of 28.7 g of NaOCl solution (from 14 to 16 wt.%. active chlorine), while maintaining constant pH of 9.5 (±0,5) by adding 30 wt.%. NaOH. Then, the solution was heated to 30°C, was added to 14.4 g SO3-trimethylamines, and the mixture was stirred for 30 minutes at 30°C. Then they dosaged to 17.6 ml of 40% wt. NaOH, followed by stirring for 1 hour at 30°C.

After cooling the solution to 20-25°C was added under stirring 352 g of a solution of ferric chloride (III) (12% wt./wt. Fe) and finally they dosaged 554 g of sodium carbonate solution (17,3% wt./wt.). After that, by adding sodium hydroxide solution was established pH 11, the solution was heated to 50°C and was kept continued for 30 minutes at 50°C. Then, by adding hydrochloric acid, the solution was acidified to pH 5-6, stood next 30 minutes at 50°C, then heated up to 97-98°C and kept for 30 minutes at this temperature. After cooling the solution to room temperature, its pH was adjusted at pH 6-7 by adding sodium hydroxide solution. Then the solution was filtered through a sterile filter, the complex precipitated with ethanol in the ratio of 1:0,85 and dried under vacuum at 50°C.

Standard
Table 11
Example 42
MS=0,05 (from example 20)
Example 43
MS=0,12 (from example 19)
Example 44
MS=0,27 (from example 18)
Example 45
MS=0,12
The content of Fe*27,0to 25.326,826,326,3
Mw168000261000278000640000160000
Mn100000142000219000409000106000
The kinetics of the decomposition θ=0,535756267-
* in terms of dry substance

The use of sulfated derivatives of maltodextrin with a molar degree of substitution >0,27 led to unstable products.

The iron content of the sulfated iron complexes remained almost the and constant with increasing degree of substitution. Indicators of molecular weight iron complexes obtained multistage synthesis, increased with increasing degree of substitution. The kinetics of dissolution at 50% showed in comparison with the standard increased values. Fe-output sulfated iron complexes reached 100%.

1. Water-soluble complex of iron with a derivative of a carbohydrate obtained from an aqueous solution of salt of iron (III) and an aqueous solution of the product obtained by the oxidation and subsequent derivatization of one or more maltodextrins, where the oxidation is carried out with an aqueous solution of hypochlorite at a pH value in the alkaline region, when one maltodextrin its dextrose equivalent ranging from 5 to 20, with the use of a mixture of several maltodextrins dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of each part of the mixture separate maltodextrin is from 2 to 40, and where subsequent derivatization performed using suitable for this purpose reagent.

2. Water-soluble iron complex with a carbohydrate according to claim 1, where the derived maltodextrin obtained by oxidation and derivatization selected from esters monobasic or polybasic carboxylic acids, products2/S3-oxidation products carboxyaniline, carbamates, ethers, amide is in, anhydrides and esters of inorganic acids.

3. The complex according to claim 1 or 2, where the derived maltodextrin obtained by oxidation and derivatization selected from esters of carboxylic acids, mixed esters of dicarboxylic acids, food carboxyaniline, products2/S3-oxidation, phosphates and sulfates.

4. The method of producing iron complex with a carbohydrate according to any one of claims 1 to 3, characterized in that one or more maltodextrins are oxidized in an aqueous solution at an alkaline pH with an aqueous solution of hypochlorite, then hold derivatization with suitable for this purpose reagent, and the resulting solution is injected into the reaction with 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 several maltodextrins dextrose equivalent of the mixture is from 5 to 20 and the dextrose equivalent of each part of the mixture separate maltodextrin is from 2 up to 40.

5. The method according to claim 4, in which the derivatization of oxidized maltodextrin hold one of the following methods:
a) esterification with organic or inorganic acids or their derivatives,
b) oxidation,
C) carboxyaniline,
d) the formation of ethers,
e) amidation,
e) about the education of carbamates,
g) formation of anhydrides.

6. The method according to claim 4, in which the derivatization hold one of the following methods:
a) carboxylation monobasic carboxylic acids or their derivatives,
b)2/S3-oxidation
C) carboxylation dibasic carboxylic acids or their derivatives,
d) carboxyaniline,
d) phosphating,
(e) sulfation.

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

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

9. The method according to any of claims 4 to 8, characterized in that the oxidized derivationally maltodextrin and salt of iron (III) is mixed in an aqueous solution having a low pH value, at which there are no hydrolysis of salts of iron (III), after which the pH was raised to pH 5-12 by adding the base.

10. The method according to claim 9, 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. Means for obtaining a medicinal product containing an aqueous solution of the iron complex with a derivative of a carbohydrate according to any one of claims 1 to 3 or obtained according to any one of claims 4 to 10.

12. Means for obtaining a medicinal product according to claim 1, intended for parenteral or oral administration.

13. The use of iron complexes with derivatives of carbohydrate according to any one of claims 1 to 3 or obtained according to any one of claims 4 to 10 for the treatment or prevention of iron deficiency.

14. The use of iron complexes with derivatives of carbohydrate according to any one of claims 1 to 3 or obtained according to any one of claims 4 to 10 for the manufacture of a medicinal product for treatment or prevention of iron deficiency.

15. Water-soluble complex of iron with a derivative of a carbohydrate according to any one of claims 1 to 3 for the treatment or prevention of iron deficiency.



 

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3 ex, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with composition for enhancing growth of hematopoetic stem cells CD34+, which contains efficient amount of immunomodelling compound, which represents 4-(amino)-2-(2,6-dioxo(3-pyperidyl))isoindoline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)pyperidine-2,6-dione or its pharmaceutically acceptable salt and efficient amount of valproic acid or trichostatin A or their pharmaceutically acceptable salt. Invention also relates to method of enhancing growth of hematopoetic stem cells CD34+, method of treatment, prevention or controlling hematological disease or disorder, method of transplantation and recovery of bone marrow, method of treatment, prevention or controlling solid tumour, method of treatment, prevention or controlling leukoses and myelomas, method of treatment, prevention or controlling myelodysplastic syndrome and method of increasing expression of embryonic hemoglobin in cells.

EFFECT: compositions by the invention synergistically increase growth of hematopoetic stem cells CD34+.

23 cl, 16 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to veterinary. Complex pharmaceutical preparation for increase of animal organism resistance, contains carnitin hydrochloride, magnesium sulfate, sorbent and filling agent, and additionally contains, at least, one water-soluble vitamin or vitamin-like substance, as such, selected from the group, including: thiamin (B1), riboflavin (B2), pantotenic acid (B3), calcium pantotenate (B5) niacin (B5, PP), nicotine amide (PP), pyridoxine (B6), folic acid (B9, Bc), cyanocobalamin (B12) vicasol (K3), pangamic acid (B15) with the following ratio, gram per 100 ml: carnitin hydrochloride 1.000-20.000; magnesium sulfate 5.000-30.000; sorbent 5.000-30.000; water-soluble vitamin or vitamin-like substance 0.001-5.000; filling agent to 100 ml. Complex pharmaceutical preparation can additionally contain 0.100-10.000 grams per 100 ml, of at least one organic acid as such selected from group, including: formic acid, acetic acid, propionic acid, butyric acid, lactic acid, malic acid, tartaric acid, citric acid, sorbic acid, succinic acid.

EFFECT: increase of animal and bird resistance in comparison with analogues.

26 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry, namely to preparing an oral food additive free from taste masking substances and containing a iron and copper source.

EFFECT: oral food additive is applied for symptomatic therapy of iron deficiency.

11 ex, 11 tbl, 10 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication for treatment of infectious disease, cancer treatment, wound healing and/or detoxification of subject, which contains nanoparticles of heterocrystalline mineral selected from group of heterocrystalline minerals SiO2, quartzite, grothite, leucoxene and rutilated quartz. Nanoparticles of said minerals have sizes from 0.5 to 200 nm, have ability to desorption in water, can be transported into cell by DNA molecule and can be applied together with anti-metabolic anti-tumour medication.

EFFECT: nanoparticles of heterocrystalline minerals demonstrate high chemical and biological activity.

13 cl, 3 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to obstetrics and gynecology, and can be used for complex treatment of iron-deficiency anemia in pregnant women. For this purpose traditional pharmacotherapy with iron-containing medication is administered. Additionally administered is "Yantar-energovit" in dose 0.5 g 3 times per day after meal for 3-4 weeks. After that, it is administered in dose 0.5 g 1 time per day for 3 weeks. Courses of additional intake of "Yantar-energovit" are alternated till fetus delivery, depending on degree of iron-deficiency anemia severity.

EFFECT: method ensures increase of treatment efficiency, reduction of number of obstetrical complications during pregnancy and labour and, thus, prevent possible perinatal loss.

2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to obstetrics and gynecology and can be used for correction of endothelial dysfunction in pregnant women with iron deficiency anemia in the second trimester of gestation. Medication "Ferretab" is administered to patients in dose 1 dragee per day per os during 3 weeks.

EFFECT: method possesses high efficiency and provides possibility of timely correction of endothelial dysfunction in case of iron deficiency anemia in order to prevent possible complications of pregnancy and early neonatal period due to elimination of tissue hypoxia and normalisation of iron level in organism.

4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly, to obstetrics, and concerns therapy of anaemia in pregnant recipients of a renal graft. That is ensured by subcutaneous introduction of recombinant erythropoietin 2000 Units 3 times a week combined with intravenous introduction of iron preparations daily for 7 days in iron dosage 100 mg in 5 ml of the preparation to increase the Hb level by at least 5 g/l. The treatment proceeds with supporting therapy that involves administering recombinant erythropoietin 2000 Units subcutaneously once a week with underlying oral introduction of the iron preparations to achieve the Hb level at least 100 g/l throughout the second and third trimesters of pregnancy.

EFFECT: administration schedule of the preparations provides higher clinical effectiveness and reduced length of therapy of anaemia with reduced postoperative complications in the given group of patients.

2 ex

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