HK1140219B - Water-soluble iron-carbohydrate derivative complexes, preparation thereof and medicaments comprising them - Google Patents

Description

Water-soluble iron-carbohydrate derivative complexes, their preparation and medicaments containing them

The subject of the invention is water-soluble iron-carbohydrate derivative complexes which are suitable for the treatment of iron deficiency, their preparation, medicaments containing them and their use for the prophylaxis or treatment of iron deficiency. The medicament is particularly suitable for parenteral use.

Anemia caused by iron deficiency can be treated therapeutically or prophylactically by administering iron-containing drugs, for which the use of iron-carbohydrate-complexes is known. A formulation which is generally effective in practice is based on water-soluble iron (III) hydroxide-sucrose complexes (Danielson, Salmonmonson, Derendorf, Geisser, Drug Res., Vol.46: 615-621, 1996). The prior art describes also the parenteral administration of iron-dextran-complexes and complexes based on poorly available pullulan (WO 02/46241), which have to be prepared under pressure and elevated temperature, including a hydrogenation step. Other iron-carbohydrate-complexes are often administered orally.

WO 2004/037865 of the applicant discloses a preferably parenterally administered iron preparation which can be relatively simply sterilised; the formulations for parenteral administration based on sucrose or dextran disclosed earlier are difficult to disinfect because they are stable only at temperatures up to 100 ℃. The formulation has reduced toxicity and poses less risk of dangerous anaphylactic shock due to dextran induction. Because of the higher stability of the complex, high dose administration or high administration speed can be achieved. The iron preparation can be produced from easily available raw materials without particular trouble. Especially water-soluble iron (III) -carbohydrate complexes based on maltodextrin oxidation products and methods for their preparation are disclosed. The iron (III) -carbohydrate complexes are obtained from aqueous solutions of iron (III) salts and of one or more oxidation products of maltodextrin with aqueous hypochlorite solutions at alkaline pH values of, for example, 8 to 12, with a dextrose equivalent of 5 to 20 in the case of one maltodextrin, 5 to 20 in the case of a mixture of maltodextrins, and 2 to 40 in the case of individual maltodextrins participating in the mixture.

T.Nakano et al, Nahrung/Food 47(2002) No.4, S.274-278 describe a process for phosphorylizing, in particular dextrins, by dry heating in the presence of phosphate. The degrees of phosphoryl substitution of dextrins mentioned are 1.07%, 2.42% and 3.2%, which are obtained depending on the temperature and moisture of the dextrin. The obtained phosphoryl-substituted product was investigated for its ability to solubilize phosphate esters. The possibility of casein phosphopeptide as calcium phosphate absorption enhancer being replaced by phosphoryl substituted dextrin was discussed. Other methods of synthesis of phosphoryl-substituted dextrins are also mentioned in said document, in particular drying of phosphate-containing solutions or drying of phosphoryl-substituted orthophosphoric esters under heat and vacuum.

M.Z.Sitohy et al, Starch53(2001), 317-. The hydrolytic stability of the phosphoryl-substituted products was investigated in acid hydrolysis and enzymatic hydrolysis and was suggested for use in biodegradable plastics in admixture with polyacrylates and urea.

US 4,841,040 describes the preparation of phosphoryl-substituted dextrins having a molecular weight of 1500 to 40000 daltons and a degree of substitution of 0.30 to 0.96 and their use as dispersants for aqueous suspensions of mineral and inorganic pigments having a relatively high solids content, as substitutes for gum arabic in gelling and ink solutions for litho-printing and as drilling fluid additives. Herein, the degree of substitution is defined by the molar ratio of the derivatized anhydroglucose unit to the total amount of anhydroglucose units in the molecule. This is hereinafter referred to as Molar Substitution (MS). The phosphoryl-substituted dextrin is obtained by: the starch is oxidized and depolymerized by reaction with sodium hypochlorite in an alkaline medium and subsequent or prior phosphoryl substitution, for example with phosphoric acid, phosphorus pentachloride, phosphorus oxychloride or a polymeric sodium orthophosphate, especially sodium trimetaphosphate.

CH-544779 describes a process for preparing phosphoryl-substituted dextrins by heating a mixture of starch and phosphoric acid solution at a pH of less than 5 with a lower oxygen content and then in a second stage further heating with a lower oxygen content until the phosphorus compound condenses with the starch product and subsequently cooling with a reduced oxygen content. The obtained dextrin phosphate shows high water solubility. The use as surface glue for paper and for the preparation of adhesives is likewise mentioned.

WO 2006/082043 describes in the preamble several methods for preparing starch phosphates, for example according to the Neukom-method (US 2,884,412) by: suspended in an aqueous alkali metal phosphate solution, filtered, dried and thermostated at temperatures of around 140 ℃, prepared in a homogeneous process with tetrapolyphosphoric acid in dimethylformamide in the presence of tributylamine (Towle et al, Methods Carbohydr, chem.6, (1972), 408-410) or else in a heterogeneous Slurry-process in benzene with phosphoric anhydride (Tomasik et al, Starch @)43(1991),66-69). This document proposes a process for preparing highly substituted starch phosphates in which the starch is dissolved in a mixture of a phosphating agent, in particular a phosphate or urea phosphate, and water and urea (in the case of a phosphating agent without urea), the water is removed and subsequently converted thermally to starch phosphate. The degree of substitution of the phosphate groups of the starch phosphate obtained is from 0.01 to 2.0 and the content of carbamate groups is small. The starch phosphates obtained are suggested as additives for mineral or dispersion-relevant building material systems, as additives for pharmaceuticals and cosmetics, as anionic components for polyelectrolyte complexes and as carrier materials.

US 3,732,207 discloses the preparation of dextrin esters with organic dibasic anhydrides, especially succinic anhydride or maleic anhydride, by heating starch or dextrin having a residual moisture content of about 3% in the presence of an organic anhydride in an acidic environment. Dextrin esters are obtained with a molar substitution of 0.02 to 0.04.

US 4,100,342 describes the preparation of dextrin esters by reacting dextrins with anhydrides of non-aromatic carboxylic acids containing 2 to 4 carboxylic acid units in acetic acid in the presence of tertiary amines as catalysts and using the obtained dextrin esters as biodegradable components for improving the detergent effect of detergents.

WO 2004/064850 and WO 92/04904 disclose dextrin sulfates and their use, either aloneOr in combination with bacterial inhibitors, as antiviral compositions, particularly for the treatment of HIV and other sexually transmitted diseases. Dextrin sulphate esters with a degree of substitution of up to 2 sulphate groups per glucose unit are prepared by hydrolysis and subsequent sulphation of starch. 2-sulfate is mainly obtained by using trimethylamine/sulfur trioxide-complex in aqueous alkaline medium, 6-sulfate is formed by using cyclic amine acid in dimethylformamide, and the obtained product is acetylated, then is sulfated with the trimethylamine/sulfur trioxide-complex in the dimethylformamide, and finally acetyl is removed by using sodium hydroxide aqueous solution to obtain the 3-sulfate. The anti-HIV effect of dextrin sulphate and its resistance are also disclosed in this documentThe function of (1).

However, none of the above documents describes the formation of iron complexes with the resulting dextrin derivatives.

It is therefore an object of the present invention to provide novel iron-carbohydrate-complexes suitable for the treatment of iron deficiency.

This object is achieved by a complex according to claim 1. Preferred embodiments of the above complexes are defined in claims 2 and 3.

The complex according to the invention is obtained by the process defined in claims 4 to 10.

According to the invention, maltodextrin is used as starting material. This is a readily commercially available starting material.

To prepare the ligands of the complexes of the invention, the maltodextrins are first oxidized in aqueous solution with a hypochlorite solution. This process is already described in WO 2004/037865, the disclosure of which is fully incorporated herein by reference.

For example, solutions of alkali metal hypochlorites are suitable, such as sodium hypochlorite solution. Commercially available solutions may be used. The concentration of the hypochlorite solution is, for example, at least 13% by weight, preferably in the order of 14 to 16% by weight, calculated as active chlorine in each case. The solution is preferably used in such an amount that about 80 to 100%, preferably about 90%, of the aldehyde groups per maltodextrin molecule are oxidized. In this way, the reducing power, which depends on the glucose fraction of the maltodextrin molecules, is reduced to about 20% or less, preferably 10% or less.

The oxidation is carried out in an alkaline solution, for example at a pH of 8 to 12, for example 9 to 11. For oxidation, it is possible, for example, to work at temperatures of the order of 15 to 40 ℃, preferably 20 to 35 ℃. The reaction time is of the order of, for example, 10 minutes to 4 hours, for example 1 to 1.5 hours.

By means of this process, the degree of depolymerization of the maltodextrin used is kept small. Without being bound by theory, it is believed that oxidation occurs primarily at the terminal aldehyde (or hemiacetal) groups of the maltodextrin molecules. This synthesis step is hereinafter abbreviated as "C₁Oxidation ", although not intended to be bound by this name.

It also catalyzes the oxidation of maltodextrin. Suitable for this is the addition of bromide ions, for example in the form of alkali metal bromides, for example sodium bromide. The amount of bromide added is not critical. This amount is kept as small as possible, so that the end product (Fe-complex) is obtained which is as easy to purify as possible. Which satisfies the catalytic amount. As noted above, although bromide may be added, it is not necessary.

Alternatively, for example, maltodextrin can be oxidized using the known ternary oxidation system hypochlorite/alkali metal bromide/2, 2, 6, 6-tetramethylpiperidin-1-oxyl (TEMPO). This process is carried out by oxidation of maltodextrin under the catalysis of alkali metal bromides or with ternary TEMPO-systems, as described, for example, by Thabret et al in Carbohydrate Research 330(2001) 21-29; the process described therein can be used in the present invention.

The oxidized maltodextrin is treated and isolated by adjusting the reaction solution to about neutral pH with a suitable acid or buffer, such as hydrochloric acid, sulfuric acid or acetic acid.

The oxidized reaction product may then be precipitated by addition of a suitable solvent in which the reaction product is substantially insoluble. As solvent, for example, ethanol can be used, preferably in a concentration of 80 to 95 wt.%, particularly preferably 90 to 94 wt.%, in volume ratio ethanol: the reaction solution is about 1: 5 to 1: 10, preferably 1: 5 to 1: 8. In addition, methanol, propanol or acetone are suitable as precipitation solvents. The precipitate is then filtered and dried in a conventional manner.

Alternatively, the reaction solution may be purified by dialysis or membrane filtration, and the product obtained by freeze-drying or spray-drying.

C₁The oxidized maltodextrins can also be used directly without isolation in the subsequent derivatization step.

Then, the obtained C is subjected to₁Derivatization of the oxidized products is carried out by conventional methods known to the skilled worker for derivatizing sugars, for example by oxidation, esterification with mono-or polyfunctional inorganic or organic acids or acid derivatives, carboxyalkylation, addition of organic isocyanates, etherification, amidation, anhydride formation and the like.

Thus, for example, esterification with organic acids or acid derivatives is possible. Any carboxylic acid or reactive carboxylic acid derivative known to the skilled person may be used for esterification, preferably an acid chloride, anhydride or bromide. Preference is given to using C₁-C₆Carboxylic acid derivatives, acetic anhydride being particularly preferred. The esterification is carried out under customary reaction conditions, for example in aqueous solution or in a suitable solvent, for example formamide, dimethylformamide, dimethyl sulfoxide or acetic acid. The reaction can be carried out in aqueous solution, for example, by adding a reactive carboxylic acid derivative, for example acetyl chloride or acetic anhydride, at a slightly alkaline pH of about 7.5 to 10, preferably 8 to 9.5 (the pH can be adjusted with any base and is kept constant during the reaction, for example alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide or potassium hydroxide, as alkali metal or alkaline earth metal carbonates). The same reactants are used when other solvents are used, and the reaction conditions are appropriately selected. The reaction can be carried out in the solvent at room temperature, with cooling or heatingAnd (6) rows. The reaction time is, for example, 0.5 to 2 hours, preferably 0.75 to 1.5 hours. The processed image C₁Oxidation is carried out as described by precipitation, filtration and drying.

Esterification with polybasic organic carboxylic acids is also possible in the same way, for example to prepare succinic, maleic, fumaric, glutaric or adipic esters, in which case the two carboxyl groups of the ester may either be present free or as alkyl esters. Anhydrides, mixed anhydrides, -chlorides or-bromides or other reactive derivatives of polycarboxylic acids are suitable for the preparation, such as, in particular, succinic anhydride, maleic anhydride, glutaric anhydride, adipic anhydride or fumaric dichloride. The reaction and treatment are carried out as described for the esterification. Esterification with succinic anhydride to succinyl-maltodextrin is particularly preferred.

C₁Oxidized maltodextrins can likewise be reacted to carboxyalkyl derivatives. Carboxyalkyl halides known to the skilled worker are suitable as reactants, for example halogenated carboxylic acids, such as chlorocarboxylic acids or bromocarboxylic acids or their sodium or potassium salts, e.g. C halogenated in any position₁-C₆Carboxylic acids, such as α -or β -bromopropionic acid or, with particular preference, chloroacetic acid or bromoacetic acid.

The reaction is carried out in a manner known to the skilled worker, for example in aqueous solution or in a suitable solvent, for example formamide, dimethylformamide, dimethyl sulfoxide or acetic acid. The reaction is carried out in aqueous solution, for example at basic pH (pH 11 to 14, preferably about 12.5 to 14, adjusted with any base, e.g. NaOH). The same reactants are used when other solvents are used, and the reaction conditions are appropriately selected. The reaction may be carried out in the solvent at room temperature under cooling or heating for, for example, 0.5 to 5 hours, preferably about 2.5 to 3.5 hours. The work-up and isolation are carried out as described for the esterification.

The esterification with the reactive derivative of a mineral acid, for example sulfation or phosphorylation, is likewise carried out in accordance with methods known to the skilled worker.

Sulphating, for example in waterIn solution or in a suitable solvent, e.g. formamide, dimethylformamide, dimethyl sulfoxide or acetic acid, with a suitable sulfating agent, e.g. SO₃-trimethylamine-complex or cyclic amine acidAt room temperature, under cooling or heating, preferably for example at 30 ℃ for a suitable time, for example from 15 minutes to 2 hours, preferably about 30 minutes. Next, the pH of the reaction solution is adjusted to be strongly basic (for example, to pH12-13) with the use of water as a solvent, and the solution is further stirred at a suitable temperature, for example, 30 ℃. After acidification to pH9.5 to 11, preferably about 10.5, with a suitable acid or buffer, e.g. HCl, precipitation and isolation is carried out, e.g. C₁As described for oxidation.

The phosphorylation is carried out according to any method known to the skilled worker (Fachleuten). One possibility consists in dissolving the dextrins in water with a phosphating agent and in adjusting the pH to a value of 2 to 6, preferably about 3. All known reagents come into consideration as phosphating agents, preference being given to using mixtures of sodium dihydrogenphosphate/disodium hydrogenphosphate in a molar ratio of from 1: 0.5 to 1: 2.5, for example 1: 1.8. The reaction solution can be precipitated, for example, with ethanol, methanol or acetone, and the precipitate separated and dried, or the reaction solution is evaporated to dryness, for example in a rotary evaporator, and further dried, preferably at elevated temperature and under vacuum. After grinding, the product is dried and heated, for example to 120 to 180 ℃, preferably 150 to 170 ℃, preferably in vacuo, and then ground again, then dissolved in water or a suitable solvent, preferably at a higher temperature, for example 50 ℃. The insoluble residue is then separated off, for example by centrifugation or filtration, and the resulting solution is purified by membrane filtration to remove free orthophosphoric acid esters. The filtering can be tracked by IR spectroscopy or conductivity measurements. After all the orthophosphoric acid esters have been removed, the solution is concentrated in a rotary evaporator and then precipitated and isolated, as described for the esterification.

C₂/C₃Oxidized derivatives can be obtained by techniquesKnown to the person C₁Oxidation of oxidized maltodextrins with suitable oxidizing agents, e.g. NaOCl or NaIO₄/NaOCl₂And (4) obtaining. The oxidation is carried out, for example, in aqueous solution or in a suitable solvent such as dimethylformamide, formamide, dimethyl sulfoxide or acetic acid, at room temperature, with heating or cooling. When water is used as solvent, the reaction is carried out at a weakly basic, constant pH of 7.5 to 9.5, preferably 8.5 to 9.0, for example by sodium hypochlorite, at about 50 ℃. The pH is then adjusted to neutral, for example by addition of HCl, and the product is subsequently precipitated and isolated, as described for the esterification.

By derivatizing with different amounts of each reactant, different molar degrees of substitution can be achieved. The molar substitution is defined herein as the molar ratio of derivatized anhydroglucose units to the total amount of anhydroglucose units in the molecule.

The product was studied by IR spectroscopy. For example, it can be determined qualitatively whether the desired functional group is incorporated into the maltodextrin. The introduction of carboxyl groups, e.g.acetyl, succinyl or carboxymethyl groups, can be carried out by 1740cm in the IR spectrum^-1The band (C ═ O-bond vibration of COOR (valency)) increases. C of proceeding₂/C₃Oxidation through 1640cm^-1Band (COO)^-C ═ O-valence bond vibration) is increased. The introduction of sulfate groups can be carried out by 1260 and 830cm^-1Confirmed by band up (SO)₄ ^2-The valence bond vibration). The phosphate group can also be introduced by³¹And P-NMR spectrum to confirm. Polymer-bound monophosphates showed broader signals at about 0 to 2ppm, while free monophosphates showed sharp signals at about 0.7 ppm.

The quantitative determination of the molar degree of substitution can be carried out by¹H-NMR spectrum or¹³C-NMR spectroscopy was carried out because the signal intensity attributed to the introduced functional groups is directly proportional to the signal intensity of the maltodextrins which are not affected by the derivatization. In the case of phosphatation, the quantitative determination of the molar substitution can also be carried out by ICP-OES (inductively Coupled Plasma-Opti)cal emision spectroscopy, total phosphate content) and ion chromatography (free monophosphate content) coupled with conductivity measurements.

To prepare the complexes of the invention, the oxidatively derivatized maltodextrins obtained are reacted in aqueous solution with an iron (III) salt. To this end, the oxidatively derivatized maltodextrin can be separated and redissolved; however, the aqueous solution of the oxidatively derivatized maltodextrin obtained can also be used directly for further treatment with the iron (III) -aqueous solution.

As iron (III) salts, water-soluble salts of inorganic or organic acids or mixtures thereof, such as halides, for example chlorides and bromides, or sulfates, can be used. Physiologically acceptable salts are preferably used. Particular preference is given to using aqueous solutions of iron (III) chloride.

It has been shown that the presence of chloride ions has a beneficial effect on the formation of the complex. The latter can be added, for example, in the form of water-soluble chlorides, such as alkali metal chlorides, for example sodium chloride, potassium chloride or ammonium chloride. As mentioned above, it is preferred to use iron (III) in the chloride form.

For carrying out the reaction, for example, an aqueous solution of oxidized maltodextrin can be mixed with an aqueous solution of an iron (III) salt. In this case, the treatment is preferably carried out such that the pH of the mixture of oxidized maltodextrin and iron (III) salt is initially strongly acidic during and immediately after mixing, or so low that the iron (III) salt does not undergo hydrolysis, for example to 2 or less, in order to avoid undesirable precipitation of iron hydroxide. The addition of acid is generally not required when using iron (III) chloride, since the aqueous solution of iron (III) chloride may itself be sufficiently acidic. After mixing, the pH may be raised, for example, to a value on the order of 5 or greater, for example up to 11, 12, 13 or 14. The increase in the pH is preferably carried out slowly or stepwise, and may be carried out, for example, by first adding a weak base, for example to a pH of about 3; this can be followed by neutralization with a stronger base. Suitable weak bases are, for example, alkali metal or alkaline earth metal carbonates, hydrogen carbonates, such as sodium carbonate and potassium carbonate or sodium hydrogen carbonate or potassium hydrogen carbonate, or ammonia. The strong base is, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide.

The reaction can be promoted by heating. Temperatures in the order of 5 c to the boiling temperature may be used, for example. Preferably the temperature is increased stepwise. It is thus possible, for example, to initially warm up to approximately 15 to 70 ℃ and to gradually increase it to boiling.

The reaction time is for example in the order of 15 minutes to several hours, for example 20 minutes to 4 hours, for example 25 to 70 minutes, for example 30 to 60 minutes.

The reaction may be carried out in a weak acid range, for example in the range of pH 5 to 6. It has been shown, however, that the pH advantageously, if not necessarily, rises to higher values during the formation of the complex, up to 11, 12, 13 or 14. To complete the reaction, the pH can be further lowered by adding acid, for example to the stated order of 5 to 6. As acid, it is possible to use inorganic or organic acids or mixtures thereof, especially hydrohalic acids, such as hydrogen chloride or aqueous hydrochloric acid.

As noted above, complex formation is typically promoted by heating. For example in a preferred embodiment, in which the pH is raised during the reaction above 5 to a range of 11 or 14, it is possible to work first at a low temperature of the order of 15 to 70 c, for example 40 to 60 c, for example about 50 c, and then after the pH has been lowered again to a value of the order of, for example, at least 5 c, it is raised stepwise to a temperature above 50 c up to the boiling temperature.

The reaction time is of the order of 15 minutes up to several hours and may vary depending on the reaction temperature. When the process is carried out at an intermediate time using a pH value of more than 5, it is possible, for example, to work at elevated pH values, for example at temperatures up to 70 ℃, for 15 to 70 minutes, for example 30 to 60 minutes, after which the reaction can be carried out after a pH value reduction to the order of at least 5, at a temperature of at most, for example 70 ℃, for a further 15 to 70 minutes, for example 30 to 60 minutes, and optionally at higher temperatures up to the boiling point for a further 15 to 70 minutes, for example 30 to 60 minutes.

After the reaction has been carried out, the resulting solution may be cooled, for example to room temperature, and optionally diluted and optionally filtered. After cooling, the pH can be adjusted to the neutral point or slightly below, for example to a value of 5 to 7, by adding acids or bases. As acids or bases, it is possible to use, for example, those mentioned previously for the reaction. The resulting solution is purified and can be used directly for the preparation of a medicament. However, it is also possible to separate the iron (III) -complex from the solution, for example by precipitation with an alcohol, such as an alkanol, for example ethanol. Isolation can also be carried out by spray drying. Purification, especially removal of salts, can be carried out in a conventional manner. This can be done, for example, by reverse osmosis (umkehrostome), in which case this reverse osmosis can be carried out, for example, before spray drying or directly before use in medicaments.

The iron content of the resulting iron (III) -carbohydrate complexes is, for example, 10 to 40% w/w, in particular 20 to 35% w/w. They are well water soluble. Neutral aqueous solutions having an iron content of, for example, 1% w/v to 20% w/v can thus be prepared. The solution may be heat sterilized. The weight-average molecular weight Mw of the complexes thus obtained is, for example, from 80kDa to 800kDa, preferably from 80kDa to 650kDa, particularly preferably up to 350kDa (determined by gel permeation chromatography, for example as described by Geisser et al in Arzneim. Forsch/Drug Res.42(II), 12, 1439-.

As described above, aqueous solutions can be prepared from the complexes of the invention. This is particularly suitable for parenteral administration. But may also be administered orally or topically. It may be sterilized at elevated temperature, e.g. at 121 ℃ and above, to reach F for a brief contact time of at least 15 minutes₀≥15。F₀This is the treatment time at variable temperature (minutes), which corresponds to a treatment time at 121 ℃ in minutes, calculated for an ideal microorganism with a temperature coefficient of destruction of the microorganism of 10. The formulations known to date must be filtered in part aseptically at room temperature and/or mixed in part with preservatives, such as benzyl alcohol or phenol. Such treatment steps or additives are not necessary according to the present invention. Can also be used forThe solution of the complex is filled, for example, into ampoules. For example, 1 to 20 wt.%, for example 5 wt.% of the solution may be filled into a container, for example 2 to 100ml, for example up to 50ml, in an ampoule or a stem ampoule (Vials). Solutions for parenteral administration may be prepared in a conventional manner, optionally together with additives common to parenteral solutions. The solution may be formulated so that it may be administered per se by injection or as an infusion, for example as a saline solution. For oral or topical administration, formulations containing the corresponding conventional excipients and auxiliaries may be formulated.

Thus, a further subject of the invention is the formation of a medicament which is particularly suitable for parenteral, intravenous and intramuscular administration, but also for oral or topical administration and which can be used, in particular, for the treatment of iron deficiency anemia. Therefore, a further subject matter of the present invention is also the use of the iron (III) -carbohydrate derivative-complex of the present invention for the treatment and prevention of iron deficiency anemia or for the production of a medicament, in particular for the parenteral treatment of iron deficiency anemia. The medicament is suitable for use in human and veterinary medicine.

According to the invention, iron complexes of maltodextrin derivatives can be prepared for the first time.

Compared to the iron-maltodextrin complexes disclosed in WO 2004/037865, the iron-maltodextrin derivative complexes according to the invention enable a targeted and fine adjustment of the molecular weight to a higher molecular weight in a wide range, which is not possible with the known complexes.

Compared to the iron-maltodextrin-complexes disclosed in WO 2004/037865, a number of iron-maltodextrin derivative-complexes show almost unchanged degradation kinetics (Θ ═ 0.5).

Most derivatized maltodextrin complexes exhibit improved stability to enzymatic degradation by amylase compared to underivatized maltodextrin, which may facilitate delayed and uniform degradation of the iron-maltodextrin derivative complexes of the invention in vivo.

The iron yield of the complex derivatives of the invention is up to 100% (especially for sulfated complex derivatives), compared to 87 to 93% for the known iron-maltodextrin-complexes, which means an economic advantage for production on a commercial scale.

Examples

The dextrose equivalent is determined gravimetrically in the present description and in the following examples. For this purpose, maltodextrin is reacted in aqueous solution with fischer-tropsch solution at boiling. The reaction proceeded quantitatively, i.e. until the fischer solution no longer faded. The precipitated copper (I) oxide was dried at 105 ℃ to constant weight and determined gravimetrically. From the values obtained, the glucose content (dextrose equivalent) is calculated in% weight/weight maltodextrin-dry matter. For example, the following solutions may be used: 25ml of Fisher's solution I, and 25ml of Fisher's solution II; 10ml of an aqueous maltodextrin solution (10% Mol/Vol) (Fischer solution I: 34.6g of copper (II) sulfate dissolved in 500ml of water; Fischer solution II: 173g of sodium potassium tartrate and 50g of sodium hydroxide dissolved in 400ml of water).

The following explains what method and apparatus are used to determine the respective properties of the maltodextrin derivative and the iron complex.

¹H-NMR: bruker Avance-400, 400MHz at D₂Solution in O, reference H₂O

¹³C-NMR: bruker Avance-400, 100MHz, at D₂Solution in O, external reference trimethylsilyl-tetradeuterated propionic acid

³¹P-NMR: bruker Avance-400, 162MHz, at D₂Solution in O, external reference concentrated H₃PO₄

IR: FT-IR Perkin Elmer 1725X, KBr pellet

ICP-OES: horiba Jobin Yvon Ultima 2, sample dissolved in H₂In O

IC：MetRohm 733IC Separation Center (including conductivity detector), sample dissolved in H₂In O

GPC: waters 515 HPLC PUMP, Waters 2410 Refraction IndexDetector, samples dissolved in H₂In O, Pullulan as a standard

Measurement of M_w: see GPC

Measurement of M_n: see GPC

Fe-content: measured by EDTA titration (e.g., Jander Jahr, Massanalyse 15. Aflage)

Degradation kinetics: p.geisser, m.baer, e.schaub; structure/histoxicity relationship of fractional ironions precursors; arznei m. -Forsch./drug research 42(II), 12, 1439-.

Analytik Jena Specord 205Spektralphotometer，untersuchterAbbaugrad 50％(Θ＝0.5)

Iron-yield: amount of Fe separated (g)/amount of Fe used (g)

Example 1

C ₁ Preparation of oxidized maltodextrins

250g of maltodextrin with dextrose equivalent 12 were dissolved in 750ml of water. 1.4g of NaBr are added and 78.4g of NaOCl solution (14 to 16% by weight of active chlorine) are metered in over 30 minutes, at which time the pH is kept constant at 9.5 (+ -0.5) by adding 30% by weight of NaOH. The pH was then adjusted to 7.0 with HCl (20% by weight) and the product was precipitated by adding ethanol (92% by weight) in a volume ratio of 1: 6 (solution: ethanol). The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

Example 2

C ₁ Preparation of oxidized maltodextrins

100g of maltodextrin (9.6 dextrose equivalent, gravimetric) was dissolved in 300ml of water at 25 ℃ with stirring and oxidized at pH10 by the addition of 30g of sodium hypochlorite solution (14 to 16 wt% active chlorine), isolated and dried as in example 1.

Example 3

C ₁ Preparation of oxidized maltodextrins

From 45g of maltodextrin (6.6 dextrose equivalent, gravimetric) and 45g of maltodextrin (14.0 dextrose equivalent, gravimetric) were dissolved in 300ml of water at 25 ℃ with stirring and oxidized at pH10 by adding 25g of sodium hypochlorite solution (14 to 16% by weight active chlorine) and 0.6g of sodium bromide, and isolated and dried as in example 1.

Examples 4 to 7

Acetylation

200g of maltodextrin (1.23Mol of anhydroglucose) obtained in example 1 were dissolved in 660ml of water at 25 ℃ and the pH was adjusted to 8.5 with 30% by weight NaOH. Acetic anhydride was added at a rate of 1.7ml/Min in the different amounts shown in Table 1, at which time the pH was kept constant at 8.5 (+ -0.5) by adding 30 wt% NaOH. The solution was stirred at a constant pH of 8.5 (+ -0.5) for one hour, then adjusted to 7.0 with 20 wt% HCl. The product was precipitated with ethanol (92% by weight) in a volume ratio of 1: 6 (solution: ethanol). The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

Different degrees of acetylation were obtained by varying the amount of acetic anhydride added. The results are shown in Table 1.

TABLE 1

Examples	Equivalent of Ac2O (based on dehydration glucose meter)	Degree of molar substitution (1H-NMR)	Yield [% ]](Mol isolated product/anhydroglucose used for Mol)
				4	1	0.84	24
5	0.67	0.61	65
				6	0.33	0.31	69
7	0.16	0.14	74
				1	-	Underivatized	84

Due to acetylation, the solubility of the maltodextrin derivative in ethanol increases, which leads to a decrease in yield and an increase in the degree of substitution.

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

By IR spectroscopy, from 1740cm^-1Acetylation can be followed by an increase in the band (C ═ O-bond vibrational of COOR). By passing¹H-NMR spectrum from 2.0 to 2.3ppm of CH₃The ratio of the intensity of the signal (acetyl) to the intensity of the signal at 3.0-4.5ppm and 5-6ppm (7 protons of anhydroglucose groups) to determine the degree of molar acetylation.

Examples 8 to 11

Succinylation

200g of C obtained in example 1₁Oxidized maltodextrin was dissolved in 655ml of water. The pH was adjusted to 8.5 with 30% by weight NaOH and succinic anhydride was added in portions over one hour at 25 ℃ at which time the pH was kept constant at 8.5 (+ -0.5) by adding 30% by weight NaOH. The pH was then adjusted to 7.0 by addition of 20% by weight HCl and the product was precipitated with ethanol (92% by weight) in a volume ratio solution: ethanol of 1: 6. The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

Different degrees of succinylation were obtained by varying the amount of succinic anhydride added. The results are shown in Table 2.

TABLE 2

Examples	Equivalent succinic anhydride (based on anhydroglucose)	Degree of molar substitution (1H-NMR)	Yield [% ]](Mol isolated product/anhydroglucose used for Mol)
				8	0.17	0.15	74
9	0.08	0.07	82
				10	0.04	0.03	84
11	0.02	0.02	70
				1	-	Underivatized	84

Succinylation does not significantly affect the solubility of the oxidized maltodextrin.

By IR spectroscopy, from 1740cm^-1Succinylation can be followed qualitatively by an increase in the band (C ═ O-bond vibrational COOR/COOH). By passing¹H-NMR spectrum from 2.4 to 2.7ppm of CH₂The molar succinylation degree was determined from the ratio of the intensity of the signal (succinyl) to the intensity of the signal at 3.0-4.5ppm and 5-6ppm (7 protons of anhydroglucosyl).

Examples 12 to 16

Carboxymethylation of

200g of C obtained in example 1₁Oxidized maltodextrin was dissolved in 660ml of water and 118g of solid NaOH was added to bring the pH to 13-14. Chloroacetic acid was added in portions over 20 minutes, followed by stirring at 25 ℃ for 3 hours. The pH was then adjusted to 7.0 by addition of 20% by weight HCl and the product was precipitated with ethanol (92% by weight) in a volume ratio solution: ethanol of 1: 6. The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

Different carboxymethylation degrees were obtained by varying the amount of chloroacetic acid added. The results are shown in Table 3.

TABLE 3

Examples	Equivalent of chloroacetic acid (based on anhydroglucose)	Degree of molar substitution (1H-NMR)	Yield [% ]](Mol isolated product/anhydroglucose used for Mol)
				12	0.35	0.034	63
13	0.23	0.024	63
				14	0.18	0.017	76
15	0.09	0.014	64
				16	0.05	0.008	63
1	-	Underivatized	84

The degree of carboxymethylation achieved does not appreciably affect the solubility of the oxidized maltodextrin.

Carboxymethylation cannot be followed by IR spectroscopy due to the low degree of substitution in these examples. (1740 cm vibrating at the C ═ O-valence bond^-1There is no clear band. ) By passing¹H-NMR spectrum, the molar carboxymethylation degree was determined from the ratio of the intensity of the anomalous proton at 5.6ppm (carboxymethylated anhydroglucose group) to the intensity of the signal of the anomalous proton at 4.8-5.8ppm (non-derivatized anhydroglucose group).

Examples 17 to 20

Sulfation

200g of C obtained in example 1₁Oxidized maltodextrin was dissolved in 600ml of water and warmed to 30 ℃. Adding SO₃-trimethylamine-complex and the mixture is stirred at 30 ℃ for 30 minutes (suspension is thereby converted into solution). 40% by weight NaOH (1.7 equivalents based on molar SO) was added at a rate of 2.8 ml/min₃18-141ml, depending on the degree of substitution, based on trimethylamine-complex) and stirring the solution at 30 ℃ for 2.5 hours. The pH was adjusted to 10.5 with 20 wt% HCl. The product was precipitated with 92% by weight ethanol in a volume ratio solution to ethanol of 1: 7 to 1: 8. The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

By changing SO₃-triethylamine-complex is added in amounts to give different degrees of sulfation. The results are shown in Table 4.

TABLE 4

Examples	Equivalent weightSO of (A)3Reactants (based on anhydroglucose meter)	Degree of molar substitution (1H-NMR)	Yield [% ]](Mol isolated product/anhydroglucose used for Mol)
				17	0.67	0.56	98
18	0.34	0.27	92
				19	0.17	0.12	93
20	0.08	0.05	86
				1	-	Underivatized	84

The yield of oxidized sulfated maltodextrins increased due to the decreased solubility of the product in ethanol.

The sulfuric acid can be qualitatively tracked by IR spectroscopyDegree of esterification (at 1260 and 830 cm)^-1Increase of spectral band of (SO)₄ ^2-The valence bond vibration). By passing¹³C-NMR spectrum from 96ppm of C₁Intensity of signal (sulfated species) with C at 103ppm₁The ratio of the intensity of the signals (non-sulphated species) to determine the degree of molar sulphation.

Examples 21 to 24

Esterification of phosphoric acid

300g of C obtained in example 1₁Oxidized maltodextrin, NaH₂PO₄And Na₂HPO₄(molar ratio 1: 1.8) was dissolved in 1.5l of water and the pH was adjusted to 3.0 with 20% by weight HCl. The solution is evaporated to dryness on a rotary evaporator at 70 ℃ and 125 mbar. The residue was dried at 50 ℃ and 125mbar for 16 hours. The product is ground and heated to 160 ℃ at 750mbar over a period of 4 hours. The material was reground and dissolved in water at 50 ℃ in a weight ratio of 1: 4.4 (solids: water) for 1 hour. The solution was cooled to 25 ℃ and the insoluble residue was separated by a centrifuge (5500Upm, 1 hour).

The resulting solution was filtered by membrane filtration with a nanofiltration membrane (Nitto-Denko NTR-7410, average NaCl-Rickhalt 10%) at 22bar and a flow rate of 180-. The removal of free orthophosphate was monitored by IR spectroscopy of the wash fractions. The oxidized phosphated maltodextrin solution was concentrated to 11 in a rotary evaporator at 60 ℃ and 80-250mbar, and the product was then precipitated with ethanol in a volume ratio of 1: 6 (solution: ethanol). By centrifuging the suspension (5500)Upm, 1 hour) and dried at 50 ℃ and 125mbar for 24 hours.

By changing the molar ratio of NaH to NaH at 1: 1.8₂PO₄And Na₂HPO₄The mixture of (a) was added in an amount to give different degrees of phosphorylation. The results are shown in Table 5.

The molar substitution is determined by means of ICP-OES (Inductively Coupled Plasma-Optical emission Spectroscopy, Total phosphate content) and ion chromatography (free monophosphate content) with measurement of the conductivity of the linkage.

By passing³¹P-NMR spectroscopy was used to determine the free monophosphate content qualitatively. Polymer-bound monophosphates showed broader signals at about 0-2ppm, while free monophosphates showed sharp peaks at about 0.7 ppm. The broad signal at-10 ppm is attributed to the oligomeric phosphate.

TABLE 5

Examples	Equivalent of PO4(based on anhydroglucose meter)	Degree of molar substitution (ICP)	Free PO4(ppm)	Free oligomeric phosphates***(ppm)	Yield [% ]](Mol isolated product/anhydroglucose used for Mol)
						21	1.85	0.25	80	Not determined	22
22	0.55*	0.08	1	22	22
						23	0.28	0.24	2	55	13
24	0.23**	0.08	58	52	18
						1	Underivatized	-	-	-	84

^*Reaction time 16 hours at 160 ℃/740mbar instead of 4 hours

^**Precipitation of the maltodextrin/phosphate solution with ethanol instead of evaporation to dryness

^***By passing³¹P-NMR to determine the content

Examples 25 to 29

C ₂ /C ₃ Oxidation (two-step synthesis)

200g of C obtained in example 1₁Oxidized maltodextrin was dissolved in 600ml of water and the solution was warmed to 50 ℃. The pH was adjusted to 8.5 to 9.0 with 20% by weight HCl and 20g NaOCl (14 to 16% active chlorine) was added in one portion. Residual amounts of NaOCl were added at a rate of 5.8 ml/min, at which time the pH was held constant at 8.5 (+ -0.5) by the addition of 30 wt% NaOH. The solution was stirred at 50 ℃ and pH8.5 (+ -0.5) for 1 hour. The pH was next adjusted to 7 with 20 wt% HCl. The product was precipitated with 92% by weight ethanol in a volume ratio of 1: 6 ethanol. The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

Example 30

C ₁ /C ₂ /C ₃ Oxidation (one-step synthesis, in situ derivatization)

200g of maltodextrin with dextrose equivalent 12 were dissolved in 660ml of water and the solution was heated to 50 ℃. 1.1g of NaBr are added and 135.2g of NaOCl solution (14 to 16% by weight of active chlorine) are metered in over 30 minutes, at which time the pH is kept constant at 9.5 (+ -0.5) by adding 30% by weight of NaOH. The solution was stirred at 50 ℃ and pH9.5 (+ -0.5) for 1 hour. The pH was next adjusted to 7 with 20 wt% HCl. And precipitating the product with 92% by weight ethanol in a volume ratio of solution to ethanol of 1: 6. The product was isolated by decanting the upper solution and dried at 50 ℃ and 125mbar for 24 hours.

By changing the addition amount of NaOCl (14-16% active chlorine)To different moles C₂/C₃-degree of oxidation. The results are shown in Table 6.

TABLE 6

Examples	Equivalent amount of NaOCl	Degree of molar oxidation: (13C-NMR)	Yield [% ]](Mol isolated product/anhydroglucose used for Mol)
				25	0.48	0.042	72
26	0.24	0.022	71
				27	0.12	0.012	88
28	0.06	Can not be verified	75
				29	0.03	Can not be verified	78
30	0.12	0.017	89
				1	-	Underivatized	84

The isolated yield of the resulting product is less improved.

By IR spectroscopy, from 1640cm^-1Band (COO)^-C ═ O-valence bond vibration) increase can track C₂/C₃-degree of oxidation.

By passing¹³C-NMR spectrum from COOH-signals at 175 and 176ppm (oxidized C)₂And C₃) Intensity and signal at 76-84ppm (unoxidized C)₂) C is obtained by the ratio of the intensities₂/C₃The molar degree of oxidation.

General pre-processing step 1: preparation of iron complexes

The iron complex was prepared from the resulting oxidized derivatized maltodextrin with 100g of maltodextrin derivative, respectively:

to 352g of iron (III) chloride solution (12% w/w Fe), 100g of oxidized derivatized maltodextrin dissolved in 300ml of water are initially added with stirring (paddle stirrer) at room temperature, followed by 554g of sodium carbonate solution (17.3% w/w).

The pH was then adjusted to 11 by adding sodium hydroxide solution, the solution was warmed to 50 ℃ and held at 50 ℃ for 30 minutes. It is then acidified to a pH of 5 to 6 by addition of hydrochloric acid, the solution is held at 50 ℃ for a further 30 minutes and then heated to 97-98 ℃ and held at this temperature for 30 minutes. After cooling the solution to room temperature, the pH was adjusted to 6-7 by adding sodium hydroxide solution. The solution was then filtered through a sterile filter and the complex isolated by precipitation with ethanol in a ratio of 1: 0.85 and dried under vacuum at 50 ℃.

Examples 31 to 33

Acetylated iron complexes

The acetylated iron complexes 31 to 33, whose properties are summarized in Table 7 below, were obtained from the maltodextrin derivatives obtained in examples 5 to 7 according to general pre-processing step 1, and compared with standard preparations, respectively, which were also obtained from C according to general pre-processing step 1₁Oxidized, but underivatized maltodextrins (as obtained in example 1) were prepared.

TABLE 7

Parameter(s)	Standard of merit	Example 31MS ═ 0.14 (from example 7)	Example 32MS ═ 0.31 (from example 6)	Examples33MS ═ 0.61 (from example 5)
					Fe content*	27.0	28.9	29.7	30.6
Mw	168000	234000	349000	511000
					Mn	100000	139000	163000	334000
Degradation kinetics theta is 0.5	35	41	46	44

^*Based on the value of the dry substance.

The use of acetylated maltodextrin derivatives with molar substitution > 0.61 formed unstable products.

The acetylated iron complex exhibits a higher iron content than the standard and the molecular weight increases with increasing degree of substitution. The degradation kinetics at 50% showed similar values compared to the standard. The Fe yield of the acetylated iron complex reaches a maximum of 97%.

Examples 34 to 36

Succinylated iron complexes

Succinylated iron complexes 34 to 36, whose properties are summarized in Table 8 below, were obtained from the maltodextrin derivatives obtained in examples 9 to 11 according to general pre-processing step 1, and compared with standard preparations, respectively, which were likewise obtained according to general pre-processing step 1 from C₁Oxidized, but underivatized maltodextrins (as obtained in example 1) were prepared.

TABLE 8

Parameter(s)	Standard of merit	Example 34MS ═ 0.02 (from example 11)	Example 35MS ═ 0.03 (from example 10)	Example 36MS ═ 0.07 (from example 9)
					Fe content*	27.0	24.3	26.9	24.4
Mw	168000	260000	347000	773000
					Mn	100000	128000	145000	188000
Degradation kinetics theta is 0.5	35	28	32	6

^*Based on the value of the dry substance.

Succinylated maltodextrin derivatives with molar substitution > 0.07 were used to form unstable products.

Succinylated iron complexes showed slightly reduced iron content compared to the standard, and molecular weight increased with increasing degree of substitution. The degradation kinetics at 50% showed similar values compared to the standard, with one exception. The Fe yield of the succinylated complex reached a maximum of 94%.

Examples 37 to 38

Carboxymethylated iron complexes

Carboxymethylated iron from the maltodextrin derivatives obtained in examples 15 to 16 according to general Pre-processing step 1Complexes 37 and 38, whose properties are summarized in Table 9 below, are compared with standard preparations, respectively, which are likewise processed in general according to step 1, from C₁Oxidized, but underivatized maltodextrins (as obtained in example 1) were prepared.

TABLE 9

Parameter(s)	Standard of merit	Example 37MS < 0.01 (from example 16)	Example 38MS ═ 0.014 (from example 15)
				Fe content*	27.0	23.3	25.5
Mw	168000	316000	404000
				Mn	100000	148000	168000
Degradation kinetics theta is 0.5	35	36	32

^*Based on the value of the dry substance.

The use of carboxymethylated maltodextrin derivatives with molar substitution > 0.01 results in unstable products.

The carboxymethylated iron complex showed a slightly reduced iron content compared to the standard and the molecular weight increased with increasing degree of substitution. The degradation kinetics at 50% showed almost the same values compared to the standard. The Fe yield of the carboxymethylated iron complex amounts to a maximum of 97%.

Examples 39 to 41

C ₂ /C ₃ -oxidized iron complexes

According to general work-Up Pre-step 1, C was obtained from the maltodextrin derivatives obtained in examples 27, 28 and 29₂/C₃Oxidized iron complexes 39 to 41, the properties of which are summarized in Table 10 below, are compared with standard formulations, respectively, which are likewise processed according to general pre-process step 1, from C₁Oxidized, but underivatized maltodextrins (as obtained in example 1) were prepared.

Watch 10

Parameter(s)	Standard of merit	Example 39MS < 0.01 (from example 29)	Example 40MS ═ 0.01 (from example 28)	Example 41MS 0.012 (from example 27)
					Fe content*	27.0	22.2	26.1	23.8
Mw	168000	275000	310000	433000
					Mn	100000	138000	150000	230000
Degradation kinetics theta is 0.5	35	33	36	39

^*Based on the value of the dry substance.

Using C with a molar substitution > 0.01₂/C₃Oxidized maltodextrin derivatives form unstable products.

The iron content does not show a consistent trend, the molecular weight increasing with increasing degree of substitution. The degradation kinetics at 50% showed almost the same values compared to the standard. C₂/C₃The Fe yield of the oxidized iron complex amounts to a maximum of 95%.

Examples 42 to 44

Sulfated iron complexes (multistep synthesis)

The sulfated iron complexes 42 to 44, whose properties are summarized in Table 11 below and which are compared with standard preparations, respectively, which were likewise prepared in accordance with general working-up step 1 from C₁Oxidized, but underivatized maltodextrins (as obtained in example 1) were prepared.

Example 45

Sulfated iron complexes (one-step synthesis, in situ derivatization)

100g of maltodextrin with dextrose equivalent 12 were dissolved in 300ml of water. 0.7g of NaBr are added and 28.7g of NaOCl solution (14 to 16% by weight of active chlorine) are metered in over 30 minutes, at which time the pH is kept constant at 9.5 (+ -0.5) by adding 30% by weight of NaOH. The solution was then heated to 30 ℃ and 14.4g SO were added₃-trimethylamine-complex and stirring is continued for 30 minutes at 30 ℃ and then 17.6ml of 40% by weight NaOH are metered in and stirring is continued for 1 hour at 30 ℃.

After cooling the solution to 20-25 ℃ 352g of iron (III) chloride solution (12% w/w Fe) were added with stirring, followed by 554g of sodium carbonate solution (17.3% w/w). The pH was then adjusted to 11 by the addition of sodium hydroxide, the solution was warmed to 50 ℃ and held at 50 ℃ for 30 minutes. The pH is then acidified to 5 to 6 by addition of hydrochloric acid, and the solution is held at 50 ℃ for a further 30 minutes, then heated to 97-98 ℃ and held at this temperature for 30 minutes. After cooling the solution to room temperature, the pH was adjusted to 6-7 by heating the sodium hydroxide solution. The solution was then filtered through a sterile filter and the complex was isolated by precipitation with ethanol in a ratio of 1: 0.85 and dried under vacuum at 50 ℃.

TABLE 11

Parameter(s)	Standard of merit	Example 42MS ═ 0.05 (from example 20)	Example 43MS ═ 0.12 (from example 19)	Example 44MS ═ 0.27 (from example 18)	Example 45MS 0.12
						Fe content*	27.0*	25.3	26.8	26.3	26.3
Mw	168000	261000	278000	640000	160000
						Mn	100000	142000	219000	409000	106000
Degradation kinetics theta is 0.5	35	75	62	67	-

^*Based on the value of the dry substance.

Sulfated maltodextrin derivatives with molar substitution > 0.27 were used to form unstable products.

The iron content of the sulfated iron complex remains almost constant as the degree of substitution increases. The molecular weight of the iron complex synthesized in multiple steps increases with increasing degree of substitution. The degradation kinetics at 50% showed an increased value compared to the standard. The Fe yield of the sulfated iron complex reaches up to 100%.

Claims (17)

1. Water-soluble iron-carbohydrate derivative-complex, obtained from an aqueous solution of the product obtained by oxidation of an aqueous iron (III) salt solution and one or more maltodextrins and subsequent derivatization, wherein the oxidation is carried out with an aqueous hypochlorite solution at a pH in the alkaline range, wherein, in the case of one maltodextrin, the dextrose equivalent thereof is from 5 to 20, in the case of a mixture of maltodextrins, the dextrose equivalent thereof is from 5 to 20, and the dextrose equivalent of the individual maltodextrins participating in the mixture is from 2 to 40, and subsequent derivatization is carried out with suitable reactants.

2. The water-soluble iron-carbohydrate-complex according to claim 1, wherein the maltodextrin-derivative obtained by oxidation and derivatization is selected from the group consisting of esters of mono-or polycarboxylic acids, via C₁C obtained by oxidation of oxidized maltodextrin₂/C₃Oxidation products, carboxyalkylation products, ethers, amides, anhydrides and esters of mineral acids.

3. The water-soluble iron-carbohydrate-complex according to claim 1, wherein the maltodextrin-derivative obtained by oxidation and derivatization is selected from the group consisting of carbamates.

4. The complex according to any one of claims 1 to 3, wherein the derivative of maltodextrin obtained by oxidation and derivatization is selected from the group consisting of carboxylic acid esters, carboxyalkylation products, by C₁C obtained by oxidation of oxidized maltodextrin₂/C₃Oxidation products, phosphates and sulfates.

5. The complex of claim 4, wherein the carboxylate is a mixed dicarboxylate.

6. Process for the preparation of iron-carbohydrate complexes according to one of claims 1 to 5, characterized in that one or more maltodextrins are oxidized in aqueous solution with aqueous hypochlorite at alkaline pH values, followed by derivatization with suitable reactants, the resulting solution is reacted with an aqueous iron (III) salt solution, wherein, in the case of one maltodextrin, the dextrose equivalent thereof is from 5 to 20, in the case of a mixture of a plurality of maltodextrins, the dextrose equivalent of the mixture is from 5 to 20, and the dextrose equivalents of the individual maltodextrins participating in the mixture are from 2 to 40.

7. The process according to claim 6, wherein the derivatization of the oxidized maltodextrins is carried out by one of the following methods

a) With organic or inorganic acids or derivatives thereof

b) Oxidation by oxygen

c) Carboxyalkylation of

d) Etherification

e) Amidation

g) Anhydride formation.

8. The process according to claim 6, wherein the derivatization of the oxidized maltodextrins is carried out by

f) To form a carbamate.

9. The method according to claim 6, wherein said derivatizing is carried out by one of the following methods

b) Through C₁-oxidation of oxidized maltodextrin C₂/C₃Oxidation of

d) Carboxyalkylation of

e) Esterification of phosphoric acid

f) And (4) carrying out sulfuric acid esterification.

10. The method according to claim 6, wherein said derivatizing is carried out by one of the following methods

a) By carboxylation with monocarboxylic acids or carboxylic acid derivatives

c) Carboxylation with dicarboxylic acids or carboxylic acid derivatives.

11. Process according to one of claims 6 to 10, characterized in that the oxidation of the maltodextrin or maltodextrins is carried out in the presence of bromide ions.

12. The process according to one of claims 6 to 10, characterized in that as iron (III) salt, iron (III) chloride is used.

13. The method according to one of claims 6 to 10, characterized in that the oxidized, derivatized maltodextrin and the iron (III) salt are mixed into an aqueous solution with a pH value so low that hydrolysis of the iron (III) salt does not occur, after which the pH value is raised to 5 to 12 by adding a base.

14. The process according to claim 13, characterized in that the reaction is carried out at a temperature of from 15 ℃ to the boiling point for from 15 minutes to 4 hours.

15. Medicament containing an iron-carbohydrate derivative-complex according to claims 1 to 5 or obtained according to the process of one of claims 6 to 14.

16. The medicament of claim 15, wherein the medicament is formulated for parenteral or oral administration.

17. Use of an iron-carbohydrate derivative-complex according to claims 1 to 5 or obtained according to a process according to one of claims 6 to 14 for the preparation of a medicament for the treatment or prevention of iron deficiency.