AQUEOUS IRON CARBOHYDRATE COMPLEXES, THEIR PRODUCTION AND MEDICAMENTS CONTAINING THEM

Abstract

A water soluble iron carbohydrate complex obtainable from an aqueous solution of iron(III) salt and an aqueous solution of the oxidation product of one or more maltrodextrins using an aqueous hypochlorite solution at a pH-value within the alkaline range, where, when one maltodextrin is applied, its dextrose equivalent lies between 5 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 5 and 20 and the dextrose equivalent of each individual maltodextrin contained in the mixture lies between 2 and 40, process for its production and a medicament for the treatment and prophylaxis of iron deficiency conditions.

Claims

1. Water soluble iron carbohydrate complex obtainable from an aqueous solution of iron (Ill) salt and an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochlorite solution at a pH-value within the alkaline range, where, when one maltodextrin is applied, its dextrose equivalent lies between 5 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 5 and 20 and the dextrose equivalent of each individual maltodextrin contained in the mixture lies between 2 and 40.

2. A process for producing an iron carbohydrate complex according to claim 1, wherein one or more maltodextrins are oxidized in an aqueous solution at an alkaline pH-value using an aqueous hypochlorite solution and the obtained solution is reacted with an aqueous solution of an iron (Ill) salt, where, when one maltodextrin is applied, its dextrose equivalent lies between 5 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 5 and 20 and the dextrose equivalent of each individual maltodextrins contained in the mixture lies between 2 and 40.

3. The process according to claim 2, characterized in that the oxidation of the maltodextrin or the maltodextrins is carried out in the presence of bromide ions.

4. The process according to claim 2, characterized in that the iron (Ill) chloride is used as the iron (Ill) salt.

5. The process according to claim 2, characterized in that the oxidized maltodextrin and the iron (Ill) salt are mixed to form an aqueous solution having a pH- value so low that no hydrolysis of the iron (Ill) salt occurs, whereafter the pH is raised to 5 to 12 by the addition of a base.

6. The process according to claims 3 to 5, characterized in that the reaction is carried out at a temperature of 15° C. up to boiling point for 15 minutes up to several hours.

7. The water soluble iron carbohydrate complex according to claim 1 formulated as a medicament in aqueous solution form.

8. The water soluble iron carbohydrate complex according to claim 7 formulated for parenteral or oral application.

9. A method of treating or preventing iron deficiency, the method comprising administering a water soluble iron carbohydrate complex of claim 1 for treatment or prophylaxis of iron deficiency.

10. The method of claim 9, wherein the water soluble iron carbohydrate complex is formulated as a medicament in aqueous solution form for treatment or prophylaxis of iron deficiency.

11. The water soluble iron carbohydrate complex according to claim 1 for treatment or prophylaxis of iron deficiency.

Description

EXAMPLE 1

[0028] 100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 30 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) at pH 10.

[0029] At first, the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0030] Then, the pH is adjusted to 11 by addition of sodium hydroxide, and the solution is heated to 50° C. and kept at 50° C. for 30 minutes. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 30 minutes and then heated to 97-98° C., and the temperature is kept for 30 minutes at this range. After cooling the solution to room temperature, the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0031] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0032] The yield is 125 g (corresponding to 87% of the theoretical value) of a brown amorphic powder having an iron content of 29.3% weight/weight (measured complexometrically).

[0033] Molecular weight mw 271 kDa.

EXAMPLE 2

[0034] 200 g maltodextrin (9.6 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 30 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) at pH 10.

[0035] At first the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0036] Then the pH is adjusted to 11 by addition of sodium hydroxide, and the solution is heated to 50° C. and kept for 30 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 30 minutes and then heated to 97-98° C., and the temperature is kept for 30 minutes at this range. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0037] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0038] The yield is 123 g (corresponding to 65% of the theoretical value) of a brown amorphic powder having an iron content of 22.5% weight/weight (measured complexometrically).

[0039] Molecular weight mw 141 kDa.

EXAMPLE 3

[0040] 100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 30 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) and 0.7 g sodium bromide at pH 10.

[0041] At first the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0042] Then the pH is adjusted to 6.5 by addition of sodium hydroxide and the solution is heated to 50° C. and kept for 60 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 30 minutes and then heated to 97-98° C., and the temperature is kept for 30 minutes at this range. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0043] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0044] The yield is 139 g (corresponding to 88% of the theoretical value) of a brown amorphic powder having an iron content of 26.8% weight/weight (measured complexometrically).

[0045] Molecular weight mw 140 kDa.

EXAMPLE 4

[0046] A mixture of 45 g maltodextrin (6.6 dextrose equivalent measured gravimetrically) and 45 g maltodextrin (14.0 dextrose equivalent measured gravimetrically) is dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 25 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) and 0.6 g sodium bromide at pH 10.

[0047] At first the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0048] Then the pH is adjusted to 11 by addition of sodium hydroxide and the solution is heated to 50° C. and kept for 30 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 30 minutes and then heated to 97-98° C. and the temperature is kept for 30 minutes at this range. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0049] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0050] The yield is 143 g (corresponding to 90% of the theoretical value) of a brown amorphic powder having an iron content of 26.5% weight/weight (measured complexometrically).

[0051] Molecular weight mw 189 kDa.

EXAMPLE 5

[0052] 90 g maltodextrin (14.0 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 35 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) and 0.6 g sodium bromide at pH 10.

[0053] At first, the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0054] Then, the pH is adjusted to 11 by addition of sodium hydroxide and the solution is heated to 50° C. and kept for 30 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 30 minutes and then heated to 97-98° C. and the temperature is kept for 30 minutes at this range. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0055] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0056] The yield is 131 g (corresponding to 93% of the theoretical value) of a brown amorphic powder having an iron content of 29.9% weight/weight (measured complexometrically).

[0057] Molecular weight mw 118 kDa.

EXAMPLE 6

[0058] A mixture of 45 g maltodextrin (5.4 dextrose equivalent measured gravimetrically) and 45 g maltodextrin (18.1 dextrose equivalent measured gravimetrically) is dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 31 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) and 0.7 g sodium bromide at pH 10.

[0059] At first, the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0060] Then, the pH is adjusted to 11 by addition of sodium hydroxide and the solution is heated to 50° C. and kept for 30 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 30 minutes and then heated to 97-98° C. and the temperature is kept for 30 minutes at this range. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0061] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0062] The yield is 134 g (corresponding to 88% of the theoretical value) of a brown amorphic powder having an iron content of 27.9% weight/weight (measured complexometrically).

[0063] Molecular weight mw 178 kDa.

EXAMPLE 7

[0064] 100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 29 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) and 0.7 g sodium bromide at pH 10.

[0065] At first, the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (Ill) chloride solution (12% weight by weight Fe).

[0066] Then, the pH is adjusted to 11 by addition of sodium hydroxide and the solution is heated to 50° C. and kept for 30 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 70 minutes. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0067] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0068] The yield is 155 g (corresponding to 90% of the theoretical value) of a brown amorphic powder having an iron content of 24.5% weight/weight (measured complexometrically).

[0069] Molecular weight mw 137 kDa.

EXAMPLE 8

[0070] 126 g maltodextrin (6.6 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25° C. and oxidized by addition of 24 g sodium hypochlorite solution. (13 to 16 weight percent active chlorine) and 0.7 g sodium bromide at pH 10.

[0071] At first the oxidized maltodextrin solution and then 554 g sodium carbonate solution (17.3% weight/weight) are added at room temperature to 352 g of a stirred iron (III) chloride solution (12% weight by weight Fe).

[0072] Then the pH is adjusted to 11 by addition of sodium hydroxide and the solution is heated to 50° C. and kept for 30 minutes at 50° C. Then, acidification to a pH of 5 to 6 is effected by addition of hydrochloric acid, the solution is kept at 50° C. for a further 70 minutes. After cooling the solution to room temperature the pH is adjusted to 6-7 by the addition of sodium hydroxide.

[0073] The solution is then filtered through a sterilisation filter and then examined for sediments. Thereafter, the complex is isolated by precipitation with ethanol in a range of 1:0.85 and then dried in vacuum at 50° C.

[0074] The yield is 171 g (corresponding to 86% of the theoretical value) of a brown amorphic powder having an iron content of 21.35% weight/weight (measured complexometrically).

[0075] Molecular weight mw 170 kDa.

Comparative Test

[0076] In the following, the characteristics of the iron carbohydrate complexes are compared with a commercially available iron sucrose complex. It can be seen that the iron content can be enhanced, the thermal treatment can be carried out at higher temperatures and the toxicity (LD.sub.50) can be lowered in accordance with the invention.

TABLE-US-00001 According to Iron hydroxide/ the invention sucrose complex Fe content [%] 5.0 2.0 pH 5-7  10.5-11.0 mw [kDa].sup.1) 80-350 34-54 Thermal treatment 121° C./15′ 100° C./35′ LD.sub.50 i.v., w.m. [mg Fe/kg >2000 >200 body weight]