Aqueous iron carbohydrate complexes, their production and medicaments containing them

Abstract

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 medicament for the treatment and prophylaxis of iron deficiency conditions.

Claims

1. An iron (III) carboxymaltodextrin complex wherein said iron (III) carboxymaltodextrin complex comprises polynuclear iron (III)-hydroxide 4(R)-(poly-(1.fwdarw.4)-O--D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate and has a weight average molecular weight in the range of from 80 kDa to 400 kDa, and wherein said 4(R)-(poly-(1.fwdarw.4)-O--D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate is derived from the oxidation of maltodextrin, wherein 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.

2. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight in the range of from 80 kDa to 350 kDa.

3. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight in the range of from 80 kDa to 300 kDa.

4. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight in the range of from 118 kDa to 271 kDa.

5. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 271,000 Da.

6. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 141,000 Da.

7. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 140,000 Da.

8. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 189,000 Da.

9. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 118,000 Da.

10. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 178,000 Da.

11. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 137,000 Da.

12. The iron (III) carboxymaltodextrin complex of claim 1, having a weight average molecular weight of 170,000 Da.

13. A medicament comprising the iron (III) carboxymaltodextrin complex of claim 1 and a pharmaceutically acceptable carrier, excipient, or additive.

14. The medicament of claim 13, wherein said medicament is an aqueous solution.

15. The medicament of claim 14, wherein said aqueous solution is a brine solution.

16. The medicament of claim 14, wherein said iron (III) carboxymaltodextrin complex is present in said aqueous solution in an amount of from 1% to 20% by weight, based on the total weight of the aqueous solution.

17. The medicament of claim 14, wherein said iron (III) carboxymaltodextrin complex is present in said aqueous solution in an amount of 5% by weight, based on the total weight of the aqueous solution.

18. A method for treating an iron deficiency condition comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the medicament of claim 13.

19. The method of claim 18, wherein said iron deficiency condition is iron deficiency anaemia.

20. The method of claim 18, wherein said medicament is administered parenterally or orally.

21. The method of claim 18, wherein said medicament is administered intravenously or intramuscularly.

22. The method of claim 18, wherein said medicament is administered via injection.

23. The method of claim 18, wherein said medicament is administered via infusion.

24. The method of claim 18, wherein said medicament is administered in the form of a single dose.

25. The method of claim 24, wherein said single dose comprises from 500 to 1000 mg of iron.

26. The method of claim 25, wherein said single dose is applied during the course of one hour.

Description

EXAMPLE 1

(1) 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.

(2) 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).

(3) 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.

(4) 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.

(5) 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).

(6) Molecular weight mw 271 kDa.

EXAMPLE 2

(7) 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.

(8) 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).

(9) 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.

(10) 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.

(11) 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).

(12) Molecular weight mw 141 kDa.

EXAMPLE 3

(13) 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.

(14) 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).

(15) 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.

(16) 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.

(17) 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).

(18) Molecular weight mw 140 kDa.

EXAMPLE 4

(19) 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.

(20) 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).

(21) 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.

(22) 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.

(23) 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).

(24) Molecular weight mw 189 kDa.

EXAMPLE 5

(25) 90 g maltodextrin (14.0 dextrose equivalent measured gravimetrically) are dissolved by stirring in 300 ml water at 25 C. and oxidized by addition of35 g sodium hypochlorite solution (13 to 16 weight percent active chlorine) and 0.6 g sodium bromide at pH 10.

(26) 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).

(27) 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.

(28) 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.

(29) 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).

(30) Molecular weight mw 118 kDa.

EXAMPLE 6

(31) 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.

(32) 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).

(33) 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.

(34) 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.

(35) 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).

(36) Molecular weight mw 178 kDa.

EXAMPLE 7

(37) 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.

(38) 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).

(39) 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.

(40) 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.

(41) 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).

(42) Molecular weight mw 137 kDa.

EXAMPLE 8

(43) 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.

(44) 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).

(45) 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.

(46) 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.,

(47) 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).

(48) Molecular weight mw 170 kDa.

(49) Comparative Test

(50) 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.

(51) TABLE-US-00001 According to the Iron hydroxide/sucrose invention 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 l.v., w.m. [mg >2000 >200 Fe/kg body weight]