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, a process for its production and a medicament for the treatment and prophylaxis of iron deficiency conditions.

Claims

1-11. (canceled)

12. 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(R),5(R),6-tetrahydroxy-hexanoate and has a weight average molecular weight in the range of from 118 kDa to 271 kDa as measured by gel permeation chromatography, and wherein said 4(R)-(poly-(1.fwdarw.4)-O--D-glucopyranosyl)-oxy-2(R),3(R),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.

13. The iron (III) carboxymaltodextrin complex of claim 12, wherein the oxidized maltodextrin is obtained by oxidation of maltodextrin in an aqueous hypochlorite solution.

14. A medicament comprising the iron (III) carboxymaltodextrin complex of claim 12 and at least one pharmaceutically acceptable carrier, excipient, or additive, wherein said medicament is an aqueous solution of said iron (III) carboxymaltodextrin complex.

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

16. The medicament comprising the iron (III) carboxymaltodextrin complex of claim 14, wherein the oxidized maltodextrin is obtained by oxidation of maltodextrin in an aqueous hypochlorite solution.

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

18. The medicament of claim 14, wherein the aqueous solution has been sterilized at a temperature of about 121 C. and above.

19. The medicament of claim 14, wherein the aqueous solution has been sterilized at a temperature of about 121 C. and above at a contact time of 15 minutes or less.

20. The medicament of claim 15, wherein the aqueous solution has been sterilized at a temperature of about 121 C. and above.

21. The medicament of claim 15, wherein the aqueous solution has been sterilized (i) at a temperature of about 121 C. at a contact time of 15 minutes or less or (ii) at a temperature of about 121 C. and above at a contact time of 15 minutes or less.

22. The medicament of claim 16, wherein the aqueous solution has been sterilized at a temperature of about 121 C. and above.

23. The medicament of claim 16, wherein the aqueous solution has been sterilized at a temperature of about 121 C. and above at a contact time of 15 minutes or less.

24. The medicament of claim 17, wherein the aqueous solution has been sterilized at a temperature of about 121 C. and above.

25. The medicament of claim 17, wherein the aqueous solution has been sterilized (i) at a temperature of about 121 C. at a contact time of 15 minutes or less; or (ii) at a temperature of about 121 C. and above at a contact time of 15 minutes or less.

26. The medicament of claim 15 for parenteral administration to a subject in need thereof in the form of a single dose of 500 mg to 1000 mg of iron.

27. The medicament of claim 26, wherein said single dose is administered over one hour.

28. The medicament of claim 20 for parenteral administration to a subject in need thereof in the form of a single dose of 500 mg to 1000 mg of iron.

29. The medicament of claim 28, wherein said single dose is administered over one hour.

30. The medicament of claim 20 for parenteral administration to a subject in need thereof in the form of a single dose of 500 mg to 1000 mg of iron.

31. The medicament of claim 30, wherein said single dose is administered over one hour.

32. The medicament of claim 24 for parenteral administration to a subject in need thereof in the form of a single dose of 500 mg to 1000 mg of iron.

33. The medicament of claim 32, wherein said single dose is administered over one hour.

34. The medicament of claim 25 for parenteral administration to a subject in need thereof in the form of a single dose of 500 mg to 1000 mg of iron.

35. The medicament of claim 34, wherein said single dose is administered over one hour.

36. The medicament of claim 15, wherein the iron (III) carboxymaltodextrin complex has a weight average molecular weight of: about 141,000 Da, or about 140,000 Da, or about 189,000 Da, or about 178,000 Da, or about 137,000 Da, or about 170,000 Da.

37. The medicament of claim 17, wherein the iron (III) carboxymaltodextrin complex has a weight average molecular weight of: about 141,000 Da, or about 140,000 Da, or about 189,000 Da, or about 178,000 Da, or about 137,000 Da, or about 170,000 Da.

38. The medicament of claim 24, wherein the iron (III) carboxymaltodextrin complex has a weight average molecular weight of: about 141,000 Da, or about 140,000 Da, or about 189,000 Da, or about 178,000 Da, or about 137,000 Da, or about 170,000 Da.

39. The medicament of claim 25, wherein the iron (III) carboxymaltodextrin complex has a weight average molecular weight of: about 141,000 Da, or about 140,000 Da, or about 189,000 Da, or about 178,000 Da, or about 137,000 Da, or about 170,000 Da.

40. A method for treating an iron deficiency condition in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a medicament of claim 14, wherein the iron deficiency condition is anemia.

41. The method of claim 40, wherein said medicament is administered (i) intravenously, (ii) by injection, or (iii) by infusion.

Description

EXAMPLE 1

[0027] 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.

[0028] 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).

[0029] 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.

[0030] The solution is then filtered through a sterilization 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.

[0031] 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).

[0032] Molecular weight mw 271 kDa.

EXAMPLE 2

[0033] 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.

[0034] 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).

[0035] 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.

[0036] The solution is then filtered through a sterilization 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.

[0037] 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).

[0038] Molecular weight mw 141 kDa,

EXAMPLE 3

[0039] 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.

[0040] 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).

[0041] 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.

[0042] The solution is then filtered through a sterilization 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.

[0043] 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).

[0044] Molecular weight mw 140 kDa.

EXAMPLE 4

[0045] 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.

[0046] 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).

[0047] 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.

[0048] The solution is then filtered through a sterilization 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.,

[0049] 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).

[0050] Molecular weight mw 189 kDa,

EXAMPLE 5

[0051] 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.

[0052] 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).

[0053] 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.

[0054] The solution is then filtered through a sterilization 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.

[0055] 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).

[0056] Molecular weight mw 118 kDa.

EXAMPLE 6

[0057] 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.

[0058] 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).

[0059] 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.

[0060] The solution is then filtered through a sterilization 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.

[0061] 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).

[0062] Molecular weight mw 178 kDa.

EXAMPLE 7

[0063] 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.

[0064] 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).

[0065] 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.

[0066] The solution is then filtered through a sterilization 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.

[0067] 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).

[0068] Molecular weight mw 137 kDa.

EXAMPLE 8

[0069] 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.

[0070] 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).

[0071] 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.

[0072] The solution is then filtered through a sterilization 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.

[0073] 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),

[0074] Molecular weight mw 170 kDa.

[0075] 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 the Iron hydroxide/ 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 >2000 >200 Fe/kg body weight]