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

1-70. (canceled)

71. A composition comprising at least one iron (III) carbohydrate complex, said iron (III) carbohydrate complex comprising: iron (III) hydroxide; and at least one oxidized maltodextrin ligand, wherein the number of glucose moieties per gluconic acid moiety in said oxidized maltodextrin ligand ranges from about 5 to about 20; wherein iron is present in an amount ranging from 20 to 35% by weight, relative to said iron (III) carbohydrate complex and wherein said iron (III) carbohydrate complex has a weight average molecular weight ranging from 118 kDa to 271 kDa.

72. The composition of claim 71, further comprising at least one pharmaceutically acceptable carrier, excipient, or additive.

73. The composition of claim 72, wherein said composition is an aqueous solution.

74. The composition of claim 73, wherein said aqueous solution is a brine solution.

75. The composition of claim 73, wherein said composition has an iron content of 1% to 20% (weight/vol), expressed in relation to the total volume of the composition.

76. The composition of claim 73, wherein said composition has an iron content of 5% (weight/vol), expressed in relation to the total volume of the composition.

77. A method for treating an iron deficiency condition comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition of claim 73.

78. The method of claim 77, wherein said iron deficiency condition is iron deficiency anaemia.

79. The method of claim 77, wherein said composition is administered intravenously.

80. The method of claim 77, wherein said composition is administered via injection.

81. The method of claim 77, wherein said composition is administered via infusion.

82. The method of claim 77, wherein said composition is administered in the form of a single dose.

83. The method of claim 82, wherein said single dose comprises from 500 to 1000 mg of iron.

84. The method of claim 83, wherein said single dose is applied during the course of one hour.

85. A composition comprising at least one iron (III) carbohydrate complex, said iron (III) carbohydrate complex comprising: iron (III) hydroxide; and at least one oxidized maltodextrin ligand, wherein the number of glucose moieties per gluconic acid moiety in said oxidized maltodextrin ligand ranges from about 5 to about 20; wherein the number of iron atoms in said iron (III) carbohydrate complex ranges from about 550 to about 1450 and wherein said iron (III) carbohydrate complex has a weight average molecular weight ranging from 118 kDa to 271 kDa.

86. The composition of claim 85, further comprising at least one pharmaceutically acceptable carrier, excipient, or additive.

87. The composition of claim 86, wherein said composition is an aqueous solution.

88. The composition of claim 87, wherein said aqueous solution is a brine solution.

89. The composition of claim 87, wherein said composition has an iron content of 1% to 20% (weight/vol), expressed in relation to the total volume of the composition.

90. The composition of claim 87, wherein said composition has an iron content of 5% (weight/vol), expressed in relation to the total volume of the composition.

91. A method for treating an iron deficiency condition comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition of claim 87.

92. The method of claim 91, wherein said iron deficiency condition is iron deficiency anaemia.

93. The method of claim 91, wherein said composition is administered intravenously.

94. The method of claim 91, wherein said composition is administered via injection.

95. The method of claim 91, wherein said composition is administered via infusion.

96. The method of claim 91, wherein said composition is administered in the form of a single dose.

97. The method of claim 96, wherein said single dose comprises from 500 to 1000 mg of iron.

98. The method of claim 97, wherein said single dose is applied during the course of one hour.

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 (III) 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 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.

[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 (III) 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 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.

[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 (III) 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 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.

[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 (III) 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 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.,

[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 (III) 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 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.

[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 (III) 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 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.

[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 (III) 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 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.

[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 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.

[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 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 i.v., w.m. [mg >2000 >200 Fe/kg body weight]