U.S. patent application number 15/088687 was filed with the patent office on 2016-07-28 for aqueous iron carbohydrate complexes, their production and medicaments containing them.
The applicant listed for this patent is VIFOR (INTERNATIONAL) AG.. Invention is credited to Peter Geisser, Erik Philipp, Walter Richle.
Application Number | 20160215071 15/088687 |
Document ID | / |
Family ID | 32102937 |
Filed Date | 2016-07-28 |
United States Patent
Application |
20160215071 |
Kind Code |
A1 |
Geisser; Peter ; et
al. |
July 28, 2016 |
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.
Inventors: |
Geisser; Peter; (St. Gallen,
CH) ; Philipp; Erik; (Arbon, CH) ; Richle;
Walter; (Gossau, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VIFOR (INTERNATIONAL) AG. |
St. Gallen |
|
CH |
|
|
Family ID: |
32102937 |
Appl. No.: |
15/088687 |
Filed: |
April 1, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14469864 |
Aug 27, 2014 |
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15088687 |
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13835400 |
Mar 15, 2013 |
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14469864 |
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13556733 |
Jul 24, 2012 |
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13835400 |
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12581212 |
Oct 19, 2009 |
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13556733 |
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10531895 |
Dec 14, 2005 |
7612109 |
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PCT/EP2003/011596 |
Oct 20, 2003 |
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12581212 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 7/06 20180101; A61K
45/06 20130101; C08B 37/0009 20130101; C08B 30/18 20130101; A61K
31/295 20130101; A61K 31/718 20130101; A61K 47/61 20170801; A61K
2300/00 20130101; A61K 33/26 20130101; A61K 2300/00 20130101; A61K
33/26 20130101; A61K 31/718 20130101; C08B 31/185 20130101; Y10S
514/814 20130101 |
International
Class: |
C08B 30/18 20060101
C08B030/18 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 23, 2002 |
DE |
10249552.1 |
Claims
1. An iron carboxypolymaltose complex of formula:
[FeO.sub.x(OH).sub.y(H.sub.2O).sub.z].sub.n[{(C.sub.6H.sub.10O.sub.5)(C.s-
ub.6H.sub.12O.sub.7)}].sub.Ik wherein the values for variables x,
y, z, n, m, 1 and k are such that said iron carboxypolymaltose
complex has an average molecular weight in the range of from about
80 kDa to about 400 kDa and an iron content in the range of from
about 24 to about 32% by weight.
2. The iron carboxypolymaltose complex of 1: wherein n is about 10
3; m is about 8; 1 is about 11; and k is about 4.
3. A medicament comprising the iron carboxypolymaltose complex of
claim 1 and a pharmaceutically acceptable carrier, excipient, or
additive.
4. The medicament of claim 3, wherein said medicament is an aqueous
solution of said iron carboxypolymaltose complex.
5. The medicament of claim 4, wherein said aqueous solution is a
brine solution.
6. The medicament of claim 3, wherein said iron carboxypolymaltose
complex is present in said aqueous solution in an amount of from
about 1% to about 20% by weight, based on the total weight of the
aqueous solution.
7. The medicament of claim 3, wherein said iron carboxypolymaltose
complex is present in said aqueous solution in an amount of about
5% by weight, based on the total weight of the aqueous
solution.
8. 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 3.
9. The method of claim 8, wherein said iron deficiency condition is
iron deficiency anaemia.
10. The method of claim 8, wherein said medicament is administered
parenterally or orally.
11. The method of claim 8, wherein said medicament is administered
intravenously or intramuscularly.
12. The method of claim 8, wherein said medicament is administered
via injection.
13. The method of claim 8, wherein said medicament is administered
via infusion.
14. The method of claim 8, wherein said medicament is administered
in the form of a single dose.
15. The method of claim 14, wherein said single dose comprises from
500 to 1000 mg of iron.
16. The method of claim 15, wherein said single dose is applied
over the course of less than one hour.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 14/469,864, filed on Aug. 27, 2014; which is a divisional of
Ser. No. 13/835,400, filed on Mar. 15, 2013, which is a
continuation of U.S. application Ser. No. 13/556,733, filed on Jul.
24, 2012, which is a continuation of U.S. application Ser. No.
12/581,212, filed on Oct. 19, 2009, which is a divisional of U.S.
application Ser. No. 10/531,895, filed on Dec. 14, 2005 (now U.S.
Pat. No. 7,612,109) and which is a national stage of Application
No. PCT/EP2003/011596, filed on Oct. 20, 2003, which claims benefit
of German Application No. 102 49 552.1, filed on Oct. 23, 2002. The
entire contents of each application is hereby incorporated by
reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Iron deficiency anemia can be treated or prophylactically
treated by the application of medicaments containing iron. In this
respect the use of iron carbohydrate complexes is known. A water
soluble iron (III) hydroxide sucrose complex is a frequently and
successfully used preparation (Danielson, Salmonson, Derendorf,
Geisser, Drug Res., Vol. 46: 615-621, 1996). It is also known in
the art to use, for parenteral application, iron dextran complexes
as well as complexes based on pullulans (WO 02/46241), which are
difficult to obtain and have to be produced under pressure at high
temperatures and involving hydrogenating steps. Other iron
carbohydrate complexes are also known for oral application.
BRIEF SUMMARY OF THE INVENTION
[0003] The present invention concerns water-soluble iron
carbohydrate complexes which are used for the treatment of iron
deficiency anemia, their preparation, medicaments containing them
and their use for the prophylaxis or treatment of iron deficiency
anemia. The medicaments are especially useful for parenteral
application.
DETAILED DESCRIPTION OF THE INVENTION
[0004] The problem to be solved by the present invention is to
provide an iron preparation which is especially to be applied
parenterally and which can easily be sterilized; the known
parenterally applicable preparations on the basis of sucrose and
dextran were only stable at temperatures up to 100.degree. C.,
which made sterilization difficult. Further, the preparation to be
provided by the invention shall have reduced toxicity and shall
avoid dangerous anaphylactic shocks which can be induced by
dextran. Also, the stability of the complexes of the preparation
shall be high in order to enable a high applicable dosage and a
high rate of application. Furthermore, the iron preparation is to
be producible from easily obtainable starting products and without
great effort.
[0005] In accordance with the present invention the problem can be
solved by providing iron (III) carbohydrate complexes on the basis
of the oxidation products of maltodextrins. Therefore, an object of
the present invention is water soluble iron carbohydrate complexes,
which are obtainable from an aqueous solution of an iron (III) salt
and an aqueous solution of the oxidation product of one or more
maltodextrins, using an aqueous hypochlorite solution at an
alkaline pH value, e.g., of 8 to 12 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.
[0006] A further object of the present invention is a process for
producing the iron carbohydrate complexes according to the
invention wherein one or more maltodextrins are oxidized in an
aqueous solution at an alkaline pH value, e.g., of 8 to 12 using an
aqueous hypochlorite solution and reacting the obtained solution
with an aqueous solution of an iron (III) 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 maltodextrin contained in
the mixture lies between 2 and 40.
[0007] The usable maltodextrins are easily obtainable starting
products, and they are commercially available.
[0008] In order to prepare the ligands of the complexes of the
invention, the maltodextrins are oxidized in an aqueous solution
with a hypochlorite solution. Suitable examples are solutions of
alkali hypochlorites such as a solution of sodium hypochlorite.
Commercially available solutions can be used. The concentration of
the hypochlorite solution, e.g., is at least 13% by weight,
preferably on the order of 13 to 16% by weight, calculated as
active chlorine. Preferably the solutions are used in such an
amount that about 80 to 100%, preferably about 90%, of one aldehyde
group per molecule of maltodextrin is oxidized. In this manner, the
reactivity caused by the glucose content of the maltodextrin
molecules is lowered to 20% or less, preferably to 10% or less.
[0009] The oxidation is carried out in an alkaline solution, e.g.,
at a pH of 8 to 12, for example 9 to 11. As an example, oxidation
can be carried out at temperatures on the order of 15 to 40.degree.
C., preferably of 25 to 35.degree. C. The reaction times are, e.g,
on the order of 10 minutes to 4 hours, e.g., 1 to 1.5 hours.
[0010] By this procedure the degree of depolymerization of the
starting maltodextrins is kept at a minimum. Only theoretically it
is assumed that the oxidation occurs mainly at the terminal
aldehyde group (acetal or semiacetal group, respectively) of the
maltodextrin molecules.
[0011] It is also possible to catalyze the oxidation reaction of
the maltodextrins. The addition of bromide ions is suitable, e.g.,
in the form of alkali bromides, for example sodium bromide. The
added amount of bromide is not critical. The amount is kept as low
as possible in order to achieve an end product (Fe-complex) which
can easily be purified. Catalytic amounts are sufficient. As stated
above, the addition of bromide is possible, however, not
necessary.
[0012] Further, it is also possible to use other oxidation systems,
such as, e.g., the known ternary oxidation system
hypochlorite/alkali bromide/2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) for the oxidation of the maltodextrins. The process to
oxidize maltodextrins catalytically with alkali bromides or with
the ternary TEMPO system is described, e.g., by Thaburet et al, in
Carbohydrate Research 330 (2001) 21-29, which method can be used
for the present invention,
[0013] In order to prepare the complexes of the invention, the
obtained oxidized maltodextrins are reacted with an iron (III) salt
in an aqueous solution. In order to do so, the oxidized
maltodextrins can be isolated and redissolved. It is also possible,
however, to use the obtained aqueous solutions of the oxidized
maltodextrins directly for the further reaction with the aqueous
iron (III) solutions.
[0014] Water soluble salts of inorganic or organic acids, or
mixtures thereof, such as halides, e.g., chloride and bromide, or
sulfates can be used as iron (III) salts. It is preferred to use
physiologically acceptable salts. It is especially preferred to use
an aqueous solution of iron (III) chloride.
[0015] It has been found that the presence of chloride ions favors
the formation of the complexes. The chloride ions can be used in
the form of water soluble chlorides such as alkali metal chlorides,
e.g., sodium chloride, potassium chloride or ammonium chloride. As
stated, the iron (III) is preferably used in the form of the
chloride.
[0016] For instance, the aqueous solution of the oxidized
maltodextrin can be mixed with an aqueous solution of the iron
(III) salt in order to carry out the reaction. Here, it is
preferred to proceed in a manner so that during and immediately
after mixing the oxidized maltodextrin and the iron (III) salt, the
pH is strongly acid or so low that no hydrolysis of the iron (III)
salt occurs, e.g., pH 2 or less, in order to avoid an undesired
precipitation of iron hydroxides. In general, it is not necessary
to add an acid, if iron (III) chloride is used, since aqueous
solutions of iron (III) chloride can be sufficiently acidic. Only
after mixing, the pH is raised to values, e.g., on the order of at
least 5, for example, up to 11, 12, 13 or 14. The pH is preferably
raised slowly or gradually which, for example, can be achieved by
first adding a weak base, for example, up to a pH of about 3, and
then neutralizing further using a stronger base. Examples of weak
bases are alkali--or alkaline earth--carbonates, bicarbonates, such
as sodium and potassium carbonate or bicarbonate, or ammonia.
Examples of strong bases are alkali--or alkaline earth--hydroxides
such as sodium, potassium, calcium or magnesium hydroxide.
[0017] The reaction can be improved by heating. For example,
temperatures on the order of 15.degree. C. up to boiling point can
be used. It is preferred to raise the temperature gradually. Thus,
for example, it is possible to heat to about 15 to 70.degree. C.
and then raise the temperature gradually up to boiling point.
[0018] The reaction times are, for example, on the order of 15
minutes up to several hours, e.g., 20 minutes to 4 hours, such as
25 to 70 minutes, e.g., 30 to 60 minutes.
[0019] The reaction can be carried out in a weakly acid range, for
example, at a pH on the order of 5 to 6. However, it has been
found, that it is useful, but not necessary, to raise the pH during
the formation of the complexes to higher values of up to 11, 12, 13
or 14. In order to complete the reaction, the pH can be lowered
then by addition of an acid, for example, to the order of 5 to 6.
It is possible to use inorganic or organic acids or a mixture
thereof, especially hydrogen halide acids such as hydrogen chloride
or aqueous hydrochloric acid, respectively.
[0020] As stated above, the formation of the complexes is usually
improved by heating. Thus, at the preferred embodiment of the
invention, wherein the pH is raised during the reaction to ranges
of at least 5 and above, up to 11 or 14, it is, for instance,
possible to work at first at lower temperatures on the order of 15
to 70.degree. C., such as 40 to 60.degree. C., e.g., about
50.degree. C., whereafter the pH is reduced to values on the order
of at least 5, and the temperature is gradually raised over
50.degree. C. up to boiling point
[0021] The reaction times are on the order of 15 minutes up to
several hours and they can vary depending on the reaction
temperature. If the process is carried out with an intermediate pH
of more than 5, it is, for example, possible to work 15 to 70
minutes, e.g., 30 to 60 minutes, at the enhanced pH, for example,
at temperatures of up to 70.degree. C., whereafter the pH is
lowered to a range on the order of at least 5 and the reaction is
carried out for a further 15 to 70 minutes, e.g., 30 to 60 minutes,
at temperatures, e.g., up to 70.degree. C., and optionally a
further 15 to 70 minutes, e.g., 30 to 60 minutes, at higher
temperatures up to boiling point.
[0022] After the reaction the obtained solution can be cooled,
e.g., to room temperature and can optionally be diluted and
optionally be filtered. After cooling, the pH can be adjusted to
the neutral point or a little below, for example, to values of 5 to
7, by the addition of an acid or base. It is possible to use, e.g.,
the acids and bases which have been mentioned for carrying out the
reaction. The solutions obtained are purified and can directly be
used for the production of medicaments. However, it is also
possible to isolate the iron (III) complexes from the solution,
e.g., by precipitation with an alcohol such as an alkanol, for
example, ethanol. Isolation can also be effected by spray-drying.
Purification can take place in the usual way, especially in order
to remove salts. This can, for example, be carried out by reverse
osmosis. It is, for example, possible to carry out the reverse
osmosis before spray-drying or before a direct application in
medicaments.
[0023] The iron content of the obtained iron (III) carbohydrate
complexes is, for example, 10 to 40% weight/weight, especially, 20
to 35% weight/weight. They can easily be dissolved in water. It is
possible to prepare neutral aqueous solutions which, e.g., have an
iron content of 1% weight/vol. to 20% weight/vol. Such solutions
can be sterilized thermically. The weight average molecular weight
of the obtained complexes, is, for example, 80 kDa to 400 kDa,
preferably 80 kDa to 350 kDa, especially preferred up to 300 kDa
(measured by gel permeation chromatography, e.g., as described by
Geisser et al, in Arzneim. Forsch/Drug Res. 42(II), 12, 1439-1452
(1992), paragraph 2.2.5).
[0024] As stated above, it is possible to provide aqueous solutions
from the complexes of the invention. These solutions are especially
useful for parenteral application. However, it is also possible to
apply them orally or topically. Contrary to the known parenterally
applicable iron preparations, they can be sterilized at high
temperatures, e.g., at 121.degree. C. and above, at short contact
times of, e.g., 15 minutes, by acquiring F.sub.0.gtoreq.15. The
contact times are correspondingly shorter at higher temperatures.
Preparations hitherto known had to be sterilely filtrated and mixed
with preservatives, such as benzyl alcohol or phenol. Such
additives are not necessary in the invention. Hence, it is possible
to fill the solutions of the complexes, for example, into ampoules.
It is, for example, possible to fill solutions having a content of
1 to 20% by weight, e.g., 5% by weight, into vessels such as
ampoules or phials, e.g., of 2 to 100 ml, e.g., up to 50 ml. The
preparation of the parenterally applicable solutions can be carried
out as known in the art, optionally using additives which are
normally used for parenteral solutions. The solutions can be
formulated in such a way that they can be administered by injection
or in the form of an infusion, e.g., in brine solution. For the
oral or topical application it is possible to formulate
preparations with usual excipients and additives.
[0025] Thus, a further object of the invention is aqueous
medicaments which are especially useful for the parenteral,
intravenous but also intramuscular application, as well as for oral
or topical application. The aqueous medicaments are especially
useful for the treatment of iron deficiency anemia. A further
object of the invention is also the use of the iron (III)
carbohydrate complexes according to the invention for the treatment
and prophylaxis of iron deficiency anemia or the production of
medicaments especially for the parenteral treatment of iron
deficiency anemia. The medicaments can be used in human and
veterinary medicine.
[0026] The advantages which are achieved with the iron (III)
carbohydrate complexes of the invention are the above-mentioned
high sterilization temperatures, as well as the low toxicity and
the reduced danger of anaphylactic shock. The toxicity of the
complexes according to the invention is very low. The LD.sub.50
lies at over 2000 mg Fe/kg, compared to the LD.sub.50 of the known
pullulan complexes, which lies at 1400 mg Fe/kg. In view of the
high stability of the complexes of the invention, it is possible to
enhance the rates of application as well as the dosages. Thus, it
is possible to apply the medicaments of the invention parenterally
in the form of a single dose. Such a single dose is, for example,
500 to 1000 mg iron. The dose can be applied, for example, during
the course of one hour. A further advantage lies in the high degree
of availability of the maltodextrins used as starting products,
which are, e.g., commercially available additives in the food
processing industry.
[0027] In the present description, as well as in the following
examples, the dextrose equivalents are measured gravimetrically. In
order to do so, the maltodextrins are reacted in a boiling aqueous
solution with Fehling's solution. The reaction is carried out
quantitatively, i.e. until the Fehling's solution is no longer
discolored. The precipitated copper (I) oxide is dried at
105.degree. C. until a constant weight is achieved and measured
gravimetrically. The glucose content (dextrose equivalent) is
calculated from the obtained results as % weight/weight of the
maltodextrin dry substance. It is, for example, possible to use the
following solutions: 25 ml Fehling's solution I, mixed with 25 ml
Fehling's solution II; 10 ml aqueous maltodextrin solution (10%
mol/vol) (Fehling's solution I: 34.6 g copper (II) sulfate
dissolved in 500 ml water; Fehling's solution II: 173 g potassium
sodium tartrate and 50 g sodium hydroxide dissolved in 400 ml
water).
EXAMPLE 1
[0028] 100 g maltodextrin (9.6 dextrose equivalent measured
gravimetrically) are dissolved by stirring in 300 ml water at
25.degree. 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.degree. C. and kept at
50.degree. 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.degree. C. for a further 30 minutes and then heated to
97-98.degree. 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.degree. 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.degree. 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.degree. C. and kept for
30 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. C. for a further 30 minutes and then heated to
97-98.degree. 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.degree. 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.degree. 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.degree. C. and kept for
60 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. C. for a further 30 minutes and then heated to
97-98.degree. 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.degree. 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.degree. 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.degree. C. and kept for
30 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. C. for a further 30 minutes and then heated to
97-98.degree. 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.degree. 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.degree. 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.degree. C. and kept for
30 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. C. for a further 30 minutes and then heated to
97-98.degree. 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.degree. 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.degree. 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.degree. C. and kept for
30 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. C. for a further 30 minutes and then heated to
97-98.degree. 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.degree. 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.degree. 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.degree. C. and kept for
30 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. 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.degree. 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.degree. 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.degree. C. and kept for
30 minutes at 50.degree. C. Then, acidification to a pH of 5 to 6
is effected by addition of hydrochloric acid, the solution is kept
at 50.degree. 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.degree. 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.degree. C./15' 100.degree.
C./35' LD.sub.50 i.v., w.m. [mg >2000 >200 Fe/kg body
weight]
* * * * *