U.S. patent application number 12/581212 was filed with the patent office on 2010-04-22 for aqueous iron carbohydrate complexes, their production and medicaments containing them.
This patent application is currently assigned to VIFOR (INTERNATIONAL) AG. Invention is credited to Peter Geisser, Erik Philipp, Walter Richle.
Application Number | 20100099647 12/581212 |
Document ID | / |
Family ID | 32102937 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100099647 |
Kind Code |
A1 |
Geisser; Peter ; et
al. |
April 22, 2010 |
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 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, process for its
production and medicament for the treatment and prophylaxis of iron
deficiency conditions.
Inventors: |
Geisser; Peter; (St. Gallen,
CH) ; Philipp; Erik; (Wittenbach, CH) ;
Richle; Walter; (Gossau, CH) |
Correspondence
Address: |
RANKIN, HILL & CLARK LLP
23755 Lorain Road - Suite 200
North Olmsted
OH
44070-2224
US
|
Assignee: |
VIFOR (INTERNATIONAL) AG
St. Gallen
CH
|
Family ID: |
32102937 |
Appl. No.: |
12/581212 |
Filed: |
October 19, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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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: |
514/58 ;
536/46 |
Current CPC
Class: |
C08B 37/0009 20130101;
A61K 31/295 20130101; C08B 31/185 20130101; A61K 45/06 20130101;
A61K 33/26 20130101; A61K 33/26 20130101; A61K 2300/00 20130101;
A61K 31/718 20130101; A61K 2300/00 20130101; Y10S 514/814 20130101;
A61P 7/06 20180101; A61K 47/61 20170801; C08B 30/18 20130101; A61K
31/718 20130101 |
Class at
Publication: |
514/58 ;
536/46 |
International
Class: |
A61K 31/718 20060101
A61K031/718; C08B 30/18 20060101 C08B030/18; A61P 7/06 20060101
A61P007/06 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 23, 2002 |
DE |
10249552.1 |
Claims
1. 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 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 (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 maltodextrins contained in
the mixture lies between 2 and 40.
3. A 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. A process according to claim 2 or 3, characterized in that the
iron (III) chloride is used as the iron (III) salt.
5. A process according to claim 2, 3 or 4, characterized in that
the oxidized maltodextrin and the iron (III) salt are mixed to form
an aqueous solution having a pH-value so low that no hydrolysis of
the iron (III) salt occurs, whereafter the pH is raised to 5 to 12
by the addition of a base.
6. A process according to any of claims 3 to 5, characterized in
that the reaction is carried out at a temperature of 15.degree. C.
up to boiling point for 15 minutes up to several hours.
7. A medicament containing an aqueous solution of an iron
carbohydrate complex according to claim 1 or 2 or obtained in
accordance with any of claims 3 to 6.
8. A medicament according to claim 7 formulated for parenteral or
oral application.
9. Use of the iron carbohydrate complexes according to claim 1, or
obtained in accordance with any of claims 2 to 6, for the therapy
or prophylaxis of iron deficiency.
10. Use of the iron carbohydrate complexes according to claim 1, or
obtained in accordance with any of claims 2 to 6, for the
production of a medicament for therapy or prophylaxis of iron
deficiency.
11. Water-soluble iron carbohydrate complex according to claim 1
for therapy or prophylaxis of iron deficiency.
Description
[0001] The present invention concerns water-soluble iron
carbohydrate complexes which are used for the treatment of iron
deficiency anaemia, their preparation, medicaments containing them
and their use for the prophylaxis or treatment of iron deficiency
anaemia. The medicaments are especially useful for parenteral
application.
[0002] Iron deficiency anaemia 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.
[0003] 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 sterilisation 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 predicable from easily obtainable starting products and without
great effort.
[0004] 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 are 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 of e.g. 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.
[0005] 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 of e.g. 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.
[0006] The usable maltodextrins are easily obtainable starting
products, and they are commercially available.
[0007] 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 is, e.g. at least 13% by weight,
preferably in 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.
[0008] 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 in the order of 15 to 40.degree.
C., preferably of 25 to 35.degree. C. The reaction times are, e.g.
in the order of 10 minutes to 4 hours, e.g. 1 to 1.5 hours.
[0009] By this procedure the degree of depolymerisation 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.
[0010] It is also possible to catalyse 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.
[0011] 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,-tetramethypiperidine-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.
[0012] 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; however, it is also
possible to use the obtained aqueous solutions of the oxidized
maltodextrins directly for the further reaction with the aqueous
iron (III) solutions.
[0013] 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.
[0014] It has been found that the presence of chloride ions favours
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.
[0015] 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 of 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. 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 acid, Only
after mixing, the pH is raised to values of e.g. in 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.
[0016] The reaction can be improved by heating. For example,
temperatures in 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.
[0017] The reaction times are, for example, in 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.
[0018] The reaction can be carried out in a weakly acid range, for
example, at a pH in 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 mixture
thereof, especially hydrogen halide acids such as hydrogen chloride
or aqueous hydrochloric acid respectively.
[0019] 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 in 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 in the order
of at feast 5 and the temperature is gradually raised over
50.degree. C. up to boiling point.
[0020] The reaction times are in 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 in 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.
[0021] After the reaction the obtained solution can be cooled to
e.g. 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.
[0022] 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 sterilised thermically. The weight average molecular weight
mw 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).
[0023] 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 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 of e.g. 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.
[0024] Thus, a further object of the invention are aqueous
medicaments which are especially useful for the parenteral,
intravenous but also intramuscular application as well as for the
oral or topical application; they are especially useful for the
treatment of iron deficiency anaemia. 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 anaemia or the production of medicaments especially
for the parenteral treatment iron deficiency anaemia. The
medicaments can be used in human and veterinary medicine.
[0025] The advantages which are achieved with the iron (III)
carbohydrate complexes of the invention are the above-mentioned
high sterilisation 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; it 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.
[0026] 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
discoloured. 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
[0027] 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.
[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 (III) 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.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.
[0030] 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.degree. 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.degree. 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.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.
[0036] 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.degree. 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.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.
[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 (III) 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.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.
[0042] 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.degree. 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.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.
[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 (III) 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.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.
[0048] 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.degree. 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 complexometricaily).
[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.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.
[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 (III) 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.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.
[0054] 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.degree. 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.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.
[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 (III) 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.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.
[0060] 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.degree. 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.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.
[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 (III) 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.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.
[0066] 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.degree. 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.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.
[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.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.
[0072] 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.degree. 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,
Comparative Test
[0075] 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/sucrose the 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.degree. C./15' 100.degree.
C./35' LD.sub.50 i.v., w.m. [mg >2000 >200 Fe/kg body
weight]
* * * * *