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`TRANSLATOR CERTIFICATION
`
`County of New York
`State of New York
`
`Date: May 27, 2015
`
`
`To whom it may concern:
`
`This is to certify that the attached translation from German into English is an accurate
`representation of the documents received by this office.
`
`The documents are designated as:
` WO2004037865
`
`
`Belinda Lai attests to the following:
`
`“To the best of my knowledge, the aforementioned documents are a true, full and accurate
`translation of the specified documents.”
`
`
`
`
`Signature of Belinda Lai
`
`
`
`Pharmacosmos, Exh. 1004, p. 1
`
`

`

`Abstract
`
`Disclosed is a water-soluble iron-carbohydrate complex obtained from an
`aqueous iron(III)-salt solution and an aqueous solution of the product obtained by
`oxidizing one or several maltodextrins with an aqueous hypochlorite solution at
`an alkaline pH value. The dextrose equivalent of the maltodextrin ranges from 5
`to 20 if a single maltodextrin is used while the dextrose equivalent of the mixture
`of several maltodextrins ranges from 5 to 20 and the dextrose equivalent of each
`individual maltodextrin contained in the mixture ranges from 2 to 40 if a mixture
`of several maltodextrins is used. Also disclosed are a method for the production
`of said complex and medicaments for the treatment and prophylaxis of iron
`deficiencies.
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`Pharmacosmos, Exh. 1004, p. 2
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`Water-soluble iron-carbohydrate complexes, their production, and medications
`containing them
`
`The object of the present invention is water-soluble iron-carbohydrate
`complexes, which are suitable for therapy of iron-deficiency anemia, as well as
`their production, medications containing them, and their use in the prophylaxis or
`therapy of iron deficiency anemia. The medications are particularly suitable for
`parenteral use.
`
`Anemia caused by iron deficiency can be treated or prevented by administration
`of medications containing iron. For this purpose, the use of iron-carbohydrate
`complexes is known. A preparation frequently successfully used in practice is
`based on a water-soluble iron (III) hydroxide saccharose complex (Danielson,
`Salmonson, Derendorf, Geisser, Drug Res., Vol. 46: 615 – 621, 1996). In the
`state of the art, iron-dextran complexes as well as complexes on the basis of
`pullulans (WO 02/46241), which are difficult to access and must be produced
`under pressure at high temperatures and with the inclusion of hydrogenation
`steps, are described. Other iron-carbohydrate complexes for oral administration
`are common.
`
`The present invention has set itself the task of making available an iron
`preparation, which can preferably be administered parenterally, and can be
`sterilized in comparatively simple manner; this is because the previous
`preparations that can be administered parenterally, based on saccharose or
`dextran, were stable only at temperatures up to 100°C, making sterilization
`difficult. Furthermore, the preparation to be made available according to the
`invention is supposed to demonstrate reduced toxicity and to prevent the
`dangerous anaphylactic shocks that can be induced by dextran. Also, the
`preparation to be made available is supposed to demonstrate great complex
`stability, so that a large application dose or a high application speed is made
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`Pharmacosmos, Exh. 1004, p. 3
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`possible. Also, it is supposed to be possible to produce the iron preparation from
`starting products that are easy to obtain, without special effort.
`
`It has been shown that this task is accomplished by means of iron (III)
`carbohydrate complexes on the basis on the oxidation products of maltodextrins.
`Therefore water-soluble iron-carbohydrate complexes that can be obtained from
`an aqueous iron (III) salt solution and an aqueous solution of the product of
`oxidation of one or more maltodextrins with an aqueous hypochlorite solution at
`an alkaline pH of 8 to 12, for example, form an object of the invention, wherein
`when using one maltodextrin, its dextrose equivalent ranges from 5 to 20, and
`when using a mixture of several maltodextrins, the dextrose equivalent of the
`mixture ranges from 5 to 20 and the dextrose equivalent of the individual
`maltodextrins contained in the mixture ranges from 2 to 40.
`
` A
`
` further object of the invention is formed by a method for the production of the
`iron-carbohydrate complexes according to the invention, in which one or more
`maltodextrins are oxidized in an aqueous solution, at an alkaline pH of 8 to 12,
`for example, using an aqueous hypochlorite solution, and the solution obtained is
`reacted with the aqueous solution of an iron (III) salt, wherein when using one
`maltodextrin, its dextrose equivalent ranges from 5 to 20, and when using a
`mixture of several maltodextrins, the dextrose equivalent of the mixture ranges
`from 5 to 20 and the dextrose equivalent of the individual maltodextrins contained
`in the mixture ranges from 2 to 40.
`
`The maltodextrins that can be used are easily accessible starting products that
`are commercially available.
`
`For the production of the ligands of the complexes according to the invention, the
`maltodextrins are oxidized in aqueous solution, with hypochlorite solution.
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`Pharmacosmos, Exh. 1004, p. 4
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`Suitable solutions are, for example, solutions of alkaline hypochlorites, such as
`sodium hypochlorite solution. The concentrations of the hypochlorite solutions
`are, for example, at least 13 wt.-%, preferably on the order of 13 to 16 wt.-%,
`calculated as active chlorine, in each instance. The solutions are preferably used
`in such an amount that about 80 to 100%, preferably about 90% of an aldehyde
`group are oxidized per maltodextrin molecule. In this manner, the reduction
`capacity caused by the glucose component of the maltodextrin molecules is
`reduced to about 20% or less, preferably 10% or less.
`
`Oxidation takes place in an alkaline solution, for example at a pH of 8 to 12, e.g.
`9 to 11. For oxidation, it is possible to work at temperatures on the order of 15 to
`40°C, preferably 25 to 35°C, for example. The reaction times are on the order of
`10 minutes to 4 hours, e.g. 1 to 1.5 hours, for example.
`
`By means of the method of procedure described, the degree of polymerization of
`the maltodextrins used is kept at a minimum. Without stating a binding theory, it
`is assumed that oxidation primarily takes place at the end-position aldehyde
`group (or acetal or hemiacetal group) of the maltodextrin molecules.
`
`It is also possible to catalyze the oxidation reaction of the maltodextrins. The
`addition of bromide ions, for example in the form of alkali bromides, for example
`sodium bromide, is suitable for this purpose. The amount of bromide added is
`not critical. It is kept as low as possible, in order to obtain an end product (Fe
`complex) that can be purified as easily as possible. Catalytic amounts are
`sufficient. As has been mentioned, the addition of bromide is possible but not
`necessary.
`
`Furthermore, it is also possible, for example, to use the known ternary oxidation
`system hypochlorite/alkali bromide/2,2,6,6-tetramethyl piperidine-1-oxyl
`(TEMPO) for oxidation of the maltodextrins. The method of procedure for
`oxidizing maltodextrins with catalysis by alkali bromides or with the ternary
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`Pharmacosmos, Exh. 1004, p. 5
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`TEMPO system is described, for example, by Thaburet et al. in Carbohydrate
`Research 330 (2001) 21 – 29; the method of procedure described there can be
`used according to the invention.
`For the production of the complexes according to the invention, the oxidized
`maltodextrins obtained are reacted with an iron (III) salt in an aqueous solution.
`For this purpose, the oxidized maltodextrins can be isolated and dissolved once
`again; the aqueous solutions of the oxidized maltodextrins that are obtained can,
`however, also be used directly for further processing with aqueous iron (III)
`solutions.
`
`Water-soluble salts of inorganic or organic acids or mixtures of them, such as
`halogenides, for example chloride and bromide, or sulfates, can be used as iron
`(III) salts. Preferably, physiologically safe salts are used. Particularly preferably,
`an aqueous solution of iron (III) chloride is used.
`
`It has been shown that the presence of chloride ions has an advantageous effect
`on complex formation. These ions can be added, for example, in the form of
`water-soluble chlorides, such as alkali metal chlorides, for example sodium
`chloride, potassium chloride or ammonium chloride. As has been mentioned, the
`iron (III) is preferably used in the form of the chloride.
`
`For reaction, the aqueous solution of the oxidized maltodextrin can be mixed with
`an aqueous solution of the iron (III) salt, for example. In this connection, the
`work is preferably done in such a manner that the pH of the mixture of oxidized
`maltodextrin and iron (III) salt during and immediately after mixing is at first
`strongly acidic, i.e. so low that no hydrolysis of the iron (III) salt occurs, for
`example amounts to 2 or less, in order to avoid undesirable precipitation of iron
`hydroxides. When using iron (III) chloride, no addition of acid is generally
`required, because aqueous solutions of iron (III) chloride can themselves be
`sufficiently acidic. After mixing has taken place, the pH can be raised to values
`on the order of equal to or greater than 5, for example up to 11, 12, 13 or 14.
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`Pharmacosmos, Exh. 1004, p. 6
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`Raising of the pH preferably takes place slowly or gradually, which can take
`place, for example, in that first a weak base is added, for example up to a pH of
`about 3; subsequently, further neutralization with a stronger base can take place.
`Alkali or earth alkali carbonates, bicarbonates, such as sodium and potassium
`carbonate or bicarbonate, are possible weak bases. Strong bases are, for
`example, alkali or earth alkali hydroxides, such as sodium, potassium, calcium or
`magnesium hydroxide.
`
`The reaction can be promoted by heating. For example, temperatures on the
`order of 15°C to boiling temperature can be used. It is preferred to increase the
`temperature gradually. For example, heating can take place to about 15 to 70°C
`at first, and then gradually increased to boiling.
`
`The reaction times are, for example, on the order of 15 minutes to several hours,
`for example 20 minutes to 4 hours, for example 25 to 70 minutes, for example 30
`to 60 minutes.
`
`The reaction can take place in the weakly acidic range, for example at a pH on
`the order of 5 to 6. However, it has been shown that it is practical, although not
`necessary, to raise the pH to higher values, up to 11, 12, 13 or 14, during the
`course of complex formation. To complete the reaction, the pH can then be
`lowered further by adding acid, for example to the aforementioned order of 5 to 6.
`Inorganic or organic acids or mixtures of them, particularly hydrohalic acids, such
`as hydrogen chloride or aqueous hydrochloric acid, can be used as acids.
`
`As has been mentioned, complex formation is generally promoted by heating.
`For example, in the preferred embodiment, in which the pH is increased beyond
`5 to 11 or 14, the work can be carried out at low temperatures, at first, on the
`order of 15 to 70°, for example 40 to 60°C, for example about 50°C, whereupon
`after renewed reduction of the pH to values on the order of at least 5, for
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`Pharmacosmos, Exh. 1004, p. 7
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`example, heating gradually takes place to temperatures above 50°C, up to
`boiling temperature.
`
`The reaction times are on the order of 15 minutes to several hours, and can vary
`as a function of the reaction temperature. When carrying out the method with the
`interim use of a pH that lies above 5, work can be carried out for 15 to 70
`minutes, for example 30 to 60 minutes, at the elevated pH, for example at
`temperatures up to 70°C, whereupon the reaction can be carried out, after the pH
`has been lowered to the order of at least 5, for another 15 to 70 minutes, for
`example 30 to 60 minutes, at temperatures up to 70°C, for example, and, if
`necessary, for another 15 to 70 minutes, for example 30 to 60 minutes, at higher
`temperatures up to the boiling point.
`
`After the reaction has been completed, the solution obtained can be cooled to
`room temperature, for example, and diluted, if necessary, and filtered, if
`necessary. After cooling, the pH can be adjusted to the neutral point or slightly
`below, for example to values of 5 to 7, by adding acid or base. The acids or
`bases mentioned above for the reaction can be used, for example. The solutions
`obtained are purified and can be used directly for the production of medications.
`However, it is also possible to isolate the iron (III) complexes from the solution,
`for example by means of precipitation using an alcohol, such as an alkanol, for
`example ethanol. However, isolation can also take place by means of spray
`drying. Purification can take place in usual manner, particularly for the removal
`of salts. This can be done, for example, by means of reverse osmosis, with such
`reverse osmosis being carried out before spray drying, for example, or before
`direct use in medications.
`
`The iron (III) carbohydrate complexes have an iron content of 10 to 40% w/w, for
`example, particularly 20 to 35% w/w. They are well soluble in water. It is
`possible to produce neutral aqueous solutions from them, having an iron content
`of 1% w/vol to 20% w/vol, for example. These solutions can be thermally
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`Pharmacosmos, Exh. 1004, p. 8
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`sterilized. The average molecular weight Mw, in terms of weight, of the
`complexes obtained in such a manner amounts to 80 kDa to 400 kDa, for
`example, preferably 80 to 350 kDa, particularly preferably up to 300 kDa
`(determined by means of gel permeation chromatography, for example as
`described by Geisser et al. in Arzneim. Forsch/Drug Res. 42(II), 12, 1439 – 1452
`(1992), paragraph 2.2.5).
`
`As has been mentioned, it is possible to produce aqueous solutions from the
`complexes according to the invention. These are particularly suitable for
`parenteral application. However, they can also be used orally or topically. In
`contrast to parenterally administered iron preparations usual until now, they can
`be sterilized at high temperatures, e.g. at 121°C and above, at short contact
`times of about 15 minutes, for example, reaching Fo ≥ 15. At higher
`temperatures, the contact times are correspondingly shorter. Previously known
`preparations had to be sterile-filtered at room temperature, and in part mixed with
`preservatives, such as benzyl alcohol or phenol. Such additives are not
`necessary, according to the invention. It is possible to fill the solutions of the
`complexes into ampoules, for example. For example, the solutions of 1 to 20 wt.-
`%, for example 5 wt.-%, can be filled into containers such as ampoules or
`injection ampoules (vials) of 2 to 100 ml, for example, up to 50 ml, for example.
`The production of the parenterally administered solutions can take place in usual
`manner, if necessary with the use of additives usual for parenteral solutions. The
`solutions can be formulated in such a manner that they can be administered as
`such, by means of injection or as an infusion, for example in saline solution. For
`oral or topical administration, preparations can be formulated with the
`corresponding usual excipients and processing aids.
`
` A
`
` further object of the invention is therefore formed by aqueous medications that
`are particularly suitable for parenteral, intravenous, but also intramuscular
`administration, as well as for oral or topical administration, and can particularly
`be used for treatment of iron deficiency anemia. A further object of the invention
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`Pharmacosmos, Exh. 1004, p. 9
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`therefore also relates to the use of the iron (III) carbohydrate complexes
`according to the invention for the treatment and prophylaxis of iron deficiency
`anemia, and for the production of medications for treatment, particularly
`parenteral treatment, of iron deficiency anemia. The medications are suitable for
`use in human and veterinary medicine.
`
`Advantages that result from the iron-carbohydrate complexes according to the
`invention are the high sterilization temperatures already mentioned above, which
`are accompanied by low toxicity and a reduced risk of anaphylactic shock. The
`toxicity of the complexes according to the invention is very low. The LD50 is more
`than 2000 mg Fe/kg, in comparison with the LD50 of the known pullulan
`complexes, which is 1400 mg Fe/kg. Because of the great stability of the
`complexes made available according to the invention, it becomes possible to
`increase not only the application speed but also the dosages. In this way, it
`becomes possible to apply the medications according to the invention
`parenterally, as a single dose. Such a single dose can amount to 500 to 1000
`mg iron, for example; it can be applied over the course of 1 hour, for example. A
`further advantage lies in the easy availability of the maltodextrins used as the
`starting products, which are commercially available additives in the foods
`industry, for example.
`
`In the present description and the examples below, the dextrose equivalents are
`determined gravimetrically. For this purpose, the maltodextrins are reacted in
`aqueous solution, with Fehling’s solution, while boiling. The reaction takes place
`quantitatively, i.e. until no further color removal from the Fehling’s solution takes
`place. The precipitated copper (I) oxide is dried to a constant weight at 105°C
`and determined gravimetrically. From the values obtained, the glucose content
`(dextrose equivalent) is calculated as % w/w of the dry maltodextrin substance.
`It is possible to work with the following solutions, for example: 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
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`Pharmacosmos, Exh. 1004, p. 10
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`500 ml water; Fehling’s solution II: 173 g potassium sodium tartrate and 50 g
`sodium hydroxide, dissolved in 400 ml water).
`
`Example 1
`
`100 g maltodextrin (9.6 dextrose equivalents, determined gravimetrically) are
`dissolved in 300 ml water at 25°C, while stirring, and oxidized at pH 10 by adding
`30 g sodium hypochlorite solution (13 to 16 wt.-% active chlorine).
`
`First, the oxidized maltodextrin solution, and then 554 g sodium carbonate
`solution (17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe),
`while stirring (blade stirrer).
`
`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 30 minutes, and afterward heated to 97 – 98°C and kept at this
`temperature for 30 minutes. After the solution has cooled to room temperature,
`the pH is adjusted to 6 – 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`125 g (corresponding to 87% of theory) of a brown, amorphous powder having
`an iron content of 29.3% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 271 kDa
`
`Example 2
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`Pharmacosmos, Exh. 1004, p. 11
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`200 g maltodextrin (9.6 dextrose equivalents, determined gravimetrically) are
`dissolved in 300 ml water at 25°C, while stirring, and oxidized at pH 10 by adding
`30 g sodium hypochlorite solution (13 to 16 wt.-% active chlorine).
`
`First, the oxidized maltodextrin solution, and then 554 g sodium carbonate
`solution (17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe),
`while stirring (blade stirrer).
`
`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 30 minutes, and afterward heated to 97 – 98°C and kept at this
`temperature for 30 minutes. After the solution has cooled to room temperature,
`the pH is adjusted to 6 – 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`123 g (corresponding to 65% of theory) of a brown, amorphous powder having
`an iron content of 22.5% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 141 kDa
`
`Example 3
`
`100 g maltodextrin (9.6 dextrose equivalents, determined gravimetrically) are
`dissolved in 300 ml water at 25°C, while stirring, and oxidized at pH 10 by adding
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`Pharmacosmos, Exh. 1004, p. 12
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`30 g sodium hypochlorite solution (13 to 16 wt.-% active chlorine) and 0.7 g
`sodium bromide.
`
`First, the oxidized maltodextrin solution, and then 554 g sodium carbonate
`solution (17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe),
`while stirring (blade stirrer).
`
`Afterward, a pH of 6.5 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 60 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 30 minutes, and afterward heated to 97 – 98°C and kept at this
`temperature for 30 minutes. After the solution has cooled to room temperature,
`the pH is adjusted to 6 – 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`139 g (corresponding to 88% of theory) of a brown, amorphous powder having
`an iron content of 26.8% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 140 kDa
`
`Example 4
`
` A
`
` mixture of 45 g maltodextrin (6.6 dextrose equivalents, determined
`gravimetrically) and 45 g maltodextrin (14.0 dextrose equivalents, determined
`gravimetrically) is dissolved in 300 ml water at 25°C, while stirring, and oxidized
`at pH 10 by adding 25 g sodium hypochlorite solution (13 to 16 wt.-% active
`chlorine) and 0.6 g sodium bromide.
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`Pharmacosmos, Exh. 1004, p. 13
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`First, the oxidized maltrin solution, and then 554 g sodium carbonate solution
`(17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe), while
`stirring (blade stirrer).
`
`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 30 minutes, and afterward heated to 97 to 98°C and kept at this
`temperature for 30 minutes. After the solution has cooled to room temperature,
`the pH is adjusted to 6 to 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`143 g (corresponding to 90% of theory) of a brown, amorphous powder having
`an iron content of 26.5% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 189 kDa
`
`Example 5
`
`90 g maltodextrin (14.0 dextrose equivalents, determined gravimetrically) are
`dissolved in 300 ml water at 25°C, while stirring, and oxidized at pH 10 by adding
`35 g sodium hypochlorite solution (13 to 16 wt.-% active chlorine).
`
`First, the oxidized maltrin solution, and then 554 g sodium carbonate solution
`(17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe), while
`stirring (blade stirrer).
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`Pharmacosmos, Exh. 1004, p. 14
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`
`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 30 minutes, and afterward heated to 97 to 98°C and kept at this
`temperature for 30 minutes. After the solution has cooled to room temperature,
`the pH is adjusted to 6 to 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`131 g (corresponding to 93% of theory) of a brown, amorphous powder having
`an iron content of 29.9% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 118 kDa
`
`Example 6
`
`A mixture of 45 g maltodextrin (5.4 dextrose equivalents, determined
`gravimetrically) and 45 g maltodextrin (18.1 dextrose equivalents, determined
`gravimetrically) is dissolved in 300 ml water at 25°C, while stirring, and oxidized
`at pH 10 by adding 31 g sodium hypochlorite solution (13 to 16 wt.-% active
`chlorine) and 0.7 g sodium bromide.
`
`First, the oxidized maltrin solution, and then 554 g sodium carbonate solution
`(17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe), while
`stirring (blade stirrer).
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`Pharmacosmos, Exh. 1004, p. 15
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`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 30 minutes, and afterward heated to 97 to 98°C and kept at this
`temperature for 30 minutes. After the solution has cooled to room temperature,
`the pH is adjusted to 6 to 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`134 g (corresponding to 88% of theory) of a brown, amorphous powder having
`an iron content of 27.9% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 178 kDa
`
`Example 7
`
`100 g maltodextrin (9.6 dextrose equivalents, determined gravimetrically) are
`dissolved in 300 ml water at 25°C, while stirring, and oxidized at pH 10 by adding
`29 g sodium hypochlorite solution (13 to 16 wt.-% active chlorine) and 0.7 g
`sodium bromide.
`
`First, the oxidized maltrin solution, and then 554 g sodium carbonate solution
`(17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe), while
`stirring (blade stirrer).
`
`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`14
`
`Pharmacosmos, Exh. 1004, p. 16
`
`

`

`5
`
`10
`
`15
`
`20
`
`25
`
`another 70 minutes. After the solution has cooled to room temperature, the pH is
`adjusted to 6 to 7 by adding sodium hydroxide.
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`155 g (corresponding to 90% of theory) of a brown, amorphous powder having
`an iron content of 24.5% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 137 kDa
`
`Example 8
`
`126 g maltodextrin (6.6 dextrose equivalents, determined gravimetrically) are
`dissolved in 300 ml water at 25°C, while stirring, and oxidized at pH 10 by adding
`24 g sodium hypochlorite solution (13 to 16 wt.-% active chlorine).
`
`First, the oxidized maltrin solution, and then 554 g sodium carbonate solution
`(17.3% w/w) are added to 352 g iron (III) chloride solution (12% w/w Fe), while
`stirring (blade stirrer).
`
`Afterward, a pH of 11 is adjusted by adding sodium hydroxide, the solution is
`heated to 50°C and kept at 50°C for 30 minutes. Afterward, acidification to a pH
`of 5 to 6 takes place by adding hydrochloric acid, the solution is kept at 50°C for
`another 70 minutes. After the solution has cooled to room temperature, the pH is
`adjusted to 6 to 7 by adding sodium hydroxide.
`
`
`
`
`15
`
`Pharmacosmos, Exh. 1004, p. 17
`
`

`

`5
`
`10
`
`15
`
`20
`
`The solution is then filtered by way of a sterile filter, and checked for sediments.
`Afterward, the complex is isolated by means of precipitation with ethanol in a
`ratio of 1 : 0.85, and dried in a vacuum at 50°.
`
`171 g (corresponding to 86% of theory) of a brown, amorphous powder having
`an iron content of 21.35% w/w is obtained (determined by means of
`complexometric titration).
`
`Molecular weight Mw 170 kDa
`
`Comparison
`
`In the following comparison, the properties of iron-carbohydrate complexes
`according to the invention are compared with a commercially available iron-
`saccharose complex. It is evident that an increased iron content is possible, that
`thermal treatment at higher temperatures can be carried out, and that the toxicity
`is comparatively reduced (LD50).
`
`
`
`According to the invention
`
`Iron hydroxide/saccharose
`complex
`2.0
`10.5 – 11.0
`34 – 54
`100°C/35’
`> 200
`
`5.0
`5 – 7
`80 – 350
`121°C/15’
`> 2000
`
`Fe content
`pH
`Mw [kDa]1)
`Thermal treatment
`LD50 i.v., w.m. [mg
`Fe/kg body weight]
`
`
`
`
`
`16
`
`Pharmacosmos, Exh. 1004, p. 18
`
`

`

`Claims:
`
`Water-soluble iron-carbohydrate complex that can be obtained from an
`1.
`aqueous iron (III) salt solution and an aqueous solution of the product of
`oxidation of one or more maltodextrins with an aqueous hypochlorite solution at a
`pH in the alkaline range, wherein when using one maltodextrin, its dextrose
`equivalent ranges from 5 to 20, and when using a mixture of several
`maltodextrins, the dextrose equivalent of the mixture ranges from 5 to 20 and the
`dextrose equivalent of the individual maltodextrins contained in the mixture
`ranges from 2 to 40.
`
`Method for the production of an iron-carbohydrate complex according to
`2.
`claim 1, characterized in that one or more maltodextrins are oxidized in an
`aqueous solution, at an alkaline pH, using an aqueous hypochlorite solution, and
`the solution obtained is reacted with the aqueous solution of an iron (III) salt,
`wherein when using one maltodextrin, its dextrose equivalent ranges from 5 to
`20, and when using a mixture of several maltodextrins, the dextrose equivalent of
`the mixture ranges from 5 to 20 and the dextrose equivalent of the individual
`maltodextrins contained in the mixture ranges from 2 to 40.
`
`Method according to claim 2, characterized in that the oxidation of the
`3.
`maltodextrin or the maltodextrins is carried out in the presence of bromide ions.
`
`Method according to claim 2 or 3, characterized in that iron (III) chloride is
`4.
`used as the iron (III) salt.
`
`Method according to claim 2, 3 or 4, characterized in that oxidized
`5.
`maltodextrin and iron (III) salt are mixed into an aqueous solution having a pH
`that is so low that no hydrolysis of the iron (III) salt occurs, whereupon the pH is
`raised to 5 to 12 by adding a base.
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`17
`
`Pharmacosmos, Exh. 1004, p. 19
`
`

`

`Method according to one of claims 3 to 5, characterized in that the
`6.
`reaction is carried out for 15 minutes to several hours, at a temperature of 15°C
`to the boiling point.
`
`Medication containing the aqueous solution of an iron-carbohydrate
`7.
`complex according to claim 1 or 2, or obtained according to one of claims 3 to 6.
`
`Medication according to claim 7, characterized in that it is formulated for
`8.
`parenteral or oral administration.
`
`Use of the iron-carbohy