(12) Unlted States Patent
`Geisser et a].
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,612,109 B2
`Nov. 3, 2009
`
`US007612109B2
`
`(54) WATER-SOLUBLE IRON-CARBOHYDRATE
`COMPLEXES, PRODUCTION THEREOF, AND
`MEDICAMENTS CONTAINING SAID
`COMPLEXES
`
`(75) Inventors: Peter Geisser, St. Gallen (CH); Erik
`Philippa Wittenbach (CH); Walter
`Richle, Gossau (CH)
`
`(56)
`
`References Cited
`
`U'S' PATENT DOCUMENTS
`3,086,009 A
`4/1963 Zuschek et al.
`3,821,192 A
`6/1974 Montgomery et al.
`i *
`191%; et 31'
`ec e ..................... ..
`FOREIGN PATENT DOCUMENTS
`
`,
`
`,
`
`536/18 5
`.
`
`(73) Assignee: Vifor (International) AG, St. Gallen
`(CH)
`
`FR
`GB
`WO
`
`1451203
`1111929
`02/46241
`
`V1966
`5/1968
`6/2002
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U-S-C- 1540’) by 108 days-
`
`(21) APP1-NO-3
`(22) PCT F1 d
`1e :
`
`10/5311895
`0 20 2003
`ct.
`,
`
`(86) PCT No.:
`
`PCT/EP03/11596
`
`§ 371 (0X1),
`(2)’ (4) Date;
`
`Dec_ 14, 2005
`
`(87) PCT Pub. No.: WO2004/037865
`
`PCT Pub. Date: May 6, 2004
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`US 2006/0205691 A1
`
`Sep. 14, 2006
`
`Foreign Application Priority Data
`
`Oct. 23, 2002
`
`(DE) .............................. .. 102 49 552
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/295
`(2006.01)
`A61K 31/721
`(2006.01)
`A61K 47/36
`(2006.01)
`A61P 7/06
`(52) US. Cl. ......................... .. 514/502; 514/58; 514/59;
`514/777; 514/814
`(58) Field of Classi?cation Search ............... .. 514/502,
`514/54, 58, 59, 777
`See application ?le for complete search history.
`
`OTHER PUBLICATIONS
`HCAPLUS abstract 1960117732 (1960),,
`HCAPLUS abstract 2003; 135397; abstracting CN 1353194 (abstract
`publicly available on Feb. 24, 2003).*
`Thaburet, J .F. et al., “Tempo-mediated oxidation of maltodextrins
`and D-glucose .
`.
`. ” Carbohydrate Research, vol. 330, pp. 21-29
`(2001).*
`Dokic, P. et al., “Molecular characteristics of maltodextrins and
`rheological behaviour of diluted and concentrated solutions,” Col
`loids and Surfaces, vol. 141, pp. 435-440 (1998).*
`English translation of CN 1353194 (Jun. 12, 2002).*
`International Search Report for PCT/EP03/11596 dated Jan. 14,
`2004, four pages.
`
`* cited by examiner
`
`Primary Examinerilohn Pak
`(74) Attorney, Agent, or FirmiRankin, Hill & Clark LLP
`
`(57)
`
`ABSTRACT
`
`Water soluble iron carbohydrate complex obtainable from an
`aqueous solution of iron (111) 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 alka
`line range, Where, When one maltodextrin is applied, its dex
`trose 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 de?ciency condi
`tions.
`
`27 Claims, No Drawings
`
`Pharmacosmos, Exh. 1021, p. 1
`
`

`

`US 7,612,109 B2
`
`1
`WATER-SOLUBLE IRON-CARBOHYDRATE
`COMPLEXES, PRODUCTION THEREOF, AND
`MEDICAMENTS CONTAINING SAID
`COMPLEXES
`
`This application is a 35 U.S.C. section 371 ?ling of PCT/
`EP2003/011596, ?led on Oct. 20, 2003, and published May 6,
`2004 as WO 2004/ 037865 A1, Which claims priority to Ger
`man Patent Application DE 10249552.1, ?led Oct. 23, 2002.
`The foregoing documents are incorporated herein by refer
`ence.
`The present invention concerns Water-soluble iron carbo
`hydrate complexes Which are used for the treatment of iron
`de?ciency anaemia, their preparation, medicaments contain
`ing them and their use for the prophylaxis or treatment of iron
`de?ciency anaemia. The medicaments are especially useful
`for parenteral application.
`Iron de?ciency 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 appli
`cation, iron dextran complexes as Well as complexes based on
`pullulans (WO 02/46241), Which are dif?cult to obtain and
`have to be produced under pres sure at high temperatures and
`involving hydro genating steps. Other iron carbohydrate com
`plexes are also knoWn for oral application.
`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 1000 C.,
`Which made sterilisation di?icult. 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.
`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. There
`fore, an object of the present invention are Water soluble iron
`carbohydrate complexes Which are obtainable from an aque
`ous 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 eg
`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.
`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 eg 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 equiva
`lent lies betWeen 5 and 20, and When a mixture of several
`maltodextrins is applied, the dextrose equivalent of the mix
`
`20
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`ture lies betWeen 5 and 20 and the dextrose equivalent of each
`individual maltodextrin contained in the mixture lies betWeen
`2 and 40.
`The usable maltodextrins are easily obtainable starting
`products, and they are commercially available.
`In order to prepare the ligands of the complexes of the
`invention, the maltodextrins are oxidiZed in an aqueous solu
`tion With a hypochlorite solution. Suitable examples are solu
`tions of alkali hypochlorites such as a solution of sodium
`hypochlorite. Commercially available solutions can be used.
`The concentration of the hypochlorite solution is, eg 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 maltodex
`trin 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.
`The oxidation is carried out in an alkaline solution, eg 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 400 C.,
`preferably of 25 to 350 C. The reaction times are, eg in the
`order of 10 minutes to 4 hours, eg 1 to 1.5 hours.
`By this procedure the degree of depolymerisation of the
`starting maltodextrins is kept at a minimum. Only theoreti
`cally it is assumed that the oxidation occurs mainly at the
`terminal aldehyde group (acetal or semiacetal group respec
`tively) of the maltodextrin molecules.
`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 puri?ed. Catalytic amounts
`are suf?cient. As stated above, the addition of bromide is
`possible, hoWever, not necessary.
`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.
`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.
`Water soluble salts of inorganic or organic acids, or mix
`tures 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.
`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 ammo
`nium chloride. As stated, the iron (III) is preferably used in the
`form of the chloride.
`For instance, the aqueous solution of the oxidiZed malto
`dextrin 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
`
`Pharmacosmos, Exh. 1021, p. 2
`
`

`

`US 7,612,109 B2
`
`3
`pH is strongly acid or so loW that no hydrolysis of the iron (III)
`salt occurs, eg 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 suf?ciently acid. Only
`after mixing, the pH is raised to values of eg 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 ?rst 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 car
`bonate or bicarbonate, or ammonia. Examples of strong bases
`are alkali- or alkaline earth-hydroxides such as sodium,
`potassium, calcium or magnesium hydroxide.
`The reaction can be improved by heating. For example,
`temperatures in the order of 15° 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° C. and
`then raise the temperature gradually up to boiling point.
`The reaction times are, for example, in the order of 15
`minutes up to several hours, eg 20 minutes to 4 hours, such
`as 25 to 70 minutes, eg 30 to 60 minutes.
`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.
`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 1 1 or 14, it is, for instance,
`possible to Work at ?rst at loWer temperatures in the order of
`15 to 70° C., such as 40 to 60° C., eg about 50° C., Whereafter
`the pH is reduced to values in the order of at least 5 and the
`temperature is gradually raised over 50° C. up to boiling
`point.
`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 ofmore than 5, it is, for example, possible to Work 15 to 70
`minutes, eg 30 to 60 minutes, at the enhanced pH, for
`example at temperatures of up to 70° 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, eg 30 to 60
`minutes, at temperatures eg up to 70° C., and optionally a
`further 15 to 70 minutes, eg 30 to 60 minutes, at higher
`temperatures up to boiling point.
`After the reaction the obtained solution can be cooled to
`eg room temperature and can optionally be diluted and
`optionally be ?ltered. 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 ofan acid or base. It is possible to use eg
`the acids and bases Which have been mentioned for carrying
`out the reaction. The solutions obtained are puri?ed and can
`directly be used for the production of medicaments. HoWever,
`it is also possible to isolate the iron (III) complexes from the
`solution eg by precipitation With an alcohol such as an
`alkanol, for example, ethanol. Isolation can also be effected
`by spray-drying. Puri?cation 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
`
`40
`
`45
`
`20
`
`35
`
`50
`
`55
`
`60
`
`65
`
`4
`carry out the reverse osmosis before spray-drying or before a
`direct application in medicaments.
`The iron content of the obtained iron (III) carbohydrate
`complexes is, for example, 10 to 40% Weight/Weight, espe
`cially, 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 com
`plexes, 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, eg as described by Geisser
`et al, in ArZneim. Forsch/Drug Res. 42(II), 12, 1439-1452
`(1992), paragraph 2.2.5).
`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, eg at 121° C. and above, at
`short contact times of, eg 15 minutes, by acquiring F0215.
`The contact times are correspondingly shorter at higher tem
`peratures. Preparations hitherto knoWn had to be sterilely
`?ltrated and mixed With preservatives, such as benZyl alcohol
`or phenol. Such additives are not necessary in the invention.
`Hence, it is possible to ?ll the solutions of the complexes, for
`example, into ampoules. It is, for example, possible, to ?ll
`solutions having a content of 1 to 20% by Weight, eg 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.
`Thus, a further object of the invention are aqueous medi
`caments Which are especially useful for the parenteral, intra
`venous but also intramuscular application as Well as for the
`oral or topical application; they are especially useful for the
`treatment of iron de?ciency anaemia. A further object of the
`invention is also the use of the iron (III) carbohydrate com
`plexes according to the invention for the treatment and pro
`phylaxis of iron de?ciency anaemia or the production of
`medicaments especially for the parenteral treatment iron de?
`ciency anaemia. The medicaments can be used in human and
`veterinary medicine.
`The advantages Which are achieved With the iron (III)
`carbohydrate complexes of the invention are the above-men
`tioned high sterilisation temperatures as Well as the loW tox
`icity and the reduced danger of anaphylactic shock. The tox
`icity of the complexes according to the invention is very loW.
`The LD5O lies at over 2000 mg Fe/kg, compared to the LD5O
`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 medica
`ments 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.
`In the present description, as Well as in the folloWing
`examples, the dextrose equivalents are measured gravimetri
`
`Pharmacosmos, Exh. 1021, p. 3
`
`

`

`US 7,612,109 B2
`
`5
`cally. In order to do so, the maltodextrins are reacted in a
`boiling aqueous solution With Fehling’s solution. The reac
`tion is carried out quantitatively, i.e. until the Fehling’s solu
`tion is no longer discoloured. The precipitated copper (l)
`oxide is dried at 105° 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 11;
`10 ml aqueous maltodextrin solution (10% mol/vol) (Fe
`hling’s solution I: 34.6 g copper (ll) sulfate dissolved in 500
`ml Water; Fehling’s solution 11: 173 g potassium sodium
`tartrate and 50 g sodium hydroxide dissolved in 400 ml
`Water).
`
`EXAMPLE 1
`
`100 g maltodextrin (9.6 dextrose equivalent measured
`gravimetrically) are dissolved by stirring in 300 ml Water at
`25° C. and oxidiZed by addition of 30 g sodium hypochlorite
`solution (13 to 16 Weight percent active chlorine) at pH 10.
`At ?rst, the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then, the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept at 50°
`C. for 30 minutes. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 30 minutes and then heated to 97-98° C.
`and the temperature is kept for 30 minutes at this range. After
`cooling the solution to room temperature, the pH is adjusted
`to 6-7 by the addition of sodium hydroxide.
`The solution is then-?ltered through a sterilisation ?lter
`and then examined for sediments. Thereafter, the complex is
`isolated by precipitation With ethanol in a range of 1 :0.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 271 kDa.
`
`EXAMPLE 2
`
`200 g maltodextrin (9.6 dextrose equivalent measured
`gravimetrically) are dissolved by stirring in 300 ml Water at
`25° C. and oxidiZed by addition of 30 g sodium hypochlorite
`solution (13 to 16 Weight percent active chlorine) at pH 10.
`At ?rst the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 30
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 30 minutes and then heated to 97-98° C.
`and the temperature is kept for 30 minutes at this range. After
`cooling the solution to room temperature the pH is adjusted to
`6-7 by the addition of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`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).
`Molecular Weight mW 141 kDa.
`
`EXAMPLE 3
`
`100 g maltodextrin (9.6 dextrose equivalent measured
`gravimetrically) are dissolved by stirring in 300 ml Water at
`25° C. and oxidiZed by addition of 30 g sodium hypochlorite
`solution (13 to 16 Weight percent active chlorine) and 0.7 g
`sodium bromide at pH 10.
`At ?rst the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 6.5 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 60
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 30 minutes and then heated to 97-98° C.
`and the temperature is kept for 30 minutes at this range. After
`cooling the solution to room temperature the pH is adjusted to
`6-7 by the addition of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 140 kDa.
`
`EXAMPLE 4
`
`A mixture of 45 g maltodextrin (6.6 dextrose equivalent
`measured gravimetrically) and 45 g maltodextrin (14.0 dex
`trose equivalent measured gravimetrically) is dissolved by
`stirring in 300 ml Water at 25° C. and oxidiZed by addition of
`25 g sodium hypochlorite solution (13 to 16 Weight percent
`active chlorine) and 0.6 g sodium bromide at pH 10.
`At ?rst the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 30
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 30 minutes and then heated to 97-98° C.
`and the temperature is kept for 30 minutes at this range. After
`cooling the solution to room temperature the pH is adjusted to
`6-7 by the addition of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 189 kDa.
`
`EXAMPLE 5
`
`90 g maltodextrin (14.0 dextrose equivalent measured
`gravimetrically) are dissolved by stirring in 300 ml Water at
`
`Pharmacosmos, Exh. 1021, p. 4
`
`

`

`US 7,612,109 B2
`
`7
`25° C. and oxidized by addition of 35 g sodium hypochlorite
`solution (13 to 16 Weight percent active chlorine) and 0.6 g
`sodium bromide at pH 10.
`At ?rst, the oxidized maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 30
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 30 minutes and then heated to 97-98° C.
`and the temperature is kept for 30 minutes at this range. After
`cooling the solution to room temperature the pH is adjusted to
`6-7 by the addition of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 118 kDa.
`
`EXAMPLE 6
`
`A mixture of 45 g maltodextrin (5.4 dextrose equivalent
`measured gravimetrically) and 45 g maltodextrin (18.1 dex
`trose equivalent measured gravimetrically) is dissolved by
`stirring in 300 ml Water at 25° C. and oxidiZed by addition of
`31 g sodium hypochlorite solution (13 to 16 Weight percent
`active chlorine) and 0.7 g sodium bromide at pH 10.
`At ?rst the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 30
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 30 minutes and then heated to 97-98° C.
`and the temperature is kept for 30 minutes at this range. After
`cooling the solution to room temperature the pH is adjusted to
`6-7 by the addition of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 178 kDa.
`
`EXAMPLE 7
`
`100 g maltodextrin (9.6 dextrose equivalent measured
`gravimetrically) are dissolved by stirring in 300 ml Water at
`25° C. and oxidiZed by addition of 29 g sodium hypochlorite
`solution (13 to 16 Weight percent active chlorine) and 0.7 g
`sodium bromide at pH 10.
`At ?rst the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 30
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 70 minutes. After cooling the solution
`to room temperature the pH is adjusted to 6-7 by the addition
`of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 137 kDa.
`
`EXAMPLE 8
`
`126 g maltodextrin (6.6 dextrose equivalent measured
`gravimetrically) are dissolved by stirring in 300 ml Water at
`25° C. and oxidiZed by addition of 24 g sodium hypochlorite
`solution (13 to 16 Weight percent active chlorine) and 0.7 g
`sodium bromide at pH 10.
`At ?rst the oxidiZed maltodextrin solution and then 554 g
`sodium carbonate solution (17.3% Weight/Weight) are added
`at room temperature to 352 g of a stirred iron (Ill) chloride
`solution (12% Weight by Weight Fe).
`Then the pH is adjusted to 11 by addition of sodium
`hydroxide and the solution is heated to 50° C. and kept for 30
`minutes at 50° C. Then, acidi?cation to a pH of 5 to 6 is
`effected by addition of hydrochloric acid, the solution is kept
`at 50° C. for a further 70 minutes. After cooling the solution
`to room temperature the pH is adjusted to 6-7 by the addition
`of sodium hydroxide.
`The solution is then ?ltered through a sterilisation ?lter and
`then examined for sediments. Thereafter, the complex is iso
`lated by precipitation With ethanol in a range of 110.85 and
`then dried in vacuum at 50° C.
`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).
`Molecular Weight mW 170 kDa.
`
`Comparative Test
`
`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 (LDSO) can be loWered in accor
`dance With the invention.
`
`According to the
`invention
`
`Iron hydroxide/sucrose
`complex
`
`5.0
`5-7
`80-350
`121° C./l5'
`>2000
`
`2.0
`10.5-11.0
`34-54
`100° C./35'
`>200
`
`Fe content [%]
`pH
`mW [M3519
`Thermal treatment
`LD5O i.v., W.m. [mg
`Fe/kg body Weight]
`
`The invention claimed is:
`1. A Water soluble iron carbohydrate complex having a
`Weight average molecular Weight (MW) of 80,000 to 400,000,
`comprising the reaction product of:
`(a) an aqueous solution of an iron (Ill) salt and
`(b) an aqueous solution of the oxidation product of
`(i) at least one maltodextrin and
`(ii) an aqueous hypochlorite solution at an alkaline pH,
`Wherein,
`
`Pharmacosmos, Exh. 1021, p. 5
`
`

`

`US 7,612,109 B2
`
`When one maltodextrin is present, the maltodextrin has a
`dextrose equivalent of betWeen 5 and 20, and wherein,
`When a mixture of more than one maltodextrin is present,
`the dextrose equivalent of each individual maltodextrin
`is betWeen 2 and 40, and the dextrose equivalent of the
`mixture is betWeen 5 and 20.
`2. A medicament comprising an aqueous solution of the
`iron carbohydrate complex of claim 1.
`3. The medicament of claim 2, Wherein the medicament is
`formulated for parenteral or oral application.
`4. The Water soluble iron carbohydrate complex of claim 1,
`Wherein the iron carbohydrate complex has a Weight average
`molecular Weight (MW) of 80,000 to 350,000.
`5. The Water soluble iron carbohydrate complex of claim 1,
`Wherein the iron carbohydrate complex has a Weight average
`molecular Weight (MW) of 80,000 to 300,000.
`6. A process for producing a Water soluble iron carbohy
`dr