United States Patent [191
`Miiller et a1.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,599,405
`Jul. 8, 1986
`
`[54] PROCESS FOR THE PRODUCTION OF
`IRON(III)HYDROXIDE/DEXTRAN
`COMPLEXES AND A STERILE
`PHARMACEUTICAL SOLUTION
`CONTAINING THEM
`[75] Inventors:
`Arthur Miiller, St. Gall; Walter
`Richie, Lustmiihle, both of
`Switzerland
`Laboratorien Hausmann AG, St.
`Gall, Switzerland
`[21] Appl. No.: 687,152
`[22] Filed:
`Dec. 28, 1984
`
`[73] Assignee:
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 283,146, Jul. 14, 1981, aban
`doned.
`Foreign Application Priority Data
`[30]
`Jul. 16, 1980 [DE] Fed. Rep. of Germany ..... .. 3026868
`
`[51] Int. Cl.‘ ............................................ .. C08B 37/02
`
`[52] US. Cl. . . . . . . . . . . . . . . . . .
`
`. . . . . . . . . .. 536/113
`
`[58] Field of Search ....................................... .. 536/113
`[56]
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,666,749 5/1972 Reumert et a1. .................. .. 536/113
`
`FOREIGN PATENT DOCUMENTS
`1196629 3/1966 Fed. Rep. of Germany .
`1954960 5/1970 Fed. Rep. of Germany .... .. 536/113
`1768361 9/1971 Fed. Rep. of Germany .
`2659799 7/1977 Fed. Rep. of Germany .
`370194 6/1963 Switzerland .
`Primary Examiner-Nicky Chan
`Attorney, Agent, or Firm-Schwartz, Jeffery, Schwaab,
`Mack, Blumenthal & Evans
`[57]
`ABSTRACT
`A process for the production of iron(III)hydroxide/
`dextran complexes in which from 2.0 to 2.6 vals of
`carbonate are slowly added to an acid solution contain
`ing a partially depolymerized dextran having an aver
`age molecular weight of from 1000 to 10,000 and an
`iron(III)salt, from 50 to 100 kg of iron ions being used
`per 100 kg of dextran, after which an alkali metal hy
`droxide or ammonium hydroxide is added to the solu
`tion in such a quantity that, including the carbonate
`added, approximately 3 vals of anions are added until a
`pH value of no less about 10.5 is reached, the suspension
`formed is converted into a solution by heating and the
`solution is worked up in known manner.
`The invention also‘relates to sterile pharmaceutical
`solutions containing these complexes.
`
`11 Claims, No Drawings
`
`Pharmacosmos, Exh. 1038, p. 1
`
`

`
`1
`
`4,599,405
`
`PROCESS FOR THE PRODUCTION OF
`IRON(III)HYDROXIDE/DEXTRAN COMPLEXES
`AND A STERILE PHARMACEUTICAL SOLUTION
`CONTAINING THEM
`
`2
`iron/dextran complexes containing from 50 to 150 mg
`of Fe/ml, i.e. having an iron content of from 5 to 15
`percent W/V.
`The object of the present invention is to provide a
`simple and safe process for producing iron(III)hydrox
`ide/dextran complexes which give stable sterile solu
`tions for injection purposes having a high iron content
`of more than 20% W/V.
`Accordingly, the present invention relates to a pro
`cess for the production of iron(III)hydroxide/dextran
`complexes, in which an alkali carbonate, ammonium
`carbonate or a carbonate of an organic base that is inert
`to the reaction components and then an alkali metal
`hydroxide or ammonium hydroxide are added to an
`acid solution containing a partially depolymerised dex
`tran and an iron(III)salt, the suspension formed is con
`verted into solution by heating and the solution is
`worked up in known manner, characterised in that
`(a) the dextran used is a dextran having an average
`molecular weight of from 1000 to 10,000,
`(b) from 50 to 100 kg of iron ions are used for 100 kg
`of dextran,
`(c) from 2.0 to 2.6 vals of carbonate are slowly added
`to the solution of dextran and iron(III)salt,
`(d) an alkali metal hydroxide or ammonium hydrox
`ide is then added to the solution in such a quantity
`that, including the carbonate added, approximately
`3 vals of anions are added until a pH-value of no
`less than about 10.5 is reached.
`The process according to the invention may be car
`ried out surprisingly easily in one apparatus, i.e. in the
`form'of a so-called one-pot process, the solutions of the
`reaction components merely having to be prepared in a
`separate vessel.
`According to the invention, preferred dextrans are
`dextrans having an average molecular weight of at least
`about 3000 and preferably of at least about 4000. The
`upper limit to the molecular weight is best at about 7000
`and preferably at about 6000. Particularly good results
`have been obtained with dextrans having an average
`molecular weight of from about 4000 to 6000. In the
`context of the invention, the average molecular weight
`‘of the dextran fraction used is understood to be the
`weight average.
`It is preferred to use a dextran solution containing at
`least 20 kg and preferably at least 30 kg of dextran in
`solution in 1001 of water. The upper limit to the concen
`tration is best at 80 kg and preferably at 60 kg of dextran
`dissolved in 100 l of water.
`The iron solutions used are best iron solutions con
`taining at least about 3% and preferably at least 5% of
`iron(III)ions (W/W). The upper limit to the concentra
`tion of iron(III)ions is best at about 10% and preferably
`at about 8% (W/W)
`It is best to use about 50 to 100 kg of iron(III)ions per
`100 kg of dextran.
`The iron(III)salts used are the salts normally used in
`the prior art, such as iron(III)chloride, nitrate, acetate,
`sulfate and other chemical equivalents. Iron(III)chlo
`ride is particularly preferred.
`The solution of the dextran in water is best produced
`by heating, for example to between 60° and 80° C. In
`
`20
`
`This is a continuation of application Ser. No. 283,146,
`?led July 14, 1981, now abandoned.
`This invention relates to a process for the production
`of iron(III)hydroxide/dextran complexes in which an
`alkali carbonate, ammonium carbonate or a carbonate
`of an organic base that is inert to the reaction compo
`nents is added to an acid solution containing a partially
`depolymerised dextran and an iron(IIDsalt, after which
`an alkali metal hydroxide or ammonium hydroxide is
`added, the suspension formed is converted into a solu
`tion by heating and the solution is worked up in known
`manner.
`There are several known processes for the produc
`tion of non-ionic, therapeutically useable iron(III)hy
`droxide/dextran complexes. The process outlined at the
`beginning is described for example in German Pat. No.
`1,196,629 and gives excellent preparations which have
`been very successfully used for controlling iron de?
`ciences in humans and animals. However, the solutions
`of these complexes as used for injection purposes only
`contain up to about 10% by weight of iron (W/V).
`(“W” stands for “weight” whilst “V” stands for “vol
`ume”). There is a considerable need to provide iron/
`dextran complexes from which it is possible to obtain
`injectable solutions having a higher iron content.
`U.S. Pat. Nos. 3,536,696 and 3,639,588 describe iron
`(III)hydroxide complexes containing dextran heptonic
`acid as complexing agent. Dextran heptonic acid is
`dif?cult to produce with the result that the process as a
`whole is not very satisfactory.
`German Offenlegungsschrift No. 17 68 361 describes
`a process for the production of iron(III)hydroxide com
`plexes in which an aqueous solution of an iron(III)salt is
`slowly neutralised with alkali, an aqueous solution of a
`dextran is then added, the pH-value of the solution is
`adjusted to between 4 and 7 and the solution is subse
`quently heated to form the complex. Injectable solu
`tions containing up to 25% by weight of iron, based on
`the volume of the solution, are said to be able to be
`produced from complexes of this type. The disadvan
`tage of this known process lies in the fact that only
`certain (oxidised) dextrans can be dissolved at pH 4 to 7,
`whereas pH-values higher than 7 are required for other
`dextrans (non-oxidised) to obtain the described iron/
`dextran complexes.
`U.S. Pat. No. 4,180,567 describes a process for the
`production of dextran/iron complexes in which the
`dextran or another polyhydroxy compound is pre
`treated with a base at a temperature of from 85° to 100°
`60
`C. The polyhydroxy compound “activated” in this way
`is then mixed with an aqueous solution of an iron com
`pound which essentially contains dialysed iron(III)hy
`droxide. The disadvantage of this process is that ?rst the
`activated dextran solution and at the same time the
`solution containing the dialysed iron(III)hydroxide
`have to be produced in two separate operations carried
`out in two separate apparatus. This process only gives
`
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`55
`
`65
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`Pharmacosmos, Exh. 1038, p. 2
`
`

`
`4,599,405
`
`5
`
`4
`kept at that temperature for about 40 minutes to 2 hours
`and preferably for about 50 to 80 minutes.
`Working up of the resulting solution of the iron(III)
`hydroxide/dextran complex may be carried out in
`known manner. Before puri?cation and isolation, the
`solution may be neutralised by the addition of a solid,
`liquid or gaseous acid, such as a cation exchanger in the
`H-form, sulfuric acid or hydrochloric acid. In order to
`eliminate undesirably high concentrations of electrolyte
`in the solution, an anion exchanger in the HO'form may
`be additionally added to the cation or alternatively the
`solution may be dialysed against water. Solid prepara
`tions readily soluble in water may be obtained from the
`solution of the new iron complexes by known methods
`such as, for example, concentrating the neutral solutions
`by evaporation under reduced pressure or by fractional
`precipitation with a water-miscible organic solvent,
`such as for example methanol, ethanol or acetone.
`In one preferred embodiment, the solution, having
`been cooled to a temperature below about 30° C. to
`room temperature, is adjusted with dilute hydrochloric
`acid to a slightly acid pH value, for example to a pH of
`from about 5 to 6 and best to a pH of the order of 5.5.
`After passing through a clarifying separator (for exam
`ple a plate centrifuge) for the purpose of separating off
`relatively coarse impurities and ?ltration of the solu
`tion, the complex may be precipitated by the addition of
`a suitable water-miscible solvent. As in the prior art,
`ethanol is preferably used for this purpose. The deposit
`is separated off, dried and contains about 28 to 35% by
`weight of Fe.
`It is surprisingly possible to be able to dissolve the
`complex obtained by the process according to the in
`vention in a high concentration in water, for example in
`a concentration of from 15 to 25% of Fe and preferably
`in a concetration of the order of 20% of Fe or higher
`(W /V)
`The present invention also relates to sterile aqueous
`pharmaceutical solutions for the treatment of iron de?
`ciences containing the iron(III)hydroxide/dextran com
`plex obtainable by the process described in the forego
`ing and the usual additives. To produce a solution such
`as this, the complex is dissolved in water by heating, for
`example to temperatures of from about 60° to 80° C.
`The solution is then sterilised. Standard additives for
`the sterilised aqueous solution include for example phe
`nol in a quantity of 0.5%.
`
`3
`one preferred embodiment of the invention, the cooled
`solution of the dextran is allowed to run into the solu
`tion of the iron(III)salt. Accordingly, there is no need
`for heating and both solutions have a temperature of
`best less than 40° C. and preferably of the order of room
`temperature.
`An alkali carbonate, ammonium carbonate or a car
`bonate of an organic base that is inert to the reaction
`components is then slowly added to the solution of
`dextran and iron(III)salt in a quantity of from 2.0 to 2.6
`vals, based on the iron(III)ions. Accordingly, where
`iron(IIDchloride is used as the iron(III)salt, from about
`2.0 to 2.6 chlorine ions are replaced by hydroxyl ions
`after the addition. The addition of the carbonate, best in
`the form of an aqueous solution, is again best made at a
`temperature below 40° C., preferably in the absence of
`heating, i.e. at room temperature. The solution is prefer
`ably added very slowly over a period of more than 2
`hours and, with particular preference, over a period of
`more than 3 hours. The carbonate solution should not
`be too dilute in order to avoid large quantities of liquid.
`Where sodium carbonate is used, which is preferred
`inter alia for reasons of cost, solutions having a concen
`tration of from about 15 to 20% (W /W ) and, more
`particularly, of from about 17 to 18%, have proved to
`_ 'be suitable. After the addition, the solution has a pH
`value of the order of 1.5 to 2.0 and preferably of the
`order of 1.7 to 1.8.
`An alkali metal hydroxide or ammonium hydroxide is
`then added. This addition is again best made in the
`absence of heating, i.e. under the same conditions under
`. which the carbonate is added. It is preferred to use
`sodium hydroxide, again inter alia for reasons of cost,
`concentrations of from about 20 to 40% and preferably
`from about 25 to 35% (W/W) being suitable. The quan
`tity in which the base is used is so large that substan
`tially all the anions of the iron(III)salt are replaced by
`hydroxyl ions. To achieve this, it is best to use a slight
`excess of base which whould amount to no more than
`5% and preferably to no more than 2%, based on the
`number of positive charges of the iron(III)ions present.
`The base is best added over a relatively short period,
`preferably over a period of from 15 to 45 m'mutes and
`more preferably over a period of from about 25 to 35
`minutes.
`After the base has been added, the solution has a pH
`value of at least about 10.5, but best of no more than 12.
`The pH value of the solution is preferably of the order
`of 11.0 to 11.5 or better still of the order of 11.2 to 11.4.
`Completion of formation of the suspension may be
`veri?ed by centrifuging a sample of the reaction solu
`tion. If there is no further precipitation after the addi
`tion of more alkali metal hydroxide to the clear superna
`tant solution, formation of the suspension may be re
`garded as complete.
`The reaction mixture is then heated until the sus
`pended fractions are dissolved. To this end, the reaction
`mixture is best heated as quickly as possible to high
`temperatures of at least about 80° C. to boiling point
`and, better still, directly to boiling point. The solution is
`
`25
`
`40
`
`50
`
`EXAMPLE
`80 kg of dextran (molecular weight 5000) are dis
`solved in 180 liters of water at 70° C. The solution
`cooled to room temperature is allowed to run into 877
`kg of an aqueous FeCl3 solution (6.4 W/W % of Fe,
`density at 20° C.=1.170). 751 kg of an aqueous soda
`solution (17.2% W/W of Na2CO3, density at 20°
`C: 1.185) are added to this mixed solution over a per
`iod of 3.5 hours with stirring (mechanical stirrer) at 25°
`C. In this way, approximately 2.3 Cl- are replaced by
`OH- in the FeClg, (corresponding to Fe(OH)2.3C10.7).
`At the same time, the pH of the reaction solution
`reaches a value of approximately 1.7. A pH-value of
`approximately 11 is obtained after the addition of 93 kg
`
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`Pharmacosmos, Exh. 1038, p. 3
`
`

`
`4,599,405
`5
`of sodium hydroxide (30 W/W % of NaOH, density at
`20° C: 1330) over a period of about 30 minutes. The
`suspension thus formed is heated to boiling temperature
`and kept at that temperature for about 1 hour. The
`resulting iron(III)hydroxide/dextran complex solution
`is cooled to 25° C. and adjusted to pH 5.5 with 21 kg of
`dilute hydrochloric acid (20.4 W/W % of HCl, density
`at 20° C.=l.l00). After passing through a clarifying
`separator (plate centrifuge) for the purpose of separat
`ing off relatively coarse impurities and ?ltration of the
`solution through a multilayer ?lter, the product is pre
`cipitated with ethanol. The deposit is washed with etha
`nol in a mixer, separated off and dried in vacuo. The dry
`material has an iron content of from 28 to 35% W/W.
`The dry iron complex is processed in distilled, pyrogen
`free water at 70° C. to form a sterile injection solution
`containing 20 W/V % of iron and 0.5% W/W of phenol
`as preservative. The solution has a relative viscosity of 20
`less than 40, as measured at 25° C.
`We claim:
`1. A process for producing stable, sterile aqueous
`pharmaceutical solution for the treatment of iron de?
`ciencies containing the iron(III)hydroxide/dextran
`complex comprising:
`(a) dissolving dextran having an average molecular
`weight of from 3,000 to 6,000 in water;
`(b) cooling the dextran solution to a temperature of
`30
`less than 40° C.;
`(0) adding the cooled dextran solution to a solution of
`FeCl; at a temperature of less than 40° C. to form a
`mixed solution having a weight ratio of from 50 to
`100 kg of iron ions per 100 kg of dextran;
`(d) adding from 2.0 to 2.6 vals of carbonate selected
`from the group consisting of alkali metal carbon
`ates, ammonium carbonate and carbonates of or
`ganic bases inert to the reaction components to said
`
`6
`mixed solution over a period of more than two
`hours;
`(e) adding an alkali metal hydroxide or ammonium
`hydroxide to the solution of step (d) to yield a
`suspension having a pH of at least about 10.5;
`(f) recovering the iron(III)/dextran complex;
`(g) dissolving said iron(III)/dextran complex in water
`to yield a stable solution having an iron content of
`at least 15% W/V.
`2. The process of claim 1, wherein about 3 vals of
`anions, including the carbonate, are added to yield said
`pH in step (e).
`3. The process of claim 1, wherein said dextran has a
`molecular weight of from about 4000 to 6000.
`4. The process of claim 1, wherein said cooled dex
`tran solution is slowly run into said FeCl; solution.
`5. The process of claim 4, wherein said dextran is
`cooled to room temperature in step (b).
`6. The process of claim 1, wherein said carbonate is
`added to said mixed solution at a temperature of less
`than 40° C.
`7. The process of claim 6, wherein said carbonate is
`added to said mixed solution at room temperature.
`8. The process of claim 1, wherein said carbonate is
`added to said mixed solution slowly over a period of
`more than three hours.
`9. The process of claim 1, wherein said addition of
`alkali metal hydroxide or ammonium hydroxide is
`added over a period of from 15 to 45 minutes.
`10. The process of claim 1, wherein said stable, sterile
`aqueous pharmaceutical solutipn contains iron in a con
`centration of from 15% to 25% W/V.
`11. The process of claim 10, wherein said iron con
`centration is at least 20% W/V.
`# it
`it
`t t
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`35
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`Pharmacosmos, Exh. 1038, p. 4