United States Patent Office
`
`3,.d‘lb?b8
`Fatentesl Feb. 5, 1%63
`
`i=1
`
`1
`
`.
`
`3,076,798
`
`y
`
`l‘fl?CESS FGR PREPARKNG A unsure HBE PGLYMALTQSE CSMEPLEX
`
`Arthur Mueller, Heinrich fichwarz, and Theodore herein,
`Sanltt Gallon, bwitserinnd, assignors to Hausmann
`Laboratories Ltd, Gallon, Eiwitzerland, a company
`No Drawing. Filed Feb. 23, 196i, Ser. No. 90,952
`*9 Claims. (6i. zen-uses)
`
`10
`
`15
`
`20
`
`25
`
`ligand. On the other hand, the complex stability of ferric
`hydroxide-carbohydrate complexes decreases with a low
`molecular ligand component whereby the thermal stability
`and shelf life of the preparations are affected adversely.
`According to this invention these disadvantages are
`eliminated by depolymerizing dextrin by means of meth
`ods known in the present state of the art, for example, by
`means of acid hydrolysis and fractionating by precipitation
`with solvents soluble in water, like alcohols and acetone,
`and from the resulting polymaltose fractions forming ferric
`hydroxide complexes having high iron content and good
`thermal stability. These complexes are formed by con
`tacting a Water-soluble, non-retrograding dextrin with an
`aqueous solution containing ferric ions and an excess of
`an alkali-hydroxide or an alkali carbonate and heating the
`reaction mixture.
`Polymaltose fractions obtained by depolymerizing dex
`trins having an intrinsic viscosity [1;] of 0.025 to 0.075 at
`25 °_ C. are suitable for the process according to this inven
`tion. Polyrnaltose fractions with lower intrinsic viscosity
`result in ferric hydroxide complexes of higher iron con
`tent. They are, however, useless for therapeutical applica
`tion due to the lower complex stability resulting in bad
`tolerancy, thermal stability and unfavorable shelf-like
`properties. 011 the other hand, polymaltose fractions hav
`ing an intrinsic viscosity [1;] of more than 0.75 at 25° C.
`result in stable complexes of good stability on storage.
`However, the iron content of these solutions is too low to
`obtain the high iron concentration necessary in a volume
`small enough to be applicable for intramuscular medica
`tion.
`For the production of ferric hydroxide-polymaltose
`complexes according'to this invention, bivalent as well as
`trivalent iron compounds can be brought to reaction with
`suitable polymaltose fractions and alkali hydroxide or
`alkali carbonate in excess. The ferrous hydroxide-poly
`maltose complex resulting from the reaction with bivalent
`iron compounds will be oxidized to the corresponding
`ferric complex. As an oxidizing agent, for example, pure
`oxygen or atmospheric oxygen can be used. Any ferric
`or ferrous compounds which will ionize in solution may be
`used in the practice of this invention. Examples of such
`compounds include ferric chloride, ferric hydroxide, ferric
`nitrate, ferric sulphate, ferric acetate, ferrous sulfate, etc.
`As examples of alkali hydroxides and alkali carbonates
`which may be used in the practice of this invention there
`may be mentioned sodium hydroxide, potassium hy
`droxide, lithium hydroxide, ammonium hydroxide, sodium
`carbonate, potassium carbonate, lithium carbonate and
`ammonium carbonate. Sodium hydroxide is the preferred
`material.
`,The ferric hydroxide-polyrnaltose complex is formed
`by heating the mixture of a water-soluble dextrin and an
`aqueous solution containing ferric ions and an excess of
`an alkali hydroxide or an alkali carbonate to a tempera
`ture of from 60 to‘ 100° C. and preferably 70 to 75° C.
`It is preferred to use from about 5 to 9 grams, and pref
`erably 7 grams, of the dextrin fraction, with an amount
`of ferric compound corresponding to 1 gram of elemental
`iron or an amount of ferrous compound corresponding to
`2 grams of elemental iron. A molar excess of alkali
`hydroxide oralkali carbonate is used over the amount
`‘theoretically required to accomplish the reaction. For
`example, from 65 to 120 ml. and preferably 70 to 80
`ml. of 10 N sodium hydroxide or of a 25 percent by
`weight aqueous solution of sodium carbonate may be
`used with an amount of ferric compound corresponding
`to 10 grams of elemental iron or an amount of ferrous
`compound corresponding to 20 grams of elemental iron.
`The alkaline ferric hydroxide-polymaltose solution, be
`u
`fore being isolated and purified, can be neutralized with
`addition of a solid, liquid, or gaseous acid, as for example
`
`This invention relates to a process of producing a new
`iron injection preparation which is suitable for parenteral
`medication for the treatment of iron de?ciency anemia in
`humans and animals.
`It is known that ferric hydroxide-carbohydrate com
`plexes can be produced by reacting suitable carbohydrates
`in a solution or suspension with ferric hydroxide or ferric
`salts and excess alkali. (United States Patent No. 2,820,
`740; Austrian Patent No. 199,794; Austrian Patent No.
`204,180.) Likewise, dextrans (polyisomaltoses) and fer
`rous salts and alkali can be converted into ferrous hy
`droxide-polyisomaltose complexes, these can be converted
`by oxidation into the corresponding ferric hydroxide com
`plex. (See Austrian Patent No. 208,003.) Furthermore,
`it is known that by heating of an aqueous solution of
`dextran together with a water soluble ferric salt and alkali
`at a pH of about 2.3 a precipitable iron complex results
`which can be depolymerized by hydrolysis to the molecular
`size desired, and, following this, can be converted by treat
`ment with excess alkali into an iron dextran complex, or, if
`necessary, can be subjected without depolymerization to
`the treatment with alkali directly. (See United States
`Patent No. 2,885,393.)
`Solutions of such ferric hy
`droxide-carbohydrate complexes should conform to the
`following standards: Ability of rapid resorption, low tox-_
`icity, high tolerancy, high iron content, preferably solu
`tions with 5 to 10% elementary iron, high thermal sta
`bility, good stability on storage and easy utilization for
`hemoglobin synthesis.
`As the known solutions of so-called “saccharated oxide
`of iron” are stable exclusively under alkaline conditions
`they can beused for intravenous injections only, but not
`for intramuscular ones. On the other hand the ferric hy
`droxide-inulin complexes, as well as the ferric hydroxide
`polyisomaltose complexes (iron-dextran complexes) can
`be used for intramuscular application in the form of neu
`tral, isotonic solutions. Solutions of the ferric hydroxide
`inulin complexes are not satisfactory in regard to thermal
`and storage stability, and some of the expensive ferric
`hydroxide-polyisomaltose complexes are not fully satis
`50
`factory in regard to good tolerancy. (See G. Hemmeler,
`Med. Hyg, 15 (1957), 359:183, Haddow A. and Homing
`E. S., J. Nat. Cancer lust, 24, 106, 1960.) After injection
`of these preparations the carbohydrate part leaves the body
`almost unchanged as the enzyme necessary for the degra
`dation of inulin or polyisomaltose is practically missing.
`Whereas, the ferric dextran preparations are well tolerated
`only in intramuscular application, the ferric hydroxide
`polymaltose complex produced according to this invention
`is suitable for intramuscular as well as intravenous
`medication.
`Of the ferric hydroxide-polymaltose preparations (fer
`ric hydroxide-dextrin complexes) known up to date, none
`conform with the above-mentioned standards required for
`' a good intramuscular applicable iron injection preparation.
`These solutions contain only about 2% iron and are there
`' fore unsuitable for the intramuscular application owing‘
`to the large volume of the solution necessary for medica
`tion. (See Lucas et al., “Blood,” vol. 7, pages 358-367,
`1952.) The ef?ciency for the complexing of iron hy
`droxide of the dextrins increases as we established, with
`the decrease of the molecular weight of the carbohydrate
`
`30
`
`35
`
`60
`
`Pharmacosmos, Exh. 1050, p. 1
`
`

`
`3,076,798
`
`10
`
`15
`
`20
`
`25
`
`30
`
`4
`alkaline anion exchanger. The ?ltrate separated from the
`exchangers is mixed in the ratio of 1 part by volume of
`solution to 2.5 parts by volume of 96 percent ethyl
`alcohol and the resulting supernatant solution is separated
`from the precipitated ferric hydroxide-carbohydrate com
`plex. The precipitate is dissoved in 100 ml. distilled
`water free of pyrogens. The alcohol remaining is re
`moved by evaporation in vacuum and the solution is
`readjusted to have an iron content of up to 10 percent.
`By addition of NaCl the solution is made isotonic and the
`solution then being practically neutral is ?lled into am
`poules and is sterilized for 30 minutes in ?owing steam.
`If the solution is ?lled into multiple dose containers, 0.5%
`phenol as a preservative can be added without adverse
`elfect.
`
`Example '3
`Thirty-?ve grams of a dextrin fraction having an in
`trinsic viscosity at 25 ° C. of [all-0.045 are dissolved in
`75 ml. distilled water while being heated. Into this solu
`tion heated at 65° C., 50 grams FeSO4.7H2O are dis
`solved; the solution is then poured into 75 ml. of warm
`water. Following this, 55 ml. 10 N sodium hydroxide
`solution is added slowly while stirring vigorously. After
`allowing the reaction to proceed for 30 minutes at a tem
`perature of 65° C., the solution is cooled and centrifuged
`to separate undissolved matter. Following this, the solu
`tion is dialyzed against well aired, ?owing and demin
`eralized water until there is a neutral reaction and no
`trace of sulfate ions. The solution which has been ob
`tained in this way is evaporated under lowered pressure
`at a temperature of 40° C. until the solution has an iron
`content of 5%. By addition of NaCl the solution is
`made isotonic; then, the solution is ?lled into ampoules
`and is sterilized for 30 minutes in ?owing steam.
`Example 4
`One hundred forty grams of a dextrin fraction having
`an intrinsic viscosity at 25° C. of [1;] =0.070 are dissolved
`with heat in 400 ml. demineralized water. The solution
`is mixed with 300 grams of a solution of ferric chloride
`(100 grams FeCl3.6HOI-I dissolved in 200 grams de
`mineralized water). The mixture is adjusted to a pH of
`about 2.4 by means of a solution of sodium carbonate and
`is heated to a temperature of about 70° C. Then, 45
`ml. 10 N NaOH are added. The mixture is left to react
`for 30 minutes at a temperature of 70° C. The cooled
`reaction product is processed to a solid preparation accord
`ing to Example 1.
`
`an acid cation exchanger, sulfuric acid, or hydrochloric
`acid. In order to get the solution free of electrolytes
`an alkaline anion exchanger can be added in addition
`besides the cation exchanger; or the solution can be
`dialysed against water. Good water soluble preparations
`in powder form are obtained according to the well known
`processes by evaporation under reduced pressure of the
`neutral solutions or by precipitation with an appropriate
`Water soluble solvent.
`The preparation produced according to this invention,
`is a water soluble, light brown, non-hygroscopic powder,
`containing about 15 to 25% iron and about 70 to 50%
`polymaltose. The highly puri?ed ferric hydroxide-poly
`maltose complex is characterized by the ratio between
`iron and the dextrin as anhydroglucose units (Cal-11005) =
`minimally 2 moles of Fe for each anhydroglucose unit.
`If HCl is added to the aqueous solution of a substance
`of this invention at room temperature, drop by drop,
`While stirring, no cloudiness occurs up to pH=1. In
`the electrophoresis the spherical colloid ferric hydroxide
`.polymaltose moves slightlycathodic in acetate buffer of
`pH 5.0.
`The ferric hydroxide-polymaltose complexes produced
`according to this invention are extremely valuable thera
`peutic agents for hemoglobin synthesis-i.e., in the treat
`.ment of iron de?ciency anemia in humans or in animals.
`Since the complex is soluble in water, an aqueous solu
`tion of it can be injected either intramuscularly or in
`travenously. Further, it may be administered by adding
`it to salt or sugar infusions. When the complex is ad
`ministered byany of the above described means, it is
`well-tolerated without the onset of undesirable local or
`general side effects. The dosage to be used will depend
`on the iron or hemoglobinde?ciency which is to be treat
`ed. Normally, a dosage corresponding to 100 mg. ele
`mental iron is administered every second day until the
`hemoglobin de?ciency is corrected. When the complex
`is administered as an additive to salt or sugar infusions,
`doses of up to 2000 mg. of iron can be tolerated although
`it is preferred to limit the aggregate dosage administered
`by this method to from 250 to 1000 mg. of iron. Aque
`ous solutions of the complex are very stable.
`Example 1
`Seventy grams of a dextrin fraction having an intrinsic
`viscosity at 25° C. of [1;]:0050 are dissolved in 300
`ml. of. distilled water while being heated. Into the solu
`tion, heated to 65° C., 180 grams of ferric hydroxide
`which has been precipitated freshly and washed free of
`electrolytes, corresponding to 10 grams elemental iron,
`Were added with vigorous stirring. Following this, 45
`ml. 10 N NaOH are given to the suspension. The reac
`tion temperature of the well stirred mixture is kept at 65 °
`to 70° C. for 30 minutes, whereas the ferric hydroxide
`is dissolving completely. The cooled reaction mixture
`is adjusted to a pH of 6.5 by means of 2 N hydrochloric
`acid; the ferric hydroxide-polymaltose complex is precip
`itated in the ratio of 1 part by volume of solution to 2
`parts by volume of 99 percent methyl alcohol; the precip
`itate is dried in the vacuum. The precipitate can be proc
`essed to an aqueous solution which is practically isotonic,
`neutral and sterile and which has an iron content of 5%.
`Example 2
`Thirty-?ve grams of a dextrin fraction having an in
`trinsic viscosity at 25° C. of [7;]:0055 are dissolved in
`100 ml. distilled water while being heated. Into the solu
`tion, heated to 75° C. 75 grams of a solution of ferric
`chloride (25 g. FeCl3.6H3O dissolved in 50 grams distilled
`Water) is added at the same temperature then while stir
`ring vigorously, 45 ml. 10 N sodium hydroxide solution
`is added slowly. After allowing the reaction to proceed
`for 15 minutes at a temperature of 75° C. the solution
`is cooled and centrifuged to separate undissolved matter.
`The solution is then adjusted to a pH of 6.2 with 90 ml.
`of a strongly acidic cation exchanger and 20 ml. strongly
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`75
`
`Example 5
`Seventy grams of a dextrin fraction having an intrinsic
`viscosity at 25 ° C. of [11]=0.055 are dissolved in 200 ml.
`distilled water while being heated. This solution is mixed
`with 150 grams of a solution of ferric chloride (50 grams
`FeCl3.6I-I2O). Into this mixture heated at 65° C. a solu
`tion of 50 grams of anhydrous sodium carbonate in 200
`ml. of water is slowly added While stirring vigorously.
`After allowing the reaction to proceed for 30 minutes at
`a temperature of 70° C., the solution is cooled and cen
`trifuged to separate undissolved matter and processed to a
`solid preparation according to Example 1.
`This application is a continuation-iu-part of our c0
`pending U.S. application‘ Serial No. 26,681, filed May 4,
`1960, now abandoned.
`We claim:
`1. A process of producing a therapeutically useful ferric
`hydroxide-polymaltose complex which comprises mixing
`an aqueous medium of a Water-soluble non-retrograding
`dextrin having an average intrinsic viscosity at 25° C.
`of from about 0.025 to 0.075 with an aqueous solution
`containing ferric ions and an excess of a member selected
`from the group consisting of alkali hydroxides and alkali
`carbonates and heating the reaction mixture to a tempera
`ture of from 60 to 100° C. to form a ferric hydroxide
`polymaltose complex and recovering said complex.
`
`Pharmacosmos, Exh. 1050, p. 2
`
`

`
`3,076,798
`6
`ferric hydroxide-polymaltose complex which comprises
`mixing an aqueous medium of a water-soluble, nonretro
`grading dextrin having an intrinsic viscosity of 0.025 to
`0.075 at ‘25° C. with a member selected from the group '
`consisting of ferric and ferrous compounds and a member
`selected from the group consisting of alkali hydroxides
`and alkali carbonates and heating the mixture to a tem
`perature of from 60 to 100° C. to form a member selected
`from the group consisting of ferric and ferrous hydroxide
`polymaltosecomplexes in said aqueous medium, adjusting
`the aqueous medium to pH 6~7, oxidizing said ferrous
`hydroxide-polymaltose complex to the ferric state and
`recovering ferric hydroxide-polymaltose complex.
`9. A therapeutically useful pure ferric hydroxide-poly
`maltose complex produced by the process of claim 1.
`
`10
`
`.
`5
`2. The process of claim 1 wherein said reaction mixture
`is heated to a temperature ‘of from 70 to 75° C.
`3.,The process of claim 1 wherein ferric hydroxide is
`formed in said aqueous medium of said water-soluble
`dextrin by adding a ferric compound and an alkali hy
`droxide to said aqueous medium.
`4. The process of claim 1 wherein a water-washed,
`freshly precipitated ferric hydroxide is added to said
`soluble dextrin.
`5. The process of claim 1 wherein ferrous hydroxide
`is formed in said aqueous medium of said water-soluble
`dextrin by adding a ferrous compound and an alkali
`hydroxide to said aqueous medium to form a ferrous hy
`droxide-polymaltose complex, oxidizing said complex to
`the ferric state and recovering the ferric hydroxide
`polymaltose complex thus formed.
`6. The process of claim 1 wherein said aqueous medium
`containing a ferric hydroxide-polymaltose complex is
`brought into contact with an ion exchange composition to
`render said complex isotonic before recovering said com
`plex.
`7. The process of claim 1 wherein said aqueous medium
`containing a ferric hydroxide-polymaltose complex is
`dialyzed to remove the alkali from said medium before
`recovering said complex.
`8. The process of producing a therapeutically useful
`
`15
`
`References Cited in the ?le of this patent
`UNITED STATES PATENTS
`
`20
`
`2,518,135
`2,820,740
`2,885,393
`
`Gaver _______________ __ Aug. 8, 1950
`London et a1. _________ __ Ian. 21, 1958
`Herb ________________ __ May 5, 1959
`
`25
`
`OTHER REFERENCES
`Bastisse: Chemical Abstracts, vol. 44, 1950, p. 5527g.
`
`Pharmacosmos, Exh. 1050, p. 3