CH397628A - Process for the preparation of therapeutically useful iron (III) hydroxide-polymaltose complexes - Google Patents
Process for the preparation of therapeutically useful iron (III) hydroxide-polymaltose complexesInfo
- Publication number
- CH397628A CH397628A CH7302359A CH7302359A CH397628A CH 397628 A CH397628 A CH 397628A CH 7302359 A CH7302359 A CH 7302359A CH 7302359 A CH7302359 A CH 7302359A CH 397628 A CH397628 A CH 397628A
- Authority
- CH
- Switzerland
- Prior art keywords
- iron
- hydroxide
- iii
- polymaltose
- solution
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 9
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 title claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 34
- 229910052742 iron Inorganic materials 0.000 claims description 17
- MSNWSDPPULHLDL-UHFFFAOYSA-K ferric hydroxide Chemical compound [OH-].[OH-].[OH-].[Fe+3] MSNWSDPPULHLDL-UHFFFAOYSA-K 0.000 claims description 13
- 229920001353 Dextrin Polymers 0.000 claims description 8
- 239000004375 Dextrin Substances 0.000 claims description 8
- 235000019425 dextrin Nutrition 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229920001202 Inulin Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229940029339 inulin Drugs 0.000 description 3
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RLSFDUAUKXKPCZ-UITAMQMPSA-N (z)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-2-en-1-one Chemical compound C1CN(C(=NN=2)C(F)(F)F)C=2CN1C(=O)\C=C(/N)CC1=CC(F)=C(F)C=C1F RLSFDUAUKXKPCZ-UITAMQMPSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000008133 Iron-Binding Proteins Human genes 0.000 description 1
- 108010035210 Iron-Binding Proteins Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- -1 iron (III) hydroxide carbohydrate Chemical class 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- MVZXTUSAYBWAAM-UHFFFAOYSA-N iron;sulfuric acid Chemical class [Fe].OS(O)(=O)=O MVZXTUSAYBWAAM-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000002692 maltoses Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229920000582 polyisocyanurate Polymers 0.000 description 1
- 239000011495 polyisocyanurate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Verfahren zur Herstellung von therapeutisch verwendbaren Eisen-(lII)-hydroxyd-
Polymaltose-Komplexen
Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung neuer Eisen-(III)-hydroxyd-Polymaltose-Komplexe, welche zur parenteralen, insbesonders intramuskulären Verabreichung geeignet sind.
Es ist bekannt, dass man Eisen-(III)-hydroxyd Kohlenhydrat-Komplexe herstellen kann, indem man geeignete Kohlenhydrate in einer Lösung oder Suspension mit Eisen-(III)-hydroxyd bzw. Eisen-(III)salzen und Alkali im Überschuss zur Reaktion bringt.
(D. B. P. Nr. 938 502; österreichische Patente Nummern 199 794 und 204180). Lösungen solcher Eisen (III)-hydroxyd-Komplexe sollen zweckmässigerweise folgenden Anforderungen genügen: rasche Resorbierbarkeit; geringe Toxizität; gute Verträglichkeit; hoher Eisengehalt - vorzugsweise Lösungen mit 5-10 % elementarem Eisen -; hohe Thermostabilität; gute Lagerfähigkeit; sowie leichte Verwertbarkeit für die Hämoglobinsynthese.
Da die bekannten Eisensaccharat-Lösungen ausschliesslich im alkalischen Milieu beständig sind, können sie nur für intravenöse, nicht aber für intramuskuläre Injektionen verwendet werden. Demgegen über sind sowohl die Eisenhydroxyd-Inulin wie auch die Eisenhydroxyd-Polyisomaltose-Komplexe (Eisen Dextran-Komplexe) als neutrale, isotonische Lösungen für intramuskuläre Applikation verwendbar. Die Eisenhydroxyd-Inulin-Komplexlösungen befriedigen bezüglich Thermostabilität und Lagerfähigkeit nicht und von den kostspieligen Eisenhydroxyd-Polyiso maltose-Komplexen werden bezüglich der Verträglichkeit nicht alle Anforderungen erfüllt (Hemmeler, G., Med. Hyg. 15 (1957) 359:183). Nach Injektion dieser Präparate verlässt der Kohlenhydrat-Anteil den Körper fast unverändert, da das zur Inulin- bzw.
Polyisomaltose-Spaltung notwendige Enzym praktisch fehlt.
Von den bis jetzt bekannten Eisenhydroxyd Polymaltose Präparaten (Eisenhydroxyd-Dextrin Komplexe) erfüllt keines die an ein gutes intramuskulär applizierbares Eisenpräparat oben gestellten Anforderungen. Solche Lösungen enthalten nur etwa 2S Eisen und eignen sich deshalb wegen dem gro ssen Volumen der zu applizierenden Lösungen nicht zur intramuskulären Injektion. Die Eisenbindungskapazität der Dextrine nimmt mit sinkendem Molekulargewicht zu. Anderseits verkleinert sich die Komplexstabilität bei Eisenhydroxyd-Komplexen mit niedrigmolekularem Ligand-Anteil, wodurch Thermostabilität und Lagerfähigkeit der Präparate ungünstig beeinflusst werden. Diese Nachteile können mit den erfindungsgemäss hergestellten Komplexen behoben werden.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man in einem wässerigen Medium ein wasserlösliches, nichtretrogradierendes Dextrin (Polymaltose) mit einer Grundviskosität bei 250 C von 0,025 bis 0,075 in Gegenwart von Eisen (III)-hydroxyd und einem Überschuss an Alkali durch Erhitzen auf 60 bis 1000 C in Lösung bringt und die entstandene Lösung praktisch neutralisiert. Das genannte Dextrin kann aus einem höhermolekularen Dextrin mittels einer dem Stand der Technik entsprechenden Abbaumethode z. B. mittels Säurehydrolyse und fraktionierter Fällung mit wassermischbaren Lösungsmitteln, wie Alkoholen und Aceton, erhalten werden.
Polymaltose-Fraktionen mit kleinerer Grundviskosität ergeben Eisenhydroxyd-Komplexe mit höherem Eisengehalt. Sie sind aber für die therapeutische Verwendung infolge der aus der niedrigeren Kom plexstabilität resultierenden schlechten Verträglichkeit, Thermolabilität sowie der ungünstigen Lagerfähigkeit wegen unbrauchbar. Demgegenüber ergeben die bei 250 C eine Grundviskosität [1 grösser als 0,075 aufweisenden Fraktionen wohl stabile, lagerfähige Komplexe. Der Eisengehalt dieser Lösungen ist aber zu niedrig, um das für intramuskulär applizierbare Eisenlösungen notwendige kleine Volumen bei hohem Eisengehalt zu erzielen.
Der Eisen - (III) - hydroxyd - Polymaltosekomplex kann nach Neutralisierung der alkalischen Lösung, das heisst nach Zugabe einer festen, flüssigen oder gasförmigen Säure, wie z. B. Kationenaustauscher in der H-Form, Schwefelsäure oder Chlorwasserstoffsäure, gereinigt und isoliert werden. Will man die bei der Neutralisierung resultierende Lösung elektrolytfrei erhalten, so kann man neben dem Kationenaustauscher zusätzlich einen Anionenaustauscher in der OH-Form einsetzen, oder gegen Wasser dialysieren. Gut wasserlösliche pulverförmige Präparate können nach bekannten Verfahren durch schonendes Eindampfen der neutralen Lösungen oder durch Fällen mit einem geeigneten wassermischbaren Lösungsmittel gewonnen werden.
Das erfindungsgemäss hergestellte Präparat fällt im allgemeinen als gut wasserlösliches, hellbraunes, nichthygroskopisches Pulver mit 15-25 % Eisen und etwa 70-50% Polymaltosegehalt an. Ein Teil dieser nichtretrogradierenden Polymaltose liegt in freier Form, das heisst als nicht mit dem Eisen-(III)-hydroxydkomplex gebundene Polymaltose vor und dient als Stabilisator für die wässerigen Lösungen der Eisen-(III) - hydroxyd - Polymaltose - Komplexe. Wird die Lösung einer derartigen Substanz tropfenweise mit 2 n HCl unter Rühren versetzt, so tritt bei Raumtemperatur bis pH = 1 keine Trübung auf. Bei der Elektrophorese wandert der Eisen-(III)-hydroxyd Polymaltose-Komplex in Acetatpuffer von pH 6,5 schwach kathodisch.
Beispiel 1
70 g einer Dextrinfraktion entsprechend einer Grundviskosität bei 25 C [? v] = 0, 050 werden in 300 ml destilliertem Wasser unter Erwärmen gelöst.
In die auf 650 C erwärmte Lösung werden 180 g frisch gefälltes, elektrolytfrei gewaschenes Eisen-(III)hydroxyd entsprechend 10 g elementarem Eisen unter energischem Rühren eingetragen. Hierauf werden 45 ml 10 n NaOH zur Suspension gegeben. Die Reaktionstemperatur des gut turbinierten Gemisches wird während 30 Minuten bei 65-700C gehalten. Das Eisen-(III)-hydroxyd geht dabei vollständig in Lösung. Das abgekühlte Reaktionsgemisch wird mittels 2 n Salzsäure auf pH 6,5 eingestellt, der Eisen-(III)hydroxyd-Polymaltose-Komplex im Verhältnis 1 Volumteil Lösung + 2 Volumteile 99 % iges Methylalkohol ausgefällt und der Niederschlag im Vakuum getrocknet. Er kann zu einer praktisch isotonischen, neutralen, sterilen, wässerigen Lösung mit einem Eisengehalt von 5 % Fe verarbeitet werden.
Beispiel 2
35 g einer Dextrinfraktion entsprechend einer Grundviskosität bei 25 0 [W] = 0, 055 werden in 100 ml destilliertem Wasser unter Erwärmen gelöst.
In die auf 750 C erwärmte Lösung werden 75 g einer Eisenchlorid-Lösung (25 g FeCl3 6 H2O gelöst in 50 g destilliertem Wasser) von gleicher Temperatur gegeben und anschliessend unter starkem Turbinieren 45 ml 10n Natronlauge langsam einlaufen gelassen. Nach 15minutiger Reaktion bei 75 C wird die Lösung abgekühlt, von eventuell ungelösten Anteilen abzentrifugiert und mit 90 ml stark saurem Kationenaustauscher und 20 ml stark basischem Anionenaustauscher auf pH 6,2 eingestellt. Das von den Austauscherharzen abgetrennte Filtrat wird im Verhältnis 1 Volumteil Lösung + 2,5 Volumteile 96% iger Athylalkohol gemischt und die überstehende Lösung vom ausgefällten Eisen-(III)hydroxyd-Komplex abgetrennt.
Process for the preparation of therapeutically useful iron (III) hydroxide
Polymaltose complexes
The present invention relates to a process for the production of new iron (III) hydroxide-polymaltose complexes, which are suitable for parenteral, especially intramuscular administration.
It is known that iron (III) hydroxide carbohydrate complexes can be prepared by reacting suitable carbohydrates in a solution or suspension with iron (III) hydroxide or iron (III) salts and an excess of alkali brings.
(D. B. P. No. 938 502; Austrian patents numbers 199 794 and 204180). Solutions of such iron (III) hydroxide complexes should expediently meet the following requirements: rapid absorbability; low toxicity; good compatibility; high iron content - preferably solutions with 5-10% elemental iron -; high thermal stability; good shelf life; and easy usability for hemoglobin synthesis.
Since the known iron saccharate solutions are only stable in an alkaline environment, they can only be used for intravenous, but not for intramuscular injections. In contrast, both the iron hydroxide-inulin and the iron hydroxide-polyisomaltose complexes (iron dextran complexes) can be used as neutral, isotonic solutions for intramuscular administration. The iron hydroxide-inulin complex solutions are unsatisfactory in terms of thermal stability and shelf life, and the costly iron hydroxide-polyiso maltose complexes do not meet all of the requirements for compatibility (Hemmeler, G., Med. Hyg. 15 (1957) 359: 183). After injection of these preparations, the carbohydrate content leaves the body almost unchanged, as it is used for inulin or
The enzyme necessary for polyisomaltose cleavage is practically absent.
None of the iron hydroxide polymaltose preparations (iron hydroxide-dextrin complexes) known to date meet the requirements set out above for a good iron preparation that can be administered intramuscularly. Such solutions contain only about 2½ iron and are therefore unsuitable for intramuscular injection due to the large volume of the solutions to be administered. The iron binding capacity of the dextrins increases with decreasing molecular weight. On the other hand, the complex stability is reduced in the case of iron hydroxide complexes with a low molecular weight ligand content, which has an adverse effect on the thermal stability and shelf life of the preparations. These disadvantages can be eliminated with the complexes prepared according to the invention.
The inventive method is characterized in that a water-soluble, non-retrograding dextrin (polymaltose) with an intrinsic viscosity at 250 C of 0.025 to 0.075 in the presence of iron (III) hydroxide and an excess of alkali by heating to 60 to 1000 C in solution and the resulting solution practically neutralized. Said dextrin can be made from a higher molecular weight dextrin by means of a degradation method corresponding to the state of the art, e.g. B. by means of acid hydrolysis and fractional precipitation with water-miscible solvents such as alcohols and acetone.
Polymaltose fractions with a lower basic viscosity result in iron hydroxide complexes with a higher iron content. But they are unsuitable for therapeutic use as a result of the poor compatibility, thermal stability and poor shelf life resulting from the lower complex stability. In contrast, the fractions having a basic viscosity [1] greater than 0.075 at 250 ° C. result in stable, storable complexes. However, the iron content of these solutions is too low to achieve the small volume required for intramuscularly administered iron solutions with a high iron content.
The iron - (III) - hydroxide - polymaltose complex can after neutralization of the alkaline solution, that is after the addition of a solid, liquid or gaseous acid, such as. B. Cation exchangers in the H form, sulfuric acid or hydrochloric acid, cleaned and isolated. If you want to keep the solution resulting from the neutralization electrolyte-free, you can use an anion exchanger in the OH form in addition to the cation exchanger, or dialyze against water. Preparations in powder form which are readily soluble in water can be obtained by known processes by gently evaporating the neutral solutions or by precipitating them with a suitable water-miscible solvent.
The preparation produced according to the invention is generally obtained as a readily water-soluble, light brown, non-hygroscopic powder with 15-25% iron and about 70-50% polymaltose content. Part of this non-retrograding polymaltose is in free form, i.e. as a polymaltose not bound to the iron (III) hydroxide complex and serves as a stabilizer for the aqueous solutions of the iron (III) hydroxide polymaltose complexes. If 2N HCl is added dropwise to the solution of such a substance with stirring, no turbidity occurs at room temperature up to pH = 1. During electrophoresis, the iron (III) hydroxide polymaltose complex migrates weakly cathodically in acetate buffer of pH 6.5.
example 1
70 g of a dextrin fraction corresponding to an intrinsic viscosity at 25 C [? v] = 0.050 are dissolved in 300 ml of distilled water while warming.
180 g of freshly precipitated, electrolyte-free washed iron (III) hydroxide corresponding to 10 g of elemental iron are introduced into the solution heated to 650 ° C. with vigorous stirring. 45 ml of 10N NaOH are then added to the suspension. The reaction temperature of the well-turbinated mixture is kept at 65-700C for 30 minutes. The iron (III) hydroxide goes completely into solution. The cooled reaction mixture is adjusted to pH 6.5 using 2N hydrochloric acid, the iron (III) hydroxide-polymaltose complex is precipitated in a ratio of 1 part by volume of solution + 2 parts by volume of 99% methyl alcohol and the precipitate is dried in vacuo. It can be processed into a practically isotonic, neutral, sterile, aqueous solution with an iron content of 5% Fe.
Example 2
35 g of a dextrin fraction corresponding to a basic viscosity at 25 ° [W] = 0.055 are dissolved in 100 ml of distilled water with heating.
75 g of a ferric chloride solution (25 g FeCl3 6 H2O dissolved in 50 g distilled water) at the same temperature are added to the solution, which is heated to 750 C, and 45 ml 10N sodium hydroxide solution are then slowly run in with vigorous turbines. After 15 minutes of reaction at 75 ° C., the solution is cooled, any undissolved constituents are centrifuged off and adjusted to pH 6.2 with 90 ml of strongly acidic cation exchanger and 20 ml of strongly basic anion exchanger. The filtrate separated from the exchange resins is mixed in a ratio of 1 part by volume of solution + 2.5 parts by volume of 96% ethyl alcohol and the supernatant solution is separated from the precipitated iron (III) hydroxide complex.
Claims (1)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7302359A CH397628A (en) | 1959-05-08 | 1959-05-08 | Process for the preparation of therapeutically useful iron (III) hydroxide-polymaltose complexes |
| DK160460A DK126683B (en) | 1959-05-08 | 1960-04-26 | Process for the preparation of injectable, durable iron (III) hydroxide-polymaltose complexes or aqueous solutions thereof. |
| ES0257899A ES257899A1 (en) | 1959-05-08 | 1960-04-29 | Improvements in or relating to process for the manufacture of therapeutic useful preparations of iron |
| SE442360A SE329236B (en) | 1959-05-08 | 1960-05-04 | |
| GB1617860A GB918929A (en) | 1959-05-08 | 1960-05-06 | Improvements in or relating to process for the manufacture of therapeutic useful preparations of iron |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7302359A CH397628A (en) | 1959-05-08 | 1959-05-08 | Process for the preparation of therapeutically useful iron (III) hydroxide-polymaltose complexes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH397628A true CH397628A (en) | 1965-08-31 |
Family
ID=4532293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH7302359A CH397628A (en) | 1959-05-08 | 1959-05-08 | Process for the preparation of therapeutically useful iron (III) hydroxide-polymaltose complexes |
Country Status (5)
| Country | Link |
|---|---|
| CH (1) | CH397628A (en) |
| DK (1) | DK126683B (en) |
| ES (1) | ES257899A1 (en) |
| GB (1) | GB918929A (en) |
| SE (1) | SE329236B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1668033A1 (en) * | 1966-10-22 | 1971-05-13 | Fisons Pharmaceuticals Ltd | New ferric hydroxide-carbohydrate complexes and processes for their production |
| FR2394295A1 (en) * | 1976-01-01 | 1979-01-12 | Nippon Zoki Pharmaceutical Co | NEW MEDICINES FOR THE TREATMENT OF ANEMIA |
| GR990100195A (en) * | 1998-06-16 | 2000-02-29 | Therapicon S.R.L. | Preparation of an anaemia-preventing complex |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI592159B (en) | 2007-11-16 | 2017-07-21 | 威佛（國際）股份有限公司 | Pharmaceutical compositions |
-
1959
- 1959-05-08 CH CH7302359A patent/CH397628A/en unknown
-
1960
- 1960-04-26 DK DK160460A patent/DK126683B/en unknown
- 1960-04-29 ES ES0257899A patent/ES257899A1/en not_active Expired
- 1960-05-04 SE SE442360A patent/SE329236B/xx unknown
- 1960-05-06 GB GB1617860A patent/GB918929A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1668033A1 (en) * | 1966-10-22 | 1971-05-13 | Fisons Pharmaceuticals Ltd | New ferric hydroxide-carbohydrate complexes and processes for their production |
| FR2394295A1 (en) * | 1976-01-01 | 1979-01-12 | Nippon Zoki Pharmaceutical Co | NEW MEDICINES FOR THE TREATMENT OF ANEMIA |
| GR990100195A (en) * | 1998-06-16 | 2000-02-29 | Therapicon S.R.L. | Preparation of an anaemia-preventing complex |
Also Published As
| Publication number | Publication date |
|---|---|
| DK126683B (en) | 1973-08-13 |
| ES257899A1 (en) | 1960-07-16 |
| GB918929A (en) | 1963-02-20 |
| SE329236B (en) | 1970-10-05 |
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