DE1768912A1 - Process for the production of iron (III) -containing complex compounds of hydrogenated dextran and hydrogenated dextran and sodium citrate or citric acid - Google Patents

Description

DR. BERG DIPL.-ING. STAPF

PATENTANWÄLTE 8 MÜNCHEN 2, H ILBLESTRASSE

Dr. Mountain Dipl.-Ing. Stapf, 8 Munich 2, HllblestraBe 20

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date

September 1

Attorney files-Wr. 17 501

Kutnowskie Zakiady Farmaceutyczne "Polfa" KUTNO / Poland.

Process for the production of iron (III) -containing Complex compounds of hydrogenated dextran and of hydrogenated jextran and sodium citrate or of citric acid.

Mgr.In? -. Jan Zbigniew Mioduszewski,

Inventor: Mgr.In? '. Mieczyslawa Helena Mioduszewska, Techn. Andrzej Januariusz Kornacki.

Jjie ^ rfindun-r refers to a method of producing : 5tel] ung of water-soluble nonionic compounds

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Documents (Art 7 g I Aba. 2 No. 1 Clause 3 of the Anderunoage ·. V. 4.9.1967 \

BATH ORIGINAL

trivalent iron and hydrogenated dextran, as well as hydrogenated dextran and sodium citrate or the Citric acid, which due to its properties can be used in human therapy and / or in veterinary medicine to combat diseases in the organism due to iron deficiency or due to disruption of iron absorption arise, own.

Similar preparations, the compounds of trivalent iron and non-hydrogenated dextran, are already known. These preparations are preferably made in insect form, find wide application in medicine. The toxicity of these compounds, commonly expressed as DLj-q, is in the mouse test with intravenous administration about 50 to 70 µg per 1 kg of living weight of the test animals. Such Values are required by the Pharmacopeia USA XVII.

Another advance in the field of iron (III) -dextran complex compounds was the production of iron-containing compounds of hydrogenated dextran. These Compounds retain the same therapeutic properties but can have significantly lower toxicity have, and are more stable in aqueous solutions. However, these connections are more difficult to make than those of the unhydrogenated üe ^ trans, being their useful

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Properties associated with the manufacturing process sin,]. According to US Pat. No. 3,234,209, iron compounds of hydrogenated dextran, which are several times less toxic than compounds of the non-hydrogenated dextran or as compounds of the hydrogenated dextran, which according to already known processes (e.g. according to TJ SA patent 3 Ü22,221 by the same authors). The low toxicity is used by the authors with their manufacturing process according to the invention related to the representation of the iron (III) hydroxide required for complex formation, This is done by partially neutralizing an iron salt solution with an ammonia solution and subsequently Dialysis is produced and used as a dialyzed colloidal solution.

According to a Swiss patent 39 382, the iron complex compound of hydrogenated dextran is prepared by electrodialysis of iron (III) salts. In this process, the solution of the hydrogenated dextran and the egg (III) salt is in the cathode compartment during dialysis and a dilute sodium chloride solution is in the anolyte compartment do.3 device. In the cathode space, there arise üed.i nr xnp- ^ n for the formation of colloidal iron (III) -h''drox; ri in the presence of hydrogenated dextran. Same-

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the anion of the originally used iron salt is removed early. The resulting from this process Mixture forms a complex compound after heating.

According to the invention, the low-toxic iron (IIl) complex compound of hydrogenated dextran is represented much more simply and cheaply, although it is not necessary is to produce colloidal iron (III) hydroxide as a starting material. This procedure does not require any dialysis or Electrodialysis machines, the elimination of these reaction steps, allows synthesis at high concentrations of the turnover substances, which in turn offers the possibility of reducing the working volume of the apparatus. This eliminates the need to concentrate very dilute solutions of the end product, which is the case with others Methods can occur.

The iron (III) complex compounds of hydrogenated dextran prepared according to the invention _{have such a low toxicity that difficulties even arise in determining the value DL 1 -Q.} The dose limit is determined more by the administered volumes of the dissolved preparation than by its toxicity. The solutions of the end product prepared for injection show neither traces of iron ions nor changes after sterilization

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in their properties. It was found that complex compounds with the favorable properties mix through of precipitated, washed and filtered iron (III) hydroxide with dry hydrogenated dextran and subsequent heating of this mixture in the presence of alkyl metal hydroxides until completely soluble in water speed of the end product formed can be obtained. The end product can subsequently from the excess of the added Alkali metal hydroxides are freed by treatment with ion exchangers. The ones with ion exchangers the treated solution can be prepared by adding the necessary quantities of sodium chloride to produce an isotonic solution, Adjustment of the concentration of the active ingredient, filtration, pouring the solution into the necessary container and subsequent thermal sterilization are brought directly to the insect form.

The solution can also be subjected to technical operations in a known manner in which the water removed and the end product can be obtained in solid form. The end product obtained in this way has after it in Dissolved water will have the same properties as the original solution.

There is some inconvenience to this procedure

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the prolonged heating time and the need for a strongly alkaline medium to carry out the Complexing process are necessary. It turned out that the reaction time can be shortened significantly if a hydroxy acid with gelatin properties is added to the reaction mixture or its sodium salt is added. Citric acid or its forms proved to be from this type of substance Sodium salt as cheap.

It was also shown that the addition of such a substance not only leads to the formation of the iron (III) complex compounds of the hydrogenated dextran accelerates and facilitates, but also the properties of the obtained End product improved.

The solutions to these connections can be made faster filter, are more stable during storage and show no tendency to form in ampoules Rainfall. They also flow from the glass walls of the ampoules and injection syringes, even at high concentrations, easier down. The beneficial therapeutic properties are retained.

It has been found that it is essential that the chelating agent be in the reaction mixture before the

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Heating is added. This facilitates homogenization of the reaction mass and accelerates the later onset of the formation of the complex compound. In this Version, the complex formation of iron and hydrogenated dextran proceeds just as easily as in the implementation with non-hydrogenated dextran and the properties of the end product are more reproducible.

It was found that the end substances which with a sodium citrate addition had been obtained, with the following Treatment with cation exchangers, in comparison for the end products that were obtained without this addition, there was no major drop in the pH value and also did not show any higher electrolytic conductivity. This indicates that the citric acid is hydrogenated with the Dextran and iron form a kind of mixed complex compounds, as is the case with the known mixed complexes of Iron, sorbitol and citric acid, which are already used in therapy, is the case.

It was also found that in the process according to the invention successfully hydrogenated dextran with a different characteristic than used in the known processes can be.

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According to the invention, favorable results are achieved if hydrogenated dextran having a reducing power determined according to Somogyi is in the range of 0.02 to 3 $, where the reducing power is based on glucose gram equivalents in 100 grams of hydrogenated dextran. In the known Process against it (cited patents) the use of hydrogenated dextran is required, in which the Somogyi's reagent remains completely unreduced. To this one To illustrate the difference more clearly should be given as an example that non-hydrogenated dextran of about the same molecular weight has a reducing power of about.

The dextran, which according to the invention is suitable for the production of complex compounds, is characterized not only by the reducing power but also by the intrinsic viscosity or the viscosity number. The intrinsic viscosity is determined at 25 ⁰ C is intended to values in the range of 0.01 to 0.2, have low if from 0.05 to 0.07.

For the preparation of the iron (III) complex compounds of the hydrogenated dextran is according to the invention as follows procedure. While stirring, the solution of a water-soluble iron salt, ideally an aqueous solution of iron (III) chloride, gradually an alkali metal

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carbonate solution added. The iron (III) hydroxide precipitate is washed with distilled water and decanted, cheap until the dissolved ones disappear Substances in the decanted liquid. The precipitate is then filtered or centrifuged separated and in the moist state with dry hydrogenated dextran, which has the properties already mentioned has mixed. The proportion of iron (III) hydroxide to hydrogenated dextran can vary within a fairly wide range so that as desired the amount of elemental Iron in the end product ranges from $ 5 to $ 30. When applied of a chelating agent, it is convenient to use this in an amount of 1 to 10 $ in relation to that of the reaction applied amount of hydrogenated dextran added in this phase in the mixture.

The mixture is stirred until it has reached a homogeneous state. Then one is dissolved in water Alkali metal hydroxide is added until the mixture has reached an alkaline reaction. The mixture is below heated with stirring. The heating is continued until the end product is completely soluble in water is.

The time required for implementation is in the event that

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where no chelating agent is added on average some hours. When adding sodium citrate, the reaction time is about 100-150 minutes.

The favorable reaction temperature is in the range from 70 ⁰ C to 10O ⁰ C.

A sample is temporarily taken from the reaction mixture and dissolved in an enormous excess of water. As soon as the sample is clearly soluble in water, heating is continued for another 10-20 minutes. Below the solution is cooled, filtered and treated with the ion exchanger.

The alkaline elements brought into the solution are removed by passing them through a filter or a Column brought layer of a weakly acidic cation exchanger are passed through. The cation exchanger can also be added to the solution, stirred and after a certain time filtered or centrifuged removed. The solution is treated with the ion exchanger until it has a temperature in the range of 5.5 to 6.6 lying pH has reached. At the same time :, the electrolytic conductivity of the solution decreases, where it is favorable this to a value of

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Tis 1x1u " ⁴ (ohms" * ¹ cm " ¹ ) at a temperature of

2U ⁰ G to bring

After that, the prepared solution can be filtered the end product can be obtained in solid form or directly as an injection form, in the first case the fabric can be dried directly in a spray dryer. The end product can also be obtained by evaporation of the solvent in vacuo or by precipitation with a water-miscible organic solvent, such as lower alcohols and acetone are separated. After the precipitation, it is advantageous to dissolve the end product with an excess of ~ To add shot of the organic solvent and to filter the precipitated end product, and in vacuo to dry.

The end product can be stored in dry form. After this Dissolving in water it has the properties of the original solutions. If it is not necessary that To separate the end product in solid form, the solution containing the product can, after demineralization, cessation the necessary iron concentration C on the ground analytical determinations), addition of sodium chloride up to isotonicity and clarification or disinfection filtration, can be obtained as an injection form. Wake up filling the

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Solution in suitable containers such as ampoules, vials and others, this can be kept in closed containers thermally at a temperature of 115 ° C for 30 minutes sterilized.

example 1

700 ml of an iron (III) chloride solution with an iron content of 15 mg elemental iron per ml were placed in a four liter glass flask with a stirrer and cooled ^{to 12 ° C.} A solution of 33 grams of anhydrous sodium carbonate was prepared separately in 1500 ml of distilled water, filtered and cooled to 12 ⁰ G.

The sodium carbonate solution became the ferric chloride solution in the course of about 60 years with vigorous stirring Dripped in minutes until the suspension has reached pH 5.9. The suspension of the precipitated iron (III) hydroxide was placed in a 6 liter glass flask, diluted to approximately 6 liters with distilled water and left to settle the hydroxide. The liquid was decanted and the precipitate again diluted with distilled water and decanted again. The same procedure was followed until there was no positive reaction was found on chlorine ions in the decanted liquid. The precipitate of ferric hydroxide

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Was filtered on the .Nutsche in vacuo and subsequently when wet with 30 grams of dry hydrogenated Dextran mixed with intrinsic viscosity of 0.058 and reducing power of $ 0.029.

10bigen a sodium hydroxide solution, 15 ml to the homogeneous mixture. Added in distilled water and heated at constant stirring to 96 ⁰ to 100 ⁰ C O. After heating for 60 minutes, a further 7.5 ml of 10% sodium hydroxide solution were added and the loss of water due to evaporation was made up to the original volume. The sample taken after 145 minutes was completely soluble in water. The solution was heated for a further 10 minutes, left to cool and then filtered through a sintered filter with a pore size of G ~ 3. The filtered solution was passed four times through a column charged with a weakly acidic ion exchanger (70 ml) of a suspension of the cation exchanger "Amberlit IRG-5Q" (trademark of Rohm and Haas). As soon as the solution has reached the electrolytic conductivity 1.26 × 10 * " ⁵ (Ohm *" cm "") and the pH value 5.6, the demineralization was ended. The solution was diluted to a concentration of 50 mg elemental iron per ml with u, 85 g sodium chloride per 100 ml solution and after dissolving with an asbestos

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Cellulose clear filter set with a density of K-5 filtered. The solution was filled into ampoules, the ampoules fused and sterilized in an autoclave at 115 G for 30 minutes.

Example 2

Iron (III) hydroxide was made in the same way and in the same way Amount as shown in Example 1.

The filtered, moist precipitate of iron (III) hydroxide was thoroughly mixed with 36 g of reduced dextran with an intrinsic viscosity of 0.059 and a reducing power of 0.020 $. 1 g iMatriumzitrat To this mixture was added, mixed, subsequently added 2R 10biger ml sodium hydroxide solution and heated at constant mechanical Kühren at 96 to 98 ⁰ G.

After 45 minutes, a sample was taken which was clearly soluble in water. After 55 minutes it became Heating ended.

The solution was cooled, filtered through a glass filter with density G-3 and filtered several times through one of 70 ml a weakly acidic cation exchanger (Amberlit IRC-50) layer existing in the form of hydrogen ions is allowed to pass through, As soon as the solution has the value 1.28x10 * "^ (0hm cm '

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and the pH reached 5.6 the deionization was carried out completed. The solution was diluted with distilled water to a concentration of 5u mg elemental iron diluted per ml of solution. Then 0.85 g of sodium chloride per 10 ml of solution was added and after dissolving of the sodium chloride, the solution was filtered through an asbestos-cellulose clarifying filter kit K-5. The solution was filled into ampoules, the ampoules fused and sterilized in an autoclave at 115 ° 0 for 3u minutes.

Example 3

Iron (.IIl) hydroxide and the iron (III) complex compound of the reduced dextran were according to the method in Example 2

procedure outlined. To this end, 30 g of hydrogenated dextran with an intrinsic viscosity of 0.059 and Reduction power 2.8> applied to the 1.5 g sodium citrate was added.

After the deionization and filtration of the solution, the end product was obtained as a dry powder by drying in a spray dryer. The inlet temperature of the air used for drying was IfO ⁰ C and the spray turbine had a speed of about 45,000 revolutions per minute. It became a brownish-red, easily water-soluble powder with a content of 28.6? &

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preserved in complex-like bonded iron. It was possible using this powder to produce solutions with properties identical to those of the original solution.

Example 4

In a glass flask with stirrer and dropping funnel was 14uO (III) chloride solution with a (iesamteisengehalt of 21.8 g and cooled to 12 ⁰ O ml of iron. To the mechanically stirred tiisen (III) chloride solution was added over approximately 50 minutes 2500 ml of a sodium carbonate solution cooled to the same temperature with about 63 g in atrium carbonate solids was added, as soon as the suspension had reached pH 5.5, the dropping was stopped.The precipitate was washed three times with distilled water by decantation and filtered in vacuo. The moist, filtered precipitate of the iron (III) hydroxide was thoroughly mixed with 84 g of hydrogenated dextran with an intrinsic viscosity of 0.055 and a reducing power of 2.32; * To the mixture was first 4 g of sodium citrate and then 24 ml of a 1% solution of sodium hydroxide were added. The mixture was heated with mechanical stirring for 25 minutes until the temp temperature had reached 75 ° and kept at this temperature for 15 minutes. Afterwards the temperature was gradually increased

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increases to reach the temperature of 95 ° O after 25 minutes. A sample of the final product taken at this time was completely soluble in water. The mixture was heated for a further 15 minutes at a temperature of 98 ⁰ U and then left to cool.

After filtering, the solution was added four times by 9U ml a cation exchange layer made of Amberlite IRC-50 until the pH value. 6.0 was passed through. the Solution was injected and sterilized as in Example 1.

Patent claims:

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Claims (6)

Patent claims: 1. Process for the preparation of iron (III) complex compounds of hydrogenated dextran, which are suitable for parenteral or enteral use in human therapy and / or in veterinary medicine, characterized in that precipitated, electrolyte-free and filtered iron hydroxide in the moist state with dry hydrogenated dextran to a homogeneous one The mass is mixed, made alkaline with a solution of sodium hydroxide, while stirring until it is completely soluble in water of the end product is heated, then cooled, filtered and treated with ion exchangers. 2. The method according to claim 1, characterized in that the used for the preparation of complex compounds hydrogenated dextran has a Somogyi reducing power in the range from 0.02 to 3.0, where the reducing power is based on glucose gram equivalents in 100 grams of hydrogenated dextran. 3. Process for the production of iron (III) mixed con) plex compounds of hydrogenated dextran and citric acid or the alkali metal salts of this acid, which are suitable for parenteral and / or enteral use in human therapy and / or veterinary medicine, thereby marked that precipitated washed and - 19 - 209820/0766 New document) ι iah. , _s ι _Λιια _ , _no ., _bau ,,,,., _rtlul , _illlllUbgee . _{v <4>a>} 9c} .., filtered iron (III) hydroxide in the moist state with dry reduced dextran and citric acid or its alkali metal salts mixed into a homogeneous mass, alkalized with aqueous solution of sodium hydroxide and is heated with stirring until the end product is completely soluble in water, after which the cooled solution filtered and treated with ion exchangers to remove the excess of the added sodium hydroxide will. 4. The method according to claim 3, characterized in that the used for the preparation of complex compounds hydrogenated dextran has a Somogyi reducing power in the range from 0.02 to 3.0, where the reducing power, based on glucose gram equivalents in 100 grams of hydrogenated dextran. 5. Use of the iron (III) complex compounds prepared according to claims 1 to 4 in medicaments. 6. Ferric dextran complex prepared by mixing of precipitated, washed, filtered iron (III) hydroxide with reduced dextran (reducing power from 0.02 to 3.0 according to Somogyi based on glucose gram equivalents / 100 g hydrogenated dextran) and optionally with citric acid or its alkali salts, alkalize with aqueous - 20 - 209820 / (1766 Sodium hydroxide solution, heating with cooling until completely soluble in water, cooling, filtering and treatment with ion exchangers. 209820/0766