DE1954960A1 - Iron dextran preparation - Google Patents

Abstract

Obtained by reaction of dextran and inorg. water-sol. ferric salts are produced by adding citric acid up to 1% concn. to an ion-free soln. of a highly purified pyrogen-free dextran in pyrogen-free water at 50-100 degrees, adjusting the pH to 9-10 and adding FeCl3 and alkali hydroxide solns. simultaneously and in stages, keeping the pH within the above levels and when addn. is complete, pptg. the iron-dextran and, if necessary re-dissolving and re-pptg. to purify. The first pptn. is effected with isopropanol and subsequent ones with EtOH.

Description

Process for the preparation of iron-dextran preparations The present The invention relates to a process for the production of iron-dextran preparations, i.e. of preparations made partly from iron and partly from a dextran compound Beatehen under dextran, more or less depolymerized dextran and dextran derivatives is selected. The preparations according to the invention are for parenteral use suitable in human medicine and veterinary therapy and they can be subcutaneous, intramascular and used intravenously.

It is already known that iron-dextran preparation in the treatment of iron deficiency anemia and used intramuscularly or subcutaneous can be injected. Recently, specially made preparations for intravenous injection has been used.

In the previously known method for producing such days Preparations are complicated to produce and the resulting preparations have even with exact monitoring of the various stages of production and those used Materials in terms of iron and dextran content vary widely in character. In addition, in many cases the production is time-consuming and difficult to carry out, mainly due to the fact that there was an unexpected accident during the procedure Gelation of ferric hydroxide occurs, especially when the process goes through strongly alkaline reaction is carried out.

The working methods used so far often have to be unsatisfactory Results were obtained because during the process of unification of the iron with the dextran unwanted sedimentation, for example of iron (III) hydroxide, has occurred is.

The after the connection of the iron with the dextran or the coupling of the iron on the dextran have passed through precipitation and purification processes quite complicated and it occurs, for example, in working methods in which dialysis is used, there is a high probability of undesirable formation of pyrogens Products, as the production time is of considerable length.

With the working methods used so far, ee is ultimately difficult Make sure you make an iron-dextran preparation in dry form, you both Behr is pure as well as easily soluble and in which the iron content is more than 15%, based on dry material.

Besides, it was also through close monitoring of the procedural stages not possible, preparations with a predetermined iron content within narrow limits (+/- 2%).

This is important in order to have a way of making it straightforward of the final forms of medicaments containing iron-dextran for human and veterinary use on the basis of a well-defined homogeneous starting material.

The inventive method enables the production of completely pure iron-dextran preparations also with a predetermined iron content of more than 15% and in any case up to 40% without this during the manufacturing process undesired precipitation or gelation phenomena occur.

The method according to the invention can also be carried out very quickly reducing the risk of pyrogens and bacterial growth is turned off.

The manufacturing method of the present invention has the following characteristics Features: (1) The use of a highly pure, ion-free dextran, for example corresponds to the purity requirements of the pharmacopoeias, with a molecular weight from 3,000 to 20,000.

(2) The use of a very pure ferric chloride.

(3) The process is carried out at a pH between 9 and 10.

(4) The connection of the iron with the dextran or the coupling of the Iron on the dextran is carried out in the presence of citric acid, thereby Gelation is avoided.

(5) The connection of the iron with the dextran or the coupling of the Iron on the dextran is carried out in such a way that a pyrogen-free solution a pure dextran with a ferric chloride solution and a sodium hydroxide solution is added simultaneously with stirring in such proportions that the pH is kept constant between 9 and 10.

(6) The reaction is carried out at 50 to 1000C.

When the iron joins the dextran, it becomes a clear solution Obtained from iron dextran, from the iron dextran by adding isopropanol under Stir until a concentration such that practically all of the iron-dextran is obtained is knocked down, is precipitated.

Then the stirring is interrupted and the excess liquid is carefully decanted from the sediment.

The sediment is redissolved in ion-free, pyrogen-free water and the solution is, when the resolution is complete, by a Seitz ES and Particle filter filtered to obtain a completely bacteria-free clear solution.

Then the iron-dextran is extracted with the help of ethanol while stirring the clear solution precipitated.

When the precipitation is complete, the stirring is stopped.

The liquid is decanted and the sediment is concentrated with Alcohol washed to half dry and checked for chloride content, the concentration should be minimal.

If necessary, i.e. if the chloride content is too high, the the latter cleaning process repeated and the last completed sediment is then dried in vacuo. Example 1 Manufacture of iron dextran with 20% elemental iron bound to the dextran Equipment: (1) A 1000 liter reaction tank with steam jacket and stirrer.

(2) Container for ferric chloride solution and sodium hydroxide solution.

(3) Sedimentation tank with stirrer.

(4) Nutsche filter.

(5) vacuum dryer.

(6) Cell filter, sparkler type.

Starting materials: (1) Was clear solution of pyrogen-free dextran with an average molecular weight of 7000 in pyrogen-free distilled Water, concentration 16%. 72 kg of dextran dissolved in water to a total volume from 450 Ltr ..

(2) ferric chloride solution. 87 kg FeCl3 (6H2O) dissolved in about 150 Liters of pyrogen-free, distilled, hot water, (3) sodium hydroxide solution, 34 ° Be, about 115 Ltr.

(4) citric acid, 5 kg, B.P.

How it works: The dextran solution is placed in the reaction vessel under Stir heated to 9000, after which the citric acid was added and dissolved will. When the citric acid is dissolved, sodium hydroxide solution becomes room temperature has, added until the dextran solution is adjusted to a pH between 9 and 10 is.

If the pE is stable between these limits, the iron XII chloride and the sodium hydroxide solution is added simultaneously from the two containers, in which the solutions are prepared, being in the reaction vessel still violently is stirred while the flow rate for the two solutions is thus regulated is that the pH of the reaction mixture is kept between 9 and 10.

The rate of addition should also be used in the case of the ferric chloride solution Do not exceed about 80 liters per hour.

The temperature of the reaction mixture is regulated during the process and held between 80 and 900C.

When the reaction is over, the generated solution becomes room temperature cooled and the pH is adjusted with 5N hydrochloric acid saf 5.8.

The solution is then transferred to a sedimentation container with a stirrer and isopropanol is added until complete sedimentation of iron-dextran is obtained.

The liquid is decanted from the sediment. Dansch is there. Sediment in the same volume of distilled, pyrogen-free water as before dissolved by sedimentation, a clear solution being obtained.

While stirring, 2 * SECA 8 3 activated charcoal and about 7 kg Hyflo Super Cel added.

The suspension is stirred evenly while gradually passing through a cell or plate filter with filter paper and immediately afterwards through a Another cell or plate filter is filtered with Seitz EK filter plates, whereby a pyrogen-free, bacteria-free and practically sterile solution is obtained.

The filtered solution is collected in a sedimentation container and it is precipitated with ethanol until complete sedimentation is obtained. The supernatant liquid is decanted and the sediment is several times washed with a small amount of ethanol.

The semi-dry sediment is then transferred into a suction filter and as much liquid as possible is sucked off, after which the semi-dry material is dried in vacuo.

The iron dextran produced in this way shows a chloride content of 0.12%, is pyrogen-free and contains 20.1% elemental iron.

B e i s p i e l 2 Manufacture of iron-dextran-glycerin-glycoside with a content of 20% elemental iron bound to the dextran.

The method described in Example 1 is used to prepare this product Procedure repeated, with the only change that as dextran starting material a dextran-glycerol-glycoside with a corresponding to those given for dextran Molecular weight is used.

A manufacturing process carried out with this material provides an end product with a content of 0.21% chloride and 20.8% elemental iron.

B e i s p i e l 3 Manufacture of iron dextran with a content of 36% elemental iron bound to daE dextran.

The procedure described in Example 1 is used in the present example repeatedly using however the following starting materials: (1) A water-clear solution of pyrogen-free dextran with an average molecular weight of 7000 in pyrogen-free distilled water, with a concentration of 15.8 %. 79 kg of dextran are dissolved in water to a total volume of 500 liters.

(2) Iron III chloride solution, 225 kg FeCl3 (6H2O), dissolved in etn 200 Liters of pyrogen-free, distilled, hot water.

(3) Sodium hydroxide solution, 34 ° Bé, approx. 270 liters.

(4) citric acid, 5 kg, B.P.

The iron-dextran produced shows a chloride content of 0.23% Pyrogen-free and contains 35.9% elemental iron.

EXAMPLE 4 Manufacture of iron dextran with 15% elemental Iron bound to the dextran.

The procedure described in Example 1 is used in the present example repeated except that the following starting materials are used: (1) One water-clear solution of pyrogen-free dextran with a average Molecular weight of 10,000 in pyrogen-free distilled water, with a concentration of 16%. se kg of dextran are dissolved in water to a total volume of 550 liters.

(2) Iron III chloride solutions, 75 kg FeCl3 (6H2O), dissolved in about 120 Liters of pyrogen-free, distilled, hot water.

(3) Sodium hydroxide solution, 34 ° Bé, about 100 liters.

(4) citric acid, 5 kg, B.P.

The iron-dextran produced shows a chloride content below 0.1%, is pyrogen-free and contains 15.3% elemental iron.

The examples described here show typical production results.

The use of dextran glycoside as a starting material instead of Dextran did not lead to any discrepancies in the results obtained.

The reason why in the examples isopropanol for the first Sedimentation and ethanol used for the second sedimentation eats that this constellation seems to be favorable to a good salt-free sedimentation and to get even end results, but it is natural for every professional clear that other sedimentation agents, such as methanol or ketones or Combinations of such solvents, can be used just as well, to get corresponding results.

EXAMPLE 5 Manufacture of iron dextran with 25% elemental Iron bound to the dextran.

The procedure described in Example 1 is used in the present example repeated except that the following starting materials are used: (1) One water-clear solution of pyrogen-free dextran with an average molecular weight of 10,000 in pyrogen-free distilled water, with a concentration of 16 %. 72 kg of dextran are dissolved in water to a total volume of 450 liters.

(2) Iron (III) chloride solutions, 116 kg FeCl3 (6H2O), roughly dissolved 70 liters of pyrogen-free, distilled hot water.

(3) Sodium hydroxide solution, 34 ° Bé, 150 Ltr.

(4) citric acid, 5 kg> B.P.

The dispersed iron dextran shows a chloride content of 0.05% Pyrogen-free and contains 25.1% elemental iron.

EXAMPLE 6 Manufacture of iron dextran with 17% elemental Bisen bound to the dextran.

The procedure described in Example 1 is used in the present example repeatedly, however using the following starting materials: (1) One water-clear solution of pyrogen-free dextran with an average molecular weight of 10,000 in Pyrogen-free distilled water, with a consentration of 16%. There are 72 kg of dextran in water to a total volume of 450 liters. solved.

(2) Iron III chloride solutions, n kg FeCl3 (6H2O) dissolved in about 50 Ltr, pyrogen-free, distilled water (hot).

(3) Sodium hydroxide solution, 34 ° Bé, about 95 liters.

(4) citric acid, 5 kg, B.P.

The iron-dextran produced shows a chloride content of 0.08% Pyrogen-free and contains 17% elemental iron.

Claims (4)

P A T E N T A N S P R Ü C H E Process for the production of iron-I) extran preparations by reaction an iextrans and an inorganic ferric salt dissolved in water, daduroh characterized in that one citric acid to an ion-free solution in a high Add volume of purified, pyrogen-free dextran in pyrogen-free distilled water, the temperature being in the range between 50 and 100 ° C, ie the pH of the reaction solution adjusts to a value between 9 and 10, ferric chloride and alkali metal hydroxide at the same time gradually adding and the pH of the reaction medium within the specified The range holds that the iron-dextran formed precipitates after the addition is complete and optionally the precipitated iron dextran precipitates again. 2. Verfahron according to claim 1, characterized in that for the first precipitate used isopropanol. 3. The method according to claim 1 or 2, characterized in that one Ethanol was used for the reprecipitation. 4. The method according to any one of the preceding claims, characterized in that that the citric acid is added in an amount up to 1%.