DK141251B - PROCEDURE FOR THE PREPARATION OF IRON SALT OR IRON COMPLEX COMPOUNDS OF CARBOXYL GROUP CONTAINING POLYMERS - Google Patents

Description

(di) PUBLICATION 141251 DENMARK (51) Int el.3 c 08 F 8/44 // A 61 K 33/26 • (21) Application No. 4089/7? (22) Filed on 24 Jul. 1973 (23) Race day 24 Jul. 1973 (44) The application presented and.

the promissory note published on 1 1 * f'® * b · 1 980

DIRECTORATE OF

THE PATENT AND TRADEMARKET SYSTEM (30) Priority from it

31 Jul. 1972, 2237586, DE

(71) DEUTSCHE GOLD- AND SILEER-SCHEIDEANSTALT VORMALS ROESSLER, Weles = Trauenstraese 9, Frankfurt, DE.

(72) Inventor: Heidrun Bertram, 6454 Grossauheim, Fuerstenbergetrasee 4, DE: Rudolf FahnensTich, 8752 Moembris, Karlesberg 28, DE: Heinz Haschke, 6454 Grossauheim, Gruenausfcrasse 17, DE.

(74) Plenipotentiary in the proceedings:

International Patent Bureau. (54) Process for Preparing Iron Salts or Compounds of Carboxyl Group-Containing Polymers.

The present invention relates to a process for the preparation of iron salts or iron complex compounds of carboxyl group-containing polymers suitable for the preparation of pharmaceutical preparations or drugs, in particular agents for the oral treatment of acute anemia or for prophylactic anemia treatment or both in warm blooded alloys.

Anemia, as is well known, is a dangerous iron deficiency disease ', such as when not treated, in newborn suckling pigs fed only with milk, resulting in a mortality of 10-15% during the first month of life. Furthermore, in warm-blooded omnivores, to which man should also be included, anemic individuals have a particularly high susceptibility to secondary diseases, such as bacterial infections, enteritis, diarrhea or dysentery, influenza, paratyphus, pneumonia, digestive disorders and the like. Anemia can also cause weight loss, skin damage and even fertility disorders.

Because of the continuous renewal of the red blood cells in the living organism, there is an ever-increasing, greater or lesser need for iron. If this need is not met at all or insufficiently, interferences in hemoglobin formation occur due to the iron deficiency. These disorders give the picture of ananias.

Therefore, for the treatment or prophylaxis of such pathological conditions, the organism must be supplied with additional iron in the form of and acceptable iron compounds of the organism. Particularly desirable in this context are such iron compounds, which, in addition, also have the greatest possible depot effect, thereby obtaining the longest possible positive effect of the compositions administered.

It is well known that "simple" iron salts, such as ferrous sulfate, are in principle suitable for the treatment of anemia. However, they have the disadvantage, apart from their very poor utilization rate, that they have only a very low deposit effect.

Significantly higher utilization rates are already achieved by using such "simple" iron salts in admixture with certain organic iron compounds.

Thus, e.g. significantly improve the utilization rate of ferrous sulfate by admixture with iron fumarate (DT-OS 1 492 881).

The best existing preparations for treating anemia are those containing iron fumarate or iron dextran. They exhibit not only better utilization, but also better storage effect than the "simple" iron salts. Despite this, their usefulness and their storage effect still leave a lot to be desired. Of course, this applies even more to their mixtures with "simple" iron salts. While iron dextran can only be used for injection and cannot be administered orally, the depot effect of iron fumarate is not sufficient to achieve a true long-term effect by a single administration (Arzneimittel-forschung 4 (1971), pp. 509-515).

With oral dextran oral administration, there is a similar unfavorable decrease in activity over time as with the use of "simple" iron salts. However, iron fumarate, e.g. in the treatment of newborn piglets for anemia, after a single administration of the preparation to achieve a fairly constant and non-decreasing iron or hemoglobin content in the blood.

On the basis of the good experience of anemia treatment which, despite the above-mentioned disadvantages and shortcomings of replacing the "simple" iron salts with organic iron compounds, such as iron fumarate and iron dextran, one could think that first and foremost the complex iron compounds of known organic complexing agents are suitable for the treatment of anemia. However, thorough experiments with newborn suckling pigs using iron complexes of ethylenediaminetetraacetic acid showed very quickly that these preparations by oral administration (on the fourth day of life) at the usual doses of the anemia treatment (corresponding to an iron content of 400 mg) are not only completely unsuitable for anemia treatment, but that they are also so highly toxic that they cause death for the treated animals within 36 hours.

Finally, use for anemia treatment of an agent with a content of orally applicable iron salts of carboxyl group-containing polymer compounds is well known (GB-PS 1,155,208). For this purpose, in particular, the iron (II) salts of vinyimethyl ether / maleic acid copolymers (1: 1), of polyacrylic acids, of polymethacrylic acids and of maleic / acrylic acid copolymers (1: 1) are described. The polymers underlying these iron salts contain, as complexing active functional groups, exclusively carboxyl groups. Also, these known iron salts lack long-term effect and, on the contrary, must be administered daily.

The present invention now relates to a process for preparing iron salts or iron complex compounds of water-soluble carboxyl group-containing polymers by mixing a water-soluble inorganic iron salt with the water-soluble polymer or an alkali metal or ammonium salt thereof in an aqueous reaction medium and isolating the formed iron or iron polymer, which is characterized by using at least one polymer having a mean degree of polymerization between 3 and 600 and which is made up of Y + W / 2 mole percent units of general formula I as a water-soluble carboxyl group-containing polymer

F1 - CH2 - C - (I) _ C00A_

U - W mole percent units of general formula II

Γ R2 1 i - CH, - C - (II)

CHO

W / 2 mole percent units of general formula III

Γ R3 - CH2 - C - (III)

2 I

CH 2 OH

V mole percent units of general formula IV

- 0 - CH - (IV) ch = ch 2 which formulas U have the value 12 to 47, V has the value 0 to 25, W has the value 4 to 12 and Y has the value 100 - (U + V) and wherein A represents an alkali metal, a hydrogen or an ammonium ion, R 1 - represents a hydrogen atom, a methyl group, o a hydroxymethyl group, an ethyl group, a chlorine atom or a bromine atom, R and 3 R are the same or different and each represents a hydrogen atom or a hydroxymethyl group, further being that if ff is different from 0, the ratio of the base mole percent of carboxyl or carboxylate groups to the base mole percent of hydroxy groups is between 1.1 and 16.

The iron salts or iron complexes prepared by this process can be used to prepare pharmaceutical preparations or drugs, optionally using other pharmaceutically active substances, and optionally using pharmaceutical carriers or other excipients or both. They may be used with particular advantage for the preparation of agents for the oral treatment of acute anemia or for prophylactic anemia treatment or both in warm-blooded allergenic agents, which may optionally contain the iron salts or iron complexes in admixture with other pharmaceutically active substances.

Surprisingly, these iron salts or complexes were found to be virtually non-toxic and acceptable to the organism. Above all, however, in contrast to the iron preparations known and used heretofore known for anemia treatment, oral administration already exhibits a quite excellent depot effect and thus is particularly suitable for the treatment of acute anemia and for anemia prophylaxis.

The polymers to be used in the process of the invention are polycarboxylates which, as functional groups, besides predominantly carboxyl or carboxylate groups further contain carbonyl groups or hydroxy groups or both. Depending on and in what amount they contain the units of the above general formulas (II) and (III), these are poly (aldehydocarboxylates), poly (hydroxycarboxylates) or poly (hydroxyaldehydocarboxylates).

The average degree of polymerization of the polymers is between 3 and 600, preferably between 3 and 300 and especially between 5 and 100. Here, the indications of the degree of polymerization of the polymer are understood to be such that the values of 3, 5, 100, 300 or 600 respectively correspond to values of the viscosity number. in dl / g, measured on 1% solutions of free poly (aldehydocarboxylic acids) or for poly (hydroxycarboxylates) and poly (hydroxyaldehydocarboxylates) measured on the underlying intermediates of poly (aldehydocarboxylic acids), of 0.023, 0.033, respectively. 0.095, 0.200 and 0.350 deciliters per For the preparation of the 1% poly (aldehydocarboxylic acid) solutions required for the measurements, the free poly (aldehydocarboxylic acids) are first poured with corresponding amounts of a 5% aqueous sulfur dioxide solution and then after a complete solution, replenishes with the same volume 10% aqueous sodium chloride solution. The viscosimetric measurements are performed at 20 ° C.

5 141251

The proportions of units of the general formulas (I) - (IV) in the polymers to be used in the process according to the invention are given in the base molar percentage according to E. Trommstorff, ie. the average proportion of the formula units concerned per 100 formula units (I) to (IV) in the polymer molecules.

As mentioned, for the parameters (D, V, W and Y) which define the proportion of the units of general formulas (I) to (IV) in the polymers to be used, U has the value 12 to 47, V the value 0 to 25, W has the value 0 to U and Y has the value loo - (U + V).

It has been found that iron complexes are prepared from a polymer in which U has a value of 20 to 47, especially 22 to 47, V has a value of 1 to 20, in particular 5 to 15, and W has a value of 0.3 x U to U. , especially 0.5x0 to U, has particularly high complex stability. This high complex stability, in turn, results in a particularly good depot effect.

For polymers where W is different from 0 and thus contains units of general formula (III), as mentioned, the ratio between the base mole percent of carboxyl or carboxylate groups and the base mole percent of hydroxyl groups must be between 1.1 and 16. Using such polymers, a particularly high complex stability is obtained, and therefor, particularly good depot effect when the ratio of the base mole percent of carboxyl or carboxylate groups to the base mole percent of hydroxyl groups is between 2 and 9 and especially between 5 and 8.

The invention therefore relates in particular to methods as defined in claims 2 and 3 for the preparation of iron complex compounds of the above-mentioned kind.

Among the polymers to be used, poly (hydroxycarboxylates), i.e. polymers for which W is practically equal to U and thus contains no or only a small proportion of units of the general formula (II).

The polymers to be used in the process of the invention are prepared in a well-known manner. Thus, poly (aldehydocarboxylates) can be particularly advantageously prepared by oxidation / polymerization of acrolein, by oxidative copolymerization of acrolein with acrylic acid, methacrylic acid, ethacrylic acid, α-chloraeryl acid or α-bromoacrylic acid or by oxidative thermopolymerization of α, unsaturated monocarboxylic acids, and with α, β-unsaturated dicarboxylic acid optionally substituted with methyl groups or ethyl groups. However, the polymerization conditions must in all cases be chosen such that the polymer's proportions of units of general formulas (I), (II) and (IV) lie within the specified range and that the required degree of polymerization is achieved. As an oxidizing agent and at the same time as polymerization initiator, peroxides or peracids are considered. Hydrogen peroxide is preferred. The content of the polymers of -C00H and -CO can be adjusted by the oxidative polymerisation by the amount used. acrolein, acrylic acid and oxidizing agent. As the peroxide compound simultaneously acts as a regulator, the degree of polymerization can be influenced simultaneously by its concentration or amount relative to the monomer.

In addition to hydroxy groups, carboxyl groups, carbonyl groups, GH 2 OH groups and semi-acetal groups of the type may be present as end groups: CH = CH - CH (Va)

Lied

as well as vinyl groups or also hydrogen atoms, e.g. in the form of groups of the type: CH, - CH -7 3 | (Vb)

_ CHO J

or

~ CH. - CH

In (Vc) COOH_ and residues of the catalyst used. Depending on the desired carboxyl group content of the polymer, the homo- or copolymerization of acrolein can be carried out as well as solution polymerization and as precipitation polymerization, preferably in aqueous medium. When using peroxide compounds as the oxidizing agent, it is first recommended to prepare an aqueous solution or suspension thereof and optionally the comonomer or part thereof, whereupon acrolein, optionally in admixture with the rest of the comonomer, is added at higher temperature, e.g. 50 - 100 ° C. In solution polymerization, the obtained polymers, optionally after concentration of the solution, can be used directly for further reaction. Here, it is often advantageous to destroy in the solution still present amounts of oxidizing agent, e.g. by adding small amounts of manganese dioxide or activated carbon. However, it is also possible to precipitate the polymers from the solution by means of a dilute acid, e.g. hydrochloric acid. Residual monomers can be recovered, e.g. by distillation directly from the reaction mixture. In this case, the distillation residue constitutes a highly concentrated aqueous solution of the polymer which can be used for further reaction if necessary. However, the distillation can also be carried out to dryness, whereby the pure polymer is obtained in solid form. In a precipitation polymerization, the polymer can be easily separated by filtration. The residual monomers are then present in the filtrate and can be reused in this form. The precipitated polymers can be further purified with water eventually under the passage of air.

In the poly (aldehydocarboxylates), the units of type (II) may also be present in fully or partially hydrated form or because of reaction with the neighboring groups in the form of cyclic structures to form cyclic, acetalic and acylalic structures: 7 141251 Γ R2 Ί - CH - ΟΙ J> H (Ila) GH ^

X) H

R2 R2 "I

In I__ - ch2_. <p <IIb) / CH \ CH.

HO ^^ O- "" R2 R2 - CH2- C- ^ CH2 ^ 'C-- (Ile) / c "\ ho ^^ o_

These special structures, since they are in easily reversible equilibrium with the simple, open carbonyl structures (II), have no special significance.

By neutralization of the poly (aldehydocarboxylic acids) prepared with the above process with an alkali metal hydroxide or with ammonia, the corresponding poly (aldehydocarboxylates) in which A may have the meaning given above, is obtained except a hydrogen atom.

The poly (hydroxyaldehyde carbocylates) and poly (hydroxycarboxylates) to be used in the process of the reaction can be prepared in a well known manner. However, polymers made by oxidative polymerization of acrolein or by oxidative copolymerization of acrolein with one of the above-described poly (aldehydoarboxylates) and subsequent treatment of the polymer with a strong base, especially an alkali metal hydroxide, are preferred, according to Cannizzaro. The treatment with a strong base can also be carried out under simultaneous condensation with formaldehyde. Polymers are obtained which further contain units of the general formulas:

j3H2OH ~ “(| H20H

- CH + - 9 - and - CBL-C -

I 2 I

C 00 A J CH 2 OH

3

These units correspond to the general formulas (I) and (III) if R and R in these formulas each represent a hydroxymethyl group. If the treatment of the poly (aldehydocarboxylates) with the strong base of Cannizzaro leads to complete reaction of all initially present units of the general formula (II), poly (hydroxycarboxylates) is formed, but the reaction is only partially accomplished, poly ( hydroxyaldehydocarboxylater).

The first poly (aldehydocarboxylic acids) obtained can be reacted in the aqueous solution or suspension with the strong base, optionally in the presence of formaldehyde.

Here, one can proceed by adding the formaldehyde in an amount approximately equal to the stoichiometric with respect to the aldehyde groups present in the polymer, and stirring for a longer time at room temperature or at elevated temperature, until approx. 100 ° C and preferably at 20-60 ° C, with base addition little by little. After 2 hours, the turnover can already amount to 60-70% of the theoretically complete turnover, and within 4-24 hours it increases to 90-100 7o. The reaction in solution gives solutions which contain, in addition to the salts of the poly (hydroxyaldehydocarboxylic acids) or poly (the hydroxycarboxylic acids). there a surplus of base. They can be evaporated to dryness after neutralization. By precipitation of the reaction mixture, e.g. with methanol, the salts are obtained in a particularly pure form. However, it is also possible, before evaporation, to neutralize the solution with a dilute acid, e.g. hydrochloric acid or preferably formic acid, sulfuric acid or phosphoric acid, or to precipitate the free acids.

Conveniently, the neutralization of the base excess should only be carried out with acids whose salts do not prevent the further reaction of the polymer compound.

In addition, for example. use of carbon dioxide, hydrochloric, sulfuric, phosphoric, formic, acetic, citric or ascorbic. However, it is advantageous to use the poly (hydroxyaldehydocarboxylic acids) or poly (hydroxycarboxylic acids) themselves in pure, solid form or in solution thereof, or, according to a particularly preferred variant, the poly (aldehydocarboxylic acids) obtained as the intermediate above, preferably the types which are readily soluble in water, in aqueous solution or in solid form, or citric acid or L (+) - ascorbic acid may be used. In this way, neutral solutions of the salts of the poly (hydroxyaldehydocarboxylic acids) or poly (hydroxycarboxylic acids) can be obtained, which can be used directly for further reaction. They preferably have G-C bonds in the main chain and can be both unbranched or slightly cross-linked. The polymers are made up of at least 2 of the above units (I) to (IV).

These units are formed in part by the treatment of the poly (aldehydocarboxylic acids) by the Gannizzaro reaction. However, in this treatment, intermolecular aldol condensation may also occur between the active CH group and the carbonyl group present in one or more neighboring chains of the aldehyde group of poly (aldehydocarboxylic acids). This creates cross-links. Said units (I) and (III) as well as optionally (II) are indispensable for the further conversion of these polymers to iron salts or iron complexes.

If the reaction of the poly (aldehydocarboxylates) with strong bases according to Cannizzaro is carried out in the presence of formaldehyde, units are formed with the general formulas (I) and (III), wherein R or R represents a hydroxymethyl group, whereby the degree of crosslinking can be controlled through it. aldehyde amount used.

However, although the oxidative polymerization or copolymerization of acrolein is a radical polymerization, there may be in the main chain of poly (aldehydocarboxylates) and also poly (hydroxy-aldehydocarboxylates) or poly (hydroxycarboxylates) produced therefrom general formula (IV) present in minor amounts, up to 25 mole percent. It is formed by polymerization during the opening of the carbonyl double bond in acrolein. However, with regard to the further reaction to the iron salts or iron complexes, they are immaterial.

Practically unimportant are also those in the polymeric present end groups which are formed depending on the reaction conditions and the reaction medium. In practice, starting with acrolein and hydrogen peroxide, at least one of the two end groups of the poly (hydroxycarboxylates) or poly (hydroxyaldehyde carboxylates) is always a hydroxy group. In all other cases, these may be -CHO, -CH2 OH, -C00H or CH2 CH groups or hydrogen atoms, as well as residues of the catalyst used.

The corresponding partial salts of poly (aldehydocarboxylic acids), poly (hydroxy-aldehydocarboxylic acids) or poly (hydroxycarboxylic acids), i.e., the so-called "hydrogen salts", can also advantageously be used in the process according to the invention.

The iron salts or iron complex compounds of the water-soluble polymers described can generally be obtained by conventional methods of preparing iron salts from other metal salts, especially alkali metal salts, or from free organic acids, e.g. by an ion exchanger, eluting a cation exchanger charged with an iron salt solution with a solution of the polyelectrolyte, or simply by adding any water-soluble inorganic iron salt to the aqueous solution of the polymer. Optionally, the side products resulting from the formation of the iron salt or complex compound may be separated. However, if these substances do not contain substances that harm the organism in the intended use, this separation may be omitted. The preferred method of preparation is the addition of an iron salt, e.g. ferrous sulfate, to a corresponding amount of a solution of one of the above-described polyelectrolyte salts, in particular a corresponding sodium salt, with stirring and at temperatures between 5 and 100 ° C, preferably between 5 and 60 ° C and especially between 15 and 30 ° C, since the relative proportions of polyelectrolyte to iron need not correspond to the stoichiometric values. However, it is convenient to choose the ratio of the number of equivalents of polyelectrolyte to moles of iron in the range 0.5-4, preferably 1.0-3 and especially 1.2-2.

In the preparation of ferric salts or complex compounds, the desired product is precipitated directly using sufficiently high concentrations of polyelectrolyte and iron salt, and thus can be readily isolated in solid form. The ferrous salts or ferrous complexes are much more easily soluble in water, but can also be readily prepared in solid form by generally known methods such as e.g. by evaporation of the solvent, precipitation by the addition of alcohols or acetone or by salting out. Since the ferrous form is the most active form of the products prepared by the process of the invention, and at the same time the ferrous salts or complexes in solution are slightly oxide resin, it is recommended to make all manipulations of these products during manufacture under the least possible or shortest possible air supply or even better. without air or under protective gas or in vacuum. In spite of this, any oxidation during manufacture which produces minor amounts of ferric compounds relative to the present ferrous compounds does not, as is the case for many known iron preparations for anemia treatment, which is due to the fact that even the pure ferric or the pure ferric complex compound still has a positive anti-anemic effect. As has already been described generally, in this preferred method of manufacture, it is not unconditionally necessary to separate the sodium sulfate formed in the production reaction.

It is particularly advantageous to carry out the preparation of the iron salts or iron complexes in such a way that in a publisher an aqueous solution of not more than 60% by weight, preferably 20-50% by weight and especially 35-45% by weight, is applied (measured at 20%). ° C) between 5 and 9, preferably between 6 and 8 and especially between 6.5 and 7.5, of an alkali metal salt, preferably the sodium salt, of the polymer compound described, to which, under good stirring and under oxygen-free atmosphere or in vacuum, preferably under CC ^, He, Ne, Ar, or, at temperatures between 5 and 100 ° C, preferably between 5 and 60 ° C, an aqueous, maximum saturated, preferably 0.5-2.5 molar solution of a ferrous salt is added. By evaporation of the water, which may advantageously be done in a vacuum, but which must at least occur under the exclusion of oxygen, the formed iron salt or iron complex can be isolated in solid form.

The iron salts or iron complex compounds of the invention may contain the iron in divalent, trivalent or partly divalent and partly trivalent form. Preferably, it should be in predominantly divalent form (at least 55% and preferably at least 75%) adjacent to the trivalent form. The iron salts or iron complexes are well suited for the preparation of pharmaceutical compositions and compositions. The pharmaceutical compositions or drugs contain as active substance at least one of the compounds prepared by the process of the invention, optionally in admixture with other pharmacologically or pharmaceutically active substances. The drugs can be prepared using the known and conventional pharmaceutical carriers and excipients.

Such carriers and excipients are e.g. described in Ullmann's EnzyklopSdie der Technlschen Chemie, Band 4 (1953), p.1-39, Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918 et seq., H.V. Czetsch-Lindenwald, Pharmaceuticals and Adjacent Areas, and Pharra. Ind., Heft 2 (1961), pp. 72 ff.

Examples thereof are gelatin, cane sugar, pectin, starch, tylose, talc, lycopodium, silicic acid, milk sugar, cellulose derivatives, stearates, emulsifiers, vegetable oils, water pharmaceutically acceptable mono- or polyhydric alcohols and polyglycols, such as polyethylene glycols, derivatives, and derivatives. of aliphatic saturated or unsaturated fatty acids with mono- or polyhydric alcohols, such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol or mannitol, which may also optionally be etherified, benzyl benzoate, dioxolanes, glycerol formals, glycol fururates, dimethylacetamates, dimethylacetamide, dimethylacetamide,

In addition, the addition of preservatives, buffers, flavors, antioxidants or complexing agents is possible. As antioxidants, e.g. sodium methahydrogen sulfite and ascorbic acid under consideration, and as preservatives e.g. sorbic acid or p-hydroxybenzoic acid ether.

In particular, the addition of other active drug substances is first and foremost.

most vitamins or antibiotics, possible or beneficial.

The iron salts or iron complexes in question exhibit a good anti-ananic effect. This effect especially surpasses the effect of known iron preparations in that the hemoglobin value after a single administration for a prolonged period at a uniformly high level.

The lowest effective dose for a single oral administration is 50 mg per day. kg body weight. As usual dose range, Koran 150-250 mg / kg is considered. The iron compounds of the invention are suitable for the treatment of acute anemia as well as for prophylactic anemia treatment.

The pharmaceutical compositions usually contain between 1 and 95% by weight, preferably between 20 and 90% by weight, and more preferably between 30 and 80% by weight of at least one of the compounds of the present invention.

The administration can be in the form of tablets, capsules, pills, dragons or liquid agents. As liquid agents, e.g. oily or aqueous solutions or suspensions or emulsions under consideration. The preferred use is capsules containing between 100 and 800 rag of active substance.

The acute toxicity of the subject compounds for mice, expressed by LD5q, is at ca. 10000 mg / kg.

The invention is further illustrated by the following examples: 12141251

Example 1

By oxidative copolymerization of acrolein with acrylic acid (0.77 mole of acrylic acid per mole of acrolein) in aqueous hydrogen peroxide solution (0.9 mole of 20 wt% hydrogen peroxide per mole of acrolein) at 65 ° C and by subsequent removal of most of the residual monomer at distillation (in vacuo), followed by neutralization and reaction according to Cannizzaro with 45% by weight aqueous sodium hydroxide solution and subsequent neutralization with a residual amount of the intermediate obtained poly (aldehydocarboxylate) solution, a poly (hydroxycarboxylic acid) sodium salt (POC-Na salt) is prepared. ) (residual carbonyl content below 1 mole percent), s6m is characterized by the following mean parameters: U * 24.8, V = * 1, W 24, Y = 74, '2, mean degree of polymerization F = 33, and a C00T / 0H ratio of 5 , 2 (below, taking into account the end groups) and an equivalent weight of the corresponding free poly (hydroxycarboxylic acid) of 81.25. To 300 g of a 40% by weight aqueous solution of this POC-Na salt is added at 22 ° C with continued stirring (wing stirrer at 300 rpm in a 2 L three-neck flask) and, under nitrogen flow, a solution of 267 g of FeSO 71100 in 500 ml of distilled water over a period of 30 minutes (i.e.

1.66 moles of iron sulfate per hour and mole of POC-Na salt). Thereby, a 17.4% by weight aqueous solution of a POC-Fe complex salt of the formula composition [Fe (POC) ^ 25] g (SO ^) ^ together with the corresponding amount of sodium sulfate is obtained. The solution is evaporated to dryness in vacuo (with nitrogen as residual gas), washed with acetone (also under nitrogen) and then dried in vacuo at 20 Torr (residual nitrogen) and 100 ° C.

Pigs receive oral administration of this polyhydroxy-carboxylic acid complex salt (hereinafter POC-Fe) on the fourth day of life. Another group is administered the ferro-complex salt of ethylenediaminetetraacetic acid (hereinafter referred to as Fe-II-EDTA).

The administered amount of the various iron preparations in all cases corresponds to 400 mg of iron per day. animals.

On the fourth, the seventh, the fourteenth and the twenty-first days of life, the hemoglobin value in the blood is determined on the piglets in grams of hemoglobin .pr. 100 ml of blood (short Hb value).

The Hb value is compared to the value in untreated control animals. The changes in the Hb values are given in the table below, in which the Hb value at the beginning of the experiment, ie. on the fourth day of life, set to 100%. This provides a clear comparison of the anti-anemic and storage effects of the tested products.

13 141251

Table 1 Hemoglobin value in g / 100 ml blood and in% by oral administration of iron preparations to piglets.

Untreated Fe-II_EDTA POC-Fe complex

Number of animals .1) J 10 4 'xi

Fourth day of life;

Hb value 8.57 - 9.63

Relatively 100.00 - 100.00

Deviation from 0-0 initial value (%)

Seventh Day of Life:

Hb value: 7.65 - 9.38

Relatively 89.3 - 97.4

Deviation from -10.7 - -2.6 initial value (7.)

Fourteenth day of life:

Hb value: 5.48 - 9.75

Relative 63.9 - 101.2

Deviation from -36.1 - +1.2 initial value (7.)

Twenty-first life:

Hb value: 6.43 - 9.90

Relatively 75.0 - 102.8

Deviation from -25.0 - + 2.8 initial value (%) ^ The animals treated with FE-II-EDTA died within 36 hours.

For the untreated animals in the control group, a significant decrease in the Hb value occurs. The Hb value of the group treated with the POC-Fe complex salt decreases slightly on the seventh day of life, but then rises until the end of the experiment and is approx.

3 7 »above the initial value. This clearly indicates an anti-anemic and a depot effect. Fe-II-EDTA turns out to be toxic.

Comparative Example 1 In this example, the effect of a known iron preparation, Fe-II fumarate, representing usual oral anemia preparations is tested. The test technique is the one described in Example 1. Fe-II fumarate is tested on 8 animals, see table: 14 141251

Age of piglets (days of life) _4. day 7 »day 14. day 21. day

Hb value in g hemoglobin per 100 ml 10.23 10.09 9.30 8.87 blood

Relative 100.0 98.6 90.9 86.8

Deviation from output Q _1> 4 _9jl _13j2 operating value 9 / o

It is clearly seen that Hb values continue to decrease throughout the experimental period despite oral administration of Fe-II fumarate.

Comparative Example 2 In the test arrangement described in Example 1, an iron salt of polyacrylic acid according to GB-PS 1 155 208 (degree of polymerization 1000) is tested for its anti-anaemic effect on 13 piglets.

Age of piglets (life days 4th day 7th day 14th day 21st day)

Hb value in g hemoglobin per 100 ml 8.91 7.97 8.66 7.17 blood

Relative 100.0 89.5 97.2 80.5

Deviation from output _10> 5 _2.8 -19.5 starting value,%

The iron salt of polyacrylic acid, after oral administration, is comparable in effect to Fe-II fumarate. After a slight increase from the seventh to the fourteenth day of life, the Hb values fall again until the end of the experiment. The starting value of 8.91 g hemoglobin per 100 ml of blood is never reached again.

Comparative Example 3 In this example, a hydrolyzed maleic anhydride-ethylene copolymer according to GB-PS 1,155,208 (briefly referred to as HEMA-Fe) is tested for its anti-anemic effect on 13 piglets. The technique used is described in Example 1. Here again, there is only one effect similar to that obtained with Fe-II fumarate. The Hb values from this experiment are given in the table below.

15 141251

Age of piglets (life days 4th day 7th day 14th day 21st day)

Hb value in g hemoglobin per 100 ml 7.99 7.96 7.81 6.22 blood

Relative 100.0 99.4 97.7 77.8

Deviation from the starting point 4 _2.3 -22.2 starting value,% The hemoglobin values decrease somewhat more slowly until the fourteenth day, but the starting value is not reached again during the entire experimental period.

Example 2

By oxidative copolymerization of 20 mole percent acrylic acid with 80 mole percent acrolein in 20 wt. a POC-Na salt is prepared which is characterized by the following parameters (without taking into account the negligible low amounts of sodium citrate from the neutralization): Average degree of polymerization * 12, C00 / OH ratio 3.2 (including the end groups), U * 24, 5, V 11.0, W 22.5, Y * 64.5 and equivalent weight of the corresponding free poly (hydroxycarboxylic acid) = 90.1.

Into a 4 liter three-neck flask is placed 1000 g of a 37% by weight solution of the poly (hydroxyaldehydeocarboxylate) described above. Hydrogen is continuously stirred and rinsed. A solution of 460 g FeSO 2, 7 H 2 O in 1340 g distilled water is added at room temperature over a period of 30 minutes. After the iron sulphate addition, an addition of 1300 ml of ethanol follows. The precipitated precipitate is aspirated (hydrogen supply as a protective reading atmosphere) and, after repeated leaching with water-alcohol mixtures, finally briefly with pure cold water and then several times with pure alcohol, dried in vacuo (residual nitrogen) at 30 mm Hg and 100 ° C. . The greenish complex salt obtained corresponds to approx. and has a total iron content of 21.4 liters (of which 86% is Fe11 and 14% Fe111).

Example 3 In a method analogous to Example 2, is prepared from a PAC-Na salt characterized by the parameters: Average degree of polymerization * 60, U «18, V» 4, W = 3, Y = * 78 and equivalent weight of the free poly ( aldehydocarboxylic acid) * 86.4, and prepared by oxidative copolymerization of 50 mole percent acrylic acid with 50 mole percent acrolein in 20 weight percent hydrogen peroxide (0.9 mole hydrogen peroxide

Claims (2)

16 141251 pr. moles of acrolein) at 65 ° C and subsequent neutralization with aqueous sodium hydroxide solution, a PAC-Fe salt of the formula composition Fe (PAC) _. The product L II has a total iron content of 20.1% by weight, thereof 95% in the form of Fe and 5% in the form of Fe Example 4 A process analogous to Example 1 is prepared from a POC-Na salt characterized by the parameters: Average polymerization rate = 60, C00 ** / OH ratio = 7.7 (taking into account the end groups) U = 18, V 4, W ** 17.5, Y = 78 and equivalent weight of the free poly (hydroxycarboxylic acid) = 80.75 and prepared as the product described in Example 3, however, with subsequent reaction with sodium hydroxide according to Cannizzaro and neutralization with a residual amount of the acidic, neutralized polymeric acid, a Fe-POC salt of the formula composition [Fe (POC) J 2 SO 2. In addition to the sodium sulphate content contingent on the process, the product contains a total iron content of 17.4%, of which 87.5% in the form of Fe11 and 12.57o in the form of Fe ^^. A process for preparing iron salts or iron complex compounds of water-soluble carboxyl group-containing polymers by mixing. a water-soluble inorganic iron salt with the water-soluble polymer or an alkali metal or ammonium salt thereof in an aqueous reaction medium and isolation of the formed iron salt or iron complex of the polymer, characterized in that as a water-soluble carboxyl group-containing polymer, at least one polymer of intermediate polymer is used, 3 and 600, which are made up of Y + W / 2 mole percent units of general formula I ~ R1 - CH2 - C - (I) C00A U - W mole percent units of general formula II R2 ~ - ch2 - C _ ( II) _ CH0_