DE2265386C2 - Process for the preparation of an iron complex and medicaments containing it - Google Patents

Description

C-COOH

/ I

Oh yo

has been received.

2. Medicament containing an iron complex prepared according to claim I in aqueous solution.

3. Medicament according to claim 2 with 5 to 100 mg r> Iron per milliliter of the aqueous iron complex solution.

20th

40

In the treatment of iron deficiency in mammals, including humans, iron can be administered orally followed by absorption through the gastrointestinal tract or parenterally by intravenous or intramuscular injection of a ferrous solution. In such solutions for parenteral administration, the iron must be present as iron (III) in a stabilized form in order to prevent gel formation and precipitation, such as, for example, precipitation of iron (III) hydrate at the physiological pH value. The iron must w also be present in such a form that, in the injection of doses nut a content of at least 100 mg of iron no toxic Ncbenrcaktionen local or general nature occur. Solutions of Eisensalzcn can γ parenter.ile for administration, are not used, mainly because of their relatively high Toxi / iiät

Various substances, ils Stabilizing agents in injections for parenterals Administration used. To avoid precipitation of ice (III) hydrate when alkalizing an aqueous To prevent dissolution of an Eiscn (III) salt, some types of stabilizing agents have already been used Used carbohydrates. An earlier preparation for parenteral administration existed in the wcsentli- (, 5 chen from an aqueous solution of a sugar-containing iron oxide. However, to prevent precipitation of iron (III) hydroxide To prevent this, the pFI-Werl had to do this Iron supplement can be alkaline, and parenteral administration of the preparation therefore often resulted in too much unwanted side effects.

Other types of stabilizers previously used in iron supplements for intramuscular injection were used are dextrins and dextrans. The use of dextrins and dextrans made it possible to prepare injection solutions with a physiological pH value. Preparations containing a complex of a low molecular weight dextran and iron, however, resulted in undesirable side effects such as local pain and discoloration of the skin surrounding the injection site, see Acta Medica Scandinavica Suppl. 342, T. Karlefors and A. Nοrdeη, “Studies on Iron-Dextran Complex ". Dextrin, a degraded starch, contains reducing groups that cause something Iron (HI) in the iron preparation to iron (IIj -ducate can. The presence of ^ isenfll) in the However, preparations is undesirable and a limiting factor in the occurrence of side effects when administered in high doses reveals that iron (II) is toxic

Yet another type of stabilizer used in the manufacture of iron supplements for intramuscular administration is a combination of sorbitol, citric acid and dextrin, see CA Patent No. 6 59 420. By the combination of sorbitol, citric acid and dextrin it was possible to stabilize iron (III) so that an iron complex with an average molecular weight of about 5000 was obtained, while the iron-dextran and iron-dextrin complexes used previously had average molecular weights above 150,000. The acute toxicity. LDio. when this iron complex was administered intraperitoneally to mice was about 50 mg per kg body weight, and this toxicity made it possible to administer iron to humans at doses not exceeding 200 mg, although it is higher than the toxicity of the iron-dextrin and iron-dextran preparations . The iron in this preparation, which is sold under the trade name "Jectofer", is in the form of particles of small particle size. so that they are quickly absorbed via the lymphatic vessels as well as via the blood vessels. However, the small size of the particles and the comparatively low average molecular weight also means that about 30% of the amount of iron administered is excreted via the kidneys. The remainder of the iron administered becomes a very high egg. Degree of blood formation exploited Although numerous advantages were achieved with iron-dextran and f.is ^ n-dextrin when using ") ectofer", there were still some disadvantages, namely the relatively high losses of iron administered via the kidneys and the acute toxicity. which, however, did not limit the usefulness of "ectofet" in the administration of single doses of no more than 200 mg iron; in humans, and thus may require a large number of inferences for a single patient. The presence of reducing groups in the dextrin can convert part of the iron (III) to iron (II) and be the cause of undesirable side effects when administered to the patient in very high single doses.

As stated above, previously used stabilizers in iron preparations contain for intramuscular injection of sugars or ticker polymers, such as dextrin or dextran, which at neutral pFI-word

15th

a stabilizing effect on an iron (III) colloid own. These previously used stabilizers usually contain reducing groups which are in Convert some amount of iron (III) in the injection solution to iron (II). Iron (H) is an undesirable one Component in iron preparations for intramuscular injection because of its toxicity and may be undesirable Cause side effects when administering the solutions to the patient. The amount of Iron (II), which is contained in the injection solution, can be a limiting factor for due to its toxicity represent the maximum dose of iron that can be given to the patient with each injection.

The main object of the invention is thus to provide an iron complex of trivalent iron and a to produce physiologically harmless, water-swellable polymer that

(i) has the ability to iron (III) at physiological

to stabilize the pH value,
(ü) causes an insignificant reduction of iron (III) to iron (II) in a solution for injection,
(iii) has the ability to form a complex with iron (III), which has a low toxicity and is absorbed to a high degree from an intramuscular depot after intramuscular injection, while only a smaller part is excreted via the kidneys, and

(iiii) has the ability to complex with ferric iron found, which has such toxicity that a dosage of more than 500 mg iron without serious side effects can be administered.

The new iron preparation is well absorbed and has a low toxicity, the dosage units with more than 500 mg iron without makes serious side effects possible

The invention relates to a process for the preparation in which an iron complex of trivalent iron and a physiologically harmless, water-swellable polymer, which is characterized in that one in aqueous solution at least one water-soluble iron (III) compound reacts with a polymer which by implementing

a) sucrose.

b) glycerine, a polyglycerine. Tetrite. Pentit, Hexit and / or heptii. a derivative partially etherified with alkyl groups having 1 to 5 carbon atoms of these and / or one partially etherified with hydroxylalkyl groups having 1 to 5 carbon atoms Derivative thereof and

c) a dihalohydrin, Fpihalohydrin and / or a diepoxide which can be derived therefrom

and subsequent reaction of the thus obtained Polymers with a C'ynnid. Acidification and hydrolysis with conversion of the carbonyl groups into groups

Pentites, for example arabitol, xylitol or ribitol (Adonil), hexites, for example sorbitol, mannitol, talitol, iditol, galactitol (dulcitol) or A-IMt, heptites, such as glyceroguloheptite (ct-glucoheptite), DG | ycero-D- idoheptite, D-glycero-D-galaheptite (a-mannoheptite), D-glycero-D-mannoheptite, D-glycero-D-glucoheptite (ß-sedoheptite), D-glycero-L-glucoheptite and glycero-idoheptite

Examples of polyglycerols are condensation products of glycerine, in which glycerine molecules condense to open-chain or cyclic ethers were like

CH ₂ OHCHOHCH ₂ -O-CH ₂ CHOHCH ₂ Oh

/
HIGH ₁ CH

CH,

CH ₂ CHCH ₂ OH
O

Another example of a tetritol is pentaerythritol
Many of the polyhydric alcohols of group b) mentioned above occur in various steric configurations and in racemic form and in the form of optical isomers. The named. Terms are intended to include all such steric and optical isomers as well as mixtures thereof.

The dihalohydrins and epihalohydrins wandein in alkaline ¹ × solution in the corresponding diepoxide to. Compounds which can be used in group c) are thus, for example, those of the general formula

CH ₂ -CH- (CH ₂ J _n -CH-R ² (I)
X OH R ¹

η = 0,1,2,3 or 4.
X = Cl, Br or 1,

R ¹ = OH ₁ Cl, Br or 1 means and

R ² = a hydrogen atom or, when R ^{1 is} the group OH, _{denotes the radical - CH 2} - X, in which X has the above meaning.

The formula I includes compounds of the general formula

CH ₂ CH (CH ₂ I _n CH CH ₂ (II)

45

50

OH

OH X

a, 'in front of η and X have the above meaning, and this In alkaline solution, compounds are converted into a diepoxide of the general formula

C COOH

/ I

OH

has been received.

A suitable partially etherified alcohol is hydroxypropyl sorbitol

Suitable polyhydric alcohols of group b) are glycerine, Tctrite, for example Thrcil or erythritol, CH ₂ -CH (CH ₂ ) ,, CH CH ₂ (III)
OO

converted, in which n has the above meaning.

Preferred compounds of group b) are the hexites and the heptites, of the compounds of Group c) the epihalohydrins, especially epichlorohydrin, are preferred.

Sodium hydroxide or potassium hydroxide can be used as the alkali in the presence of which the polymerization is carried out be used. The alkali can either be in the form of a solution or in the solid state

such as in the form of tablets. Alkaline earth hydroxides, such as barium hydroxide, can also be used as alkalis, but are generally less useful. That the preferred alkali is sodium hydroxide.

The polymer used according to the invention is produced and worked up analogously to that in FIG DE-OS 22 47 021 described operation.

During the polymerization of the starting materials, mixtures of reaction products with widely varying Molecular weights obtained. It is not possible to give the reaction products an exact uniform ascribed to chemical structure. Working up the intermediate reaction product obtained after the polymerization is believed to be a means of increasing the molecular weight distribution of the intermediate reaction product change so that low molecular weight components are removed. To identify the product the methods described below were therefore used. The specified and described Designations and methods can also be found in the examples where the respective reaction product is marked. The term "end product" as used below denotes that after the work-up including, if necessary, an addition of water, which is mentioned above. received Polymer product.

A. The weight loss on drying is obtained by drying the end product at about 105 ^° C. until a constant weight is obtained. The weight loss is given in% by weight, calculated on the end product.

B. The water contents in the final product are determined according to the Karl Fischer method, which among others in Pharmacopoeia Nordica. Volume 1. Ropes 75th is described. The water contents are in % By weight, based on the end product.

C. The sodium (Na ⁺ ) contents in the final product are determined using a flame spectrophotometer and are given in% by weight based on the final product in dry form.

D. The chloride ion contents (Cl) are determined by potentiometric titration and are given in% by weight, calculated on the end product or the end product in dry form. The amounts of Na ^f and Cl which are given show the amounts of salt present in the polymer preparation and do not mean that chloride ions are incorporated into the polymer.

E. The contents of dry organic matter in the final product are calculated as the weight of the End product excluding the weight loss during drying and excluding the weight of Na * and Cl are calculated and are in. Grams or in wt .-%. calculated on the end product.

F. The (I hold on carboxyl groups in the final solution be determined.

(i.The iron complexing capacity of the final product can be determined in the following way:
Ks the following solutions are used:

I. Distilled water
Lactic acid
Sodium hydroxide
Polymer (organic
Dry matter)

II. Sodium Hydroxide
Distilled V * barrels

225 ml

90 ml (1.20 mol)

148 ml (0.90 mol)

202.5 g

288 g (7.3 moles)

1200 ml

III. Ferric chloride hexabydrate. FeCl ₁ -6H ₃ O
Distilled water

fV. Hydrochloric acid 6-n

V. Distilled water

Vl. Ethanol, 95.5%

27Og (I ₁ OMoI)
405 ml
about 150 ml
about 2.21

about 14.81

Separate solutions of the ferric chloride, sodium hydroxide and polymer are prepared. The lactic acid (90 ml), ² / i of the volume of water (15OmI) and sodium hydroxide (148 ml) were separately mixed with each other before the polymer was added. The remainder of the water (75 ml) was used to rinse the kettles used and it was added to the solution. The resulting mixture was erhitzi I with stirring to 80 ⁰ C. To the mixture I were alternately with vigorous stirring 9x90 <Til portions of the sodium hydroxide solution (M), a total of 4.86 mol NaOH, unc ¹ J 60 ml portions of the iron (III) chloride solution (III). total 1.0 mol added. The addition was made dropwise over 1 minute for the sodium hydroxide and dropwise over 2 minutes for the ferric chloride. There was a waiting period of 2 minutes between each addition. 1 minute after the last addition of ferric chloride solution, 167 ml (058 mol) of sodium hydroxide (II) were added. The temperature of the reaction mixture was then held at 80 ° C for 35 minutes, after which the mixture was cooled to 25 ° C. Thereafter, the volume of the reaction mixture was adjusted to 2250 ml using distilled water, and 5100 ml of ethanol was added over 15 minutes to 30 minutes with vigorous stirring. Stirring was then continued for an additional 10 minutes. The resulting precipitate was allowed to settle for 30 to 60 minutes, after which the mother liquor was filtered off with suction. The precipitate was filtered off

and washed once with 900 ml of dilute ethanol (2 parts by volume of ethanol and 1 part by volume of distilled water). The precipitate was then dissolved by adding 1350 ml of distilled water heated to 40 ° C. while stirring. After the addition of the precipitate, the solution was heated ^{to 80 ° C. in about 30 minutes.} The mixture was then kept at 80 ° C. for a further 30 minutes while stirring. The solution was then cooled to 25 "C and neutralized using 6η-hydrochloric acid, which was added dropwise with vigorous stirring over 20-25 minutes until the pH of the mixture was 6.2. Usually 140-150 The reaction mixture was freed from undissolved matter, whereupon the volume was adjusted to 2100 ml with distilled water. A second precipitate was made by adding 4575 ml of ethanol to the solution over 15 to 20 minutes while stirring Stirring was continued for a further 2 minutes. The precipitate was left overnight. The mother liquor was then filtered off with suction and the solid was filtered off with suction and three times using 900 ml of dilute ethanol (ethanol to water 2: 1) and three times with it washed with undiluted ethanol (900 ml), whereupon it was ^{dried in vacuo at 40 °} C. for 4 to 5 hours or overnight.

The following parameters were determined in the dried iron drainage:

1. Yield of dried iron preparation, measured in grams.

2. Yield of complex-bound iron, calculated in% of the total amount ah Eiseh (III), the had been added during the reaction.

3. Iron content in the dried iron preparation in% by weight, calculated on the dried iron preparation.

H. Absorption of an intramuscular injection solution prepared using the dried iron preparation obtained in G above. in rabbits. The injection solution of the dried iron preparation obtained and described under G above was prepared according to the following method. 125 ml of distilled water were ^{heated to 80 °} C. in a three-necked round-bottom flask with a condenser, thermometer and stirrer. Dried iron preparation obtained as described above was added in small portions over 15 minutes with vigorous stirring. Dried preparation corresponding to 7.5 g of iron was added. The solution thus obtained was kept 50 minutes to 80 "C, whereupon it was cooled to 25 ° C. Ml After diluting with distilled water to 150, the obtained solution was filtered, transferred to 10 ml AinpulIen and 20 minutes at l20 ^e C The injection solution obtained had a total iron content of about 50 mg per ml.

The absorption tests in rabbits were carried out in the following manner. The solution for injection was injected deep into the gluteal muscle of rabbits at doses of 20 mg Fe per kg body weight. Male albino rabbits weighing 2 to 3 kg were always used. The animals were in different time intervals after injection, and the glutes were killed by the legs replaced. The muscles and skin around the injection site were moistened with sulfuric acid and nitric acid oxidized, and the iron content was then determined using a colorimetric rhodanide method. It was found that the iron is absorbed very quickly

more than 60% of the iron administered was absorbed, after 7 days more than 85% of the iron was absorbed and after 14 days more than 90% of the iron. It was also found that the amount of iron decreased after 24 hours was mostly eliminated. was less than 15%. Thus it can be seen that iron supplements for intramuscular Injections made in accordance with the present invention compare favorably with those currently in existence and intramuscular iron supplements available on the market.

From the results of the gel filtration with the commercial product Sephadex G: 15. G: 25 and G: 50 it can be concluded that the average molecular weight of the polymer in the "end product" designated shape is in the range of 700 to about 5000 It has also been found that polymers which are after the gel filtration tests have an average molecular weight in the range from 1500 to 5000, Iron complexes result in the form of a

(1) [PolymerJ = C = O + injection solution particularly advantageous with regard to the Absorption and excretion are when the studies were carried out in rabbits.

I. The intrinsic viscosity of the polymer in many cases ranged from about 0.020 to about 0.080 dl / g.

The amount of carboxyl groups in the polymer used is generally 0.2 to 1.5 milliequivalents, calculated per gram of the organic dry matter, which was determined as described under E above.

The polymerization of the starting materials can be carried out in a medium which, with respect to the Reactant solutions is indifferent. Examples of such indifferent media are benzene and white spirit. However, aqueous solution is the preferred medium.

The reaction conditions with regard to the relative proportions of sucrose, polyhydric alcohol and the starting materials of group (c) can be varied to a considerable extent. Also the reaction temperature and the manner in which the reactants are brought together can be appreciable can be varied. As examples of possible variations in the relative proportions of the reaction partners it can be mentioned that per mol of the polyhydric alcohol 0.1 to 1.0 mol of sucrose and 0.05 to 5 mol Starting compounds (c) can be used. The reactor temperature is advantageously around 20 "C to the boiling point of the reaction mixture. The preferred reaction temperature is 75 to 85 ° C. The amount of alkali that should be present or added during the reaction depends strongly on the amount of starting compounds (c). Usually the total amount of hydroxyl is ions present during the reaction. 1.5 to 4.5 moles per mole of polyhydric alcohol. Sodium hydroxide is expediently used as the alkali. That so The resulting polymer contains "protected" aldehyde and keto groups. which come from sucrose (sucrose does not reduce Fehling's solution). These aldehyde and keto groups are then in one

/. pla.UVII IW.UMIUIIJ31UIV. UUlUIt ^ .U3cll £ VUII OttUIC Ul CIIlCII brought reactive state. The hydrolysis is likely to have little effect on that

Etheric bonds connecting the monomers in the polymer structure and the main structure of the polymer are therefore likely to be left intact after this acidification. In the third reaction stage, the polymer containing the activated aldehyde and keto groups, is reacted with cyanide ions, said ion Cyanic ¹ to form a Cyanohydrinverbindung to the carbonyl groups in the polymer are added. In the fourth reaction stage, the cyanohydrin compound is hydrolyzed, whereby the cyano groups are converted into carboxyl groups. Using this four-step process, a polymer containing the above-described amount of carboxyl groups can be produced without using a hydroxycarboxylic acid as a starting material.
Schematically, the last three stages can go through

the following reaction schemes are explained:
^ - »[PolymerJ = C-CN

Acidification (2) [Polymeric — CN »[Polymeric — CN

OH

hydrolysis
(3) [Polymeric — CN ► [Polymeric —COOH

OH

The reaction between the carbonyl-containing polymer and cyanide (equation 1) is now somewhat in Discussed details. The reaction is preferably carried out using an alkali metal cyanide such as KCN or NaCN. The reaction is preferably carried out in aqueous solution. but it can also be in highly polar organic solvents, such as pyridine or dimethylformamide, can be carried out. the Reaction with the cyanide is expediently carried out at a pH value of 7 to II. preferably at a pH value of about 9. The reaction temperature can can be varied, but is usually a temperature favorable in the range from 20 to 50 ° C. The reaction rate increases with the temperature, but at Temperatures above about 50 ° C can be used by the cyanide reactant be hydrolyzed.

When the above reaction (2) is substantially completed. the reaction product obtained is hydrolyzed. The hydrolysis is preferably carried out by heating the reaction solution to a temperature of 90 to 100 ⁰ C. Hydrolysis is facilitated by bubbling a gaseous medium such as air or nitrogen through the solution to remove the ammonia that is formed during the hydrolysis.

It is not necessary to present the cyanohydrin product isolate from hydrolysis. The reaction product obtained in the above equation (I) can be hydrolyzed directly will. If desired, however, the hydrolysis can be facilitated by, for example, by Ion exchange, an excess of cyanide ions removed prior to hydrolysis.

According to the method of the invention, an iron complex compound suitable for intramuscular injections in human medicine and veterinary medicine is suitable, manufactured in such a way that one in a alkaline aqueous solution

a) at least one water-soluble iron (III) salt and

b) the physiologically harmless, water-swellable polymer, which is constructed as described above and is able to form complexes with iron (III) at alkaline pH, whereupon the iron-containing complex is precipitated and the precipitate is purified and dried. The reaction between the iron (III) salt and the polymer takes place at a pH which occurs at the end of the reaction a value of 10 to 14 was brought by the addition of alkali.

The iron must be in the trivalent form, since the iron (II) compound does not have the desired stability result. Suitable water-soluble iron (III) compounds are about iron (III) chloride, which is preferred Iron (III) nitrate, sulfate and acetate as well as double salts such as iron (III) ammonium sulfaL

The dried preparations can contain 5 to 40% by weight, especially 20 to 36% by weight, of iron, and the injectable solutions can contain 5 to 100 mg iron per ml, especially about 50 mg iron per ml. It is generally desirable that the iron concentration in the injection solution is as high as possible so that the injected volume can be kept small, but in some cases can also be less concentrated Preparations may be more suitable.

OH

The dry iron preparation is prepared in such a way that the polymer, which was prepared as described above, with a water-soluble iron (III) compound, preferably

ίο iron (IIl) chloride, converts, after which the obtained ferrous complex precipitated and the precipitate cleaned and, if necessary, dried. The pH in the reaction mixture becomes such set to be brought to a value of 10-14 at the end of the reaction. The one in the The amount of polymer used in the reaction can be in the range from 1 to 15 g, advantageously from 3 to 6 g as a dried product, per gram of iron. The reaction temperature is expediently in the range of 0 ° C to 100 ° C. In the first embodiment described below, the temperature is preferably at about 80 ° C. The pH of the acidic reaction mixture is gradually increased to a value of 10-14 during the reaction. Can be used as alkali Sodium hydroxide can advantageously be used. The iron complex is precipitated from the reaction solution using a nonsolvent for the complex. Ethanol is expediently used. When the solution of the iron complex is to be used directly, the complex will not precipitate after the final dissolution.

Redissolving is conveniently carried out for the purification of the precipitate by the addition of the precipitate to distilled water at a temperature of about 40 ⁰ C. The temperature is then increased to about 80 ° C and held there for some time. The solution is then cooled to room temperature and the pH from about 5.5 to about 10, preferably to about 6 to 8, with a suitable acid such as HCl. set.

In one embodiment of the method for reporting uCS trocrccncr; i ^ scnprapsratcs άίγί * c; r; c alkaline aqueous solution of the polymer and optionally made of lactic acid. Lactic acid can be added in an amount from 0 to about 10 grams per gram of iron. Then, the mixture is heated to about 80 ⁰ C, and proportions of iron (III) compound in aqueous solution and amounts of alkali in aqueous solution are alternately added. In this way

so the pH of the reaction mixture is kept constant alkaline. The polymer is in an amount from 1 to 15 g, calculated as dry matter, per gram of iron added. Preferably 3 to 6 g Polymer, calculated as dry product, used per gram of iron. The reaction mixture can then left to stand for some time and then cooled to room temperature. The iron complex formed is then made using a nonsolvent for the complex, expediently of ethanol, precipitated The precipitate formed is separated and purified by repeated dissolving in water, precipitation and washing, and finally becomes dried

In another embodiment of the method for producing the dry iron preparation a first aqueous solution is prepared containing the polymer and the total amount of it to be used Iron (IIi) salt contains 1 to per gram of iron

15 g of Polynier used in the first aqueous solution. The preferred ratio is 3 to 6 grams of polymer per gram of iron. To the resulting acidic solution, to which no lactic acid is added appropriately, alkali is added at a temperature in the range of 0 to about 60 "C gradually If all alkali has been added, the temperature of the reaction mixture is increased to about 8O ⁰ C, kept at this level for some time and then ^{lowered to about 25 °} C. The iron complex formed is then worked up by precipitation and redissolving as described above, with the exception that a little more polymer in alkaline aqueous solution is expediently added with each redissolving For example, if two precipitations and redissolutions occur, about ¹ Å of the initially added amount of polymer can be added with each redissolution.

When preparing an injection solution of the dry iron preparation, the dry iron preparation is dissolved in water and sterilized by autoclaving. The dry iron preparation is added in portions to distilled water at a temperature of about 80 ^° C. while stirring. When all of the dry iron preparation has been added, the temperature is held at 80 ° C for an additional time, such as about 50 minutes, after which the solution is cooled to about 25 ° C, optionally diluted with distilled water, filtered and dispensed into bottles which treated in the autoclave at about 120 ° C for about 20 minutes. A typical preparation obtained in this way contains about 50 mg iron per milliliter.

As can be seen from the following examples, the iron preparations are sterilized in the form Solutions for injection absorbed well when tested in rabbits, while concurrent with excretion in iron, which is often less than 15% 24 hours after administration, is low. the acute intraperitoneal toxicity of the injectable iron supplements in mice was found to be in the range FROM 3GC lmS 500 Π "ιι je ivtiCigfarriu"! iN-OrpcrgcwiCui lying. The acute interperitoneal toxicity of Jectofer® lies in tests with the same Mouse strain at about 50 mg / kg body weight. The low toxicity of the manufactured according to the invention Iron supplement in combination with its high absorption and low excretion makes it possible to administer doses containing more than 500 mg of iron. Anyone can do two such doses To be given to patients at one time.

example 1

Production of the polymer SEG 35/71 from sorbitol,
Sucrose and epichlorohydrin

A 5 l round bottom flask with stirrer, dropping funnel, The thermometer and cooler were at 45 ° C 150 ml of distilled water, 34 g of NaOH, 300 g of sorbitol and 150 g Sucrose added 200 ml of epichlorohydrin were then added continuously over 55 minutes. The temperature was raised to 75 ° C. over 20 minutes, calculated from the start of the addition of the epichlorohydrin The temperature of 75 ° C was maintained during the polymerization, which under effective Stirring was carried out because the reaction mixture becomes very viscous at the earth stage of the synthesis.

The materials listed below were portioned added according to the following scheme:

85 g NaOH in solid form;

20 g NaOH, dissolved in distilled water on a

Volume of 28 ml
55 ml epichlorohydrin.

250 ml of benzene and 200 ml of distilled water were also used because of the increasing viscosity of the Reaction mixture added during the course of the reaction.

Time Added Added amount of hydrin (G) Amount added Epichlorine NaOH amount (ml) 5 of NaOH solution 15th 10 (min) 10 (G) 60 10 20th 75 10 90 10 105 120 50 10 135 10 25th 150 10 165 180 195 210 5 14th 30th 225 14th 240 246 250 ml of benzene

248

are added
200 ml of distilled water will be
added

At 285 minutes, cooling of the reaction mixture began simultaneously with the slow addition of 40 ml 5-m HCI. 100 ml of 6-m HCl were then added, the polymer being an easily mobile suspension in

the temperature in the reaction mixture was 56 ° C, and at 330 minutes the cooling was stopped.

The temperature was then 30 ° C. 70 ml of 2M NaOH were added, after which the pH value after 15 Minutes measured is <0. The reaction mixture was filtered through double filter papers. the Filtration was very slow and was done overnight

so continued. The next day the filtration was stopped and the filtrate had formed two phases. on a small amount of sticky residue remained on the filter. The different factions were defined as follows:

Filtrate, benzene phase F 1, discarded.
Filtrate, water phase F 2.
Residue on the filter, F 3, discarded.
F 2 was highly iridescent and was therefore filtered through a Seitz filter plate Ko2. The filtrate was still iridescent, but considerably less than before the filtration.

Designation: Filtrate F 4, volume 1070 ml.
_{& 5} residue on the filter. F 5. very small amount, thrown away.

F 4 was diluted to 120OmI with water. The pH was 0.02. 3000 ml of 99.5% ethanol

were added with vigorous stirring and the mixture stood for 60 minutes.

Designation: Mother liquor F 6. Thrown away

Remainder F 7, volume 750 ml.

F 7 was made with 150 ml of distilled water and 1500 ml 99.5% ethanol mixed. The mixture was allowed to stand for 2 hours.

Designation: mother liquor F 8

Remainder F 9, volume 650 ml.

F 9 was mixed with 325 ml of distilled water. The mixture was stirred for 10 minutes and then 1300 ml of 99.5% ethanol were added. The mixture was allowed to stand for 30 minutes.

IO

15th

g: mother liquor F 10
Remaining FIl, volume 630 ml.

FIl was with 315ml distilled water and with 1260 ml of 99.5% ethanol were mixed, after which the mixture was allowed to stand for 40 minutes.

Designation: mother liquor F 12 remainder F !! volume 500 ml.

F 13 was mixed with 100 ml of distilled water and 1000 ml of 99.5% ethanol. The mixture was allowed to stand for 30 minutes.
Designation: mother liquor F 14
Remainder F 15.

F 15 was washed three times with 250 ml of 99.5% aqueous ethanol, after which it was dried in vacuo at 5O ⁰ C for 60 minutes, to radicals of the ethanol to be removed. The dried F 15 was diluted to 493 g with distilled water and designated SEG 35/71 F 16.

25th

35

50

Analysis of SEG 35/71 F 16

Weight loss on drying 32.7%

Na content ⁺ 4.7%, calculated on the dried sample

Cl content - 7.2%, calculated on the dried sample

The product SEG 35/71 F 16 was used as the starting material

icMet! at u6i'S ^ fiiucSc OF SCG 35/71 Vcrw'cfiutäi, WO the cyanohydrate reaction was carried out.

45

Production of the polymer SEG 36/71
by implementing SEG 35/71 with potassium cyanide

Raw materials

I. 273 grams of polymer SEG 35/71 F16. The substance contains reducing groups corresponding to 18 g of glucose. 500 ml of distilled water, 0.5 ml of 25% NH ₄ OH.

Ii. A solution of 15 g of KCN corresponding to twice the equivalent amount of glucose plus about 10% glucose in excess, calculated on 18 g glucose, in 50 ml distilled water.

Solution I was added to a round bottom flask equipped with a magnetic stirrer, dropping funnel, thermometer and condenser with a receptacle. Solution II was added to solution I at room temperature, then allowed to stand for 30 minutes. The temperature was now ^{raised to 40 °} C. and held there for 120 minutes. The solution was then allowed to cool and stand at room temperature for 3 days. The temperature was then ^{increased to 70 °} C. in 90 minutes, while a stream of air was passed through the solution at the same time. After 15 minutes at 70 ⁰ C, the heating was stopped and allowed the temperature to 30 ⁰ C fall. 2-M HCl was added slowly and with vigorous stirring to a pH of about 6. The solution was then reheated to about 70 ⁰ C währenu simultaneous ventilation. After this repeated heating and ventilating, which was carried out for 60 minutes, the solution was allowed to whereafter the pH was adjusted to about I with 2-M HCl cool down to room temperature ^s a. The acidified solution was allowed to stand until the next day, after which it was heated to 7O ⁰ C for 30 minutes. After the solution was cooled, it was checked for the presence of cyanide ions. The test showed that no cyanide ions were present. The solution was evaporated to about half its volume in vacuo and the pH was adjusted to 5 using NaHCCh. 10 g of activated charcoal were added with stirring. After 15 minutes the mixture was filtered through a Seitz No. Ko2 filter plate. The filter plate was washed with distilled water. The wash water was mixed with the filtrate and the resulting mixture was evaporated to about 250 ml in vacuo. Two volumes of 99.5% ethanol were added and the mixture was allowed to stand for 30 minutes. After that, two phases had formed, which were designated as follows:

Easy phase: F 1

Heavy phase: F 2, volume 230 ml

F 2 was made with 1/5 volume of distilled water and 2 parts by volume of 99.5% ethanol mixed. The mixture was allowed to stand for 30 minutes, whereby formed two phases, which were named as follows:

Easy phase: F 3
Severe phase: F ^ -

F 4 was mixed with 1/2 volume of distilled water and with 2 volumes of 99.5% ethanol. TvIdIi let üttb Gciiiiaüi btehcn 30 fvitnuts, whereby Muh formed two phases, which are drawn as follows became:

Easy phase: F 5

Heavy phase: F 6, volume 210 ml

F 6 was mixed with 21 ml of distilled water and with 105 ml of 99.5% ethanol. After 30 minutes the light phase (F 7) was poured off. The heavy phase (F 8) was twice with 105 ml of 99.5% Ethanol and washed three times with acetone, whereupon it was dried in vacuo to remove residual acetone to remove. The dried fraction was diluted to 231 g with distilled water and used as SEG 36/71 F 9.

Analysis:

Weight loss on drying 35.5%

K ⁺ 3.3% content, calculated on the dried sample

Na content ⁺ 2.6%, calculated on the dried sample

CI- 6.2% content, calculated on the dried sample

Content of carboxyl groups 0.54 milliequivalents per gram of organic dry matter

Manufacture of dry iron preparation SEM 67/71
with a content of polymer SEG 36/71 F 9

An amount of the polymer SEG 36/71 F 9 corresponding to 60 g of organic dry matter was dissolved in 300 ml of distilled water at room temperature. A solution containing 60 g of FeClj-6H2O in 100 ml of distilled water was mixed with the polymer solution at room temperature. 1000 ml of 1M NaOH were added to the resulting mixture with stirring. After 70 minutes at room temperature, the temperature of the mixture was increased to 80 ° C. The mixture was kept at this temperature for 20 minutes, after which it was cooled to room temperature and filtered through a Seitz filter plate Ko2. The filtrate was diluted to 1900 ml with distilled water and 3800 ml of 99.5% ethanol was added with vigorous stirring. After 20 minutes, the resulting precipitate was filtered off and dissolved in a mixture of 600 ml of distilled water, 15 g of polymer, calculated as organic dry matter, and 20 ml of 1M NaOH. The temperature was increased to 80 ° C. and held at this level for 25 minutes after which the solution was cooled to room temperature. To the cooled solution, 1M HCl was added to pH 6.7 with vigorous stirring. The solution was then filtered through a Seitz EKS filter plate. The filter plate was washed with distilled water which was mixed with the filtrate. The pH of the mixture was adjusted from 7.7 to 73 using 1-m HCl, after which the volume was adjusted to 1000 ml with distilled water. 2000 ml of 99.5% ethanol was added with vigorous stirring. After 30 minutes, the resulting precipitate was filtered off and washed with 100 ml of ethanol, which was diluted to the same concentration as the mother liquor, and with 100 ml of ethanol diluted to TS ⁰ A and finally three times with 150 ml of 99.5% ethanol. The washed precipitate was dried in vacuo at 50 ° C. Yield 74 g, total iron content 22.8%, calculated on the original sample.

Example 2
Preparation of the injection solution SEM 67/71 A

130 ml of distilled water were added to a 500 ml round flask with stirrer, thermometer and condenser, and this was heated to 30 ° C. 323 g of the dry iron preparation SEM 67/71 obtained in the previous example were added to the water for 10 minutes while stirring added. The temperature of the mixture was calculated at 80 ° C. for 70 minutes from the start of the addition of the dry iron preparation. The received! The solution was then cooled to room temperature and the pH adjusted to 7.1 using 1M HCl, after which the volume was adjusted to 150 ml with distilled water. The solution was then filtered through a Seitz filter plate Ko2 and through a Pyrex glass filter. The filter was filled into an ampoule and treated for 20 minutes at 120 ° C. in an autoclave

Analysis:

Total iron amount 50.5 mg / ml
Amount of Fe ²⁺ 0.98 mg / ml
Viscosity 10.7 cps
pH 7.7

Iron absorption in rabbit muscle after 7 days 86%. Excretion of iron in rabbit urine rend of the first 24 hours after injection 2%.

»9 682/14

Claims (1)

Patent claims: I. Process for the preparation of an iron complex from trivalent iron and one physiological harmless, water-swellable polymer, characterized in that in aqueous solution reacts at least one water-soluble iron (I! I) compound with a polymer, that by implementing to a) sucrose, b) glycerine, a polyglycerine, tetritol, pentitol, hexitol and / or heptitol, one with alkyl groups with 1 to 5 carbon atoms partially etherified derivative thereof and / or a derivative thereof partially etherified with hydroxylalkyl groups having 1 to 5 carbon atoms and c) a dihalohydrin. Epihalohydrin and / or a diepoxide derived therefrom and then reacting the polymer thus obtained with a cyanide, acidifying and hydrolyzing converting the carbonyl groups into groups