DE2112140A1 - Iron preparation - Google Patents

Description

Prof. Dr. Hellmuth C. Heinrich

University of Hamburg

Eppendorf University Hospital

The representatives:

Dr. Horst Bezzenberger
Dr. Gerhard Irmisch
Dr. Karl-Friedrich Gross

Authorized recipient:

FARBWERKE HOECHST AG

formerly Master Lucius & Brüning

623O Frankfurt (Main) 80

File number: HOE 71 / S 002

Date: March 12, 1971 Dr. Ka / sf Iron supplement

Iron deficiency is the most widespread human deficiency in both developing and highly developed industrialized countries. It occurs much more frequently than all protein and vitamin deficiency diseases combined. Deferred and prelate duck iron deficiency states in which about 25 $ of total body iron making up iron reserves have been g consumes about 1, can be in central Europe at least ho i> of all menstruating women and fo prove at 100 'all late pregnancy, duration of blood donors and toddlers. The cause of the worldwide spread of manifest, latent and prelatent iron deficiency states is the inadequate iron content of human food and the poor absorbability, especially of the dietary iron contained in plant foods, eggs, milk and liver.

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For oral iron prophylaxis and therapy have been used so far Iron (II) salts of inorganic and organic acids in used in numerous commercial preparations.

The main disadvantages of these iron (II) salt preparations are!

1 . As the dose of iron rises, the percentage falls Iron absorption strongly decreases. For example, female patients with depleted iron reserves resorb (prelate iron deficiency)

the end

ο, 56 mg Fe ²⁺ : 81 5 mg Fe ²⁺ : 40 50 mg Fe ²⁺ : 17th

2. Most foodstuffs and luxury items (bread, pasta, Vegetables, coffee, tea, etc.) so strongly inhibit ferrous iron resorption through the formation of iron complexes that only T / 3 to 1/5 of the amount of ferrous iron that can be absorbed in an empty state can be included. If the iron salt preparations cannot be taken on an empty stomach, Therefore, administration with or after meals requires a large increase in the amount of ferrous iron (from 100 mg Fe / d to 300 - 400 mg Fe / d), thus for hemoglobin regeneration sufficient amounts of 15 - 30 mg Fe / d be absorbed.

3. Most oral iron salt supplements are used in the due to inadequate absorbability, the high daily dosage of 200-300 mg required in particular empty stomachs from $ 30-50 of those treated with it poorly tolerated and cause bloating, nausea and vomiting. This intolerance of the ferrous salt preparations leads to premature discontinuation, especially in patients with sensitive stomachs and pregnant women oral iron treatment.

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k. Other disadvantages of the oral iron salt preparations belonging to the state of the art are the unpleasant metallic taste of the ferrous iron and the sometimes irreversible blackening of the teeth and damage to the gums, which occurs more and more frequently with iron treatment carried out over several months to years with increasing duration of therapy.

It has now been found that the above-mentioned disadvantages of the oral iron salt preparations are remedied by the application of a medicament can be avoided, which is characterized by a content of hemoglobin (= ferric hemoglobin or methemoglobin) is.

Surprisingly, the following were found for iron prophylaxis or therapy significant advantages when using such a hemiglobin preparation.

a) In contrast to that with increasing ferrous iron dose

32+

strongly decreasing Fe absorption (see above) is the Iron absorption from hemoglobin surprisingly largely independent of the dose in the physiological range. A doubling of the hemiglobin iron dose therefore leads to a doubling with the same percentage absorption iron absorption.

b) During the ferrous iron absorption by simultaneously Ingested food and luxury items is strongly inhibited, hemiglobin iron absorption remains under the same conditions Surprisingly undisturbed. The fasting intake required to achieve a sufficient rate of absorption of ferrous salt preparations is particular Impossible or very annoying for infants, small children and the elderly and therefore often the reason in practice for interrupting oral iron treatment. Hemiglobin preparations however, can without impairment

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be added to other foods (e.g. milk in babies) for iron absorption.

c) The hemiglobin, chemically firmly bound in the porphyrin skeleton is so chemically and biologically inert that it is typical of inorganic and organic salts of Perro iron Irritation of the stomach lining that occurs at $ 30-50 of that with the usual iron salt commercial preparations treated iron deficiency patients for bloating, nausea and vomiting leads, cannot cause. This superior gastric tolerance of hemiglobin iron is particular for the oral iron treatment for pregnant women and other stomach sensitive women Beneficial to patients.

d) In contrast to the two to five times worse absorbability of ferrous iron than that of ferrous iron from orally administered iron salts surprisingly becomes that in hemoglobin in trivalent form Bound iron from patients with iron deficiency is absorbed significantly better than the divalent hanging globin iron (Table 1).

Patients with depleted Fe reserves

- ^ Fe absorption (4d dose)
ⁿ * a t% 5 mg hemiglobin-Fe 16 22 + 1.7 5 mg hemoglobin Fe 16 18 + 1.2 Absorption quot.
X
a
$ 95 trust area
Significance, 2p 1.24
1, 08 - 1, 40
4.0.005

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Table Ί; Absorption of hemiglobin-iron and hemoglobin-iron in persons with depleted iron reserves.

e) During the extraction of hemoglobin, even under the most gentle working conditions, it cannot be prevented that part of the hemoglobin is irreversibly oxidized to form hemiglobin. Hemoglobin preparations are therefore not uniform and contain between TO and kO $ Hemiglobin-r The remaining 60 to 90 $ of hemoglobin are not stable and can also be oxidized to Hemiglobin during storage. While iron-II-salt preparations and also hemoglobin preparations must be particularly stabilized against oxidation (e.g. by adding ascorbic acid or sealing against atmospheric oxygen), hemiglobin preparations are stable against oxidation during preparation and storage Precautions are prepared and are still stable and uniform even with prolonged storage.

The hemiglobin used according to the invention is produced by oxidation of that from animal erythrocytes separated hemoglobin. It can be obtained, for example, as follows.

The erythrocytes are centrifuged off from heparinized animal blood and washed three times with 0.9% NaCl. After hemolysis, the erythrocyte membranes and stromal proteins become first at pH 5> 8 and then at pH 7j1 precipitated and separated by centrifugation. (McQuarrie and Beniams, Proc. Soc. Exp. Biol. Med. 8jS, 627 095 * 0; Nyman, scan. J. Cl in. Labor. Invest .JM., Suppl. 39 0959) » The hemoglobin in the supernatant exists in cellulose acetate electrophoresis (pH 8.6) and recycling dextran gel chromatography (Sephadex G-200) from a

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Fraction and does not contain any protein impurities. "Hemoglobin preparations obtained in this way usually contain $ 15-30 hemoglobin. Gentle oxidation with NaNO produces, for example, 1.44 g hemoglobin (= 5 mg Fe or 89.6 µmol
NaNO-) oxidized quantitatively to hemoglobin. The oxidation of hemoglobin to hemoglobin can also occur with others
gentle oxidizing agents are carried out. Hemiglobin preparations produced in the manner described contain more than $ 99 hemiglobin and are in contrast to oxidation-sensitive hemoglobin preparations
stable on storage.

The medicament according to the invention can expediently consist predominantly (up to $ 100) of hemiglobin. It
however, it is common to use pharmaceutical auxiliaries and additives
such as milk sugar, corn starch, talc,
Add tragacanth, magnesium stearate, etc. The medicament can for example in the form of a tablet, a
Dragees, but preferably as a powder or as
Syrup administered-, be administered. Appropriate pharmaceutical auxiliaries such as vegetable oils, glycerine, alcohol, etc. can be used for a liquid preparation. Agents such as, for example, those that correct the taste, such as sugar and vitamins, substances that promote absorption or other substances known as medicaments can easily be added. Also carbonates
or bicarbonates, preferably alkali or alkaline earth metals, can be added to produce effervescent mixtures. It is also possible to combine the medicament directly with the food, preferably a baby food such as milk, milk food, fruit or vegetable juices or porridges, ready-to-eat meals for babies or toddlers, etc.

The preparation according to the invention can, for example, have a content of about 3-100 ^ i, preferably from about 30 to
have about 99 fo hemiglobin. For certain preparations

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it may be advantageous to have a content of about 50 to about 95 / & hemiglobin to choose.

The dosage units of the preparation according to the invention can contain about 1 to about 20 g, preferably about 6 to about 20 g, but in particular about 10 to about 15 g of hemiglobin. Are smaller DosierungseLnheiten desired, for example for the prophylaxis in infants, children or menstruating, they may g a Hämiglobingehalt of for example about 1 to 6, preferably from about 1.5 to about 3 p.

The dosage units are to be applied depending on their hemiglobin content in such a way that for prophylactic purposes (for example for infants, toddlers, school children, menstruating women, pregnant women) about 3 to about 10 g hemiglobin, for therapeutic purposes a multiple thereof, for example about 10 g / day be applied.

The preparation according to the invention is produced in a manner known for the production of pharmaceutically active preparations, for example by mixing, Mixing, pressing and / or filling into the selected packaging units.

The hemiglobin-containing preparation according to the invention therefore, due to the considerable advantages outlined above, compared to the previous application of iron salts represents an enrichment of the technology, which could not be foreseen according to the state of the art.

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Claims (2)

Claims 1. Oral iron preparation, characterized by a Hemiglobin content. 2. Process for the production of an oral iron preparation, characterized in that one hemiglohin in an brings itself into a pharmaceutically effective preparation in a known manner and optionally with others Active ingredients, auxiliaries and additives mixed. 203841 / 1U91