NO138967B - DEVICE FOR IMPROVING THE EFFICIENCY OF A CENTRAL HEATING SYSTEM - Google Patents

Description

Process for the production of iron preparations for oral use.

The present invention relates to a method for the production of iron preparations for the treatment of iron deficiency by

■oral administration.

The treatment of iron deficiency is now mainly based on oral administration of iron. The reason for this is, among other things, that parenteral iron treatment, for example by intramuscular or intravenous iron injections, cannot be carried out by the patient himself, and is usually accompanied by a certain risk of the patient's reaction, and will also often result in local unwanted effects. at the site of administration, such as pain and strong discoloration of the skin. Deaths have even occurred as a result of shock arising from parenteral iron administration. The risk is always greater with parenteral than with oral administration.

Even when given orally, common iron preparations cause up to 20 per cent of them

• treated any side effects in the digestive system, such as diarrhoea, nausea, constipation and a general feeling of discomfort. Some people cannot tolerate any form of iron preparations at all. How serious the side effect is is mostly dependent on the size of the iron dose administered, which must usually be several times greater than the amount of iron to be absorbed. In order to overcome the disadvantages of the current iron preparations, it has been proposed to divide the total amount of iron taken over a whole day and to administer the iron in repeated small doses at intervals during the day, but this

is, however, inappropriate for the patient and does not solve the problems of eliminating the unwanted side effects in a satisfactory manner.

Another disadvantage of the previously known oral iron preparations has been the difficulty of building up the iron stores in the body quickly enough. These preparations will only increase the iron content of the stores at an acceptable rate at the beginning of the administration period. Further supply of iron to the warehouses necessitates administration over very long periods of time.

Liquid preparations for oral administration have the additional disadvantage that the iron taste is unpleasant for most patients, and they discolour the patient's teeth.

There is therefore a great need for iron preparations, especially in tablet form, which have a significantly improved absorption compared to previously known preparations, as such a preparation would make it possible to administer a smaller dose with the same or greater effect, but with a lower frequency and degree of side reactions. Such an improved preparation would also make it possible to completely or partially replace the intramuscular or intravenous iron injection which has hitherto been unavoidable in some cases.

One purpose of the invention is to provide iron preparations which comprise an absorption promoter which greatly increases the absorption of the iron component upon oral administration.

From American patent no. 2,851,394, it is known that dioctyl sodium sulfosuccinate has an absorption-increasing effect on certain drugs, including ferrous sulfate. To the extent that such an effect exists, it may be related to the surface tension-lowering effect of the dioctyl sodium sulfosuccinate used, which enables somewhat better penetration of the active substance into the absorbing capillaries in the gastric terminal canal. According to the present invention, however, a promoter specific for ferrous compounds is used which does not exhibit the medium surface tension-lowering effect indicated above, but actively participates as an energy donor in the transport of iron from the intestine to the plasma and is metabolized. In practice, it has been shown that the increase in absorption induced in the latter way is markedly superior to that obtained by using a surface tension-lowering agent.

According to the invention, pharmaceutical iron preparations are obtained that can be given orally, which comprise a mixture of a ferrous compound and which promotes iron absorption a succinate (as defined below), both the ferrous compound and the succinate being physiologically harmless and easily soluble in digestive fluids or intestinal fluids or both.

If desired, the preparations can comprise a physiologically harmless carrier. With the expression "physiologically harmless" as used in connection with ferrous compounds, succinates and carriers, it is meant that the substance is not harmful to humans when administered in the desired manner.

Examples of soluble ferrous compounds which can be used in the preparations according to the invention are inorganic, organic and complex ferrous compounds, such as ferrous sulphate, ferrous chloride, ferrous gluconate and ferrous sulphate-glycine complex.

The absorption promoter in the preparations is a succinate, an expression used here for succinic acid or a salt of succinic acid. Examples of suitable salts of succinic acid are sodium, ammonium and magnesium succinate.

The amount of succinate added is not critical, but the increase in absorption obtained is greater the greater the amount of succinate administered (compare figure 2 in the drawing). When determining the correct ratio between ferrous compound and succinate to achieve the desired absorption, it must be taken into account that the administration of a small amount of iron gives a greater percentage of absorption than a larger one. When the iron dose that is administered amounts to approx. 10 mg, 30 mg to 500 mg of succinic acid is particularly suitable for the purpose. This corresponds to 1.5

—24 equivalents of succinic acid per equivalent iron. For larger iron doses, for example approx. 30 mg of iron, the amount of succinic acid component is preferably between 35 mg and 750 mg, that is y2 to 12 equivalents of succinic acid per equivalent iron. Preferably, the number of equivalents of succinate exceeds the number of equivalents of iron.

The iron preparations produced according to the invention may contain other substances, so that they provide therapeutically usable mixtures which are suitable for special purposes. Such a preparation includes tablets, containing a pharmaceutical carrier (such as filler, binder, lubricant and disintegrating agents), together with the essential ingredient, but in some cases other dosage forms may be advantageous, such as solutions, capsules and syrups.

Examples of suitable solid carriers are starch, gelatin, talc, stearic acid and magnesium tearate. Suitable binders include liquid glucose, starch paste, acacia solution and gelatin solutions. Common tableting substances used in pharmaceutical practice can be used, provided that these are miscible with the ferrous compound and the succinic acid.

Other additives which are useful in the preparation of oral iron preparations can also be advantageously included, such as stabilizers, for example sorbitol and ascorbic acid, surfactants, pH regulators, vitamins, flavourings, sugar and the like.

The iron preparations produced according to the invention are particularly well suited for solid preparations, such as tablets and capsules, as they make it possible to use highly soluble ferrous compounds, such as ferrous sulphate and ferrous chloride. When such compounds are used, the iron salt dissolves quickly, so that a high concentration is achieved in the digestive tract.

Due to their greatly increased absorption compared to previously known iron preparations without absorption promoters, the preparations according to the invention allow administration with significantly reduced iron doses, so that digestive side effects therefore do not occur, or are reduced. With preparations according to the invention, it is also possible to fill the body's stores more quickly by oral administration, so that the need for intramuscular and intravenous iron treatment is reduced.

There have been major differences of opinion with regard to the absorbency of the various iron compounds that have previously been proposed for oral use, and the actual route of absorption has not been determined with certainty. This comes to some extent from the difficulties in objective measurement and comparison of the absorption of different compounds. The method that is usually used is to follow the regeneration of hemoglobin in patients with iron deficiency after treatment with iron. In this method, different groups of patients are treated with different iron compounds and the regeneration achieved is compared at certain intervals. Very often, however, the results from such experiments are misleading and an objective observer would often draw conclusions that differ from those drawn up by the experimenter.

The most important source of error and difficulty in comparing different iron compounds, when the method mentioned above is used, is connected with the many factors that affect the rate of absorption. The latter varies between different individuals and also for a single individual, depending on such factors as the degree of anaemia, the size of iron doses and the presence of iron in the iron stores, from which the iron can be mobilized, for example in acute haemorrhagic anaemia. A single researcher has often investigated the effect of just one iron compound. The test conditions are therefore quite often different for different investigations, and this, as mentioned above, has a significant impact on the results. Furthermore, different amounts of iron have been given to different groups of patients and the effect has been compared, which gives misleading results, as the degree of absorption depends, among other things, on the amount of iron administered (percentage absorption from a small dose is greater than from a large dose).

Patients with acute bleeding anemia have not always been expressly excluded as test subjects and the degree of anemia has not always been defined, etc. Therefore, misleading results are easily obtained. Where the case of acute bleeding anemia has been included in the samples, high absorption has practically always been observed, if the absorption is determined from the hemoglobin increase, because iron can be obtained partly from the iron that is absorbed and partly from the body's own stores. In subjects with pronounced iron deficiency anemia, faster regeneration is obtained than in subjects whose average degree of anemia is less pronounced. Furthermore, the amount of iron administered in a number of studies has been so large that the amount of iron absorbed has not exerted any decisive influence

on the regeneration rate, that is

the amount has in all groups compared,

exceeded the amount of iron that was necessary for the bone marrow for optimal regeneration speed.

A comparison procedure that has given rise to a lack of clarity is the determination of the so-called utilization coefficient for different iron compounds. The term "utilisation coefficient" refers to the percentage of iron supplied that has been absorbed in a certain period of time and utilized for the formation of haemoglobin. This comparison procedure can be misleading for several reasons, the most important of which is that the daily amount of iron supplied in different research series has been of different orders of magnitude. Since none have been carried out

attempt calculated to find the smallest

daily amount of iron that provides optimal regeneration will a utilization coefficient

which is calculated in this way will only be roughly inversely proportional to the daily amount of iron supplied, and not an objective measure of the absorbability of different iron compounds. In addition, it can

be improperly high if the case of acute bleeding anemia and a substantial amount

iron in their iron stores is included in the tests because one could then theoretically have utilization coefficients that are greater than 100 per cent, as small doses of iron are used, which is absurd.

From the foregoing it is clear that an iron preparation cannot be considered medically justified simply because clinical studies carried out in the traditional way are believed to indicate envtherapeutic action.

A special technique for the study of iron absorption has now been devised and by means of which it is now possible to obtain reliable values of the absorption ratio of iron under different conditions. The method is in principle based on the use of two iron isotopes — Fer>5 and Fe«!l

— and subsequent determination of the radioactivity in blood, faeces, etc. This technique has been used partly to study the general factors that influence the absorption mechanism and partly to

compare the absorption for different iron preparations. In the first investigations, the amount of iron absorbed per unit of time has been determined by labeling orally taken iron with an isotope of radioiron

(for example Fes<s>) and simultaneously intravenous

administration of a tracer dose of another isotope of radioiron (Fes<»>) for continuous determination of efflux of

iron from plasma, which has not previously been possible. With this method, the following facts, among other things, have been established or confirmed: 1. A tenfold increase in iron concentration in the orally administered solution only leads to a fivefold increase in the iron concentration in the colon. Part of the introduced iron is precipitated, absorbed or reacts with proteins in the gastrointestinal lumen. 2. In patients with iron deficiency, the rate of absorption of iron is significantly higher than in those without iron deficiency. 3. Reduced iron stores lead to increased iron absorption. 4. Iron stores in the body can be increased by oral administration of iron, which was previously doubted. 5. The transport of iron from the intestines through the mucosa to the plasma only goes in this direction. 6. The factors that influence the rate of transport of iron from the intestines to the plasma, that is, the rate of absorption, are the iron concentration in the intestines and the concentration of transferrin-bound iron (that is, true serum iron) and transferrin in plasma. The last two factors are again influenced by the erythropoesic effect and the condition of the iron stores. 7. The so-called "mucosal block" is and can be an effect of changed concentration gradients between different departments, intestinal lumen — mucosal cells — plasma. 8. Under pathological conditions, the rate of absorption also depends on the size of the intestinal area and the nature of the mucosa in those departments where iron can exist in ion form. 9. The serum iron-transferrin system forms a kind of regulatory mechanism by means of which increased need for iron results in increased iron absorption. This regulatory mechanism will only prevent anemia and haemosiderosis within certain limits. It has now become possible to develop a method which provides a correct comparison between the absorbency of different iron compounds. According to this method, the absorbance is measured for '. different iron compounds simultaneously and : on the same patient using two iron isotopes, and an apparatus for the simultaneous determination of the radiation intensity for these two isotopes. The principle arrangement for these samples for each patient is shown in figure 1. In the figure A, and A2 are the total amounts of Fes'-<>> which are administered and secreted respectively and B, and B, the corresponding quantities of Fess. The total amount of iron that is absorbed is represented by A and B respectively, and the part of absorbed iron which takes part in the formation of red blood cells (erythropoiesis) is represented by a and b respectively. The part that is absorbed and stored in the iron stores in the body is represented by a and (3 respectively. That is kelial absorption ratios - are proportion-B nal with the measured — provided that varia- b tion in the distribution of iron absorbed between erythropoiesis and the stores a and a, and b and (3 respectively for each individual is small, which has been shown to be the case in separate samples. 30 mg of iron was administered to patients on an empty stomach every morning in 10 days, on days with equal data marked with Fess, and on days with different data Fess". The iron doses marked with Fes" were given as a solution of ferrous sulfate and were used as a reference in all experiments. On the five alternating days when iron was marked with Fess, Was the iron compound whose absorption ratio was to be tested given.

In this way, five pairs of doses were obtained on the same individual. The effect of different absorptions on different days was thereby reduced and also the effect of variations in distribution of the absorbed iron between erythropoiesis and stores. In addition, the impact of variations of other factors known and unknown, reduced and the subject constitutes his own control. The average value of the absorption rate for the five pairs of doses for an individual, that is — in Figure 1, was obtained

b

by analysis of Fess and Fess) in blood samples, which were taken no earlier than two weeks after the last iron dose. This absorption rate was therefore not affected by the average distribution of absorbed iron between red blood cells and stores. The actual absorption has in some cases been determined by quantitative collection of faeces for at least 18 days. The total amount of isotope added to each test subject is very small, usually approx. 20 |.iC Fes» and 20 Fess. The procedure was controlled by administering both isotopes as ferrous sulphate, whereby an average absorption rate of 1.02 was achieved with a distribution of approx. 5 percent

By means of this method for measuring the absorption ratio, the long-held opinion that ferrous sulphate is among the best absorbed of iron compounds in general is confirmed. Preliminary investigations with solutions of the sparingly soluble ferrosuccinate have shown a somewhat greater absorption than that obtained from a solution of ferrous sulphate. However, different results are obtained when these substances are administered in the form of tablets due to their different solubilities. Before any absorption can occur, the tablets must disintegrate and the iron compound dissolve. The absorption of iron takes place essentially exclusively in the upper part of the small intestine and it therefore only takes place for a limited time after the administration of an iron dose. The disintegrating time for the tablets and also the solubility and speed of iron are of great importance in determining the amount of absorption. Thus, if ferrous sulfate and ferrosuccinate are compared, it is found that both the solubility and the dissolution rate for ferrosuccinate are less than one-tenth of the corresponding values for ferrous sulfate at the lowest pH that usually exists in the stomach (approx. pH equal to 1). As the decomposition time for iron tablets is relatively long, usually more than 30 minutes, the dissolution of the iron compounds in the tablet will mainly take place in the upper part of the small intestine. However, the degree of solubility and dissolution rate for ferrosuccinate and ferrous sulfate is only 1:20 at the higher pH value for the small intestine (pH approx. 5-6). The conditions for dissolution and absorption of ferrosuccinate are therefore even less favorable than in the stomach. The significantly lower dissolution rate for ferrosuccinate is the probable reason why, despite the slightly increased absorption of iron from solutions of ferrosuccinate, the absorption of iron from tablets of ferrosuccinate is not better than the absorption from tablets of ferrous sulphate.

Table 1 shows the amounts (in g Fe/ml) of ferrosuccinate and ferrous sulfate that have gone into aqueous solution after different times for shaking 40 g of ferrous sulfate (FeS04

. 7H2O) and 20 g of ferrosuccinate (trihydrate) respectively in 50 ml of solvent at 37° C at different pH values.

The basis of the present invention is that the absorption of iron in the gastrointestinal lumen is stimulated by succinic acid and similar compounds.

Figure 2 shows comparative absorption tests on 21 test subjects using the double isotope method between FeS04 and FeS04 to which different amounts of succinic acid have been added, in which the increase in absorption achieved by the addition of succinic acid is expressed as a percentage of the absorption achieved under the same conditions, as only FeSO 4 was used. The dose administered was equal to 30 mg Fe. The test results indicated on the curve refer-

rer for test subjects with an absorption range of 5-20 per cent for FeS04. If people are studied who have a greater need for iron, and therefore show higher absorption, a significantly higher increase in absorption is achieved (200 per cent). As can be seen from Figure 2, the absorption increases strongly with increasing amounts of succinic acid and with an addition of

150 mg succinic acid per 30 mg of iron, the increase in absorption amounts to no less than 100 per cent.

A possible explanation for this surprising absorption-promoting effect could be that the transport of iron from the intestines to the plasma is energy-absorbing and that succinic acid is taken up in this system as one energy donor. This explanation is strengthened by the observation that the addition of malonic acid blocks the absorption-promoting effect of succinic acid. (Malonic acid blocks the entire intracellular enzyme succinode-hydrogenase, which is necessary for the energy absorptions with metabolism for succinic acid.)

That the effect of succinic acid is connected with the transport through the intestinal walls and is not a result of stimulated haemopoiesis or increased storage of iron in the stores is shown by the fact that the presence of succinic acid does not measurably affect further metabolism of iron in the body. During these investigations, the transition of iron in plasma was continuously measured using radio iron. After one hour, succinic acid was administered in an amount corresponding to the previous absorption tests, but no measurable increase in the transition could be detected.

The fact that ferrous sulphate and succinic acid are each essential parts of the preparation does not mean that the poorly soluble ferrosuccinate is precipitated in the upper part of the small intestine. Since the solubility of ferrosuccinate in the upper part of the small intestine is approx. 4 mg/ml (compare Table I pH 5.5) and the amount of gastric and intestinal fluid available is at least 50 ml., ferrosuccinate will not precipitate unless the amount of iron in each dose is at least 200 mg. Such a dose is approx. 5 times larger than the one normally used.

The invention is illustrated in the following examples. The order of mixing operations shown in the examples can of course be modified to suit each particular case.

Example 1.

Solution containing approx. 40 mg Fe per 10 ml.

The ferric chloride, the succinic acid and the flavorings in the proportions stated above are dissolved in 30 ml of water, after which 50 ml of a sugar solution containing 30 g of sugar is added while stirring. The resulting solution is diluted with water to a volume of 100 ml.

Example 2.

Solution containing approx. 30 mg Fe per 10 ml.

The succinic acid and ferric chloride are dissolved in the sorbitol solution and approx. 30 ml of water. The flavorings are added and then the pH is adjusted to 4.0 with 5N sodium hydroxide solution. Water is finally added to a volume of 100 ml.

Example 3.

Syrup containing

about. 50 mg Fe per 10 ml.

Succinic acid and 2 g of sodium hydroxide are dissolved with stirring in 110 g of 70% sorbitol solution, after which ferrous sulfate and ascorbic acid are added and dissolved. The pH value is adjusted to 4.0 with sodium hydroxide. Flavorings are then added and the volume adjusted to 100 ml with sorbitol solution.

Example 4.

Resolution containing

about. 24 mg Fe per 10 ml.

The ascorbic acid, aneurin hydrochloride, riboflavin phosphate and nicotylamide are dissolved in the sorbitol solution. Dissolve the succinic acid and the ferrogluconate in 50 ml of water. The two solutions are mixed, after which the flavorings and saccharin sodium are added. The pH value is adjusted to 3.5 with sodium hydroxide and the volume to 100 ml with water.

Example 5.

Tablet containing approx. 30 mg Fe.

Ferrous sulphate, succinic acid and indifferentia are mixed in the above quantities and pressed into tablets of 9 mm diameter. The tablets formed were coated in the usual way with sugar, gelatin, starch and talc.

Example 6.

Tablet containing approx. 30 mg Fe.

The powders were mixed in the above proportions, pressed into tablets of 11 mm diameter and then coated.

Example 7.

Tablet containing approx. 20 mg Fe.

The ferrous sulphate and succinic acid are moistened with a 5% solution of polyvinylpyrrolidone in ethanol and granulated. The vitamins and indifferentia are mixed in the dry granules. The mixture is pressed into tablets of 10 mm diameter and coated.

Example 7.

Tablet containing approx. 20 mg Fe.

Ferrous sulphate and the ammonium succinate are granulated with a 10% solution of the gelatin. The starch and talc are mixed into the dry granules, after which the mixture is pressed into tablets of 11 mm diameter and coated.

Example 9.

Tablet containing approx. 30 mg Fe.

Ferrous sulfate — aminoacetic acid complex equivalent to 30 mg Fe

The ingredients are thoroughly mixed in the above ratio and pressed into tablets with a diameter of 11 mm and coated.

Example 10.

Tablet containing approx. 30 mg Fe.

The ingredients are carefully mixed in the above ratio and pressed into tablets of 9 mm diameter and coated.

Example 11.

Capsules containing approx. 30 mg Fe.

The two substances are mixed and hard gelatin capsules are filled with the mixture. Alternatively, the two powders are mixed with paraffin liquidum, after which the mixture is given in soft gelatin capsules.

Example 12.

Capsule containing approx. 30 mg Fe.

The ingredients are mixed thoroughly and hard gelatin capsules are filled with the mixture.

Example 13.

Syrup containing approx. 40 mg Fe per 10 ml.

The ferrous compound and the succinic acid are dissolved in 100 ml of sugar syrup while heating to 40-50° C. The flavorings are then added while stirring.

Example 14.

Tonic containing approx.

30 mg Fe per 10 ml.

The vitamins are dissolved in the sorbitol solution. In a solution of 2 g of succinic acid in 40 ml of water, 0.4 g of caffeine is dissolved, after which the two solutions are mixed and ferrous sulphate and aromatic substances and saccharin sodium are added while stirring. The pH value of the solution formed is adjusted to 3.5 and the solution is diluted with water to 100 ml.

Claims (2)

1. Process for the production of iron preparations for oral use, and which have high absorption in the mucous membranes of the gastrointestinal tract, characterized in that a ferrous compound that is easily soluble in the digestive and intestinal fluids is added to an absorption-enhancing agent that is easily soluble under the existing conditions of absorption, comprising succinic acid or a salt of succinic acid in an amount more than equivalent to the amount of the ferrous compound, the resulting mixture then being worked up in a known manner into pharmaceutical preparations, ready for use. . 2. Method according to claim 1, characterized in that the absorption-increasing agent is added in an amount of up to 24 equivalents per equivalent iron.