MXPA00001172A - The use of erythropoietin and iron preparations for producing pharmaceutical combination preparations for treating rheumatic diseases - Google Patents

Abstract

The invention relates to the use of single forms of administration of an erythropoietin preparation and of a physiologically suitable iron preparation corresponding to an equivalent quantity of 1-40 mg of ions of iron to produce a pharmaceutical combination preparation for treating rheumatic diseases.

Description

USE OF ERYTHROPOYETINE AND IRON PREPARATIONS FOR THE PRODUCTION OF COMBINATION PREPARATIONS PHARMACEUTICALS FOR THE TREATMENT OF DISEASES RHEUMATIC Field of Invention The present invention concerns the use of erythropoietin and iron preparations for the production of pharmaceutical combination preparations. These combination preparations comprise individual administration forms of a preparation of erythropoietin and a physiologically compatible iron preparation corresponding to an equivalent amount of 1-40 mg of iron ions for the treatment of rheumatic diseases.

Background of the Invention Pharmaceutical combination preparations containing erythropoietin and iron preparations are known from PCT Patent Application WO 97/09996. The preparations are used especially for the optimization of the Ref: 32641 erythropoiesis in the treatment of diseases in which a stimulation of erythrocyte formation is sought.

The use of erythropoietin for the treatment of chronic inflammations, especially rheumatoid arthritis, is known from WO 96/14081.

Therapeutic treatment for patients suffering from rheumatic diseases has not yet been possible to use in a satisfactory treatment regimen. In this regard, there is a need to improve methods of treatment, such as, for example, in the treatment of rheumatoid arthritis, lupus erythematosus, Bechterew's disease, etc.

The rheumatic disease of the locomotor system and the disease of the inflamed joints are worldwide among the main causes of chronic pain and various bodily injuries. All the elements of the muscular skeletal system are in a dynamic equilibrium and these form, a change in the structural and functional state constantly depending on the filling and mechanical requirements. This system is susceptible to trauma and is responsible for locating and systematizing inflammatory disorders. Acute inflammatory conditions or damaged tissues often result in chronic conditions, possibly due to constant movements and filling mechanisms.

Joint diseases belong to diseases of the locomotor system and are sub-divided into those that concern the periarticular tissue and those that are true diseases of the joints (for example osteoarthritis). The symptoms and diagnoses can frequently lead to a generalized, systemic disease or also to a disease that emanates primarily from other systems or organs.

Immune mediated inflammation plays an important role in the course of the pathology of rheumatic disorders. In many cases, immune-mediated inflammation is the basis of numerous systemic connective tissue diseases. Infectious processes are also significant, mainly in diseases such as rheumatic fever, Lyme borreliosis or reactive arthritis. The etiology of rheumatic diseases can be due to multiple factors, whose genetic reasons and environmental effects also have an important influence.

Pain is the main symptom of most rheumatic diseases, especially diseases of the joints. Until now, the causes of joint pain is not completely clear. A therapeutic control of joint pain is currently possible only in an inadequate manner. Also, the decisive factors of a loss of functions previously have not been fully clarified. Many of the diseases of the joints show remarkable differences between the sexes; in this way, SLE occurs mainly in women, whereas ankylosing spondylitis occurs more frequently and with a stronger form in men. The reasons for this are similarly unclear.

The incidence, prominence and consequence of diseases of the locomotor system depend on age and sex. Some diseases occur only in childhood (chronic juvenile arthritis); others, such as SLE or ankylosing spondylitis, begins mainly in young adults, polymyalgia rheumatica and granulomatous arteritis on the other hand almost never occur before the age of 55. The cP, SLE, gout and other serious inflammatory rheumatic diseases show a different initial prominence with increasing age. Most of these diseases of the locomotor system cause chronic pain.

No medication that has a satisfactory activity is available to alleviate these chronic rheumatic diseases. The therapeutic principles used in the treatment are often based on and often dependent on factors such as the patient's age and general situation and the extent of the inflammatory activity and the consequences (intensive pain, extension of the impediment). The treatment plan used in practice for patients with various diseases of the locomotor system is made up of different measures and is in this aspect frequently dependent on the attending physician. A uniform and generally accepted method of treatment has not yet been established.

Description of the invention.

Surprisingly it has been found that a positive influence on the general disease picture in patients with rheumatic diseases and an improvement in the general health and quality of life of these patients can be realized with the help of an optimal amount of EPO and iron in the form of a corresponding combination preparation. In addition, an optimal activity of the EPO is carried out and, respectively, of the iron preparation used. In particular, the costs of EPO treatment can be clearly reduced so that, for example, lower doses of the active substance can be administered. The combination preparations according to the invention are especially suitable for the treatment of diseases of the inflammatory joints. In addition, clear pain relief can be performed in many patients.

In the meaning of the present invention these are the specially used pharmaceutical combination preparations containing from 250-20,000 U of an erythropoietin preparation and 1-40 mg of an equivalent amount of iron ions of the physiologically compatible iron preparation, whereby the erythropoietin preparation and the iron preparation can be presented in separate administration forms or in a simple administration form. The combination preparations preferably contain 1-30 mg, particularly 3-20 mg, of an equivalent amount of iron ions of a physiologically compatible iron preparation, especially an Fe (II) or Fe (III) complex.

Suitable erythropoietin preparations in the meaning of the present invention are those active substances which are comparable with respect to the physiological effects of human EPO's. Suitable EPO preparations are, for example, recombinant human EPO (rhEPO, see European Patent EP 0,205,564 or EP 0,411,678) or also the corresponding modifications of these proteins. As modifications are, for example, such proteins with molecular weights greater than or less than 34,000 Da (molecular weight of urinary EPO), likewise the isoforms of the enzyme or proteins with different glycosylation. In particular, proteins chemically modified by PEG (polyethylene glycol) can also be used. In addition, such proteins which are derived by deletions, substitutions or additions of one or more amino acids of the amino acid sequence of natural EPO with a length of 166 amino acids are also basically considered. These proteins have physiological properties essentially comparable to rhEPO. In particular, these proteins have biological properties that cause bone marrow cells to increase the production of reticulocytes and corpuscle red blood cells and / or to increase the synthesis of hemoglobin or iron reuptake. Instead of these proteins, low molecular substances, which are denoted as EPO mimetics, and which bind to the same biological receptor can be used. These mimetics can preferably also be administered orally. The amount of such proteins or mimetics to be administered is determined by comparing the biological activity between the EPO and its active substances.

The oral resorption of the iron is only about 1 mg per day and under extreme filling (in the case of oral administration of about 300 mg of Fe (III) / day) less than 3 mg per day. Therefore, intravenous administration of iron preparations is increasingly preferred. Two intravenously administrable preparations are available in the German drug market at present. These are the drugs "Ferrlecit" and "Ferrum Vites". The "Ferrlecit" is a complex of iron gluconate (III), while the "Ferrum Vites" is a complex of saccharate and iron hydroxide (III).

The various problems of a high dose, long-term oral iron therapy, can be avoided relatively simple by the intravenous, subcutaneous administration of iron (III) salts physiologically compatible during the hemodialysis treatment, since in this case there is an access intravenous, safe subcutaneous and injection can be performed without additional burden to the patient. The intravenous administration of iron preparations is, however, significant, since the administration of high doses has side effects that are taken into consideration, first when large quantities are to be injected rapidly. In addition, intravenous administration of iron preparations causes problems to the reactions of the acute phase when the iron dose given is very high or does not correlate optimally with the dose of EPO. Iron poisoning can occur in the case of a very high dose of iron-containing preparations. Elemental iron has a toxic effect on the gastrointestinal tract and on the cardiovascular and central nervous systems. The lethal dose of elemental iron varies between 200 and 250 mg / kg. the most frequently used iron tablets are ferrous sulfate (containing about 20% elemental iron), ferrous fumarate (containing about 30% elemental iron) and ferrous gluconate (containing about 10% elemental iron).

Iron preparations in the meaning of the present invention are oral or parenteral administration forms. These may basically be individual preparations, which contain a physiologically compatible iron salt or an iron complex compound as the active substance, or else combination preparations, which in addition to the physiologically compatible iron preparation contain other active substances, such as, for example, vitamins, folic acid, thiamine chloride, riboflavin, pyridoxine, ascorbic acid, nicotinamide, calcium pantothenate, etc.

Physically compatible iron salts or iron complex compounds are, for example, iron (II) sulphate, iron fumarate (II), iron citrate (II), iron gluconate (II), iron succinate (II) ), iron chloride (II), iron glycine sulphate complex (II), iron aspartate (II), iron sodium gluconate complex (III), iron hydride (III) polyimatose complex or ferrisorbi citrate complex tol. Preferred iron preparations with especially Fe (III) complexes, especially those with a molecular weight between 30,000 and 100,000 D. Especially preferred is Fe (III) saccharate. Here, reference can be made to the commercially available "available" Ferrus Vitis "(manufactured by Neopharma, Germany.) By virtue of the low iron dose according to the invention, it is also possible to use unstable iron complexes, such as iron gluconate (molecular weight around 1,000 D, Ferrlecit), in the combination preparation, although these unstable iron complexes release relatively large amounts of ionized iron, which can cause toxicity in the case of intravenous administration of large amounts .

The following will be understood with respect to the amount of iron preparation, basically the equivalent amount of iron ions, Fe (II) or Fe (III) ions, which is administered. By this standardization the amount of an arbitrary iron preparation can be calculated on the basis of this known molecular weight. In the case of iron gluconate (III) x 2 H20, for example, the amount of iron is 80.5 mg when an amount of 695 mg of the iron preparation is administered. When, for example, 280 mg of anhydrous iron (II) succinate is administered, the amount of iron is 95.2 mg.

In the meaning of the present invention, it will be understood under the term "combination preparation" not only those packets of medicament in which the preparation of EPO and the iron preparation are present in juxtaposition in a finished commercial unitizable package (also so-called combination pack), but also those packets of medicaments that contain either an appropriate amount of an EPO preparation or an appropriate amount of an iron preparation in the form of respective individual preparations, with the individual preparations with respect to the amount of contents being presented in such a way that it can be administered in the meaning of the invention for the combined dose with the other respective preparation. In these cases this is usually included with the preparations of the pharmaceutical preparation or of the imported medicine inserted in a package of medicine that is required by law in many countries and that contains the instructions or information concerning the combined dose of the individual preparations. Preferably, the combination preparations can be presented in a simple administration form in which the respective amounts of the EPO preparation and the iron preparation are present in juxtaposition in a container.

For the treatment of patients with hemodialysis, the combination preparation according to the invention contains, for example, from 250 to 15,000 U (the abbreviation "IU" for International Units may also be used in place of the abbreviation "U") of a EPO preparation, especially from 500 to 10,000 U. Preferred doses are 250 U, 500 U, 1,000 U, 2,000 U, 5,000 U, 7,500 U and 10,000 U per individual dose.

The amount of iron ions is advantageously greater than 30 mg, preferably 3-20 mg, especially 5-20 mg, and particularly about 10 mg. For the treatment of patients with anemia, the optimum dose is 500 to 10,000 U, preferably around 1,000-3,000 U. In this case, the amount of iron ions is advantageously greater than 30 mg, for example 3-15 mg and especially around 5 mg.

The concentrations of the EPO and the iron complex according to the invention allow in this combination an adjustment and optimal treatment of patients suffering from rheumatic diseases and in the case of intravenous iron therapy they do not initiate the reactions of the acute phase.

The treatment with the combination preparation is carried out once to five times a week, preferably four times a week, with the total amount of iron per patient not exceeding 100 mg per week. In the treatment of patients with rheumatic diseases, a total amount of 80 mg, especially 50 mg, of iron ions per week, should not be advantageously exceeded. A particular advantage of the combination preparation according to the invention in clinical practice lies in the fact that they can be used not only in the correction phase, but also in the maintenance phase of iron therapy of hemodialysis patients without causing toxicity. Until now, different amounts of iron have been administered, with high doses initially of iron ions being administered in the correction phase compared with the maintenance phase. Surprisingly, this different dose is not long required when using the combination preparations according to the invention. The amount of the erythropoietin preparation and the iron preparation correlate optimally with each other in the combination preparation according to the invention in such a way that a differentiation between the maintenance dose and the correction dose is not required. Hereby, an increase in safety in the treatment of patients is made, since the possibility of errors with respect to the optimal dose of the individual preparations no longer exists.

In a further preferred embodiment the combination preparation contains in addition to a component a preparation which has a suppressive activity on TNF-alpha. Preferably, this is a glycocorticoid, such as, for example, cortisone, a cortisone analogue or a prednisolone derivative or a folic acid antimethal agent, such as, for example, methotrexate. Preferred compounds are prednisone, prednilolone, 6a-methyl-prednisolone, triamcinolone, paramethone, dexametha ona, betamethasone, cortisone, cortisol and 16-methylene-prednisone. The anti-inflammatory activity of the EPO / iron dose intensifies synergistically.

When the combination preparations are used, it is possible to administer the preparations, preferably the EPO preparation and the iron preparation, in a so-called determined combination, ie in a simple pharmaceutical formulation in which the compounds are present. This may comprise, for example, injection solutions, infusion solutions or lyophilisates, which, for example, are filled in ampoules. This form of administration. it has the advantage that the EPO preparation is stabilized by the iron complex during the production and storage of the administration form. The determined combination of the active substances in the form of a lyophilisate has the additional advantage of being handled simply and safely. The lyophilizate is dissolved in the ampule by the addition of a pharmaceutically usual injection medium and administered intravenously.

It is also possible to provide the preparations in the form of separate pharmaceutical formulations. As a rule, this is done in the form of individual unit packs comprising several containers, with the first container being a form of administration (lyophilized, injection solution or infusion solution) containing the erythropoietin preparation and the second container being a suitable administration form for the iron preparation and optionally the third container being an appropriate administration form of a TNF-alpha suppressant. The unit packages may also contain several individual dose preparations of the respective preparations, so that, for example, a unit packet contains the required number of individual administration forms for a particular period (for example for weekly doses).

This free combination, which can be made available in a single unit package (medication package) also has the advantage that each patient being treated can be prescribed a particular individual amount of an EPO preparation, an iron preparation and optionally of a TNF-alpha suppressant. In addition, these combination preparations offer the advantage of greater safety when therapy is performed, since in each case the optimum synchronized amount of the individual preparation is determined and an error otherwise with commercially available individual preparations, which are supplied in Different doses can be mostly excluded. Moreover, it must be borne in mind that in different countries medicinal preparations are frequently marketed in different doses for reasons of national requirements and therefore there is an increased danger of error with variable proportional amounts of the individual active substances. In addition, the combination preparations according to the invention minimize the risk of an inadvertently very high iron dose, which can possibly be given when using iron preparations with separate ingredients in drug packages together with the dose of a preparation of erythropoietin A safe and simple therapy to be handled by the person performing the treatment or in the area of the medical realization by patients, is guaranteed by the combination preparation according to the invention In the present case this is, for example , it is also possible to provide an active substance such as an injection solution and the other active substance (iron complex) as a form of administration for oral administration.

Where the EPO preparation is made available as a lyophilizate, the drug packages (combination packs) contain the corresponding amount of the EPO preparation in glass ampoules or in cartridges. The iron preparation can be presented in solid form (tablet, powder, granulate, lyophilized, etc.) or also in liquid form in a separate container. In addition, the combination pack preferably contains a reconstituted solution in order to dissolve both the lyophilized active substance alone or also together with the solid iron preparation. If the iron preparation is presented as a ready-to-use solution, the solution can be mixed together with the EPO solution. when the combined administration of the EPO and iron preparation is carried out. Basically, the iron preparation can be made available as a concentrate to be added to conventional infusion solutions, by means of which long administration can be effected for several hours. In this case, a small volume of the iron complex containing the solution (about 0.5-10 ml) is added to the ready-to-use injection solution of about 500-1000 ml.

Combination preparations in the meaning of the present invention are also those packages of units having a determined optimum amount of the EPO preparation and the iron preparation to be administered weekly. Advantageously, 5,000-50,000 U of an EPO preparation is administered weekly. This total dose can be divided into several partial doses for daily administration (this is 7 times per week) or for the administration of 1-6 partial quantities per week. The amount of the iron preparation to be administered weekly may optionally be divided into an amount corresponding to the total weekly dose or also in several partial amounts for a repeated administration per week together with the erythropoietin preparation.

A further possibility in the meaning of the present invention comprises providing in each case, individual administration forms for the preparation of erythropoietin or the iron preparation as an independent medicine, with the individual preparations being formulated in such a way as to contain the required amounts of the individual substances for the combination according to the invention of the EPO preparation and the iron preparation. As a rule, the packets of medicament contain an insert from the package previously described containing the corresponding instructions for administration in combination with the EPO preparations or with the iron preparations in the required quantities. As a corresponding instruction can also be presented as a package printed in the medication package (secondary packaging) or in the primary packaging (ampoule, metal band bubble, etc). Thus, in the case of the medicine containing the EPO with 250-20,000 U of EPO this is, for example, indicated immediately after this preparation can be specially administered together with an iron complex preparation containing 1-40 mg , preferably 5-30 mg, of iron. In the case of iron preparation this is an inverse indication to the combined administration with 250-20,000 U of an erythropoietin preparation.

A further possibility to provide EPO preparations comprises making available corresponding multi-dose preparations containing the EPO preparation in high amounts compared to the individual doses. These preparations are especially suitable for use in clinics where a large number of patients are treated daily. These multi-dose preparations contain the EPO preparations in doses greater than 500,000 U, especially greater than 100,000 or 50,000 U. The multi-dose preparations have the advantage that they allow the authorized medical personnel to remove any dose of the preparation from EPO, for example by the withdrawal of corresponding quantities by volume of the finished injection solution. This is especially advantageous in the treatment of patients with different dose requirements of the active substance or in the treatment of children in whom a lower dose of the EPO preparation is required. For an injection solution of, for example, 100,000 U of an EPO preparation, preferably freshly prepared at the beginning of the day, it may be performed, if circumstances permit, all the patient treatments required during this day without the need for prepare separate injection solutions for each individual patient. This can result in significant time savings or to ease the workload for qualified medical personnel. Preferably, the individual EPO doses are withdrawn in the range of 250 U, 500 U, 1, 000 U and 10, 000 U.

The multi-dose preparations can also be presented in the form of solutions, which are filled into cartridges. These cartridges are suitable for use in so-called pens, which allow administration by the same patients and the withdrawal of an individual dose. For example, these cartridges contain the EPO preparation in an amount of 10,000 or 20,000 U, whereby dose ranges of, for example, 250 U, 500 U, 1,000 U or 2,000 U are possible by appropriate withdrawal adjustments. of volume.

The production of the pharmaceutical administration forms is carried out in accordance with the usual processes known in medical technology using pharmaceutically usual adjuvants.

In connection with the diagnosis of rheumatic diseases and disorders of iron metabolism, the concentration of ferritin serum in the meaning of the present invention can be determined especially. When a true iron deficiency occurs in addition to an already present rheumatic disease or anemia, then ferritin does not increase (this mainly results below 90-95 ng / ml). In the case of simultaneous clinical symptoms of infection, inflammation or malignancy, this points to a valuable combination of iron deficiency and anemia in conjunction with rheumatic disease. Since the ferritin serum in this case also reacts in the sense of an acute phase protein, the ferritin erythrocyte can be better evaluated diagnostically. Iron that is not required for erythropoiesis is stored by means of transferrin in two types of storage groups. The most important warehouse is ferritin. This is a heterogeneous family of proteins that surround an iron core. This is soluble and represents the active stored form in the liver (hepatocytes), spinal cord, spleen (macrophages), erythrocytes and in serum (around 100-300 μg / 1). The ferritino group fabric is very skillful and quickly available when the iron is required. The circulating ferritin serum originating from the reticular endithelial system and its circulating concentration runs parallel with the total body iron (each ng / ml corresponds to 8 mg of iron reserve).

By performing the combination therapy with the combination preparation according to the invention, the maximum weekly dose can be decided in a very simple way by the determination of the diagnostic parameters of the state of the iron, especially the iron, the transferrin, the saturation of transferrin, the transferrin receptor and the transferrin parameters. The patient is instructed to adjust optimally for phase correction and maintenance when ferritin is 100-300 μg / 1 (corresponding to the stored iron (II) of 800-1200 mg) and the saturation of transferrin is 20-40% Preferably, the concentration of ferritin is at least 100 μg / 1, especially at least 150 μg / 1, and maximum 300 μg / 1, especially a maximum of 250 μg / 1. The iron concentration is advantageously between 10-20 μmol / 1 (corresponding to about 56-112 μg / dl) and the transferrin concentration is between 30-60 μmol / 1 (corresponding to about 240-480 mg / dl) . Transferrin saturation is defined as the ratio of serum / iron concentration in plasma to serum / concentration of transferrin in plasma (multiplied by a correction factor of 1.41). This is a non-dimensional number that is independent of the patient's hydration status. Transferrin saturation is calculated according to the formula Transferrin saturation (%) = (iron [mg / dl] x 100) / (transferrin [mg / dl] x 1.41) An optimal patient adjustment is made when the saturation ratio of transferrin (in%) the concentration of ferritin (in μg / 1) is in the range of 5-40%. This parameter is defined as the saturation of trans ferrina / ferrina (saturation of TfF). This is calculated according to the formula Saturation of TfF = (transferrin saturation in%) x 100 / (ferritin [μg / 1]) The value for this parameter is preferably in the range of 10-40, especially at 15-25 [% x 1 / μg] - The optimal adjustment of the patient is checked diagnostically by means of this parameter, for example with the administration of 1 to 6 ampoules, preferably up to 3, 4 or 5 ampoules, per week (one ampoule contains 500-7,500 units of rhEPO and 1 ampoule). -20 mg iron complex).

In order to truly exclude undesirable side effects, the acute phase CRP parameter (5 mg / 1 ± 100%) [CRP = C - reactive protein] is measured, with the CRP being present in the best labeled protein of an inflammatory reaction . Other parameters are TNF-alpha (Alpha Necrosis Tumor Factor) and IL-6 (interleukin 6) or IL-1, IL-2 and IL-8. TNF-alpha can be < 30 pg / ml (in plasma, ELISA) and IL-6 can be < 20 pg / ml (in plasma, ELISA). In addition, liver parameters GPT (glutamate pyruvate ransaminase), GOT (glutamate oxaloacetate ransaminase) and? -GT (Tamil gamma-transferase) can be determined and can be placed in the following ranges (determination at 37 ° C): GPT: < 50 U / 1; GOT: < 50 U / 1; ? -GT: < 40 U / 1, in this connection, the GPT parameter is currently set to the first position in liver diagnostics.

In addition, if desired, hematological control parameters such as hematocrit (number of corpuscles of red blood cells in the total volume) or increase in hypochromic erythrocytes can be performed. When the control parameters show a high increase, the weekly iron dose is reduced and then the additional rhEPO can be administered. When the control parameters, primarily the transferrin saturation, show a low value, the weekly iron dose has to be increased.

Furthermore, in the meaning of the present invention it has surprisingly been found that what is established for patients of an individual therapeutic dose of EPO and iron ions for the treatment of anemia can be effected by determining the soluble TfR (transferrin receptor). The optimal therapeutic dose of EPO and iron (III) is obtained when the concentration of soluble TfR does not increase greatly. In order to ensure that sufficient iron mobilization is present, the iron dose i.v. and the dose of EPO are increased in shifts until a stabilization is reached.

This corresponds to a concentration of 1,500-2,000 μg / 1 TfR.

For combination therapy with the combination preparation according to the invention, for the treatment of anemia, the maximum weekly dosage can be decided in a very simple manner by determining the diagnostic parameters transferrin receptor (TfR) and ferritin and ratio of TfR to ferritin. The patient is indicated to optimally adjust in the correction and maintain the phase when ferritin is 100-300 μg / 1 (corresponding to the stored iron (III) of 400-1200 mg) and the TfR / ferritin is > fifteen.

The concentration of TfR is advantageously between 1,500-2,500 μg / 1. The ratio of TfR concentrations (in μg / 1) to ferritin (in μg / 1) is especially in the range of 15-35, preferably in values above 20.

The optimal adjustment of the patient Czech diagnostically by means of this parameter, for example, administering 1 to 6 ampoules, preferably 3, 4 or 5 ampoules, in the week (one ampoule contains, for example, 3,000 U of rhEPO and 5 mg of iron complex. in this connection, these are not hemodialysis patients, but patients who (for example rheumatic patients), because otherwise cause anemia, are treated with EPO and / or iron preparations.

As already indicated, in order to actually exclude unwanted side effects, the CPR parameter of the acute phase (2-10 mg / 1) [CRP = C - reactive protein] is measured; in addition to the liver GPT parameter (glutamate pyruvate transaminase), which may be < 50U / 1 at 37 ° C (<30U / L at 25 ° C) can be determined. In addition, if desired, hematological control parameters such as hematocrit (number of corpuscles of red blood cells in the total volume) or increase in hypochromic erythrocytes can be performed. In this connection, the reticulocytes can be increased to a value of more than 15 / 1,000-30 / 1,000. The typical hemoglobin concentration is 12-18 g / dl. When soluble TfR shows a high increase, the weekly iron dose has to be increased up to 35 mg. When soluble TfR shows low values, the weekly dose of EPO has to be increased.

The determination of the state of the iron is carried out by the analysis of the sample of body fluids (blood, serum, urine, etc.) of the patients in question. In order to determine the state of the iron, the iron concentration, transferrin, ferritin and transferrin receptor, transferrin saturation and trans ferrin / ferrine saturation are determined in particular. In the case of hemodialysis patients, iron, transferrin, ferritin and transferrin saturation parameters are preferably determined in accordance with usual analytical methods. The determination of the saturation value of transferrin / ferritin is especially relevant.

In the case of patients with anemia, whose anemia is not caused by hemodialysis, the concentration of ferritin and the concentration of the transferrin receptor are determined first. The determination of the ratio of transferrin receptor to ferritin (transferrin receptor / ferritin saturation value) is especially relevant.

In this regard, an optimal combination preparation according to the invention for the treatment of patients with rheumatic diseases comprises from 500-10,000 U, especially from 2,000-4,000 U, from an EPO preparation and from 3-10 mg, preferably from 5 to 10 mg. mg of iron ions, preferably a Fe (III) complex, by means of which the EPO preparation and the Fe (III) complex can be presented in separate administration forms or in a simple administration form. The administration forms according to the invention also allow an administration of the iron preparation from 1 to 3 days before the preparation of EPO in order to raise the iron stock before starting the EPO treatment.

The concentration of iron in the blood and the ability to bind the iron is determined in clinical chemistry in order to investigate the metabolism of the iron. Both tests must always be carried out, since the relationship of these measured results to each other is important. Usually, normal serum levels are between 75 and 150 μg / dl in men and between 60 and 140 μg / dl in women. The bonding capacity of the total iron is between 250 and 450 μg / dl. The level of iron serum varies during the course of the day. This decreases in the case of an iron deficiency and in the case of anemia associated with chronic diseases. This is increased in the case of hemolysis and in the case of syndromes with over-filling of iron (for example, hematochromatosis or hemas iderosis). Patients under oral iron medication may have normal iron serum levels, although iron deficiency is present in them. The ability to bond the total iron (= transferrin x 2) is increased in the case of an iron deficiency; or the other side is reduced in the case of anemia in the course of chronic diseases.

On the other hand, the serum level of ferritin is determined. Ferritin is a reserve iron glycoprotein, of which there are typical tissue isoferritins and which can be determined immunologically in serum, for example, by a radioimmunosest (RIA) or also by turbidimetric methods. The ferritin value is a measure of reserve iron in the fabric. In most laboratories, the normal range is between 30 and 300 ng / ml and the geometric mean value is 88 in men and 49 in women. Serum ferritin values are placed in close relation to the body's total reserve iron. Therefore, a serum level of reduced ferritin is found only in the case of iron deficiency. An increased level is found in the case of over filling of iron. Similarly, there is an increase in serum ferritin level in liver damage or in association with many neoplasms where ferritins can also bind to acute phase proteins. The transferrin serum receptor can also be determined by an immunosorbent enzyme increase test (enzyme-linked immunosorbent assay, = ELISA). In this, a monoclonal antibody against the soluble receptor is used. The reference range is between 0.5-3 mg / 1. The level increases in the case of a slight deficiency in the reserve iron. The concentrations of ferritins of specific erythrocytes can be determined in order to characterize the reserve iron, especially when the ferritin serum is not usable in the case of damaged tissue or by acute phase reactions.

In addition, the level of erythrocyte ferritin is also determined in order to investigate the metabolism of the iron. The erythrocytes are separated from leukocytes and thrombocytes (which likewise contain ferritin) in heparinized blood by centrifugation. The lysis of the erythrocytes and the immunological determination of the reserve ferritin follows then. The ferritin erythrocyte reflects the state of the reserve iron during the preceding 3 months (that is, during the life time of an erythrocyte). Normal values are generally between 5 and 48 grams of atom (ag) per erythrocyte. The values < 5 were found in deficient iron anemias and high values (frequently> 100) were found in the case of overfilling of iron (for example, hematochromatosis). The determination of zinc protoporphine prot has a similar affirmative validity.

The invention is illustrated below in the base of an example that was made. 11 patients with visible rheumatoid arthritis and chronic inflammatory anemia (Hb in the case of women <12 g / dl, in the case of men <13 g / dl), were treated for 12 weeks with 150 IU of EPO / kg of 2x body weight weekly sc and-additionally by i.v. of sucrose of iron 200 mg / week in the appearance of an iron deficiency. A subsequent observation period took place for an additional 12 weeks.

The course of therapy was investigated based on the primary efficacy criteria (SF-36 vitality scale, fatigue scale (MAF), isometric muscle strength (MSI)) and the secondary efficacy criterion, named the activity parameters of the disease DAS (acronym in English for Disease Activity Score), RADAI [acronym in English of Rheumatoid Arthritis Disease Activity Index (index of activity activity of rheumatoid arthritis)] as well as the parameter of the acute phase CRP (C - reactive protein): Results: As is evident from the attached Figure 1, the therapy proceeded positively. With regard to muscle strength, an MSI average increased by 8% was recorded, vitality was increased by an average of 14% on the SF-36 vitality scale and fatigue decreased by 8.3 out of 50 possible points.

The effects of therapy on the parameters of DAS, RADAI and CRP disease activity can be concluded from Figure 2.

In this way, at the beginning of the therapy, the DAS had a value of 6.5, which was placed at 5.67 at the end of the therapy. The RADAI was 5.29 at the beginning of therapy and 4.57 at the end of the therapy, and the CRP (mg / dl) was 3.47 at the beginning of therapy and 2.99 at the end of the therapy.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (12)

Claims

1. The use of erythropoietin preparations in the form of a) individual administration forms of an erythropoietin preparation suitable for individual doses of the active substance in a physiologically effective amount and b) a physiologically compatible iron preparation corresponding to an equivalent amount of 1-40 mg of iron ions for the production of a pharmaceutical combination preparation for the treatment of rheumatic diseases.

2. The use according to claim 1, wherein the individual administration form of the erythropoietin preparation contains the active substance in an amount of 250-20,000 U.

3. The use according to claim 1 or 2, wherein the pharmaceutical combination preparation is used for the treatment of inflammatory diseases of the joints.

4. The use according to any of claims 1 to 3, wherein the combination preparation contains 500-10,000 U of an erythropoietin preparation.

5. The use according to any of claims 1 to 4, wherein the iron preparation contains an equivalent amount of 1-30 mg of iron ions.

6. The use according to any of the rei indications 1 to 5, wherein the iron preparation contains an equivalent amount of 3-20 mg of iron ions.

7. The use according to any of claims 1 to 6, wherein the iron preparation is a complex with a molecular weight between 30,000-100,000 D, preferably Fe (III) saccharate.

8. The use according to any one of claims 1 to 7, wherein the iron preparation is Fe (III) gluconate.

9. The use according to any of claims 1 to 8, wherein the combination preparation additionally contains a preparation having a suppressive action on TNF-alpha, preferably a glycocorticoid preparation or a preparation having an antimethate of folic acid.

10. A process for the production of a pharmaceutical combination preparation according to claims 1 to 9, characterized in that a physiologically effective amount of an erythropoietin preparation is formulated in the form of individual administration forms and 1-40 mg of an equivalent amount of iron ions of a physiologically compatible iron preparation as well as optionally a preparation of corticosteroid glycocortics together or separately from one another with pharmaceutically customary carriers and adjuvants and making the respective preparations available as combination preparations.

11. The process according to claim 10, characterized in that 250-20,000 U of an erythropoietin preparation in the form of individual administration forms are formulated.

12. A package of pharmaceutical unit, characterized in that it comprises 250-20,000 U of an EPO preparation in individual dose forms and from 1 to 40 mg of an equivalent amount of iron ions of a physiologically compatible iron preparation as well as optionally a preparation of gluco-corticosteroid as a form of individual administration in a container or as separate administration forms in separate containers for the treatment of rheumatic diseases.