MXPA99011664A - Pharmaceutical combination preparations containing erythropoietin and modified haemoglobins - Google Patents

Abstract

The invention relates to pharmaceutical combination preparations containing erythropoietin and one or several modified haemoglobins. The inventive combination preparations are used especially for treating manifest anaemia. The inventive pharmaceutical combination preparation comprises a) individual forms of administration of an erythropoietin preparation suitable for an individual dose of a quantity of 3,000 - 7,000 U of the active agent and b) 50 - 100 ml of one or several modified haemoglobins. The erythropoietin preparation and the modified haemoglobin can be provided in separate or single forms of administration.

Description

PHARMACEUTICAL COMBINATION PREPARATIONS CONTAINING ERYTHROPOYETIN AND MODIFIED HEMOGLOBINS DESCRIPTION OF THE INVENTION The invention relates to pharmaceutical combination preparations containing preparations of erythropoietin and one or more modified hemoglobins. Combination preparations are especially useful for the treatment of manifested anemias. The object of the present invention is a pharmaceutical combination preparation consisting of a) individual administration forms of an erythropoietin preparation suitable for the individual dosing of the active substance in an amount of 3000-7000 U and b) 50-100 ml of one or more modified hemoglobins, with the preparation of erythropoietin and hemoglobin present in separate administration forms or in a single administration form. The macromolecule ferritin (molecular weight at least 440 kD depending on iron content) plays an important role in the diagnosis of anemia. An estimate of the level of iron reserve is possible when determining the saturation of ferritin and transferrin (M: ick, W: Pungerra, P. Lehman, "Ferritin in iron metabolism and the diagnosis of anemia", pages 5-22, 38-50, 65-77, 94-97, 2nd expanded edition 1994, published by Springer Vienna, New York) being the totality of iron stored as basic ferritin in the REF .: 32140 organs of deposit like the liver, the spleen and the bone marrow, of approximately 800-1200 mg. A lower concentration of ferritin is the definitive characteristic for detecting iron deficiency states and their difference from other causes of hypochromic anemia, such as for example chronic inflammations and tumors. It is known to treat the anemias produced by transfusions in patients in hemodialysis with recombinant erythropoietin (rhEPO), it being necessary as a rule to perform a substitution of iron in parallel to EPO therapy. This iron substitution is carried out by means of the intravenous administration of iron (III) salts, there being two iron preparations administrable intravenously on the German medicinal market. Those medications are "Ferrlecit" and "Ferrum Vites". "Ferrlecit" is a complex of iron (III) gluconate, while "Ferrum Vites" is a complex of iron oxide (III) saccharate. However, it has become evident that in the case of overt anemias with manifest iron deficiency and problems of iron utilization (<30 mg / dl ferritin), the substitution of iron with the preparations mentioned has disadvantages, since for the For treatment of overt anemias, relatively large amounts of pharmacologically harmless iron salt should be infused. The use of the aforementioned iron preparations entails the possibility of unexpected circulatory reactions until collapse, especially when large quantities must be injected relatively quickly. WO 96/15805 discloses a hemoglobin therapy for the hemodialysis according to which low dose of stroma-free hemoglobin is administered, for a period of 1 to 45 minutes in order to achieve a hemo stabilization to avoid a reduction in pressure blood in sensitive patients. However, this described therapy is not successful in cases of overt iron deficiency anemia. WO 95/24213 also discloses the use of natural hemoglobin or reclosing or chemically modified derivatives thereof for the treatment of anemia. In addition, this document describes the combined administration of one of the aforementioned hemoglobin with one or more hematopoietic growth factors, among others with EPO. Examples 4 and 5 as well as some of the figures show that a combined administration of EPO and hemoglobin rh tends to May hematopoiesis. However, this document does not describe a practical therapeutic regimen for the optimal regulation and treatment of patients with overt anemias. Also, from this it is not evident that as in the case of patients treated with EPO, it is possible to produce an optimal EPO effect without avoiding an EPO resistance.

It has now been found that the use of relatively high infusion amounts of 50-100 ml of hemoglobin (approximately 100-200 mg Fe2 *) together with 3000-7000 U of PE is surprisingly advantageous for the treatment of overt anemias (the abbreviation " IU "can also be used in place of the abbreviation" U "for international units). The subject of the invention in accordance with this is also combination preparations containing 3000-7000 EPO and 50-100 ml of one or more modified hemoglobins, with EPO and modified hemoglobin present in separate administration forms or in a single form of administration. According to the invention, 3000-7000 U of an erythropoietin preparation and 50-100 ml of one or more modified hemoglobins are used as the optimum dose depending on the clinical picture of the anemia. Thus in the case of manifest anemias without problems of iron distribution, a high dose of Fe2 +, approximately 80-100 ml (approximately 160-200 mg Fe + 2), preferably 85-95 ml, in the form of a modified hemoglobin a lower dose of EPO between 3000 and 5000 U is administered according to the invention. When there is a problem of iron distribution in the case of overt anemias, a higher dose of EPO of about 5000-7000 U of EPO, preferably 6000-7000 U, especially about 7000 U of EPO and a high dose of Fe2 +, is preferably administered, about 80-100 ml, preferably about 100 ml, in the form of one or more modified hemoglobins. For the treatment of iron utilization problems in the case of overt anemias, the combination preparation according to the invention preferably contains 3000-7000 U of EPO and 80-100 ml of a modified hemoglobin, preferably about 5000 U of EPO , and approximately 100 ml of one or more modified hemoglobins. For the treatment of iron deficiency anemias manifested the combination preparation also preferably contains 3000-7000 U of EPO and 80-100 ml of modified hemoglobin. As hemoglobin modified according to the invention, all the hemoglobins described in WO 95/24213 page 20, lines 15 to page 27, line 2 are suitable in principle. In particular, there are also hemoglobin crosslinked or polymerized crosslinked hemoglobin, such as diacetylsalicylic acid (diaspirin), cross-linked hemoglobin (DCL-Hb) or other blood substitutes based on modified hemoglobins. For example, the following preparations come into consideration as modified hemoglobins; Hem Assistmr (Baxter, human DCLHb), PolyHememr (Northfield, Upjohn, human Hb; cross-linked and polymerized); Hemopuremr (Biopure, Upjohn, bovine Hb, polymorphized); Optromr (Somatogen, Eli Lilly; recombinant human Hb); Hem01ink (Hemosol, Fresenius, human Hb, cross-linked and polymerized); Human bovine Hb modified with PEG (manufactured by Enzon, Hb modified with polyethylene glycol); Human Hb modified with polyoxyethylene (Apex Ajinomoto manufacturers). The hemoglobins can also be used according to the invention in the form of hemoglobin preparations containing pharmaceutically compatible auxiliaries known per se. Such preparations are described, for example, in W 95/24213. Suitable erythropoietin preparations in the meaning of the present invention are those active substances which are comparable with respect to the physiological effect of human EPO's. Suitable preparations of EPO are for example recombinant human EPO (rhEPO, see European patent EP 0,205,564 or EP 0,411,678) or also corresponding modifications of these proteins. Modifications are possible, for example those 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, basically those proteins that are derived by means of deletions, substitutions or additions of the amino acid sequence of natural EPO with a length of 166 amino acids fall into consideration. These proteins have essentially physiological properties comparable to rhEPO. In particular, these proteins have biological properties that cause the cells of the bone marrow to increase the production of reticulocytes and corpuscles of red blood cells and / or increase the synthesis of iron absorption hemoglobin. Instead of these proteins they can also use low molecular weight substances, which are denoted as EPO mimics, and which bind to the same biological receptor. These mimetics can also be administered orally. The amount of those proteins or mimetics that have to be administered is determined by comparing the biological activity between EPO and those active substances. The concentrations according to the invention of EP and Fe2t of hemoglobin allow in their combination an optimal treatment of anemia, especially the treatment of overt anemias. The treatment with the combination preparation is preferably carried out once a week, the amount of hemoglobin of 300 ml per week should not be exceeded (eg, infusions of 3 x 100 ml). Within the meaning of the present invention, it is to be understood under the term "combination preparation" no sol those packets of medicaments in which the preparation of EPO and hemoglobin are present in juxtaposition in a marketable finished unitary package (called combination pack), but also those packets of medicament containing an adequate amount of an EPO preparation or an adequate amount of a hemoglobin in the form of the respective individual preparations, the individual preparations being presented with respect to the amount of contents, so that they can be administered in the meaning of the invention for the dose combined with the other respective preparation. In these cases, generally together with the preparations of the pharmaceutical manufacturer or the importer of the medicine, there is an insert in the package that is required by law in many countries and which contains addresses or information related to the combined dose of the individual preparations. The combination preparations may preferably be present in a single administration form in which the respective amounts of the EPO preparation and the hemoglobin are present in juxtaposition in a container. This can be, for example, a solution for injection or infusion or its lyophilisate, which is for example found in ampoules. This form of administration has the advantage that EPO is stabilized by means of the modified hemoglobin during the production and storage of the administration form. In the case of a lyophilisate, the EP0 / after its dissolution is activated by means of the modified hemoglobin. The fixed combination of the two active substances in the form of a lyophilisate also has the advantage that it can be handled simply and safely. The lyophilizate is dissolved in the ampule by the addition of pharmaceutically customary injection media and administered intravenously. It is also possible to administer the EPO preparation and the modified hemoglobin in the form of separate pharmaceutical formulations (free combination) simultaneously or, however, also successively. This free combination that can be presented in a unit package has the advantage of greater flexibility. Thus, these administration forms also allow modified hemoglobins to be administered 1-3 days before the administration of EPO. This free combination that can be presented in a single unit package (medication package) also has the advantage that each individual patient to be treated can be prescribed a particular individual amount of an EPO preparation and a hemoglobin. further, these combination preparations offer the advantage of greater safety when therapy is performed, since in each case the optimal synchronized amount of the individual preparation is fixed. Safe therapy and simple handling by the personnel performing the treatment or in the area of self-medication performed by the patients is guaranteed, by means of the combination preparation according to the invention. When the EPO preparation is in the form of a lyophilisate, the medicine packs (combination r packs) contain the corresponding amount of the EPO preparation in glass ampoules or in cartridges. The hemoglobin can be presented in solid form (lyophilized) or also in liquid form in a separate container; In addition, the combination pack preferably contains a solution for reconstitution in order to dissolve either the lyophilized EPO alone or also together with the hemoglobin. If the hemoglobin is present in the form of a ready-to-use solution, the solution can be mixed together with the EPO solution when the combined administration of EPO and hemoglobin has to be carried out. Basically hemoglobin can also be presented in the form of a concentrate for addition to conventional infusion solutions, by such means a more prolonged administration of more than several hours can be effected. The combination preparations in the meaning of the present invention are also those unit packages which in each case have individual administration forms of the preparation of erythropoietin or hemoglobin as independent drugs, the individual preparations being provided in such a way that they contain the required amounts of the individual substances for the combination according to the invention of the preparation of EPO and hemoglobin. As a rule, the medicine packages contain the insert of the previously described package containing the corresponding instructions for the combined administration with EPO or with hemoglobin in the required amount. A corresponding instruction may also be present as package form in the medication package (secondary packaging) or in the primary package (vial, bubble strips, etc.). Thus, in the case of the EPO-containing medicament with 3000-7000 U of EPO it is indicated, for example, that such preparation must be administered especially together with a hemoglobin preparation containing 50-100 ml of one or more modified hemoglobins. In the chaos of the hemoglobin preparation in which there is an inverse indication of the combined administration with 3000-7000 U of an erythropoietin preparation. Another possibility to provide an EPO preparation is to present the corresponding multi-dose preparations containing the EPO preparation in larger amounts compared to the individual doses. These preparations are especially suitable for use in clinics in which a large number of patients are treated daily. These multi-dose preparations contain the EPO preparation in doses of up to 500,000 U, especially up to 100,000 or 50,000 U. Multi-dose preparations have the advantage that they allow trained medical personnel to extract any dose of the EPO preparation, for example. extracting 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 EPO preparations is required. Of a solution for injection, for example 100,000 U of EPO, preferably freshly prepared at the beginning of the day, can be performed if circumstances allow, all the treatments required to patients during the day without the need to prepare separate injection solutions for each of the individual patients. This can lead to significant time savings or facilitate the workload of trained medical personnel. Preferably, individual EPO dosi are extracted in the range of 3000 U, 5000 U and 7000 U. Multi-dose preparations may also be present in the form of solutions and cartridges. These cartridges are suitable for use in the so-called pens, which allow the administration by the patients themselves and the extraction of an individual dose. For example, these cartridges contain the EPO preparation in an amount of 10,000 or 20,000 U, being possible to obtain different dose intervals by means of the appropriate adjustment of the extracted volume. The production of the pharmaceutical administration forms of the invention is carried out in accordance with the usual processes known in pharmaceutically customary pharmaceutical adjuvant technology. The process for the production of the pharmaceutical combination preparation, which contains the combination of combination preparations according to the invention and the pharmaceutical unit package containing the combination of preparations according to the invention, are likewise objects of the invention. When performing therapy, the parameters of ferritin diagnostic and transferrin saturation should be controlled. The ferritin value is in the normal range when it rises to 400 μg / 1 ± 50%. The saturation of transferin should amount to 20-40%. The invention will now be illustrated in more detail on the basis of exemplary embodiments. Example 1: Patients with manifest iron deficiency (ferritin <12 ng / ml, transferrin saturation <15% hemoglobin> 12 g / dl) receive 5000 U of rhEPO once a week and 100 ml of a modified hemoglobin preparation, preferably DCL-Hb, by infusion. ,'three times per week. This treatment is repeated for another five weeks until the values of ferritin, transferrin saturation and hemoglobin or hematocrit are in the normal range. 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.

Claims (14)

CLAIMS Having described the invention as above, s claims as property contained in the following claims:

1. - Preparation of pharmaceutical combination characterized in that it consists of a) individual administration forms of a preparation erythropoietin suitable for the individual dosage of the active substance in an amount of 3000-7000 U and b) 50-100 ml of one or more hemoglobins with a Fe2 + content of 100-200 mg.

2. - Preparation of combination according to claim 1, characterized in that it contains 3000-7000 U d a preparation of eritrspoietin and 80-100 ml of modified hemoglobin with a content of 160-200 mg of Fe2. "

3. - Preparation of combination according to claim 1 or 2, characterized in that it contains 5000-7000 of a preparation of erythropoietin and 80-100 ml of modified hemoglobin with a content of 160-200 mg of Fe2 *

4. - Preparation of combination according to

5. Claim 3, characterized in that it contains 6000-7000 of an erythropoietin preparation and approximately 100 ml of modified hemoglobin 5. - Combination preparation according to claim 1, characterized in that it contains 3000-5000 U of an erythropoietin preparation and 80-100 with a content of 160-200 mg of Fe, preferably 85-95 ml of modified hemoglobin

6. - Combination preparation according to claim 1, characterized in that it serves for the tra tamient of manifest anemia.

7. Preparation of combination according to one of claims 1 to 4 characterized in that it serves for the treatment of manifest anemia with problems of distribution of iron.

8. Preparation of combination according to claim 5, characterized in that it serves for the treatment of manifest anemias without problems of iron distribution.

9. - Process for the production of pharmaceutical combination preparations according to claims 1 to 8, characterized in that 3000-7000 U of u prepared erythropoietin in individual administration forms and 50-100 ml of modified hemoglobin with u content is formulated of 100-200 mg Fe2 + together or separated from each other by usual carrier or auxiliary substances, and the preparations obtained are presented in the form of combined preparations. 10.- Use of preparations of erythropoietin with 3000-700 U EPO and 50-100 ml of one or several hemoglobins modified with a content of 100-200 mg Fe2 + for the production of a pharmaceutical combination preparation for the treatment of overt anemias. 11.- Use of preparations of erythropoietin with 5000-7000 U EPO and 80-100 ml of one or several modified hemoglobins with a content of 160-200 mg Fe2 + for the production of a pharmaceutical combination preparation for the treatment of overt anemias with problems of iron distribution. 12.- Use of preparations of erythropoietin with 3000-5000 U EPO and 80-100 ml of one or several modified hemoglobins with a content of 160-200 mg Fe2 + for the production of a pharmaceutical combination preparation for the treatment of overt anemias without problems of iron distribution. 13. - Individual pharmaceutical package characterized in that it includes 3000-7000 U of an erythropoietin preparation in individual administration forms and 50-100 ml of one or several modified hemoglobins with a content of 100-200 mg Fe2 +, as unique administration forms in a container or as separate administration forms in separate containers. 14. Individual package according to claim 13, characterized in that the preparation of erythropoietin and hemoglobin are in the form of injectable or infusible solutions.