Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-02-07
2002-08-27
Horlick, Kenneth R. (Department: 1656)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S021800
Reexamination Certificate
active
06440932
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention is concerned with pharmaceutical combination preparations containing erythropoietin preparations and one or more modified haemoglobins. The combination preparations are especially useful for the treatment of manifest anaemias.
The object of the present invention is a pharmaceutical combination preparation which comprises a) individual administration forms of an erythropoietin preparation suitable for the individual dosing of the active substance in an amount of 3,000-7,000 U and b) 50-100 ml of one or more modified haemoglobins, with the erythropoietin preparation and modified haemoglobin being present in separate administration forms or in a single administration form.
The macromolecule ferritin (molecular weight at least 440 kD depending on the iron content) plays a significant role in the diagnosis of anaemias. An estimation of the fullness level of the iron reservoir is possible by determining the ferritin and the transferrin saturation (M.Wick, W. Pingerra, P. Lehmann “Ferritin in iron metabolism and diagnosis of anaemias”, pages 5-22, 38-50, 65-77, 94-97, 2
nd
expanded edition 1994, published by Springer Vienna, New York), with the totality of the iron stored as basic ferritin in the depot organs liver, spleen and bone marrow amounting to about 800-1200 mg. A lower ferritin concentration is the definitive characteristic for detecting iron deficiency states and their difference from other causes of hypochromic anaemia, such as e.g. chronic inflammations and tumours.
It is known to treat transfusion-mediated anaemias in haemodialysis patients with recombinant erythropoietin (rhEPO), with it being necessary as a rule to carry out an iron substitution in parallel to the EPO therapy. This iron substitution is effected by the intravenous administration of iron(III) salts, with two intravenously administerable iron preparations being available on the German medicament market at present. These are the medicaments “Ferrlecit” and “Ferrum Vites”. “Ferrlecit” is an iron(III) gluconate complex, while “Ferrum Vites” is an iron(III) oxide saccharate complex.
It has, however, become evident that in the case of manifest anaemias with manifest iron deficiency and iron utilization disorders (<30 mg/dl ferritin) iron substitution with the mentioned preparations has disadvantages, since for the treatment of manifest anaemias relatively large amounts of a pharmacologically harmless iron salt have to be infused. The use of the aforementioned iron preparations holds the possibility of unexpected circulatory reactions up to collapse, especially when large amounts have to be injected relatively rapidly.
In WO 96/15805 there is described a haemoglobin therapy for haemodialysis according to which very low doses of stroma-free haemoglobin are administered over a period of 10 to 45 minutes in order to achieve a haemostabilization and to avoid a lowering of blood pressure in sensitive patients. However, this described therapy is not successful in the case of manifest iron deficiency anaemias.
Also, WO 95/24213 describes the use of natural or recombinant haemoglobin or their chemically modified derivatives for anaemia treatment. Furthermore, this document discloses the combined administration of one of the aforementioned haemoglobins with one or more haematopoietic growth factors, inter alia with EPO. Examples 4 and 5 as well as some of the Figures show that a combined administration of EPO and rh haemoglobin lead to an increased haematopoesis.
However, this document does not disclose a practical therapeutic regime for an optimal regulation and treatment of patients with manifest anaemias. Also, it is not evident therefrom, as in the case of patients treated with EPO, that it is possible to produce an optimal EPO effect without avoiding an EPO resistance.
SUMMARY OF THE INVENTION
It has now been found that the use of relatively high infusion amounts of 50-100 ml of haemoglobin (about 100-200 mg Fe
2+
) together with 3,000-7,000 U of EPO is surprisingly advantageous for the treatment of manifest anaemias (the abbreviation “IU” can also be used in place of the abbreviation “U” for International Units).
The object of the invention are accordingly also combination preparations which contain 3,000-7,000 U of EPO and 50-100 ml of one or more modified haemoglobins, with the EPO and the modified haemoglobin being present in separate administration forms or in a single administration form.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the invention 3,000-7,000 U of an erythropoietin preparation and 50-100 ml of one or more modified haemoglobins are used as the optimal dose depending on the clinical picture of the anaemia. Thus, in the case of manifest anaemias without iron distribution disorders, a high dose of Fe
2+
, about 80-100 ml (about 160-200 mg Fe
2+
), preferably 85-95 ml, in the form of a modified haemoglobin and a lower dose of EPO between 3,000 and 5,000 U is administered in accordance with the invention.
When there are iron distribution disorders in the case of manifest anaemias, a higher EPO dose of about 5,000-7,000 U of EPO, preferably 6,000-7,000 U, especially about 7,000 U of EPO, and a high Fe
2+
dose, about 80-100 ml, preferably about 100 ml, in the form of one or more modified haemoglobins is preferably administered.
For the treatment of iron utilization disorders in the case of manifest anaemias the combination preparation in accordance with the invention preferably contains 3,000-7,000 U of EPO and 80-100 ml of a modified haemoglobin, preferably about 5,000 U of EPO, and about 100 ml of one or more modified haemoglobins. For the treatment of manifest iron deficiency anaemias the combination preparation likewise preferably contains 3,000-7,000 U of EPO and 80-100 ml of a modified haemoglobin.
As modified haemoglobins in the meaning of the invention there are suitable in principle all haemoglobins described in WO 95/24213page 20, line 15 to page 27, line 2. In particular, these are also cross-linked haemoglobins or cross-linked haemoglobin polymerizates, such as e.g. diacetylsalicylic acid (diaspirin), cross-linked haemoglobin (DCL-Hb) or other blood substitutes based on modified haemoglobins. For example, the following preparations come into consideration as modified haemoglobins: Hem Assist® (Baxter; DCL human Hb); PolyHeme® (Northfield, Upjohn, human Hb, cross-linked and polymerized); Hemopure® (Biopure, Upjohn; bovine Hb, polymerized); Optro® (Somatogen, Eli Lilly; recombinant human Hb); HemOlink® (Hemosol, Fresenius; human Hb, cross-linked and polymerized); PEG-modified bovine Hb (manufactured by Enzon; polyethylene glycol-modified Hb); polyoxyethylene-modified human Hb (manufactures Apex and Ajinimoto). The haemoglobins can also be used in accordance with the invention in the form of haemoglobin preparations which contain pharmaceutically compatible adjuvants known per se. Such preparations are described, for example, in WO 95/24213.
As suitable erythropoietin preparations in the meaning of the present invention there come into consideration those active substances which are comparable with respect to the physiological effect of human EPOs. Suitable EPO preparations 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. As modifications there come into consideration, for example, such proteins with molecular weights higher or lower than 34,000 Da (molecular weight of urinary EPO), likewise isoforms of the enzyme or proteins with different glycosylation. In particular, proteins chemically modified by PEG (polyethylene glycol) can also be used. Further, there basically also come into consideration such proteins which are derived by deletions, substitutions or additions from the amino acid sequence of the natural EPO with a length of 166 amino acids. These proteins have essentially comparable physiological properties to rhEPO. In particular, these proteins have biological properties which cause bone marrow cells
Feuerstein Jürgen
Lehmann Paul
Town Michael Harold
Horlick Kenneth R.
Johnston George W.
Rocha-Tramaloni Patricia S.
Roche Diagnostics GmbH
Strzelecka Teresa
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