Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-10-23
2004-03-23
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06710028
ABSTRACT:
The present invention concerns pharmaceutical combination preparations containing erythropoietin and iron preparations. The preparations are used particularly to optimize erythropoiesis for the treatment of diseases in which it is intended to stimulate the formation of erythrocytes.
The subject matter of the present invention is a pharmaceutical combination preparation comprising 250-20,000 U of an erythropoietin preparation and 1-40 mg of an equivalent amount of iron ions of a physiologically compatible iron preparation in which the erythropoietin preparation and the iron preparation can be present in separate forms of administration or in a uniform administrative form.
It is known that anaemia and in particular the anaemia of haemodialysis patients caused by transfusion can be treated with recombinant erythropoietin (rhEPO). Anaemia in chronic diseases is worldwide the second most frequent form of anaemia.
A reduced new production of erythrocytes is in the foreground of anaemias that are caused by reduced erythropoiesis in the bone marrow or by disturbances of iron re-utilization. When the new formation of erythrocytes declines daily by 1%, anaemia cannot be clinically diagnosed until after 1-3 weeks. The daily iron requirement for a normal erythropoiesis is 25 mg. Of this only about 1 mg is derived from the food, the main requirement is normally met by re-utilization of the haemoglobin iron after the degradation of aged erythrocytes. The release of iron from the reticular cells is greatly reduced in chronic diseases. The iron is retained in the reticuloendothelial system and is no longer available for erythropoiesis. One therefore also speaks of an “inner iron deficiency” in which normal compensation mechanisms are incompletely triggered. A reticulocytopenia and an absence of a hyperplasia of the erythropoiesis that would be needed to compensate for the anaemia are typical. A reduced erythropoietin secretion or activity may also be an additional pathogenetic factor. A significant change in iron metabolism is for example the absence of a compensatory increase in transferrin formation. The underlying disorder is therefore the lack of iron release from the iron stores (in the reticuloendothelial cells) into the plasma (and thus also into the erythron) as a result of which the normal compensation mechanisms are not triggered. The administration of recombinant erythropoietin is utilized therapeutically to significantly increase the number of erythrocytes.
In clinical chemistry the concentration of serum ferritin is determined to diagnose anaemia and disorders of iron metabolism. If a real iron deficiency occurs in addition to the anaemia of chronic diseases then there is no increase in ferritin (it usually remains below 90-95 ng/ml). If at the same time there are clinical signs of infection, inflammation or malignant disease, this value indicates a combination of iron deficiency and anaemia accompanied by a chronic disease. Since in these diseases the serum ferritin can also react in the sense of an acute phase protein, the erythrocyte ferritin can be utilized better diagnostically.
The total body iron is ca. 3.5 g in men and 2.5 g in women. Iron is actively metabolised and present in storage compartments. In the active pool of a man an average of 2100 mg is present in haemoglobin, 200 mg in myoglobin, 150 mg in enzymes of the tissue (haem and non-haem) and 3 mg in the iron transport compartment. Iron is stored intracellularly in the tissue as ferritin (700 mg) and as haemosiderin (300 mg).
The bioavailability of the iron can be pathophysiologically disturbed resulting in a reduced iron absorption in the body. Of the approximately 10 mg that is daily available through the diet an adult only absorbs about 1 mg. In iron deficiency the absorption increases, but seldom above 5-6 mg, if no additional iron is supplied. The exact mechanism for the absorption of iron has not been elucidated. The mucosal cells of the small intestine play a decisive role in the regulation. The most important signal for the mucosa appears to be the total iron content of the body. It has been shown that the serum ferritin concentration correlates inversely with the amount of absorbed iron.
The iron is transferred from the intestinal mucosal cells to transferrin. This iron transport protein has two iron binding sites. It is synthesized in the liver. Hence there is a mechanism whereby iron is received by cells (e.g. mucosa of the small intestine, macrophages) and transferred to specific membrane receptors of erythrocytes, placental cells or liver cells. The transferrin-iron-receptor complex reaches the inside of the erythrocyte precursor cells by endocytosis where the iron is passed onto the mitochondria. Here haem is formed from iron and protoporphyrin.
Iron that is not required for erythropoiesis is transferred by transferrin into two types of storage pool. Ferritin is the most important store. This is a heterogeneous family of proteins which surround an iron core. It is soluble and represents the active storage form in the liver (hepatocytes), bone marrow, spleen (macrophages), erythrocytes and in the serum ( about 100 ng/ml). The tissue ferritin pool is very labile and is rapidly available when iron is required. Circulating serum ferritin is derived from the reticuloendothelial system and its circulating concentration parallels that of the total body iron (each ng/ml corresponds to 8 mg iron store).
In the case of haemodialysis patients it has turned out that the iron requirement of patients treated with rhEPO is quite considerable. As a rule an additional iron therapy is usually carried out on these patients since EPO can only develop an optimal action when the corresponding iron stores in the body are as full as possible. Hitherto high doses of iron preparations have been commonly administered to fill up the iron stores as much as possible. However, excessive doses of iron preparations can also lead to undesired side-effects in the patients. In particular the intravenous administration of iron preparations is not physiologically safe due to the extreme toxicity of iron ions. The use of certain iron preparations is usually warned against for patients with known allergic reactions e.g. for asthmatics. It is possible to assess the fill status of the iron stores by determining the protein ferritin and by determining the transferrin saturation (M. Wick, W. Pingerra, P. Lehmann “Eisen-stoffwechsel, Diagnose und Therapie der Anämien”, pages 5-14, 38-55, 65-80, 94-98; third extended edition, September 1996, Springer publishers Wien, N.Y.) whereby the transferrin saturation represents the flow of iron from the depots to the bone marrow whereas the serum ferritin value is a measure for stored iron.
The iron stores are considered to be “full” when the serum ferritin is <150 &mgr;g/l and a transferrin saturation of 20% is present. P. Grützmacher et al. describe in Clinical Nephrology, Vol. 38, No. 1, 1992, p. 92-97 that under these conditions one can assume a maximum response to EPO therapy.
In the iron therapy of EPO-treated dialysis patients one currently refers to a “correction phase” and a “maintenance phase”. In the correction phase the highest possible doses of iron preparations are administered in order to fill up the iron stores as rapidly as possible. In this case suitable iron preparations are expediently administered as an intravenous bolus injection. In the maintenance phase the iron stores are then kept filled with low doses of iron. Suitable iron preparations are no longer administered in this phase as a rapid bolus injection but in the form of conventional infusion preparations or by oral administration.
The iron requirement of a haemodialysis patient treated with rhEPO can be quite considerable in the correction as well as in the maintenance phase. 150 mg iron is required to synthesize 1 g/dl haemoglobin in the correction phase that either has to be covered by endogenous iron stores or has to be supplied exogenously. The iron requirement is also increased in the maintenance phase since small los
Johnston George W.
Kemmerer Elizabeth
Nichols Christopher James
Rocha-Tramaloni Patricia S.
Roche Diagnostics GmbH
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