Iron-carbohydrate complexes, administered either through oral or parenteral route, are used for the treatment of anemia due to iron deficiency. Iron-sucrose injection is widely used in treatment of the iron deficiency and iron deficiency anemia and patients undergoing chronic Hemodialysis receiving supplemental erythropoietin therapy.
Iron-sucrose injection replenishes body iron stores in patients with iron deficiency. Iron is a mineral that the body needs to produce red blood cells. When the body does not get enough iron, it cannot produce the number of normal red blood cells needed to keep a person in good health. This condition is called iron deficiency (iron shortage) or iron deficiency anemia. Iron is sometimes lost with slow or small amounts of bleeding in the body that a person would not be aware of and which can only be detected by a patient's physician. The physician can determine if iron supplement is necessary for the patient.
Some conditions may increase the need for iron in patients. These include bleeding problems, burns, hemodialysis, intestinal diseases, stomach problems, stomach removal, use of medicines to increase red blood cell count, etc.
Iron supplements are available in the following dosage forms:
Oral: Ferrous fumarate, Ferrous gluconate, Ferrous sulfate, Iron-Polysaccharide
Parenteral: Iron-Dextran, Iron-Sorbitol, Iron-Sucrose, Sodium-Ferric-Gluconate Complex
In the current scenario, iron-sucrose complex is used orally or parentrally for the treatment of iron deficiency anemia in patients. When iron-sucrose complex is given orally it will not be absorbed 100% from the GI tract. Hence, the absorbed iron-sucrose complex given orally is not adequate to stock up or maintain iron stores necessary for hematopoiesis during erythropoietin therapy.
To have high availability in the conditions like chronic hemodialysis, iron-sucrose is given through intravenous route. Iron sucrose is taken up by cells of the reticuloendothelial system, which release ionic iron that binds to transferrin, which in turn, transfers it to the bone marrow for erythropoiesis or to ferritin and the iron storage pool in the marrow, spleen and liver.
Thus in the human body, the metabolism of iron involves a series of reactions wherein the valence of the iron changes from Fe3+ to Fe2+ and vice versa.
Metabolism of Iron Sucrose
Iron-sucrose is dissociated into iron and sucrose by the reticuloendothelial system and iron is transferred form the blood to a bone marrow. Ferritin, the iron storage protein binds and sequesters iron into a nontoxic iron that is easily available. The iron binds to plasma transferrin which carries iron through the extracellular fluid for supply to the tissues. The transferrin receptors presented in membrane binds transferrin iron complex which is then internalized in vesicles. Further, iron is released within the cell and transferrin-receptor complex returns to the cell membrane. Transferrin without iron is then released to the plasma. The intracellular iron becomes hemoglobin on circulating red blood cells.
When the amount of available iron exceeds ferritin's iron storage mechanism, an aggregated ferritin called hemosiderin is formed, which is a normal constituent of the monocyte-macrophage system. Hemosiderin is composed of molecules of ferritin, which have lost part of their protein shell and become aggregated. Hemosiderin accounts for about one third of normal iron stores and accumulates as insoluble granules in the cells of the reticuloendothelial system.
Upon administration to a patient, an iron-sucrose complex is removed from the blood stream as a particle by the macrophages of the reticuloendothelial system and metabolized to replenish the body's iron stores of hemosiderin, ferritin and transferrin. The rate of removal from the blood stream is dependent on both the colloidal ferric hydroxide's particle size and composition.
Iron-sucrose complex is composed of colloidal ferric hydroxide particles as core in complex with sucrose.
U.S. Pat. No. 6,911,342 claims in vitro method to control and monitor the batch-to-batch bioequivalence of iron-sucrose complexes, by measuring the colloidal ferric hydroxide's rate of reduction from trivalent iron to divalent iron. In the method, iron-sucrose complex is treated with a reducing agent and T75 for reduction kinetics of the complex is measured, wherein the T75 of less than 20 minutes indicates an effective bioequivalence of iron in the complex.
It is stated in U.S. Pat. No. 6,911,342 that the colloidal ferric hydroxide complexes are dark red to brown solutions with a strong adsorption band at 450 nm. As the reduction to ferrous hydroxide occurs, the color is discharged, resulting in a decrease in absorbency. This decay (or dissociation) can be easily monitored in a temperature controlled (37±1° C.) system.
In U.S. Pat. No. 6,911,342, T75 time for the reduction of the iron-carbohydrate complex is used to determine the relative bioequivalence by reducing the complex with an appropriate reducing agent. Preferred reducing agents disclosed in the US patent are reduced flavin mononucleotide, dithionite, thioglycolate, hydroquinone, lactate, citrate, bicarbonate, pyruvate, succinate, fructose, cysteine, sorbitol and ascorbic acid. The reducing agent may be present in an amount sufficient to drive the reduction reaction to completion or at least to substantial completion.
A preferred bioequivalence standard for an iron-sucrose formulation is met if T75 reduction time is not more than 20 minutes (preferably 9 to 18 minutes) and its reduction reaction plot of “Log(% Trivalent Iron Concentration)” versus “Time” is linear with a correlation coefficient absolute value of not less than 0.98.
Improvement in the method to control and monitor the batch-to-batch bioequivalence of iron-sucrose complexes is desirable.