IRON AND ZINC BASED PHARMACEUTICAL FORMULATION FOR IRON
DEFICIENCY TREATMENT
Field of Invention
The present invention relates to a pharmaceutical formulation, particularly providing high iron absorption, for use in preventing and treating iron deficiency and iron deficiency anemia of various origins.
Background of Invention
Iron, which is incorporated into the basic structure of hemoglobin, a protein providing the transport of oxygen in blood, bears great importance in binding the oxygen taken in the lungs to hemoglobin and transporting it to tissues, and therefore is an essential element with respect to proper tissue development in humans. Iron is not present in foodstuffs in adequate amounts, and if it is taken exogenously, it may cause various disorders, since it is absorbed difficultly. Anemia associated with iron deficiency, for instance, is one of the symptoms frequently encountered in blood diseases, and occurs when the blood hemoglobin level drops below a lower limit.
Iron deficiency is still the most-frequently occurring nutritional problem worldwide and iron deficiency anemia is present in around 30% of the world population. Iron deficiency is still a significant public health problem not only in underdeveloped countries, but in the developed countries' disadvantageous groups (infants, adolescents, pregnant women, and ethnical groups in inadequate socioeconomic conditions) as well. According to the report published by the World Health Organization (WHO), the occurrence rate of iron deficiency anemia in developing and developed countries is 36% and 8%, respectively.
Prevalence of iron deficiency anemia: It is the most common cause of anemia worldwide. Anemia is present in 30% of the world population and at least half of this rate is due to iron deficiency.
Infants and pregnant women compose the groups which are most susceptible to anemia. Anemia prevalence is determined to be as 43% in infants and 51% in pregnant women. Anemia prevalence is 37% in school-age children, 35% in nonpregnant women, and 18% in adult males. No certain prevalence figures are available for adolescents and elder people. The prevalence of adolescents is generally considered to be close to that of adult women.
Although anemia associated with iron deficiency has many causes, it is more frequently seen in societies with lower socioeconomic levels and with bad nutritional habits. The causes of anemia may comprise, inter alia, delayed commencement of dietary supplements, excessive caw milk consumption by babies, vegetarian nutrition, misapplied weight-loss diets, and eating disorders. In addition, acute or chronic blood loss, e.g. ulcerative hemorrhage or menstrual bleeding and parasitary infections increase the iron need, particularly during the first year of life and the adolescent period in which rapid growth occurs, resulting in possible anemia cases.
The presence of high amounts of iron in the intestine during oral treatment triggers oxidative damage. Therefore, losses are encountered in the formation, destruction, and functions of intestinal mucosal cells. Zinc ensures the stability of intestinal cells and cell walls, thereby providing protection against the peroxidative damage of iron. The studies conducted reports that the presence of zinc in the medium reduces iron-dependent hydroxyl radical formation at intestinal mucosa and protects the cells against iron-dependent lipid peroxidative damage.
In zinc deficiency, however, atrophy, flattening, and blunting occur at intestinal villuses and in result, the absorption functions of intestines start deteriorating. No satisfactory outcomes can be achieved in iron deficiency treatments, which are conducted when zinc deficiency is prominent. As a matter of fact, since iron can
not be absorbed adequately and since iron storages can not be filled entirely, frequent recurrences occur in anemia therapies.
In cases when iron is used together with zinc, it is known to maintain the iron:zinc rate between 1:1 and 2.5:1 , in order to avoid the absorption of both elements from interfering each other negatively.
Folic acid cannot be produced in the human body, since PABA cannot be synthesized and the first glutamate cannot be added to the molecule. Folic acid plays role in the cellular DNA synthesis and is absolutely required during the formation stage of new cells. It is also required for erythrocytes to be regenerated during anemia. Deterioration occurs in the metabolism of cells which are rapidly destructed and regenerated in folic acid deficiency. The most-susceptible cells are normoblasts, leukocyte cells, platelet cells, intestinal epithelial cells with the fastest division and regeneration rates. The susceptibility of erythrocytes gives rise to megaloblastic anemia. In folic acid deficiency there may occur megaloblastic anemia, neural tube and other congenital birth defects, hyperhomosysteinemia.
Vitamin C, a water soluble and potent antioxidant that cannot be synthesized by humans, is assistive in iron absorption. It plays roles in carnitine synthesis, the conversion of tryptophan to serotonin and thyroxin, the conversion of corticosteroids and aldosteron cholesterol to bile acids, immune system functions, preventing cancer, and in collagen synthesis.
An effort towards preventing and treating disorders associated with iron deficiency is known from the application WO 2006024241. WO 2006024241 discloses a preparation in the form of tablet or aqueous suspension for preventing or treating iron deficiency, this preparation containing between 6 and 26% ferrous fumarate and between 74 and 94% haemoderivative in powder form, with an ionic iron/haem iron ratio of between 30 and 70% and an amino acid concentration of between 20 and 30 μmol/100μmol of proteins.
The patent JP 2006193428 discloses a prophylactic or ameliorative agent for iron deficiency anemia, comprising an iron compound containing various iron salts, e.g. ferrous fumarate, extracts of Eleutherococcus Senticosus, and rutin and/or a rutin derivative.
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Description of Invention
The object of the present invention is to provide a pharmaceutical formulation ensuring high iron absorption for efficiently preventing and treating iron deficiencyo and anemia associated with iron deficiency.
Another object of the present invention is to provide efficient iron, zinc, and folic acid, as essential agents, in proportions which will not interfere the absorption of each other, against malnutrition-associated macrocytes anemias, anemias due to5 hemorrhage, zinc deficiency co-occurring with iron deficiency, and zinc deficiency co-occurring with megaloblastic anemia.
A further object of the present invention is to provide efficient iron absorption against iron deficiencies during pregnancy, in infants and children, and against0 latent iron deficiency.
The pharmaceutical formulation according to the present invention preferably comprises 3 to 20 mg/ml iron, 1 to 20 mg/ml zinc, 1.5 to 60 mg/ml vitamin C, and 0.015 to 0.50 mg/ml folic acid. A more preferred pharmaceutical formulation5 according to the present invention comprises 5 to 12 mg/ml iron, 4 to 10 mg/ml zinc, 5 to 40 mg/ml vitamin C, and 0.08 to 0.40 mg/ml folic acid. The most preferred pharmaceutical formulation according to the present invention comprises 7 to 9 mg/ml iron, 5 to 7 mg/ml zinc, 10 to 20 mg/ml vitamin C, and 0.1 to 0.2 mg/ml folic acid. According to a preferred formulation of the present invention, the0 fructose amount may be kept between 30 mg/ml and 250 mg/ml, but this amount may be kept in more preferred formulations between 100 mg/ml and 200 mg/ml and in most preferred formulations between 120 mg/ml and 180 mg/ml.
The formulation according to the present invention further comprises excipients, or auxiliary agents, such as sorbitol, sodium saccharin, fructose, sodium hydroxide, nipagin, sodium saccharin, neohesperidin dihidrochalcone, orange, lemon and mandarin essences citric acid, as well as deionized water.
As an alternative to fructose, the formulation according to the present invention may contain mixed saccharide materials, such as sucrose, glucose, mannose, galactose, lactose, or a mixture thereof.
The proportions of fructose given above builds iron-fructose complexes with iron, thereby enhancing the dissolution rate and the absorption of iron.
The excipient citric acid is similarly supportive in iron absorption, but is also pH lowering, as well as maintaining the stability of vitamin C. According to a preferred formulation of the present invention, the citric acid amount may be kept between 1.5 mg/ml and 600 mg/ml, but this amount may be kept in more preferred formulations between 50 mg/ml and 300 mg/ml and in most preferred formulations between 90 mg/ml and 110 mg/ml.
As an alternative to citric acid for use in the formulation according to the present invention, other organic acids, carrying one or more carboxyl groups and organic side chains, e.g. tartaric acid, malic acid, may be included into the formulation.
The iron employed in the pharmaceutical formulation according to the present invention is divalent iron (Fe (M)) based on its high absorption rate, but this fact does not exclude the use of trivalent iron (Fe (M)) from the scope of the present invention. Iron and zinc are included in a formulation according to the present invention preferably in the form of ferrous fumarate (C4KkFeO4) iron salt and zinc sulfate (ZnSO4) zinc salt, respectively.
The iron salt may also be in the form of ferrous gluconate, ferrous succinate, ferrous glutamate, ferrous lactate, ferrous citrate, ferrous tartrate, ferrous pyrophosphate. According to a preferred embodiment according to the present
invention, the source of iron may be in the form of iron-EDTA, iron ammonium ortophosphate, iron Il ammoniumsulfate iron complexes.
In another formulation according present invention, the source of iron may be in the form of iron III protein succinate, iron III polymaltose, iron III Sodium-EDTA, carbonyl iron, iron chloride.
As for the zinc salt, it may be in the form of zinc sulfate mono or heptahydrate, zinc acetate, zinc carbonate, zinc chloride, zinc gluconate, zinc picolinate.
The formulation according to the present invention is preferably in the form of a syrup, but it can also be prepared in any oral liquid forms, including the aqueous suspension form. Thus, the oral administration thereof may be facilitated as compared to the tablet form, especially for children. Said "liquid form" further comprises effervescent tablet compositions, which are convenient for oral administration once they are dissolved in water.
The constituents making up an exemplary composition according to the present invention are listed as follows:
Constituent Mass per 5 ml syrup (mg) Ferrous f umarate 121
Zinc sulfate 66
Folic acid 0.2
Vitamin C 50
Example 2:
Constituent Mass per 5 ml syrup (mg) Ferrous f umarate 121
Zinc sulfate 66
Folic acid 0.2
Vitamin C 50 Fructose 750
Example 3:
Constituent Mass per 5 ml syrup (mg)
Ferrous fumarate 121 Zinc sulfate 66 Folic acid 0.2 Vitamin C 50 Fructose 750 Citric acid 500 mg
Example 4:
Constituent Mass per 5 ml syrup (mg)
Ferrous fumarate 121 Zinc sulfate 66 Folic acid 0.2 Vitamin C 50 Sorbitol 1500
Propylene glycol 250 Ethyl alcohol 250 Nipagin M sodium 5
Example 5:
Constituent Mass per 5 ml syrup (mg)
Ferrous fumarate 121 Zinc sulfate 66 Folic acid 0.2 Vitamin C 50
Sorbitol 1500
Neohesperidin dihydrochalcone 5
Citric acid 500
Propylene glycol 250
Ethyl alcohol 250
Nipagin M sodium 5
Sodium saccharine 5
Sunset yellow 0.03
Orange essence 2
Lemon essence 2
Mandarin essence 2
Grapefruit essence 2
Deionized water quantum sufficit to complete to 5 ml
Example 6:
Constituent Mass per 5 ml syrup (mg)
Ferrous fumarate 121 Zinc sulfate 66 Folic acid 0.2 Vitamin C 50 Sorbitol 1500
Propylene glycol 250 Ethyl alcohol 250 Nipagin M sodium 5 Sodium saccharine 5 Sunset yellow 0.03 Orange essence 2 Lemon essence 2 Mandarin essence 2 Grapefruit essence 2 Deionized water quantum sufficit to complete to 5 ml
The proportion between iron and zinc in a formulation according to the present invention is preferably 1 to 2.5; the proportion between vitamin C and iron is preferably 0.5 to 3; and the proportion between folic acid and iron is preferably between 0.005 to 0.025. In another preferred formulation according to the present invention, the proportion between iron and fructose is preferably 0.04 to 0.1 and the proportion between vitamin C and citric acid is 1 to 10.