MX2008004461A - Improved toleration iron supplement compositions - Google Patents

Abstract

The invention relates to compositions and methods for the treatment or prophylaxis of iron deficiency, and in particular of iron deficiency anemia, by administering a composition containing an effective amount of a pharmaceutically acceptable ferrous iron salt;and an effective amount of polysaccharide iron complex.

Description

COMPOSITIONS OF IRON SUPPLEMENT WITH IMPROVED TOLERANCE BACKGROUND OF THE INVENTION The Field of the Invention The present invention relates to compositions for treating or preventing iron deficiency in mammals, and in particular in humans, by administering to mammals with iron deficiency or potentially deficient an effective amount of a composition that it contains a pharmaceutically acceptable salt of iron, and an iron polysaccharide complex. Description of Related Technique Iron deficiency anemia is the most common form of anemia, and is perhaps the most common nutrient deficiency in the world. Iron-deficiency anemias are associated with insufficient iron in the diet, poor absorption of iron by the body, and / or blood loss. These conditions can often appear in humans and other animals as a result of, or related to, physiological events, such as growth, pregnancy, menstruation, or in relation to pathological events, such as hemorrhage, feeding deficiencies. Iron deficiency anemia affects 20% from women approximately, to 50% of pregnant women, approximately and approximately 3% of men. Because anemia develops when the iron stored in the body is emptied, and because women generally have smaller amounts of iron stored than men (and increase iron loss through menstruation), women are at greater risk of suffer the effects of anemia than men. However, men and post-menopausal women are also at risk of anemia if they suffer from gastrointestinal blood loss that is the result of ulcers or certain types of cancer, or the use of non-spheroidal anti-inflammatory drugs (NSAIDs). In addition, patients who are undergoing erythropoietin therapy (EPO) (for example, those with various types of kidney disease) may also suffer from iron deficiency anemia when their iron stores are emptied due to increased iron use, making new cells of red blood cells. The groups at highest risk of anemia include pre-menopausal women, pregnant women or lactating women (due to an increased need for iron), infants, children, or adolescents who experience rapid growth (and therefore experience an increased need for iron). ), women and men with a dietary intake poor in iron, individuals with diseases or conditions that produce gastrointestinal blood loss, and individuals with Gaucher's disease. Without enough iron in the blood, red blood cell cells can not efficiently carry oxygen through the body, which is necessary for normal functioning of the cells. Common symptoms of anemia include one or more of the following: pallor, fatigue, irritability, weakness, shortness of breath, irritated tongue, brittle nails, itching (unusual food cravings), lack of appetite, headache, and shaled sclerotics blue. The diagnosis of iron deficiency anemia is typically confirmed by low hematocrit and hemoglobin, small red cells, low serum ferritin, low levels of saturation transfer, low levels of ferric serum, high iron holding capacity, and bloody stools . The treatment of anemia, in addition to identifying the source of iron deficiency, typically involves the administration of iron supplements, often with the concomitant administration of vitamin C to aid iron absorption. While this can be done by intravenous or intramuscular injection when necessary, A highly tolerated way of oral dosing is much more desirable. Oral dosage forms of iron (ferrous) iron, such as ferrous sulfate, ferrous gluconate, ferrous succinate, and ferrous fumarate, are often used because the ferrous form of iron has a better absorption than the less soluble ferric form that can be precipitated in the body. Schmitt, J. of Renal Nutrition, 2, 126-128 (1992). These ferrous supplements are more effectively absorbed on an empty stomach. However, this is not tolerable for many people due to the collateral gastrointestinal effects; Some individuals may take the oral dosage form with food. However, certain types of food (eg, dairy products and other foods with high calcium content) may reduce the efficacy of iron absorption, and for some patients, collateral gastrointestinal effects limit the amount of ferric supplement that may be prescribed. In addition, the administration of vitamin C may not be desirable for some patients (particularly those who are undergoing dialysis). An alternative to ionic oral iron dosage forms is the iron polysaccharide complex (P1C) which has been shown to have equivalent efficacy at increasing values of hemoglobin and hematocrit as ferrous sulfate and / or ferrous fumarate, but is better tolerated. Newton et al., Clinical Triais Journal, 17, 106-111 (1980); Piccinni et al., Pan. Med., 24, 213-220 (1982). P1C is a synthetic complex of ferric iron and carbohydrate. It does not suffer from some of the disadvantages of ferrous iron supplements, since it does not readily ionize or combine with inhibitory substances in the intestine, while remaining sufficiently soluble to cross the mucosal barrier of the intestinal lumen. It is believed that P1C is absorbed via an active transport mechanism in which iron is transferred on the surface of the intestinal mucosa to a carrier (transferente) for transport in the bloodstream. P1C also seems to produce less collateral gastrointestinal effects than ferrous sulfate. Johnson et al., "A Prospective Open-Label Study Evaluating the Efficacy and Adverse Reactions of the Use of Niferex®-150 in ESRD Patients Receiving EPOGEN®." ("An Unrestricted Prospective Study Assessing the Efficacy and Adverse Reactions of the Use of Niferex®-150 in ESRD Patients Receiving EPOGEN®.") However, P1C is comparatively expensive compared to ferrous iron supplements.

As a result, while both ferrous salts and P1C are known as oral iron supplements that provide efficacy in the treatment of iron deficiency anemia, they have been considered as alternative treatments: if patients have difficulty with collateral gastrointestinal effects using less expensive ferrous salts, then this regimen can be replaced with a more expensive, but better tolerated, P1C regime to achieve equivalent efficacy. If patients lack the necessary transfer to effect absorption of P1C, then a ferrous salt regimen can be used. SUMMARY OF THE INVENTION The inventors have found that administering an oral ferric supplement composition, which contains ferrous iron salts and P1C, provides an unexpectedly well-tolerated method for treating iron deficiency anemia, and provides a composition that can be administered to the patient. a wide variety of patients, regardless of their ability to absorb iron through a particular physiological mechanism. Particularly, the compositions of the invention provide therapeutic levels of iron in the blood, with unexpectedly increased tolerance, independent of ability of the patient to absorb iron via a particular absorption mechanism. If the patient is unable to absorb ferrous iron (for example, due to low levels of ascorbic acid, collateral gastrointestinal effects, etc.), then sufficient iron is available through the P1C administered in the composition of the invention. If the patient is unable to absorb the P1C due to insufficient transferrin in the small intestine, then enough iron is available through the ferrous iron administered. As a result of this discovery, the present invention relates to an orally administrable iron supplement composition for the treatment or prophylaxis of iron deficiency, comprising: an effective amount of pharmaceutically acceptable ferrous iron salt; and an effective amount of iron polysaccharide complex. The invention also relates to a method for the treatment or prophylaxis of iron deficiency, comprising: administering to the patient in need thereof an effective amount of a composition comprising: an effective amount of pharmaceutically acceptable ferrous iron salt; and an effective amount of ferric complex polysaccharide. DETAILED DESCRIPTION OF SPECIFIC MODALITIES As described above, the invention relates to an effective amount of a pharmaceutically acceptable ferric iron salt; and an effective amount of ferric complex polysaccharide. The composition may also contain an effective amount of iron absorption facilitator, such as ascorbic acid, and a pharmaceutically acceptable carrier, linker, or excipient, such as microcrystalline cellulose, sodium starch glycolate, magnesium stearate, alcohol, water or its derivatives. The ferrous iron salt can be any ferrous iron salt conventionally used to treat iron deficiency anemia, but is preferably selected from the group consisting of ferrous fumarate, ferrous gluconate, ferrous sulfate, and ferric succinate. It has been found that ferrous fumarate gives particularly convenient results. The ferric iron salt is typically present in amounts ranging from about 30% by weight to about 32% by weight, more particularly between about 20% by weight and about 25% by weight, based on the total weight of the composition. The ferric complex polysaccharide (P1C) can include any P1C compound suitable for use as a ferric supplement, such as that sold under the name Niferex®, FerUs 150, Iferex 150, Ferrex 150, Myferon 150 and Polylron 150. The P1C is generally present in amounts ranging from about 38% by weight to about 46% by weight of iron in the P1C and, more particularly, between about 80% by weight and about 85% by weight in the formula. If a ferric improver is present, it is desirably included in an amount ranging from about 5% by weight to about 10% by weight, more particularly between about 5% by weight and about 10% by weight, based on the total weight of composition . As an alternative, a ferric enhancer can be administered separately from ferrous iron-the composition of P1C. If present, the connector, carrier, or excipient is present in an amount ranging from about 5% by weight to about 10% by weight, more particularly between about 5% by weight and about 10% by weight, based on the weight total composition.

To show the unexpectedly beneficial results obtained by the use of ferrous iron and P1C, and to explain more fully the compositions and methods of the invention, the following experiments were carried out under the direction of the inventors. EXAMPLE To compare the ferric absorption and tolerance characteristics of ferrous fumarate, administered as a composition of 487 mg / mL (comparative composition) and a composition containing ferrous fumarate and P1C, administered as a composition of 348 mg / mL (inventive composition) , Sprague Dawley Crl: CD (SD) rats were randomly assigned to 3 groups as indicated in the chart below: TABLE The solution of the test material or control vehicle was administered once a day by oral administration, and the individual dose volumes were calculated based on the most recent body weight data for each animal. General health / mortality controls and cases about to die twice a day were carried out, and detailed clinical observations were made on days 1, 8, and 15 before dosing. The parameters of the hematology were evaluated for all the animals on days 1, 7, and 14. The blood collection for the evaluation of serum iron concentration was also performed in these days, and blood samples were obtained via the plexus orbital, while the animals were under light anesthesia by isoflurane. All animals were subjected to a complete necropsy examination under programmed euthanasia.

Blood samples for hematology tests were collected in volumes of approximately 200 μL in tubes containing anticoagulant K2EDTA, and were evaluated for red cell count (RBC), hemoglobin concentration (Hb), hematocrit (Hct), bad corpuscular volume (MCV), the concentration of bad corpuscular hemoglobin (MCHC), the bad corpuscular hemoglobin (MCH), reticulocyte count (Retic), the morphology of red blood cells, the white blood cell count (BC), the neutrophil count (Neut), lymphocyte count (Limph), monocyte count (Mono), eosinophil count (Eos), and basophil count (Baso). Serum iron was measured by taking approximately 1 mL of blood samples in a serum separator tube. The segmented neutrophils, platelets, and lymphocytes changed in a similar manner for both Groups 2 and 3, indicating that the immune response to the ferrous fumarate and the inventive composition was more or less the same. Both Groups 2 and 3 exhibited similar significant increases also in the serum ferric levels. However, Group 2 showed complete interior changes different from those shown by Group 3, namely the emptying of body fat, thyroid nodules, lymph nodes reddish jaws, reddened stomach mucosa, small thymus, foci in the thymus, and dark fecal matter. By contrast, the only great inner results that Group 3 showed were a reddened thymus and dark stool. Based on these results, it is concluded that both compositions provide equivalent efficacy at increasing levels of iron in the serum, but that the Group 3 material (i.e., the composition of the invention) is significantly better tolerated than is the fumarate ferrous alone, although the concentration of the ferrous fumarate dose is the same in both compositions. In other words, the results support the conclusion that the addition of P1C to ferrous fumarate surprisingly allows the same concentration of ferrous fumarate to be better tolerated than if the P1C was not added.

Without wishing to be bound by any theory, it is believed that the increase in tolerability observed with the composition of the invention occurs as a result of distributing the total iron content in the composition between compounds that provide iron to the patient's bloodstream via two different mechanisms. . The ferrous iron salts are readily absorbed in the large intestine, by the direct dissolution and absorption of ferrous iron by the bloodstream. The available iron of the P1C is absorbed in the small intestine via an active protein transport mechanism. Although the reason that this diversity of absorption mechanisms results in greater tolerability is not well understood, it is believed that the result extends to any pharmaceutically acceptable ionic iron salt when administered in combination with P1C. The composition of the present invention may desirably be administered in amounts ranging from about 4.0 mg / kg of ferrous salt (eg, as ferrous fumarate) and 4.0 mg / kg of P1C, more particularly, from about 10.0 mg / kg of salt ferrous and 10.0 mg / kg of P1C to obtain good efficacy at increasing levels of iron in the serum, while avoiding adverse reactions. The composition is typically administered as a liquid or elixir, combined with alcohol and water as an excipient, at a concentration ranging from about 200 mg / ml to about 600 mg / ml of ferrous fumarate and from about 200 mg / ml to about 600 mg / ml of P1C. Those of skill in the art will understand that different concentrations of each component can be administered, depending on the degree of iron deficiency. Without However, the total administration must not exceed the toxicity limits of ferrous fumarate (approximately 200-250 mg / kg) or P1C (approximately 5000 mg / kg).

Claims (17)

1. CLAIMS 1. An orally administrable iron supplement composition for the treatment or prophylaxis of iron deficiency, comprising: an effective amount of a pharmaceutically acceptable ferrous iron salt; and an effective amount of ferric complex polysaccharide.
2. 2. The composition of claim 1, wherein the pharmaceutically acceptable ferrous iron salt is present in an amount ranging from about 100% by weight to about 200% by weight, based on the total weight of the composition.
3. 3. The composition of claim 1, wherein the ferric complex polysaccharide is present in an amount ranging from about 100 wt% to about 200 wt%, based on the total weight of the composition.
4. 4. The composition of claim 1, further comprising a pharmaceutically acceptable linker, excipient, or carrier.
5. 5. The composition of demand 1, further comprising an effective amount of a ferric absorption facilitator.
6. 6. The composition of claim 5, wherein the iron absorption facilitator is ascorbic acid, or a pharmaceutically acceptable salt thereof.
7. 7. The composition of claim 5, wherein the iron absorption facilitator is present in an amount ranging from about 5% by weight to about 10% by weight, based on the total weight of the composition.
8. 8. The composition of claim 1, wherein the ferrous iron salt is selected from the group consisting of ferrous sulfate, ferrous fumarate, ferrous succinate, and ferrous gluconate.
9. 9. The composition of claim 8, where the ferrous iron salt is the ferrous fumarate.
10. A method for the treatment or prophylaxis of iron deficiency, comprising: administering to a patient in need thereof, an effective amount of a composition comprising: an effective amount of a pharmaceutically acceptable ferrous iron salt; and an effective amount of iron polysaccharide complex.
11. 11. The method of claim 10, wherein the pharmaceutically acceptable ferrous iron salt is present in the composition in an amount ranging from about 20% by weight to about 40% by weight, based on the total weight of the composition.
12. 12. The method of claim 10, wherein the polysaccharide iron complex is present in the composition in an amount ranging from about 20% by weight to about 40% by weight, based on the total weight of the composition.
13. 13. The method of claim 10, wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, or carrier.
14. 14. The method of claim 10, further comprising administering an effective amount of a ferric absorption facilitator.
15. 15. The method of claim 14, wherein the facilitator of ferric absorption is ascorbic acid or a pharmaceutically acceptable salt thereof.
16. 16. The method of claim 10, wherein the ferrous iron salt is selected from the group consisting of ferrous sulfate, ferrous fumarate, ferrous succinate, and ferrous gluconate.
17. 17. The method of claim 10, wherein the ferrous iron salt is ferrous fumarate.