WO2007108712A1

WO2007108712A1 - Kit and method for treating or preventing anemia caused by iron deficiency

Info

Publication number: WO2007108712A1
Application number: PCT/RU2006/000122
Authority: WO
Inventors: Tatyana Vyacheslavovna Popkova
Original assignee: Tatyana Vyacheslavovna Popkova
Priority date: 2006-03-17
Filing date: 2006-03-17
Publication date: 2007-09-27

Abstract

This invention relates to kits and methods for treating or preventing anemia caused by iron deficiency in a subject in need thereof. The invention provides the kit comprising a therapeutically effective amount of an iron compound and a pharmaceutically acceptable carrier in a first unit dosage form; an amount of aqueous liquid composition with concentration of calcium less than mg/L in a second dosage form; container means for containing said first and second dosage forms; and an instruction describing the method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination said first unit dosage form and said second dosage form. Preferably, the first unit dosage form of the kit is an effervescent tablet. Further, invention provides the method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination a therapeutically effective amount of an iron compound and an amount of water with concentration of calcium less than 10 mg/L; wherein said water is selected from the group consisting of drinking water, distilled water, and purified water.

Description

KIT AND METHOD FOR TREATING OR PREVENTING ANEMIA CAUSED BYIRON DEFICIENCY

Technical Field

The present invention relates to kits and methods for treating or preventing anemia caused by iron deficiency.

Background of the Invention

Iron deficiency is defined as decreased total iron body content. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. The typical causes of iron deficiency are too little iron in the diet, poor absorption of iron by the body, and loss of blood (including from heavy menstrual bleeding).

Iron deficiency anemia is the most common form of anemia. Approximately 20% of women, 50% of pregnant women, and 3% of men are iron deficient. Iron deficiency anemia occurs when iron deficiency is sufficiently severe to diminish erythropoiesis and cause the development of anemia. Anemia caused by iron deficiency can be diagnosed by low blood iron level, hemoglobin, and red blood cell count.

It is important to treat or prevent anemia caused by iron deficiency because anemia diminishes the capability of individuals who are affected to perform physical or mental labor, and it diminishes both growth and learning in children. Iron fortification of foods and oral iron supplements are typically used to restore normal total iron body content and, thus, to treat or prevent anemia caused by iron deficiency.

It is well-documented that several dietary factors (e.g., inositol phosphates, calcium, and certain structures in polyphenols) inhibit iron absorption, whereas other factors (e.g., ascorbic acid, meat, fish, and poultry) enhance iron absorption. Hallberg L. et al.. Am. J. Clin. Nutr .1991; 53: 112-19. It is known that calcium is a weak inhibitor of iron absorption and no inhibition was seen when the amount of calcium in a meal was < 50 mg. Hallberg L. et aL, Am. J. Clin. Nutr. 2000; 71 :1147-60. Accordingly, calcium amounts that can be delivered with drinking water are less than the calcium amounts that demonstrated above to be inhibitory for iron absorption. It is unknown whether usual calcium levels in drinking water can affect iron bioavailability if this water is used by a subject for improving swallowing solid iron supplements or dissolving an effervescent iron supplement prior to the oral administration.

Surprisingly, I found that calcium levels in drinking water that is used typically for improving swallowing a solid iron supplement or dissolving an effervescent iron supplement prior to the oral administration this supplement is the factor that affects iron bioavailability. High calcium water diminishes both iron absorption and efficacy iron supplements for treating iron deficiency. In contrast, low calcium water improves both iron absorption and efficacy iron supplements for treating iron deficiency.

The calcium levels in drinking water are not regulated now since this element does not destroy health. The World Health Organization in the Guidelines for drinking water quality (WHO, 1993) did not set any either minimum or maximum recommended calcium limits in drinking water. The levels of calcium in drinking water prepared from natural water is not a constant and frequently vary from 0 to 120 mg/L depending on Earth region and method of preparation of drinking water.

Thus, there is the great need in control of calcium level in water which is used by a subject for dissolving iron effervescent supplements or facilitating the swallowing the solid iron supplements to achieve reproducible iron bioavailability. Non-reproducible and variable iron bioavailability is potentially harmful to human's health because of insufficient iron bioavailability leads to iron deficiency anemia, whereas iron overdose can lead to fatal poisoning. Also, there is the great need in the use of water with low calcium level

(<10 mg/1) for dissolving iron effervescent supplements or facilitating the swallowing the solid iron supplements to achieve an optimal iron bioavailability for treating or preventing anemia caused by iron deficiency.

These requirements of low calcium levels (<10 mg/1) are generally correct to any liquid aqueous composition (e.g. beverage) which is used for dissolving iron effervescent supplements or facilitating the swallowing the solid iron supplements.

It is an object of the present invention to provide a kit comprising a therapeutically effective amount of an iron compound and a pharmaceutically acceptable carrier in a first unit dosage form; an amount of aqueous liquid composition with concentration of calcium less than 10 mg/L in a second dosage form; container means for containing said first and second dosage forms; and an instruction describing the method of treating or preventing anemia caused by iron deficiency. Further, it is an object of the present invention to provide a method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination a therapeutically effective amount of an iron compound and an amount of water with concentration of calcium less than 10 mg/L; wherein said water is selected from the group consisting of drinking water, distilled water, and purified water.

Disclosure of Invention

The present invention provides a kit comprising a therapeutically effective amount of an iron compound and a pharmaceutically acceptable carrier in a first unit dosage form; an amount of aqueous liquid composition with concentration of calcium less than 10 mg/L in a second dosage form; container means for containing said first and second dosage forms; and an instruction describing the method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination said first unit dosage form and said second dosage form.

Preferably, the iron compound is selected from the group consisting of ferrous lactate, ferrous tartrate, ferrous fumarate, ferrous sulfate, ferrous folate, an iron dextran, ferric oxyhydroxide dextran, ferrous pyrophosphate, ferrous cholinisocitrate, a chitosan derivative of iron, an oligosaccharide derivative of iron, feiτous acetyl salicylate, ferrous gluconate, ferrous diphosphate, carbonyl iron, ferric orthophosphate, ferrous glycine sulfate, ferrous chloride, ferrous ammonium citrate, ferric ammonium citrate, ferric ammonium tartrate, ferric phosphate, ferric potassium tartrate, ferric albuminate, ferric cacodylate, ferric hydroxide, ferric pyrophosphate, ferric quinine citrate, ferric valerate, ferrous fructate-ascorbate, saccharated iron oxide, iron oxide, ferric chloride, ferrous iodide, ferrous nitrate, ferrous glycerophosphate, ferrous formate, an amino acid and iron salt, an iron salt of a protein hydrolysate, ferrous succinate, ferrous glutamate, ferrous citrate, ferrous carbonate, an iron-sugar-carboxylate complex, ferrous sucrate-malate, ferrous fructate-citrate, ferrous sucrate-ascorbate, and ferrous sucrate citrate.

As used herein, the term "therapeutically effective amount" means an amount of the iron compound in the first unit dosage form sufficient to achieve a significant increase in iron levels, hematocrit, hemoglobin, and/or blood erythrocyte counts when said amount is administered to a subject in need thereof. Depending on the iron compound used the amount used may be different. Preferably, the therapeutically effective amount of the iron compound is 10 to 250 mg per the first unit dosage form.

Preferably, the first unit dosage form is an effervescent or non- effervescent anhydrous powder, granulate, tablet or micro-encapsulated product. These anhydrous powder, granulate, tablet or micro-encapsulated product is manufactured by methods well-known from the art.

More preferably, the first unit dosage form is an effervescent tablet comprising a pharmaceutically acceptable effervescent system comprising an alkaline carbonate and an organic acid.

Nonexclusive examples of the alkaline carbonates which can be used in practicing the present invention are sodium bicarbonate, potassium bicarbonate, carboxylysine, sodium carbonate, potassium carbonate and mixture of these compounds. The organic acids which can be used in practicing the present invention are compounds capable of reacting with alkaline carbonates to release carbon dioxide when they are brought to contact with a sufficient amount of water. Nonexclusive examples of suitable acids are citric acid, fumaric acid, adipic acid, succinic acid, tartaric acid and mixture of these compounds.

Preferably, the effervescent tablet further comprises an effective amount 5 of ascorbic acid or a pharmaceutically acceptable salt thereof. The ascorbic acid can be used as L-ascorbic acid, D,L-ascorbic acid or pharmaceutically acceptable salts thereof. Preferably, the effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof is 10 to 1000 mg per the tablet. Preferably, the ascorbic acid or a pharmaceutically acceptable salt thereof will i o be used in a molar ratio to the iron compound from 2 : 1 to 8 : 1.

The effervescent tablet of the invention may be prepared by methods well-known from the art. For example, the process for the manufacture of the effervescent tablet comprises the steps of: treating the iron compound by spraying it with a solution or emulsion containing a hydrophilic polymer (e.g. is polyvinylpirrolidon) to form coated granulate of the iron compound; premixing the constituents forming the effervescent system preferably in form of granules; premixing the other constituents in the form of powders (e.g. ascorbic acid, sweeteners, and flavors); mixing the products resulting from the previous steps; and forming the effervescent tablet. 0 The aqueous liquid composition of the invention is any water-based liquid composition with concentration of calcium less than 10 mg/L suitable for the human use. Preferably, the aqueous liquid composition with concentration of calcium less than 10 mg/L is selected from the group consisting of beverage, drinking water, distilled water, and purified water. More preferably, the 5 concentration of calcium in said aqueous liquid composition is less than 1 mg/L. The beverage of the invention can be prepared by adding to the water with concentration of calcium less than 10 mg/L any sweeteners or additives such as flavors, extracts, essences, nutrients, or minerals.

The drinking water of the invention can be prepared by ion-exchange treatment or reverse osmosis of natural water. These processes are widely used in industry and provide drinking water with desired concentration of calcium < 10 mg/L and even less than 1 mg/1.

The distilled water of the invention can be prepared from natural water by two-step process comprising water evaporation and condensation which process provides desired water with concentration of calcium even less than 1 mg/L.

Preferably, the amount of the aqueous liquid composition in the second unit dosage form is from 25 to 10000 ml, more preferably, from 100 to 150 ml.

The container means of the invention is any means suitable for containing the separate first dosage forms (e.g. an effervescent or non-effervescent anhydrous powder, granulate, tablet or micro-encapsulated product) and second dosage forms (e.g. bottle). Nonexclusive examples of such container means include package, box, bottle, and tube.

The instruction of the invention describes the method to be used by a subject to treat or prevent anemia caused by iron deficiency which method comprises administering orally to a subject in need thereof stepwise or in physical combination said first unit dosage form and said second dosage form.

In the preferred embodiment of the invention, the method comprises administering orally to a subject the aqueous solution of the therapeutically effective amount of an iron compound wherein said aqueous solution is formed by mixing an effervescent tablet as the first unit dosage form with distilled water as the second dosage form. In practicing the methods of the invention, the components of the kit are administered for 1 day or longer, more preferably, for 30 to 90 days to achieve desired therapeutic effect in treating or preventing anemia caused by iron deficiency. Preferably, the components of the kit are administered to a subject fasted overnight. Preferably, the subject of the invention is human. More preferably, the subject of the invention is women or pregnant women.

Further, the present invention provides a method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination a therapeutically effective amount of an iron compound and an amount of water with concentration of calcium less than 10 mg/L; wherein said water is selected from the group consisting of drinking water, distilled water, and purified water. Preferably, the concentration of calcium in said water is less than 1 mg/L.

The therapeutically effective amount of an iron compound may be different depending on the iron compound used. Generally, the iron compound will be used in a unit dosage forms such as anhydrous powder, granulate, tablet and micro-encapsulated product. Preferably, the therapeutically effective amount of the iron compound is 10 to 250 mg per the unit dosage form. The amount of water for the use in the method of the invention is from 25 to 500 ml, preferably, from 100 to 150 ml.

In practicing the invention, the method can further comprises the step of administering orally to said subject a nutritional supplement comprising an effective amount of calcium at time of 1 to 12 hours after administering the iron compound. This step is directed to eliminating possible side effects on bone and tooth metabolism which effects may result from administering water with concentration of calcium <10 mg/L. Because of reproducible regimen of administering iron compound to a subject with using the kits and methods of the invention, it is now possible to achieve reproducible results in treating or preventing anemia caused by iron deficiency. Because of providing optimal conditions for delivering iron into circulation with using the kits and methods of the invention, it is now possible to achieve optimal results in treating or preventing anemia caused by iron deficiency.

The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1

This example demonstrates the kit:

The first unit dosage form: effervescent tablet.

3AMEIWIOmHH JIHCT (πPABHJIO 26)

Total: 4200 mg

The effervescent tablet is manufactured by a process comprising the steps of: treating the ferrous (II) sulfate by spraying it with a solution or emulsion containing polyvinylpirrolidon (Povidon K-30) to form coated granulate; premixing the constituents forming the effervescent system comprising sodium bicarbonate and citric acid preferably in form of granules; premixing the other constituents in the form of powders (ascorbic acid, sweeteners, and flavors); mixing the products resulting from the previous steps; and forming the effervescent tablet. The tablets are packaged in the container by 30 tablets per container.

The second unit dosage form: distilled water. Distilled water is prepared by distillation of natural water. Water with concentration of calcium <1 mg/L is bottled into bottles with volume 100 ml. The bottles are packaged in the container by 30 bottles per container.

The container means: the effervescent tablets and the bottles are packaged in the container by 30 tablets and bottles per container.

The instruction for the kit use is enclosed: mixing the first unit dosage form with the second unit dosage form of the kit to provide an aqueous composition comprising a therapeutically effective amount of an iron compound; and administering orally said aqueous composition to a subject in need thereof singly a day for 30 days. Example 2

This example demonstrates the kit:

The first unit dosage form: effervescent tablet.

Total: 4200 mg

The effervescent tablet is manufactured by a process as described in the example 1. The tablets are packaged in the package by 30 tablets per package.

The second unit dosage form: distilled water. Distilled water is prepared by reverse osmosis of natural water. Water with concentration of calcium <1 mg/L is bottled into bottles with volume 100 ml. The bottles are packaged in the container by 30 bottles per container.

3AMEIMIOmHH JIHCT (πPABHJIO 26) The instruction for the kit use is enclosed: mixing the first unit dosage form with the second unit dosage form of the kit to provide an aqueous composition comprising a therapeutically effective amount of an iron compound; and administering orally said aqueous composition to a subject in need thereof singly a day for 30 days.

Example 3

This example demonstrates the method for treating or preventing anemia caused by iron deficiency.

Woman (44 years) with chronic iron deficiency anemia historically received oral iron supplements 100 mg ferrous (II) sulfate per tablet with 250 mg ascorbic acid and used drinking water with concentration of calcium about 120 mg/L to facilitate swallowing the tablet. This method historically did not result in increase in blood iron levels, hemoglobin, and erythrocyte counts in blood. Administering the tablet of 100 mg ferrous (II) sulfate and 250 mg ascorbic acid to oral cavity and drinking about 100 ml distilled water with concentration of calcium < 1 mg/1 to facilitate swallowing the tablets for 28 days singly a day resulted in increasing blood hemoglobin level since 90 g/1 before treating to 100 g/1 after treating, and increasing erythrocyte counts since 3.75 million per ml to 4.01 million per ml.

Example 4

This example demonstrates the method of treating or preventing anemia caused by iron deficiency. Three women with chronic iron deficiency anemia received daily for 28 days singly a day a solution prepared by mixing effervescent iron supplement comprising 100 mg ferrous (II) sulfate and 500 mg ascorbic acid with 100 ml of drinking water with concentration of calcium about 120 mg/1 (control) or, one month later, a solution prepared by mixing the same amount of ferrous (II) sulfate and ascorbic acid with 100 ml of distilled water with concentration of calcium < 1 mg/1. Mean rate of hemoglobin rise was 0. 45 g/1 per day vs. 0.05 g/1 per day in the control.

Claims

WE CLAIM:

1. A kit comprising:

(a) a therapeutically effective amount of an iron compound and a pharmaceutically acceptable carrier in a first unit dosage form; (b) an amount of aqueous liquid composition with concentration of calcium less than 10 mg/L in a second dosage form;

(c) container means for containing said first and second dosage forms; and

(d) an instruction describing the method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination said first unit dosage form and said second dosage form.

2. The kit as claimed in the claim I₅ wherein the iron compound is selected from the group consisting of ferrous lactate, ferrous tartrate, ferrous fumarate, ferrous sulfate, ferrous folate, an iron dextran, ferric oxyhydroxide dextran, ferrous pyrophosphate, ferrous cholinisocitrate, a chitosan derivative of iron, an oligosaccharide derivative of iron, ferrous acetyl salicylate, ferrous gluconate, ferrous diphosphate, carbonyl iron, ferric orthophosphate, ferrous glycine sulfate, ferrous chloride, ferrous ammonium citrate, ferric ammonium citrate, ferric ammonium tartrate, ferric phosphate, ferric potassium tartrate, ferric albuminate, ferric cacodylate, ferric hydroxide, ferric pyrophosphate, ferric quinine citrate, ferric valerate, ferrous fructate-ascorbate, saccharated iron oxide, iron oxide, ferric chloride, ferrous iodide, ferrous nitrate, ferrous glycerophosphate, ferrous formate, an amino acid and iron salt, an iron salt of a protein hydrolysate, ferrous succinate, ferrous glutamate, ferrous citrate, ferrous carbonate, an iron-sugar-carboxylate complex, ferrous sucrate-malate, ferrous fructate-citrate, ferrous sucrate-ascorbate, and ferrous sucrate citrate.

3. The kit as claimed in the claim 1, wherein the therapeutically effective amount of the iron compound is 10 to 250 mg per the first unit dosage form.

4. The kit as claimed in the claim 1, wherein said aqueous liquid composition is selected from the group consisting of beverage, drinking water, distilled water, and purified water.

5. The kit as claimed in the claim 1, wherein the concentration of calcium in said aqueous liquid composition is less than 1 mg/L.

6. The kit as claimed in the claim 1, wherein said first unit dosage form is an effervescent or non-effervescent anhydrous powder, granulate, tablet or micro-encapsulated product.

7. The kit as claimed in the claim 1, wherein said first unit dosage form is an effervescent tablet comprising a pharmaceutically acceptable effervescent system comprising an alkaline carbonate and an organic acid.

8. The kit as claimed in the claim 7, further comprising an effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.

9. A method of treating or preventing anemia caused by iron deficiency which comprises administering orally to a subject in need thereof stepwise or in physical combination a therapeutically effective amount of an iron compound and an amount of water with concentration of calcium less than 10 mg/L; wherein said water is selected from the group consisting of drinking water, distilled water, and purified water.

10. The method as claimed in the claim 9, wherein the iron compound is selected from the group consisting of ferrous lactate, ferrous tartrate, ferrous fumarate, ferrous sulfate, ferrous folate, an iron dextran, ferric oxyhydroxide dextran, ferrous pyrophosphate, ferrous cholinisocitrate, a chitosan derivative of iron, an oligosaccharide derivative of iron, ferrous acetyl salicylate, ferrous gluconate, ferrous diphosphate, carbonyl iron, ferric orthophosphate, ferrous glycine sulfate, ferrous chloride, ferrous ammonium citrate, ferric ammonium citrate, ferric ammonium tartrate, ferric phosphate, ferric potassium tartrate, ferric albuminate, ferric cacodylate, ferric hydroxide, ferric pyrophosphate, ferric quinine citrate, ferric valerate, ferrous fructate-ascorbate, saccharated iron oxide, iron oxide, ferric chloride, ferrous iodide, ferrous nitrate, ferrous glycerophosphate, ferrous formate, an amino acid and iron salt, an iron salt of a protein hydrolysate, ferrous succinate, ferrous glutamate, ferrous citrate, ferrous carbonate, an iron-sugar-carboxylate complex, ferrous sucrate-malate, ferrous fructate-citrate, ferrous sucrate-ascorbate, and ferrous sucrate citrate.

11. The method as claimed in the claim 9, wherein the concentration of calcium less than 1 mg/L.