DESC:Technical Field:

The present invention relates to novel synergistic nutritional compositions for treating iron deficiency anemia (IDA).

Particularly, the invention relates to synergistic nutritional compositions comprising combination of iron fortificant and hepcidin antagonist present in an effective amount, wherein iron fortificant is ‘ferric maltol complex’ and hepcidin antagonist/inhibitor is ‘ergocalciferol’ (i.e., vitamin D2). Further, the composition increases iron absorption and controls iron deficiency anemia by enhancing hemoglobin level in a subject.

Background and Prior art:

Iron is an essential element for blood production. About 70 percent of human body's iron is found in the red blood cells (RBCs) called hemoglobin and in muscle cells called myoglobin. Hemoglobin is essential for transferring oxygen in our blood from the lungs to the tissues. Myoglobin, in muscle cells, accepts, stores, transports and releases oxygen. In absence of fair amount of iron, body can't make enough healthy oxygen-carrying red blood cells. A lack of red blood cells is called as iron deficiency anemia. This deficiency can affect everything from brain function to immune system's ability to fight off infections.

Iron has other important functions too. Iron is also necessary to maintain healthy cells, skin, hair, and nails.

Iron from the food is absorbed into the body by the cells that line the gastrointestinal tract; the body only absorbs a small fraction of the iron ingest. The iron is then released into the blood stream, where a protein called transferrin attaches to it and delivers the iron to the liver. Iron is stored in the liver as ferritin and released as needed to make new red blood cells in the bone marrow. When red blood cells are no longer able to function (after about 120 days in circulation), they are re-absorbed by the spleen. Iron from these old cells can also be recycled by the body. Serum ferritin, transferrin saturation, transferrin receptor, and erythrocyte protoporphyrin are indicators used as biochemical evidence of iron deficiency.

The University of California, San Francisco has reported that about 25 percent of the iron in the body is stored as ferritin, found in cells and circulates in the blood. The average adult male has about 1,000 mg of stored iron (enough for about three years), whereas women on average have only about 300 mg (enough for about six months). When iron intake is chronically low, stores can become depleted, decreasing hemoglobin levels.

When iron stores are exhausted, the condition is called iron depletion. Further decrease in the amount of iron may be called latent iron deficiency (LID) or iron-deficient erythropoiesis (IDE) and still further decrease produces iron deficiency anemia.

Iron deficiency is the most common form of malnutrition in the world, affecting more than 2 billion people globally. Iron deficiency anemia (inadequate amount of red blood cells caused by lack of iron) is highly prevalent in less-developed countries but also remains a concern in developed countries where other forms of malnutrition have already been nearly eradicated. Iron deficiency is not the only cause of anemia, but where anemia is prevalent, iron deficiency is usually the most common cause. The prevalence of anemia, defined by low hemoglobin or hematocrit (the ratio of the volume of red blood cells to the total volume of blood), is commonly used to assess the severity of iron deficiency in a population.

Iron deficiency anemia is caused by blood loss, insufficient dietary intake, or poor absorption of iron from food. Sources of blood loss can include heavy periods, childbirth, uterine fibroids, stomach ulcers, internal bleeding-colon cancer and urinary tract bleeding, pregnancy, celiac disease or intestinal surgery such as gastric bypass, endometriosis, frequent blood donation, etc.

Poor absorption of iron from food may occur as a result of Crohn's disease or a gastric bypass. In the developing world, parasitic worms, malaria, and HIV/AIDS increase the risk of iron deficiency anemia. In women of childbearing age, heavy menstrual periods can be a source of blood loss causing iron deficiency anemia. According to the National Heart, Lung, and Blood Institute (NHLBI), an estimated 20 percent of women of childbearing age have iron deficiency anemia. Pregnant women are even more likely to have iron deficiency anemia because they require greater amounts of blood to support their growing babies. People who do not consume much iron in their diet, such as vegans or vegetarians, are also at increased risk of developing iron deficiency anemia.

If anemia or iron deficiency is left untreated, it can lead to other health problems. These include: pregnancy complications such as a child may be born prematurely or with a low birth weight, less well in mental ability, delayed growth in infants and children, tiredness, tachycardia (an abnormally fast heartbeat), heart failure, and like thereof.

Further, excess iron intake can also be harmful; the iron overload leads to fatigue, vomiting, diarrhea, headache, irritability, cirrhosis of the liver, heart disease, and joint problems.

Iron deficiency anemia represents a major public health problem, particularly in infants, young children, pregnant women, and females with heavy menses. Oral iron supplementation is a cheap, safe, and effective means of increasing hemoglobin levels and restoring iron stores to prevent and correct iron deficiency. Many preparations are available, varying widely in dosage, formulation (quick or prolonged release), and chemical state (ferrous or ferric form). Oral iron supplements, which are usually in the form of ferrous (Fe2+) salts, are toxic to the gastrointestinal mucosa, and so intolerance is common, resulting in poor bioavailability and failure of treatment. The sugar derivative maltol strongly chelates iron, rendering it available for absorption and stabilized in the less toxic ferric (Fe3+) form.

The results demonstrate that in patients intolerant of ferrous compounds, ferric trimaltol corrects iron deficiency and has a low incidence of side-effects (Alimentary Pharmacology & Therapeutics, 12(9):845-8, October 1998).

There are different methods and compositions of ferric maltol available in the prior art.

WO2017167963A1 discloses method for producing ferric maltol compositions, wherein maltol is reacted with a ligand modified ferric hydroxide and/or a ligand coated ferric hydroxide. The composition is used for the treatment of iron deficiency anemia.

WO2016063228A1 invention relates to a dosage regimen of ST10 (ferric maltol) for use in the treatment of patients suffering from iron deficiency with or without anemia. The invention specifically relates to the use of ST10, wherein the dose is between 40 mg and 90 mg twice daily.

Further, IN248503 discloses a method of forming an iron hydroxypyrone compound comprising reacting an iron salt of a carboxylic acid and a hydroxypyrone in an aqueous solution at a pH greater than 7, wherein the aqueous solution comprises a base, particularly sodium hydroxide.

IN201627029488 reports liquid or liquid suspension of iron hydroxypyrone for treating iron deficiency anemia.

GB2128998 B relates to a compound containing iron complex of 3-hydroxy-4-pyrone containing maltol and the ferric cation present in 3:1 proportion.

Further, GB2553099A discloses use of iron hydroxypyrone in the prevention and/or treatment of iron deficiency in a subject, having an elevated hepcidin level.

Likewise, US6635631B2 discloses a method of making an iron composition for use in medicine comprising iron in the ferric state and a hydroxypyrone, wherein the iron compound and hydroxypyrone are mixed in the dry state in the ratio of 1:2 to 1:1.

Fuchssteiner H, et al.(Inflamm Bowel Dis. 2015 Mar;21(3):579-88) and C. Schmidt, (Aliment Pharmacol Ther. 2016 Aug; 44(3):259–270) report that ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease (IBD).

Pablo E. Pergola et al. [Adv Chronic Kidney Dis. 2019;26(4):272-291] reported oral iron preparations in development for IDA in patients with chronic kidney disease (CKD). Ferric maltol (Feraccru/Accrufer-Shield Therapeutics, Inc.) is approved in the European Union and the United States for the treatment of IDA in adults and in Switzerland for the treatment of IDA in patients with inflammatory bowel disease.

Ferric maltol demonstrated improvements in Hb vs placebo with a favorable tolerability profile in a pivotal phase 3 trial in patients with Non-Dialysis Dependent CKD (NDD-CKD). Sucrosomial iron, which has been evaluated in IDA associated with CKD and several other clinical settings, demonstrated improved tolerability over IV iron.

However, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis.

It is further observed that hepcidin level is also affected by iron deficiency anemia. Hepcidin is a peptide hormone that is synthesized primarily in the liver. It functions as an acute-phase reactant that adjusts fluctuations in plasma iron levels by binding to and inducing the degradation of ferroportin, which exports iron from cells. In iron deficiency, the transcription of hepcidin is suppressed. This adaptive mechanism facilitates the absorption of iron and the release of iron from body stores.

The antibacterial protein hepcidin regulates the absorption, tissue distribution, and extracellular concentration of iron by suppressing ferroportin-mediated export of cellular iron. Hepcidin plays a central role in this process because it is the essential regulating factor of iron absorption. The divalent iron transported into the blood by ferroportin is converted into trivalent iron by oxidases (ceruloplasmin, hephaestin), the trivalent iron then being transported to the relevant places in the organism by transferrin (see for example “Balancing acts: molecular control of mammalian iron metabolism”, M. W. Hentze, Cell 117, 2004, 285-297).

Mammalian organisms are unable to actively discharge iron. The iron metabolism is substantially controlled by hepcidin via the cellular release of iron from macrophages, hepatocytes and enterocytes.

Hepcidin is a peptide hormone produced in the liver. It is well known as iron-regulatory hormone. Hepcidin acts on the absorption of iron via the intestine and via the placenta and on the release of iron from the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from what is known as pro-hepcidin, pro-hepcidin being coded by the gene known as the HAMP gene. The formation of hepcidin is regulated in direct correlation to the organisms iron level, i.e., if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed, if iron and oxygen levels are low, or in case of increased erythropoiesis less hepcidin is formed.

In the small intestinal mucosal cells and in the macrophages hepcidin binds with the transport protein ferroportin, this conventionally transports the phagocytotically recycled iron from the interior of the cell into the blood.

Hepcidin plays an important part here when iron metabolism is impaired by chronic inflammation. In case of inflammation, in particular, interleukin-6 is increased, triggering an increase in hepcidin levels. As a result, more hepcidin is bound to the ferroportin of the macrophages, thus blocking the release of stored iron, which ultimately leads to anemia of chronic disease or anemia of inflammation (ACD or Al).

It becomes apparent that the hepcidin-ferroportin system directly regulates the iron metabolism and that a disorder of the hepcidin regulation mechanism, therefore, has a direct effect on iron metabolism in the organism.

Theoretically, the hepcidin-ferroportin regulation mechanism acts via two following opposite principles:
On the one hand, an increase of hepcidin leads to inactivation of ferroportin, thus blocking the release of stored iron from the cells into the serum, thus decreasing the serum iron level. In pathological cases a decreased serum iron level leads to a reduced hemoglobin level, reduced erythrocyte production and thus to iron deficiency anemia.
On the other hand, a decrease of hepcidin results in an increase of active ferroportin, thus allowing an enhanced release of stored iron and an enhanced iron uptake e.g., from the food, thus increasing the serum iron level. In pathological cases, an increased iron level leads to iron overload.
Human hepcidin, a polypeptide expressed predominantly by hepatocytes (liver cells), is believed to be an important iron-regulatory protein that negatively regulates intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic iron stores. Overproduction of hepcidin appears to play a primary role in the pathophysiology of anemia and/or in anemia of chronic disease.
The use of hepcidin antagonists is generally the possibility, for example, by inhibition of hepcidin-expression or by blocking the hepcidin-ferroportin interaction to act on the regulation mechanism of hepcidin directly, and thus via this route blocking of the iron transport pathway from tissue macrophages, liver cells and mucosa cells into the serum via the transport protein to prevent ferroportin. Thus, hepcidin expression or hepcidin antagonists are associated with such inhibitor substances and are suitable to produce pharmaceutical compositions or medicaments in the treatment of anemia, in particular anemia with chronic inflammation. These substances can be used for the treatment of such disorders or diseases, because they directly influence the increase in the release of recycled haem iron by macrophages, as well as an increase in the iron absorption of iron released from the food in the intestinal tract.

CN101816674A provides the ‘angelica polysaccharides’ as hepcidin inhibitor that inhibits the expression of hepcidin and iron-deficiency anemia.

WO201123722A1 discloses novel ‘quinoxalinone’ hepcidin antagonists for treatment of iron metabolism disorders, such as iron deficiency disorders and anemia, especially anemia in conjunction with chronic inflammatory disorders (ACD and AI).

Further US9102688B2 discloses ‘sulfonaminoquinoline’ hepcidin antagonists for use in the treatment of iron metabolism disorders, in particular, anemia in connection with chronic inflammatory diseases.

Additionally, US20120214798A1 discloses novel ‘ethanediamone’ hepcidine antagonists and WO201129832A1 discloses novel ‘thiazol and oxazol’ hepcidine antagonists. Further, ‘Miraxanthin-V, Liriodenin and Chitranone’ as hepcidin antagonist in silico for Iron Deficiency Anemia are reported in some article (IOP Conf. Series: Materials Science and Engineering 333 (2018) 012079).

Further, WO201634617A1 relates to the use of valproic acid or the derivatives thereof in the treatment of hepcidin abnormalities including hemochromatosis rheumatism.

As the cited hepcidin antagonists are chemically processed, they may include toxic solvents. Also, the active substances comprise inorganic compounds like sulfur and amine, which may cause side effects to the human body.

In the light of the above, there is a need to develop cost-effective, efficient, nutritional dosing regimen for iron supplementation that can be useful for any age groups with high bioavailability and with less side effect.

Recently, a study has shown that supplementation of vitamin D facilitates increased haemoglobin levels. Specifically, vitamin D binds to vitamin D response elements (VDREs) in the promoter region of hepcidin (hepcidin antimicrobial peptide, HAMP) and thereby reduces hepcidin expression, supplementing healthy adults with vitamin D decreased hepcidin levels and significantly increased haemoglobin levels.
By knowing the need for iron supplement to counter the blood related diseases, particularly IDA, the present inventors have developed synergistic combination of iron supplement agent along with hepcidin antagonist, which are categorized under nutrients with no adverse effect. The developed composition enhances the absorption efficiency of iron element in the body giving a greater biological effect from a smaller dose of iron and also reducing side effects.

Objective:

The primary object of the invention is to provide dietary supplement for improving iron absorption capacity in the body.

Another object of the invention is to provide synergistic nutritional compositions for treating iron deficiency anemia.

Further object of the invention is to provide synergistic nutritional composition comprising combination of iron fortificant and hepcidin antagonist present in an effective amount.

Furthermore, another object of the invention is to provide nutritional composition that gives synergistic effect for enrichment of iron by increasing the total amount of iron stored in the body, and concomitantly enhancing iron export and thus increased systemic levels of iron in an individual afflicted with iron deficiency.

Summary:

To meet the above objectives, the inventors of the present invention carried out thorough experiments to establish significant effect of the active nutrients present in the composition that improve iron deficiency related disorders in a subject in need thereof.

In another aspect, the invention relates to synergistic nutritional composition of iron supplement for treating iron deficiency anemia (IDA).

In another aspect, the invention relates to synergistic nutritional composition comprising iron fortificant and hepcidin antagonist, which are present in an effective amount.

In yet another aspect of the invention, the invention provides potent synergistic nutritional composition comprising ‘ferric maltol complex’ as iron fortificant and ‘ergocalciferol’ (i.e., vitamin D2) as hepcidin antagonist/inhibitor along with pharmaceutically acceptable excipients.

In another aspect, the instant invention provides synergistic nutritional compositions comprising combination of ferric maltol complex and ergocalciferol for treatment in a subject suffering from iron deficiency anemia (IDA).

In yet another aspect, the invention relates to synergistic nutritional compositions, wherein ferric maltol complex is present in the range of 1 to 100 mg (equivalent to elemental iron Fe3+) and ergocalciferol is present in the range of 0.1 mcg to 50 mcg, preferably 0.5 to 50 mcg , more preferably 0.5 to 25 mcg along with pharmaceutically acceptable excipients/carriers.

In yet another aspect, the invention relates to synergistic nutritional composition, which is particularly useful for treating iron deficiency anemia, wherein ferric-maltol complex allows efficient uptake of elemental ferric iron into enterocytes thus increasing the stored iron, on the other hand (vitamin D2) ergocalciferol expresses enhancement of iron export and thus increases systemic levels of iron in an individual afflicted with iron deficiency anemia.

Abbreviations:
IDA: iron deficiency anemia
LID: latent iron deficiency
IDE: iron-deficient erythropoiesis
HAMP: hepcidin antimicrobial peptide
HCT: Hematocrit
RBC: Red blood cells
Hb: Hemoglobin
IDA: Iron Deficiency Anemia
CMC: Carboxymethyl cellulose

Brief description of the figures:

Fig 1 depicts feed consumption of experimental animals, where G1-Normal Control, G2- Anemic Control, G3-Ferric Maltol, G4-Vit D2, G5-Composition 1, G6-Orofer® XT
Fig 2 depicts hematological parameters of experimental animals where G1-Normal Control, G2- Anemic Control, G3-Ferric Maltol, G4-Vit D2, G5-Composition 1, G6-Orofer® XT
a) Hemoglobin b) Red blood cells c) Hematocrit

Detailed Description:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

It is further to be understood that all terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting in any manner or scope.

Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain.

In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art. The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Also, the term ‘composition’ does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.

The term “pharmaceutically/nutraceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Particularly, the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, as well as solvates, co-crystals, polymorphs and the like of the salts.

The present invention provides synergistic nutritional composition comprising iron supplement agent or fortificant along with suppressor of iron-regulatory hepcidin.

According to the invention the ‘iron supplement agent’ is also referred to as ‘iron enhancing agent’, nutrient, or ‘iron fortificant’. ‘Hepcidin antagonist’’ can be also referred as ‘hepcidin suppressor’ or ‘hepcidin inhibitor’ or ‘hepcidin controlling agent’. The present composition may be also referred as iron supplement composition(s). ‘Iron-deficiency anemia’ is anemia caused by a lack of iron. Anemia is defined as a decrease in the count of red blood cells or the amount of hemoglobin in the blood.

In another preferred embodiment, the invention provides a synergistic nutritional composition(s) for treating iron deficiency anemia (IDA), wherein the composition comprising a therapeutic blend of iron fortificant and hepcidin antagonist along with pharmaceutically acceptable excipients.

Particularly the invention relates to synergistic nutritional composition comprising specific combination of ‘iron fortificant’ and ‘hepcidin antagonist’ which are present in an effective amount. The term ‘fortificant’ refers to the salt of iron that delivers the elemental iron in the right amount to the blood cells with improved bioavailability.

More particularly, the invention provides synergistic nutritional composition comprising ‘ferric maltol complex’ as iron fortificant and ‘ergocalciferol’ (i.e., vitamin D2) as hepcidin antagonist/inhibitor along with pharmaceutically acceptable excipients.

In another embodiment, the invention relates to synergistic iron supplement composition comprising therapeutically effective amount of ferric-maltol complex present in the range of 1 to 100 mg (equivalent to elemental iron Fe3+) and ergocalciferol present in the range of 0.1 mcg to 50 mcg along with pharmaceutically acceptable excipients/carriers.

In another embodiment, the synergistic composition comprising effective amount of ferric maltol complex, which can be used in any acceptable solid or liquid forms such as amorphous, crystals, colloids, powder, granules, suspension, emulsion, slurry, fine particles, nano particles, microcapsules, encapsulated or embedded core, coat, matrix , beadlets and like thereof.

‘Ferric maltol complex’ is also designated as 3-hydroxy-2-methyl-4H-pyrane-4-one iron (III) complex, or ‘ferric trimaltol’ or ‘ferric (III) maltol complex’ or ‘iron(3+);2-methyl-4-oxopyran-3-olate’, or ‘iron, tris(3-hydroxy-2-methyl-4H-pyran-4-onato-O3,O4).

Ferric Maltol

It is an iron complex consisting of a single ferric iron ion (Fe3+) chelated, with high affinity, to three maltol molecules. Maltol is a natural sugar derivative used in foods and it binds with high affinity to the iron until it is released directly into the area of the gastrointestinal system, where it is best absorbed. It has high bioavailability and better tolerability compared with ferrous iron salt complexes, due to reduced exposure of free iron throughout the gastrointestinal tract.

According to the present invention, ferric maltol complex provides iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins in the body (transferrin and ferritin, respectively) and thereby increases hemoglobin levels in a subject in need thereof.

It is noteworthy that the available iron in the gut lumen is in the ferric state, thus alleviating the potential problem of free radical mediated luminal toxicity associated with ferrous iron.

In another embodiment, the invention relates to synergistic iron supplement composition comprising therapeutically effective amount of ferric-maltol complex present in the range of 1 to 100 mg (equivalent to elemental iron Fe3+) along with pharmaceutically acceptable excipients/carriers.

In another embodiment, the invention provides the synergistic nutritional composition comprising effective amount of ‘ergocalciferol’ as hepcidin antagonist. Hepcidin concentration is inversely associated with hemoglobin concentration and positively associated with anemia risk.

The ergocalciferol is also known as ‘vitamin D2’. Ergocalciferol (Vit-D2) is produced in plants and enters human diet through consumption of plant sources. It is rich in mushrooms, lichen and other microorganisms.

Ergocalciferol

‘Ergocalciferol’ is a secosteroid formed by a photochemical bond breaking of a steroid, specifically, by the action of ultraviolet light on ergosterol, a form of provitamin D2.

Further vitamin D2 obtained from the present composition augments iron absorption by lowering mRNA expression of hepcidin mediated by the presence of vitamin D response elements (VDREs) identified in the promoter region of the hepcidin gene. ‘Ergocalciferol’ is the biologically active form of vitamin D.

The composition of the present invention comprising ergocalciferol, promotes erythropoiesis by increasing erythroid progenitor proliferation and decreasing pro-inflammatory cytokines. Additionally, by decreasing hepcidin-stimulatory pro-inflammatory cytokines, through direct transcriptional regulation of the HAMP gene, and suppressed hepcidin expression.

It may be noted that decrease in pro-inflammatory cytokines and hepcidin, increases iron bioavailability for erythropoiesis and hemoglobin synthesis by restoring iron recycling, preventing iron sequestration in macrophages, and removing impairments on iron absorption, thus protecting against anemia.

As iron is required for a number of diverse cellular functions, a constant balance between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis. As the body lacks a defined mechanism for the active excretion of iron, iron balance is mainly regulated at the point of absorption.

Hepcidin is the master regulator of systemic iron homeostasis, coordinating the use and storage of iron with iron acquisition. The present synergistic composition decreases expression of hepcidin leading to increased cell surface ferroportin and increased iron absorption.
Hepcidin is homeostatically regulated by iron and erythropoietic activity.

In another embodiment, the present composition actively suppresses hepcidin secretion in a subject suffering from iron deficiency anemia, allowing increased absorption of dietary iron and replenishment of iron stores. Apart from enhancing iron absorption, it enables the rapid release of stored iron from macrophages and hepatocytes and augments the supply of iron for erythropoiesis. It also facilitates cellular iron efflux.
In another embodiment, the invention relates to synergistic iron supplement composition comprising therapeutically effective amount of ergocalciferol present in the range of 0.1 mcg to 50 mcg along with pharmaceutically acceptable excipients/carriers. The mcg or µg unit can be interchanged with ‘IU’ unit (1 IU is the biological equivalent of 0.025 mcg ergocalciferol).

In another embodiment, the present composition provides synergistic effect, wherein one moiety increases the elemental iron uptake into enterocytes thus increasing the stored iron, and other moiety enhancing iron absorption, this enables the rapid release of stored iron from macrophages and removing impairments on iron absorption, thus protecting against anemia in significant manner.

The therapeutic efficacy of the instant iron supplement is comparatively higher than the active nutrients i.e., ferric maltol and ergocalciferol when administered alone or separately.

In one preferred embodiment, the invention provides a synergistic nutritional composition comprising 95 to 99 % w/w ferric maltol enriched with 12 to 14.5% w/w of elemental iron and 0.0001 to 0.03% w/w of ergocalciferol along with pharmaceutically acceptable excipients.

In another preferred embodiment, the amount of ferric maltol is present in the range of 200-250 mg containing 12.0 to 14.50% of elemental iron. Particularly the present synergistic nutritional composition comprising 12 to 14.5 % elemental iron by weight of total ferric maltol.

In another preferred embodiment, the present invention provides a synergistic nutritional composition comprising 200 to 250 mg of ferric maltol enriched with elemental iron i.e. with 12-14.5% of elemental iron and 0.5 to 50 mcg of ergocalcifeol along with pharmaceutically acceptable excipients.

In yet another preferred embodiment, the present composition comprises 200000 to 250000 mcg of ferric maltol enriched with 12- 14.5 % of elemental iron along with 0.5 to 50 mcg of ergocalcifeol.
In another embodiment, the present synergistic nutritional composition is useful for treating subject suffering from latent iron deficiency (LID) or iron-deficient erythropoiesis (IDE), iron deficiency anemia (IDA), Chronic Kidney Diseases (CKD), Inflammatory bowel diseases (IBD), Cancer, Anemia of chronic disease, Heavy Menstrual Periods, Pregnancy. Infections, Chronic Heart Failure (CHF), Carcinomas.

An “effective amount of nutrients” is an amount sufficient to prevent, treat, reduce, and/or ameliorate the symptoms and/or underlying causes of iron deficiency particularly IDA.

In the context of the present invention, the terms “treatment” and the like refer to alleviate or slow the progression, prophylaxis, attenuation, or cure the pre-existing or occurrence of iron deficiency. The present composition is used for treating iron deficiency anemia in a subject in need thereof, means either the administration of the remedy to prevent the onset or occurrence of anemia, or treat pre-existing cause of iron deficiency anemia.

The ‘subject in need thereof’ pertains to subject preferably mammal, more preferably human with pre-existing iron deficiency anemia or in a subject to prevent occurrence of iron deficiency anemia.

The therapeutically effective amount of such nutrient will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

Thus, a "therapeutically effective" amount is an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides some alleviation, mitigation, and/or reduction of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or decrease in at least one clinical symptom of a disease or disorder (such as iron deficiency anemia as disclosed herein).

A “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, solvents or waters of hydration.

The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases, halides, sulphates, phosphates, nitrate, metal ions, minerals, chelates, complex, esters, oxide, amines which are well known in the art.

As used herein, the term “pharmaceutically acceptable carriers/vehicles/diluents or excipients” is intended to mean, without limitation, any adjuvants, carriers, excipients, sweetening agents, diluents, preservative, dye/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, complexing agents, stabilizers, isotonic agent, solvent, emulsifier, encapsulating agent, polymers, coating agent, wax, encapsulating polymeric delivery systems. Excipients may also include, antiadherents, antioxidants, binders, pH-modifier, solvents, coatings, compression aids, disintegrants, emollients, , fillers (diluents), film formers, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, anticaking agent, food additives, or waters of hydration.

In some embodiment of the invention, the diluents are selected from starches, hydrolyzed starches, and partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulfate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.

In some embodiment of the invention, the amount of diluent in the nutritional composition/formulation is present in the range of 0.5 % to 40% by wt. of the total composition/formulation.

In further embodiment, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose hydroxyl ethylmethyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colorants and wax.

In some embodiment of the invention, the amount of binder in the nutritional composition/formulation is present in the range of 0.1% to 30% by wt. of the composition/formulation.

Further according to the invention, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potassium benzoate, sodium oleate, sodium stearate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, and talc or the like.
In some embodiment of the invention, the amount of lubricant in the nutritional composition/formulation is present in the range of 0.1% by wt. to 5% by wt. of the total composition/formulation.

The solubilizing agent is selected from polysorbate 80, sodium lauryl sulfate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like. The amount of solubilizing agent or surfactant in the nutritional composition/formulation of the present invention ranges from 0.1% to 10%, preferably 0.1% to 5% by wt. of the composition/formulation.

In some embodiment, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, methyl cellulose, agar, bentonite, xanthan gum, sodium croscarmellose, sodium starch glycolate, cross linked sodium carboxymethylcellulose or the like.
In some embodiment of the invention, the amount of glidant present in the nutritional composition/formulation ranges from 0.1% by wt. to 5% by wt. of the total composition/formulation.

In some embodiment, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

In some embodiment of the invention, the amount of solvent in the nutritional composition/formulation is used in a quantity sufficient to 100% by wt. of the composition/formulation.

The additional additives include polymer, a plasticizer, a sweetener, and a powdered flavor, preservative, colorant, surfactant and other excipients. The powdered flavor composition includes a flavourant associated with a solid carrier, coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof.
In some embodiment of the invention, the additives are used in the range of 0.5 to 30 % w/w of unit dose.

In some embodiment, the synergistic nutritional compositions, wherein the amount of diluent is present in the range of 0.5 to 30%; the amount of binder is present in the range of 0.1 to 20%; the amount of lubricant is present in the range of 0.1 to 5.0 %; the amount of glidant is present in the range of 0.1 to 5.0%; the amount of additive is present in the range of 0.5 to 10%; the amount of surfactant is present in the range of 0.1 to 5.0%, by weight of total composition.

Notably, the instant synergistic composition is non-hazardous, non-toxic and safe for human consumption without any side effects, therefore the instant composition can also be used under preventive therapy in healthy subjects.
The present nutritional composition is used to manage iron deficiency conditions in the subject in need thereof, means the administration of the remedy either to prevent occurrence or for pre-existing cause of IDA.

In another embodiment, the invention relates to synergistic composition which can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Therapeutic (prescription) supplements are generally administered by the oral or I.V. routes for the treatment of indications including iron deficiency anemia, iron deficiency and anemia of chronic disease. The therapeutic administration of materials of the present invention may be in conjunction with other therapies.

Particularly the present composition can be administered to subject in a form suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, granulate for sublingual use, effervescent tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, or syrup. Further the composition can be formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular or infusion.

In a preferred embodiment, the nutritional composition/formulation is formulated for oral administration. Specifically, the solid nutritional compositions, for example, can be in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions or modified release formulations. The oral administration of an effective dose of the composition improves hemoglobin level, red blood cells and hemotocrit level in a subject suffering with IDA, wherein the subject is human.

An effective dose is a dose that produces a desirable clinical outcome by, for example, improving a sign or symptom of anemia or slowing its progression. Accordingly, the effective unit dose can be formulated in the range of 100 to 500 mg, preferably 200-300 mg and administered daily once or twice or thrice based on the intensity of the IDA.

In another embodiment, the invention provides novel oral nutritional composition comprising ferric salt in specific combination with vitamin D along with pharmaceutically acceptable excipients, wherein ferric salt is ferric maltol enriched with elemental iron and vit D is ergocalciferol. This oral composition is used for treatment of iron deficiency anemia.

In yet another embodiment, the invention provides novel oral nutritional composition comprising 200-250 mg (1mg ~ 1000mcg) of ferric maltol salt enriched with 12.0 to 14.5 % of elemental iron in combination with 0.5 to 50 mcg of ergocalciferol with pharmaceutically acceptable excipients.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.

All references cited herein are incorporated by reference in their entireties. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.

This invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all changes or alterations which come within the ambit of equivalency are intended to be encompassed therein.

EXAMPLES:

Example: 1
i. Composition 1a: Synergistic Blend
Ingredient % w/w
Ferric Maltol 95 to 99 %
(containing 12.0-14.5 % of Fe3+)
Ergocalciferol 0.0001-0.03 %

ii. Composition 1b: Synergistic Blend
Ingredient weight in mcg
Ferric Maltol 200000-250000 mcg containing
12-14.50%
(Elemental Iron)
Ergocalciferol 0.5 to 50 mcg

Proprietary blend containing 200- 250 mg equivalent to 200000 mcg -250000 mcg of ferric maltol containing 12-14.50% elemental Iron + 0.5 to 50 mcg of Ergocalciferol. Therapeutic proprietary blend with the proportionate excipients filled in soft gel, hard gel, veg capsule by known technique. Further the blend with the proportionate excipients is compressed to get tablet in coated or uncoated form.

iii. Composition 2: Tablet/Capsule
Ingredient Unit dose
Ferric maltol 200-250 mg
(200000-250000 mcg)
(Containing 12-14.5% of Iron)
Ergocalciferol 0.5-5 mcg
Excipient 1-20%
Average Wt 100%
Average wt in mg 200-300 mg

iv. Composition 3: Tablet/Capsule
Ingredient w/w% Unit dose
Ferric Maltol 95 to 99 %
Ergocalciferol 0.001 to 0.03%
Diluent 0.5-10%
Binder 0.1-10 %
Glidant 0.1-3%
Lubricants 0.1-3%
Additives 0.5-5%
Solvent QS

v. Composition 4: Tablet/Capsule
Ingredient mg per unit dose
Ferric Maltol 240
(12.5% elemental Fe3+)
Ergocalciferol 1 mcg
Microcrystalline cellulose 1-10
Silicon dioxide 1-10
Hydroxypropyl methylcellulose 1-10
Zinc Stearate 1-5
Crospovidone 1-5
Talc 1-5
Magnesium stearate 1-5
Sodium lauryl sulphate 1-5
Sucrose 1-10
Propylene Glycol QS
Water QS
Average weight 240-260

vi. Composition 5: Tablet/Capsule
Ingredient mg per unit dose
Ferric Maltol 240
(12.5% elemental Fe3+)
Ergocalciferol 1 mcg
Microcrystalline cellulose 1-15
Silicon dioxide 2-10
Hydroxypropyl methylcellulose 2-20
Magnesium stearate 2-10
PVP K-30 2-10
Talc 1-20
Polysorbate 80 2-20
Manitol 2-20
IPA QS
Water QS
Average weight 260-300mg

The present composition is stable for 06 months under the accelerated condition [40°C, 75% RH], where the purity of the active ingredients is above 95%.

Example 2: Animal Study
Evaluation of anti-anemic activity on test substance against phenyl hydrazine induced anemic experimental rats.

Animal House conditions-
Lighting: 12/12 hour light-dark cycle
Temperature: 22±3°C
Relative Humidity: 30 to 70%
Animals had continuous access to fresh, potable, uncontaminated drinking water.
Feed: Normal chow diet

Each animal was marked by picric acid and numbering was given individually to each animal. Each cage was numbered separately to identify the group. In each cage single animal was housed in standard stainless-steel cage having facilities for pelleted food and drinking water in bottle. The study was approved by Institutional Animal Ethical Committee (IAEC) of Radiant Research Services Pvt. Ltd.

Test System and Animal Husbandry
Species: Rat
Strain: Wister;
Sex: Male
No. of animals: 36 Animals (n=6 per group)
Body weight: 210-230 gm
CPCSEA Registration Number-1803/PO/RcBi/S/2015/CPCSEA

Group, Designation and Dose Levels

Table 1: Animal grouping and treatment details
Group Treatment Dose No. of Animals
G1 Normal Control 0.5 % CMC 6
G2 Anemic control 0.5 % CMC 6
G3 Ferric Maltol (30mg Fe3+) 10.29 mg/kg 6
G4 Vit-D2 (Ergocalciferol) 10.29 mg/kg 6
G5 (Composition 1a) 10.29 mg/kg+10.29 mg/kg 6
G6 Orofer XT 10.29 mg/kg 6

Experimental Procedure:
The anti-anemic activity Anemia was induced in rats by intraperitoneal administration of phenyl hydrazine (40 mg/kg) daily for 2 days. Rats that developed anemia were randomly divided into 6 group’s six animals each; G1 was non anemic animals (normal control) received of 0.5% CMC. G2 was served as anemic control received of 0.5% CMC, G3 animals received as (Ferric Maltol) test substance G4 animals received as (vit D2) test substance, G5 animals received as (Composition 1a) test substance and G6 animals received as reference substance (Orofer® XT ) through oral administration, by suspending in CMC solution. The entire test Substance was administered orally, once daily for 10 days. On 11th day, blood was collected in EDTA coated tubes, for Hematological parameter analysis. The following parameters like, Red Blood Cell count (RBC), Hemoglobin (Hb) and Hemotocrit (HCT) were evaluated in EDTA blood.

Results:
Table 2: Effect of test substance on rat body weight
Group Body weight (gms)
Day: 0 Day: 7
G1 221.3+0.95 230.5+1.26*
G2 221.7+1.23 215.0+1.53
G3 220.8+1.05 224.0+1.00*
G4 221.2+1.05 223.3+1.20*
G5 221.0+0.86 226.3+0.61*
G6 221.2+1.20 228.0+1.00*
*Values were expressed as Mean± SEM

Table 3: Eeffect of test substances on Feed Consumption
Group Week-1 Feed Consumption
G1 99.83+2.49*
G2 68.67+1.01
G3 80.65+0.54*
G4 79.33+0.87*
G5 85.67+0.79*
G6 88.17+0.88*
*Values were expressed as Mean± SEM

The values were expressed in Mean ± SEM. The significance of in vivo data was analyzed by one way anova followed by Dunnet test. P < 0.05 was considered as statistically significant.

Table 4: Eeffect of test substances on Hematological parameters
Group Hematology on Day 11
Hb RBC HCT
G1 14.18+0.16* 5.81+0.09* 46.50+0.56*
G2 7.37+0.15 2.48+0.08 23.33+0.33
G3 9.10+0.16* 3.08+0.08* 29.00+0.37*
G4 8.22+0.08* 2.85+0.03* 26.83+0.31*
G5 10.42+0.13* 3.53+0.07* 32.33+0.21*
G6 11.80+0.07* 3.89+0.058* 35.5+0.42*
*Values were expressed as Mean± SEM
Discussion

This study focuses on the use of infectious and noninfectious rat models of inflammation that have been shown to manifest anemia.

The rats were randomly divided into 6 group’s six animals each. G1 was non anemic animals (normal control) received of 0.5% CMC. G2 was served as anemic control received of 0.5% CMC, G3, G4, G5 animals received as test substance G6 animals received as reference (Orofer® XT). Anemia was induced in rats by intraperitoneal administration of phenyl hydrazine (40mg/kg) daily for 2 days. The mean body weight of the G2 anemic control decreased when compared to that G1 normal group. G3, G4, G5 test substances treatment and G6 animals (Orofer XT) reference (Table-2). The mean feed consumption of the G2 anemic control decreased when compared to that G1 normal group, G3, G4, G5 test substances treatment and G6 (Orofer® XT) reference animals (Table 3). The mean hematology analysis like RBC count, Hemoglobin content and Hemotocrit count of the G2 anemic control decreased as compared to that G1 normal group, G3, G4, G5 test substances treatment and G6 (Orofer® XT) animals (Table 4).

In this study, it has been shown that the test substance G3, G4, G5 improved the anemic condition of the treated animals when compared with the phenyl hydrazine induced anemic control rats.

Conclusion: Overall result concluded that the combination of Ferric Maltol and Vit D2 (G5) showed better anti-anemic activity than test substances (G3) and (G4).
,CLAIMS:We Claim:

1. A synergistic nutritional composition(s) for treating iron deficiency anemia (IDA) comprising a therapeutic blend of iron fortificant and hepcidin antagonist along with pharmaceutically acceptable excipients, wherein the iron fortificant is ferric maltol enriched with elemental iron and the hepcidin antagonist is ergocalciferol.

2. The synergistic nutritional composition as claimed in claim 1, wherein the ferric maltol enriched with elemental iron is present in the range of 95-99% by weight of total composition and ergocalciferol is present in the range of 0.0001 to 0.03% by weight of total composition.

3. The synergistic nutritional composition as claimed in claim 1, wherein the elemental iron is present in the range of 12-14.5 % by weight of total ferric maltol.

4. The synergistic nutritional composition as claimed in claim 1, wherein the ferric maltol is in present in the range of 200-250 mg.

5. The synergistic nutritional composition as claimed in claim 1, wherein the ergocalciferol is present in the range of 0.5 to 50 mcg.

6. The synergistic nutritional composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from a diluent, a binder, a surfactant, a lubricant, a glidant, an additive, a solvent and mixtures thereof.

7. The synergistic nutritional composition as claimed in claim 5, wherein the amount of diluent is present in the range of 1 to 30%; the amount of binder is present in the range of 0.1 to 20%; the amount of lubricant is present in the range of 0.1 to 5.0 %; the amount of glidant is present in the range of 0.1 to 5.0%; the amount of additive is present in the range of 1 to 10%; and the amount of surfactant is present in the range of 0.1 to 5.0%, by weight of total composition.

8. The synergistic nutritional composition as claimed in claim 1, wherein oral administration of an effective dose of the composition improves hemoglobin level, red blood cells and hemotocrit level in a subject suffering with IDA, wherein the subject is human.

9. The synergistic nutritional composition as claimed in claim 1, wherein the effective dose for daily oral administration is in the range of 200 to 500 mg.

10. A synergistic nutritional composition for treating iron deficiency anemia comprising a combination of ferric maltol enriched with elemental iron and ergocalciferol along with pharmaceutically acceptable excipients.

11. The synergistic nutritional composition as claimed in claim 10, wherein the amount of ferric maltol enriched with elemental iron ranges from 95 to 99 % by weight of total composition and the amount of ergocalciferol ranges from 0.0001 to 0.03% by weight of total composition.

12. The synergistic nutritional composition as claimed in claim 10, wherein the elemental iron is present in the range of 12.0- 14.5 % by weight of total ferric maltol.

13. The synergistic nutritional composition as claimed in claim 10, wherein the composition comprises 200-250 mg of ferric maltol having 12.0 to 14.5% of elemental iron and 0.5 to 50 mcg of ergocalciferol along with pharmaceutically acceptable excipients.