FIELD OF INVENTION
The present invention relates to a novel stable chewable composition comprising microencapsulated Ferric Saccharate along with one or more pharmaceutically acceptable excipients wherein the said chewable compositions are devoid of metallic taste of iron. The present invention also discloses the process of preparation of said chewable composition and use of same in conditions associated with iron deficiency and as nutritional supplement.
Iron is essential to most life forms and to normal human physiology. Iron is an
integral part of many proteins and enzymes that maintain good health. Iron is an
essential element for blood production. About seventy percent of our body's iron is
found in the haemoglobin present in red blood cells and in muscle cells called
myoglobin. Hemoglobin is essential for transferring oxygen in your blood from the
lungs to the tissues. The majority of iron is contained in red blood cell hemoglobin
(~2 gm iron) and is recycled in the process of erythrophagocytosis by
reticuloendothelial macrophages (Pantopoulos K, Porwal SK, Tartakoff A,
Devireddy L. Mechanisms of mammalian iron
homeostasis. Biochemistry. 2012;51(29):5705–5724). Myoglobin, in muscle cells, accepts, stores, transports and releases oxygen. Iron is a component of certain proteins, essential for respiration and energy metabolism, and as a component of enzymes involved in the synthesis of collagen and some neurotransmitters. Iron also is needed for proper immune function Dev S, Babitt JL. Overview of iron metabolism in health and disease. Hemodial Int. 2017 Jun;21 Suppl 1:S6-S20).
Iron is also essential for the regulation of cell growth and differentiation. A deficiency of iron limits oxygen delivery to cells, resulting in fatigue, poor work performance, and decreased immunity (Haas JD, Brownlie T, IV. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr 2001, 131, 676S-690S). The average adult human contains about 0.005% body weight of iron, or about four grams, of which three quarters is in haemoglobin. Iron deficiency is a progressive condition that begins with normal

body iron status, which becomes subnormal or depleted because of low dietary iron intake, inadequate intestinal iron absorption or increased iron losses. As this process continues, synthesis of iron-containing proteins, such as Hb, becomes compromised. Finally, Hb concentration falls. 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 decreases may be called iron-deficient erythropoiesis and still further decreases produce iron deficiency anemia.
Blood loss is the most common cause of iron deficiency. In men and postmenopausal women, iron deficiency is almost always the result of gastrointestinal blood loss. In menstruating women, genitourinary blood loss often accounts for increased iron requirements. Oral contraceptives tend to decrease menstrual blood loss, whereas intrauterine devices tend to increase menstrual bleeding. Other causes of genitourinary bleeding and respiratory tract bleeding also increase iron requirements. There is a significant, continuing need for an iron supplement which can be administered to a human patient in order to safely and efficaciously deliver a nutritionally relevant amount of iron to the patient.
Several oral compositions are known for the use as nutritional or dietary supplement containing iron. Oral dosage forms comprise a higher dose of iron for treating iron deficiency symptoms. These preparations include simple iron salts such as ferrous sulfate, ferrous gluconate, ferrous fumarate, ferrous orotate and others. Various low molecular weight iron, Fe(III), compounds intended for use as oral or nutritional supplements are known. One of the major drawback of these oral iron supplements is very bad metallic taste of iron. This leads to palatability and non-compliance issues. Because of unpleasant taste, chewable tablets of iron are not preferred. Also, the most common side effect with oral formulations of iron is stomach upset. Further the oral formulations of iron have very low bioavailability.
In order to avoid a bad metallic taste, stomach upset various approaches like preparing iron complex, expensive taste masking technology such as coating of iron

containing granules or tablets, encapsulation of bitter tasting active ingredients, admixing taste masking flavours, use of capsules are reported in field of invention. Well known methods for taste masking generally have involved coating of the particles of the active ingredient and/or the tablet containing such active ingredient. Unfortunately, with various coating materials or combinations of coating materials many of these approaches provide coating materials having limited water solubility and are therefore applied from organic media. The other technique is complexation of iron with different sweetners. Iron saccharate (Sucroferric oxyhydroxide or Iron Sucrose) is one of the many reported iron compounds used as a source of iron in patients with iron deficiency. Marketed products containing iron saccharate still suffer from patient compliance issues (e.g. failure to consistently ingest iron supplements, owing to unpleasant side effects, unpleasant taste or odor, inconvenient tablet size, or some combination of these) which exist with regard to prior art iron supplements.
Generally, chewable hematinic tablets are preferred when people are reluctant to take tablets or capsules because of swallowing difficulties. Children and aging population particularly face such problems with oral formulations and prefer chewable tablets. Various chewable oral formulations like chewing gum, tablets containing iron as iron saccharate are reported in literature.
Chewable tablets containing 500 mg iron as sucroferric oxyhydroxide in a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches are marketed under the under name of Velphoro chewable tablets. The active ingredient sucroferric oxyhydroxide contains 750 mg sucrose and 700 mg starches (potato starch and pregelatinised maize starch) per tablet. Even though the active ingredient contains higher amount of sucrose, the most common adverse effects reported with the administration of said formulation is abnormal taste of the Product, tooth discoloration, nausea, vomiting, flatulence, dyspepsia, constipation, abdominal pain(https://www.medicines.org.uk/emc/product/3532/smpc#UNDESIRABLE_E FFECTS; Table 1). Also, as the formulation contains large amount of starch, it is to be used with caution in diabetic patients.

US Patent Application No. 20140004223 discloses a chewing gum composition that imparts a mouth-moistening effect when orally consumed by an individual.
PCT Application No. 2014152351 discloses a taste masked pharmaceutical composition, comprising: particles of a pharmaceutically active agent coated or encapsulated with polymers (combination of hydrophobic low molecular weight polymer, and high molecular weight polymer) in an amount in the range of about 10 to 50 percent by weight of the substrate.
PCT Application No. 2012145611 discloses a chewing gum product including an encapsulated solid peroxide composition.
Korean Patent Application No. 2004010145 discloses a gum composition, which comprises 49.0 to 62.5% by wt. of a gum base, 10 to 12.0% by wt. of fructose, 8.4 to 14.6% by wt. of glucose, 5.9 to 7.3% by wt. of ascorbic acid, 6.4 to 7.6% by wt. of vitamin, 3.9 to 5.6% by wt. of calcium, 1.8 to 2.8% by wt. of iron, 0.8% by wt. of natural flavor and 0.3% by wt. of stearic acid. The gum base is introduced into a freezer and frozen for 5 to 10min at -95 to -110 °C. Then, the frozen gum base is ground to 0.05 to 0.1mm and encapsulated.
Great Britain Patent No. 983132 discloses a chewable hematinic two-layered tablets comprise two medicaments which are normally incompatible, wherein the first medicament is granulated and compression coated with an inert sugar granulation, the second medicament being granulated and compressed superimposed on one face of the sugar coated layer.
Palatability and mouthfeel are important characteristics to be considered in providing a chewable dosage form for iron medicament or nutritional supplement. Unfortunately, iron even in complexed form with sweetners such as saccharin, sucrose, etc is bitter or otherwise have unpalatable taste, or an unacceptable mouthfeel, due to the metallic taste and odour of the compound, or poor mouthfeel of the Product. These characteristics make it difficult to prepare acceptable dosage forms using the current state of the art for chewable dosage forms, since

objectionable taste and/or mouthfeel continues to be a problem and make it less likely to obtain dosage compliance by the user.
Various attempts have been made to prepare chewable tablets or chewing gums of iron, which not only mask the bitter taste, are palatable but also reduces the side effects associated with oral administration of iron compositions.
Despite these disclosures there is need for a chewable tablet, particularly for children, that is pleasant tasting and provides improved mouthfeel qualities. There is also need for a chewable tablet that is pleasant tasting, has acceptable mouthfeel, can conveniently be administered, accepted by persons of all age groups whether paediatric or geriatric, and does not promote tooth decay or dental caries. Such a formulation can lead to improved patient acceptance and compliance with a dosing regimen.
SUMMARY OF THE INVENTION
The present invention provides a stable taste masked chewable tablet of microencapsulated iron saccharate, sweetners, antioxidants and optionally along with one or more excipients. The compositions of present invention not only taste mask the bitter metallic taste and odour of iron but also have improved palatability and patient compliance. Iron saccharate is microencapsulated in polymer coating in such a way that the microcapsules so obtained have a particle size less than 50 micrometres to have an improved bioavailability. Microcapsules further formulated with antioxidants, natural sweetners and flavouring agent so as to obtain a stable taste masked chewable tablets of iron with improved palatibility. Ferric Saccharate (in microencapsulated form) chewable tablet of the present invention is a dietary source of absorbable (heme) iron which is good in taste, aroma and easy to use. Its microencapsulated technology helps to improve its bioavailability while its formulation has improved the masking so much that it can chewed without any metallic taste of iron in it. The compositions of present invention are suitable for administration to persons of all age groups including paediatric and geriatric

patients. The compositions of present administration are suitable for administration as therapeutic drug for treatment of iron deficiency diseases or as nutritional supplement.
One of the aspects of present invention provides a stable taste masked chewable tablet comprising microencapsulated ferric saccharate optionally along with one or more pharmaceutically acceptable excipients.
Another aspect of present invention provides a stable taste masked chewable tablet for use in iron deficiency diseases or as nutritional supplement, wherein the chewable tablet comprises microencapsulated ferric saccharate along with one or more pharmaceutically acceptable excipients.
Another as aspect of present invention provides a stable taste masked chewable tablet comprising microencapsulated ferric saccharate along with one or more pharmaceutically acceptable excipients, wherein the average size of the microcapsules is in range of 5 µm to 50 µm.
The pharmaceutical acceptable excipients are one or more selected from the group consisting of diluents, binders, disintegrants, antioxidants, stabilizers, sweeteners, flavoring agents, taste enhancing agents, coloring agents, glidants and lubricants.
Another aspect of present invention provides a stable taste masked chewable tablet for use in iron deficiency diseases or as nutritional supplement, wherein the tablet comprises microencapsulated ferric saccharate, coated ascorbic acid, sorbitol, sucralose, lactose, xylitol, polyvinylpyrrolidone, colloidal silicon dioxide, magnesium stearate and flavouring agents.
Another aspect of present invention provides a stable taste masked chewable tablet composition comprising granules of microencapsulated iron with one or more pharmaceutically acceptable excipient, wherein the granules are obtained using wet granulation technique.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable taste masked chewable tablet composition, wherein the tablet comprises microencapsulated ferric saccharate along with one or more pharmaceutically acceptable excipients in correct proportions so that the said tablet composition is devoid of any metallic taste or odour of iron or ferric saccharate.
While developing a chewable tablet composition of iron, inventors of present invention observed that encapsulating the ferric saccharate helps in reducing the metallic taste of iron. Further, particle size of the microcapsules, selection of antioxidant, selection of other excipients, amount of excipient used and process of preparation were critical factors for developing the compositions of present invention which are not only devoid of metallic taste and odour of iron but are also palatable and acceptable to persons or patients of all age groups. Inventors of the present invention developed a right balance of taste masking and improved absorption of iron from the composition by microencapsulating the ferric saccharate in cross linked alginate polymers, controlling the average particle size of the microcapsules between 5 µm to 50 µm, use of antioxidants such as ascorbic in coated form which increases the absorption of iron and at the same time does not result in drug excipient interaction, selecting the diluents which help in taste masking the metallic taste of iron and use of flavouring agent.
One of the aspect of the present invention provides a stable taste masked chewable tablet comprising microencapsulated ferric saccharate, wherein the ferric saccharate is microencapsulated using a polymer. The polymer used for microencapsulation include hydrophilic, hydrophobic or lipophilic polymers selected from the group consisting of hydroxy propyl methyl cellulose, cellulose polymers, alginates, ethyl celluloses, hydroxyethyl celluloses, ammonio methacrylate copolymers, methacrylic acid copolymers, methacrylic acid-acrylic acid ethyl ester copolymers, methacrylic acid esters neutral copolymers, dimethylaminoethylmethacrylate, and vinyl methyl ether/maleic anhydride copolymers, their salts and esters.

Microencapsulation was performed using the techniques known in the technical field of invention. Ferric saccharate is microencapsulated in calcium alginate matrix.
The stable taste masked compositions of present invention contains iron as Ferric saccharate in microencapsulated form. The elemental iron present in the compositions of present invention is in amount 10mg to 1000mg, more specifically 30mg to 500mg. The amount of elemental iron in the microencapsulated chewable dosage form of present invention is 30mg.
The compositions of the present invention can be administered as therapeutic drug in patients suffering from iron deficiency diseases or as nutritional supplement. Iron deficiency diseases includes Iron deficiency anemia, anemias associated chronic diseases, aplastic anemia, hemolytic anemia, sickle cell anemia, anemias associated with bone marrow diseases or other diseased conditions requiring administration of iron. The tablet compositions of the present invention can be administered as nutritional supplement to healthy individuals especially in individuals where the dietary intake of iron is poor or mensurating women, pregnant women, children in their growing stage, or persons who suffer from bleeding disorders such as haemophilia, von Willebrand diseases.
The compositions of present invention comprise excipients, which are selected from the group consisting of the group consisting of diluents, binders, disintegrants, stabilizers, antioxidants, sweeteners, flavoring agents, taste enhancing agents, coloring agents, glidants and lubricants. It can be appreciated by those skilled in the art that other pharmaceutically acceptable excipients used for preparing chewable tablet may also be used to prepare the Iron chewable tablet of the present invention.
Diluents, which include but are not limited to sucrose, mannitol, xylitol, lactose, acesulfame potassium, aspartame, dextrose, fructose, saccharin, sodium saccharin, sorbitol and mixtures thereof can be used. The preferred diluents of the present invention includes sorbitol, lactose and xylitol. The diluents present are preferably

in the range of 10 to 90% by weight of tablet. Diluents of this invention can also serve other functions namely as a sweetener.
Binders include but are not limited to spray dried lactose, compressible starch, cellulose, alkylcelluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose, low substituted hydroxypropyl cellulose and hydroxypropyl methylcelluiose, sodium carboxymethyl cellulose or mixtures thereof, pregelatinised maize starch, polyvinylpyrrolidone. The binder used in the present invention is polyvinylpyrrolidone. The binders present are preferably in the range of 0.1 to 30% by weight of tablet.
The compositions of present invention may include disintegrants. Disintegrants, which include but are not limited to crospovidone, sodium starch glycolate, starches such as maize starch and dried starch, croscarmellose sodium and cellulose products such as microcrystailine cellulose, microfine cellulose, low substituted hydroxypropylcellulose and the like, either used singly or in admixture can be used. The disintegrants are preferably present in the range of 0 to 20% by weight of tablet.
Antioxidants or stabilizers are selected from the group consisting of citric acid and its salts, ascorbic acid, tocopherols, butylated hydroxyanisole (BHA), butylhydroxytoluene (BHT), t-Butylhydroquinone (TBHQ), sodium ascorbate, calcium ascorbate, fatty acid esters of ascorbic acid, lactic acid sodium lactate, tartaric acid, sodium hydrogen tartrate, sodium hydrogen phosphate, phosphates and lecithins. The antioxidant used in the compositions of present invention is ascorbic acid. Ascorbic acid is known to enhance the absorption of iron but it is well known in the prior art that ascorbic acid reacts with iron and leads to drug excipient interaction. In order to avoid compatibility issues and at the same to stabilize and increase the absorption of iron from the compositions of present invention, ascorbic acid was coated with a non-functional coating. Coated ascorbic acid was incorporated in the compositions of present invention.

Sweeteners include but are not limited to natural sweeteners such as sugars e.g. fructose, glucose, sucrose, sugar alcohols such as mannitol, xylitol, lactose, sorbitol or mixtures thereof and artificial sweeteners such as sodium saccharine, sucralose, sodium cyclamate and aspartame. The sweetening agents are preferably present in the range of 0.1 to 90% by weight of tablet.
Flavoring agents, as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. Representative flavoring agents include but are not limited to orange flavor, banana flavor, lemon mint flavor, strawberry flavor, grape flavour, chocolate flavour, vanilla flavor and cream flavor. A preferred flavoring agent of the present invention is combination of chocolate flavour and vanilla flavour. The flavoring agents present are preferably in the range of 0.01 to 5% by weight of tablet.
Taste enhancing agents include but are not limited to sodium chloride, glycine, citric acid, tartaric acid and the like and mixtures thereof. The taste enhancing agents present are preferably in the range of 0 to 10% by weight of tablet. Coloring agents include but are not limited to titanium dioxide pigments, lake colors and iron oxide pigments.
Glidants, lubricants and anti-caking agent include but are not limited to colloidal silicon dioxide, talc powder, magnesium stearate, calcium stearate, zinc stearate, magnesium oxide, sodium stearyl fumarate, hydrogenated vegetable oil, sodium lauryl stearate, stearic acid, cornstarch, and mixtures thereof. Combinations of Glidants, lubricants and anti-caking agent with one or more surfactants may also be used. Preferred glidant, lubricants and/or anticaking agents of the present invention include colloidal silicon dioxide, talc and magnesium stearate. Each of the glidants, lubricants and/or anticaking agents present in the compositions of present invention are preferably in the range of 0.1 to 5% by weight of tablet.

Excipients for pharmaceuticals and nutritional supplements familiar to the skilled person are also described for example in the following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, PJ., American Pharmaceutical Association, Washington, 2nd edition 1994.
The compositions of the present invention are prepared by direct compression, dry granulation or wet granulation techniques. The compositions of present invention were prepared by wet granulating microcapsules of ferric saccharate and excipients using binder solution. The granules so obtained were mixed with glidants, lubricants, anticaking agents and flavouring agent and then compressed into tablets. The formulation can be designed as a compressed tablet or caplet by standard tableting techniques, and optionally coated using standard coating equipment and methods known in the art such as coating pans, automatic coater or fluid bed coater.
The composition according to the invention can comprise further active ingredients such as vitamins and minerals. Vitamins include, but are not limited to, vitamin A, beta carotene, vitamin C (ascorbic acid), vitamin D3 (cholecalcipherol), vitamin E (tocopherol acetate), vitamin Bl (thiamine), vitamin B2 (riboflavin), nicotinamide, vitamin B5 (panthothenic acid), vitain B6 (pyridoxine), folic acid, vitamin Bl 2 (cyanocobalamin), vitamin Kl and biotin. Minerals include, but are not limited to, calcium salts such as calcium carbonate, calcium phosphate, calcium glycerophosphate; magnesium salts such as magnesium phosphate or magnesium oxide; zinc salts such as zinc citrate; selenium salts such as sodium selenate; potassium iodide; manganese salts such as manganese sulphate; molybdate salts such as sodium molybdate; chrom salts such as chromium chloride; sodium chloride and potassium chloride.
The composition according to the invention is administered orally one or more, preferably up to three, more preferably up to two times per day. With each administration the number of dosage forms taken in at the same time should not exceed two.

The composition according to the present invention can be used as nutritional supplement or as dietary supplement for balancing the supply of iron in a patient. A patient, for the purpose of this invention, is a mammal, including a human.
Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases.
While the invention has been described in term of its specific embodiments, certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example 1: Chewable Tablet Composition

Process of Preparation:
1. Microencapsulated Ferric Saccharate, coated ascorbic acid, sorbitol, sucralose and xylitol were sifted and dry mixed.
2. Binder solution was prepared by dissolving polyvinylpyrrolidone in ehanol with continuous stirring until a clear solution was obtained.
3. The dry mix of Step 1 is wet granulated using the binder solution of Step 2 until a coherent wet mass was obtained. The coherent wet mass so obtained was air dried for 10-20mins till the odour of ethanol was completely removed. The wet mass was sieved and the granules were further dried in a fluidized bed drawer.
4. The dried granules of step 3 were further mixed thoroughly with lubricants and flavouring agents.
5. The powder of step of 4 is then compressed into tablets.
Example 2: Tablet testing
Tablets prepared as per Example 1 were observed physically and were subjected to hardness and friability test as per the standard procedure.

Example 3: Accelerated Stability Studies
The composition of present invention were kept in stability chambers at a temperature 40°C±2°C and humidity 75±5% relative humidity. Samples of tablets were analyzed for description, identification, microbial limit test and assay as per specification provided in Table 3 below at initial and 6 month time period. Results of accelerated stability studies are reproduced below.

The compositions of present invention were found to be stable.
Example 4. Taste Masking and Sensory Testing:
Sensory testing was performed for the evaluation of acceptance of the product prepared according to Example 1 using Hedonic scoring or scaling. Hedonic scale is the term used in tasting panels where the judges indicate the extent of their like or dislike for the food. It is the most widely used scale for measuring food acceptability. Below is the chart describing the 9- point hedonic scale.
Thirty healthy volunteers from age group 20 to 45 were selected. Each volunteer was given chewable tablets prepared according to present invention. Volunteers were given instruction to chew the tablets and rate their experience for appearance of the chewable tablet of present invention, its texture, taste, flavour, aroma and overall acceptability of chewable tablet of present invention as per the Hedonic scale. The results obtained from all the volunteers were then averaged. The averaged results obtained from the study are provided in Fig 1.

Scale 9 of Hedonic scale was taken as 100% for statistical purpose. More than ninety percent volunteers were satisfied with the overall acceptability of the Product. Taste of the formulation was acceptable to ninety percent of the volunteer. Volunteers were asked to specify the taste and odour of the formulation. More than 90%) of the volunteers specified that the taste of the formulation is similar to that of the milk chocolate and no odour of formulation.
Although the preferred embodiment as well as the construction and use have been specifically described, it should be understood that variations in the preferred embodiment could be achieved by a person skilled in the art without departing from the spirit of the invention. The invention has been described with reference to specific embodiment which is merely illustrative and not intended to limit the scope of the invention as defined in the claims.

We Claim:
1. A stable taste masked chewable tablet comprising microencapsulated ferric saccharate optionally along with one or more pharmaceutically acceptable excipients.
2. The taste masked chewable tablet of Claim 1, wherein the average size of the microcapsules is in range of 5 µm to 50 µm.
3. The taste masked chewable tablet of Claim 1, wherein the ferric saccharate is microencapsulated in calcium alginate coating.
4. The taste masked chewable tablet of Claim 1, wherein the amount of elemental iron in the said composition is 10mg to 1000mg.
5. The taste masked chewable tablet of Claim 4, wherein the amount of iron in elemental form is 30mg to 500mg.
6. The taste masked chewable tablet of Claim 1, wherein the pharmaceutically acceptable excipient is one or more selected from the group consisting of diluents, binders, disintegrants, antioxidants, stabilizers, sweeteners, flavoring agents, taste enhancing agents, coloring agents, glidants and lubricants.
7. The taste masked chewable tablet of Claim 6, wherein one or more antioxidants are selected from the group consisting of citric acid and its salts, ascorbic acid, tocopherols, butylated hydroxyanisole (BHA), butylhydroxytoluene (BHT), t-Butylhydroquinone (TBHQ), sodium ascorbate, calcium ascorbate, fatty acid esters of ascorbic acid, lactic acid sodium lactate, tartaric acid, sodium hydrogen tartrate, sodium hydrogen phosphate, phosphates and lecithins.
8. The taste masked chewable tablet of Claim 7, wherein the antioxidant is ascorbic acid.
9. The taste masked chewable tablet of Claim 1, where in the composition is prepared by direct compression, dry granulation or wet granulation.
10. A stable taste masked chewable tablet for use in iron deficiency diseases or as nutritional supplement, wherein the tablet comprises microencapsulated

ferric saccharate, coated ascorbic acid, sorbitol, sucralose, lactose, xylitol, polyvinylpyrrolidone, colloidal silicon dioxide, magnesium stearate and flavouring agents.