FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
"A synergistic pharmaceutical composition for the efficacious treatment of mild and borderline iron deficiency anemia as well as prophylaxis of iron deficiency
anemia "
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: B- Wing, 10w Floor, BSEL Tech Park, Sector 30 A, Plot No. 39/5 & 39/5A, Opp. Vashi Railway Station, Navi- Mumbai- 400 703, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and its use thereof.

Technical Field of Invention:
The present invention relates to pharmaceutical compositions for the efficacious treatment of mild and borderline anemia as well as prophylaxis of iron deficiency anemia with reduced side effects. More particularly, this invention relates to pharmaceutical compositions comprising ferrous ascorbate offering elemental iron with folic acid, Vitamin B12 and pharmaceutically acceptable auxiliaries.
Background of Invention:
'Anemia' derived from the Greek word meaning "without blood", refers to a deficiency of red blood cells (RBCs) and/or hemoglobin. This deficiency in RBCs results in reduced ability of blood to transfer oxygen to the tissues. Since all human cells depend on oxygen for survival, varying degrees of anemia can have a wide range of clinical consequences.
Anemia can be classified in a variety of ways, based on the morphology of RBCs under etiologic mechanisms, and discernible clinical spectra. To mention a few some of the principal types are iron-deficiency anemia, aplastic anemia, hemolytic anemia, sickle-cell disease and such like.
Many things can cause anemia, but the three main bodily mechanisms that produce it include, excessive blood loss (acutely such as a hemorrhage or chronically through low-volume loss), excessive blood cell destruction (hemolysis) or deficient red blood cell production. Dietary iron deficiency is a cause of deficient red blood production in menstruating and pregnant women. Among many other causes, anemia can result from inherited disorders, nutritional problems (such as an iron or vitamin deficiency), infections, some kinds of cancer, or exposure to a drug or toxin.
The symptoms of anemia are as variable as its causes but may include fatigue, pallor, dyspnoea, palpitations, headache, faintness, or lightheadedness, tinnitus, anorexia and gastro-intestinal disturbances, and loss of libido; tachycardia., heart failure, and retinal hemorrhage may occur in severe anemia.
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The treatment of anemia depends upon its type, cause, person's age, overall health, medical history, extent of the disease. Almost all iron deficiency anemias respond readily to treatment with iron. The treatment of choice is oral administration of a ferrous salt. The goals of providing oral iron supplements are to supply sufficient iron to restore normal storage levels of iron and to replenish hemoglobin deficits.
Anemia in pregnancy is a very common phenomenon. For formation of mature erythrocytes (red blood corpuscles) containing the adequate amount of hemoglobin; iron, folic acid and Vitamin B12 are required. Therefore, the supplementation of these three ingredients in the required amounts is essential for treatment as well as prophylaxis of pregnancy anemia. Also, the combined supplementation of folic acid and vitamin B12 is a recent accepted therapy for treatment of hyperhomocysteinemia which in turn will reduce pregnancy complications such as IUGR, preterm labour, pre-eclampsia, placental abruption, intrauterine fetal death, thromboembolic disease in pregnancy, HELLP-syndrome.
WO/2006/068697 and its corresponding US2006/0134227 application disclose nutritional or dietary supplement compositions through administration of iron in ferric form with organic acid and optionally similar iron absorption promoters.
Supplemental iron is available in two forms: ferrous and ferric. When supplements including commonly used ferrous (Fe2+) salts (also referred to as iron (II) salts) are ingested and exposed to gastric juices having an acidic pH of between 1 and 3 in the stomach, the ferric iron (Fe2+) is converted to ferric iron (Fe3+). It is this ferrous state of the iron that is most absorbed by the small intestine. However, conversion of the ferrous iron (Fe2+) to the ferric iron (Fe3+) form causes gastric upset and abdominal pain. In fact, a large percentage of patients that consume common iron salts complain of gastrointestinal tract upset. Further, such conversion results in a small, unsatisfactory percentage of the total iron in the supplement being absorbed. It would therefore, be desirable to have a supplement wherein the iron is absorbed without an accompanying gastrointestinal upset and discomfort. This discomfort can be prevented by gastric acidity
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or solubilizing agents (e.g. ascorbate). Iron is absorbed by intestinal mucosal cells in the duodenum and upper jejunum. Once absorbed, iron is coupled to transferrin, which is present in the blood stream, and delivered to the cells of the body.
Iron preparations (such as, ferrous ascorbate) are soluble in water or in dilute acid (such as in the stomach) are generally of high bioavailability.
WO/2005/074658 application discloses a pharmaceutical composition for the treatment of iron-deficiency anemia comprising carbonyl iron. But among all the available iron salts, ferrous ascorbate is considered to be the salt which offers highest bioavailability of iron coupled with highest safety.
Studies have shown that ferrous ascorbate scores over carbonyl iron with regards absorption of iron, which is not depending on gastric hydrochloric acid as well as gastrointestinal safety.
Although for the treatment of iron deficiency anemia, a wide range of iron compounds is available in the market, the level of iron uptake of these compounds by the body is quite low thereby, necessitating the administration of relatively high dosage levels of the compound. The administration of high dose, poorly absorbed, iron complexes may cause siderosis of the gut wall and a variety of side effects such as nausea, vomiting, constipation and heavy malodorous stools
Bn form is used for foods and in nutritional supplements and it's deficiency can cause several forms of anemia. Vitamin Bi2 (Cobalamin) deficiency is a common cause of macrocytic anemia. Studies show that supplementation with oral vitamin B,2 is a safe and effective treatment for the B,2 deficiency state.
Most of the pregnancy related anemia cases are benefited by 30-60 mg elemental iron supplementation. They donot require supplementation of higher (100 mg) quantity of iron. And, 30-60 mg elemental iron is indicated for prophylaxis of anemia. Moreover, Vit B12 in a synergistic combination helps red blood corpuscle formation.
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In clinical practice it has been observed that 100 mg elemental iron /day may be a higher (more than required) dose for mild & borderline grades of anemia. This is in line with the known fact that iron absorption is highest in severe anemia cases and will be least in borderline anemia cases. With 50 mg elemental iron supplementation, the desired hemoglobin rise is reported in such patients.
Mild & borderline anemia patients complain for gastrointestinal irritation, nausea, vomiting when prescribed 100 mg elemental iron. These side effects can be reduced (almost nullified) with 50 mg elemental iron supplementation
Therefore, in view of the aforementioned problems associated with prior art preparations it is clear that there still exists a need for improved formulations of ferrous ascorbate with folic acid & Vitamin Bi2, which are safe, reliable, and convenient for oral administration, stable, and with minimal side effects.
Objects of the Invention:
It is an object of the present invention to provide synergistic pharmaceutical composition comprising Ferrous Ascorbate offering elemental iron, Folic acid and Vitamin Bi2, in solid oral dosage forms.
It is another object of the present invention to provide synergistic composition for the treatment of mild anemia (9.5 - 10.9 g/dl hemoglobin) and borderline anemia (11-11.5 g/dl hemoglobin) thereby achieving the desired hemoglobin rise with minimal to no side effects.
Summary of the Invention:
In accordance of the present invention there are provided composition for treating iron deficiency anemia comprising a therapeutically effective amount of ferrous ascorbate and a therapeutically effective amount of folic acid & Vitamin Bi2.
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The present invention further discloses pharmaceutical composition for the treatment of mild anemia (9.5-10.9 g/dl hemoglobin) and borderline anemia (11-11.5 g/dl hb) and prophylaxis of anemia.
Detailed Description:
The present invention describes pharmaceutical composition comprising ferrous
ascorbate, Vitamin B12 and folic acid as active ingredients and other pharmaceutically
acceptable excipients selected from disintegrants, binding agents, gelling agents,
dispersion agents, lubricants, solvents, colorants, film coating polymers or combinations
thereof.
The active ingredients act synergistically in the effective treatment of mild and borderline
iron deficiency anemia and prophylaxis of iron deficiency anemia.
Ferrous ascorbate, a synthetic molecule of ascorbic acid and iron is indicated in the treatment of iron deficiency anemia. It has the advantage of providing both ferrous ion and ascorbate in the same compound. Ferrous ascorbate is present in the composition in an amount of 25 - 35 mg preferably 33 mg effective in the treatment of mild and borderline iron deficiency anemia and prophylaxis of iron deficiency anemia.
Folic acid a water-soluble vitamin in the B-complex group acts as a co-enzyme in the formation of red blood cells and nucleic acid. Folic acid deficiency results in a particular type of anemia thus, there is a need for folic acid for preventing anemia. Folic acid present in the composition is in an amount of 2 - 8 mg preferably 5 mg indicated for the treatment of mild and borderline iron deficiency anemia and prophylaxis of iron deficiency anemia.
Vitamin Bt2 is a water-soluble vitamin in the B-complex group. Vitamin B12 is present in the composition in an amount of 15(ig. Vitamin B12 plays important role in formation of mature erythrocytes (red blood corpuscles) containing the adequate amount of hemoglobin. It is indicated in treatment of mild and borderline iron deficiency anemia and prophylaxis of iron deficiency anemia.
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Due to folic acid & Vitamin B12 component, the product can be also used for treatment of hyperhomocysteinemia and reducing pregnancy complications such as IUGR, preterm labour, pre-eclampsia, placental abruption, placental insufficiency, intrauterine fetal death, thromboembolic disease in pregnancy. Therefore, by virtue of these indications too, it is a novel product.
The diluent is selected from dicalcium phosphate, lactose, starch, cellulose, magnesium carbonate, maltodextrin, and / or microcrystalline cellulose in the range of 1-75 %.
The disintegrants are crospovidone, carmellose sodium, sodium cmc, carboxy methyl cellulose, cellulose, and / or sodium starch glycollate in the range of 1 - 30%.
The lubricant is selected from zinc stearate, magnesium oxide, magnesium aluminium silicate, and/or magnesium stearate in the range of 0.5 - 5.0 %.
The binder is selected from HPMC, hydroxy propyl cellulose, starch paste, starch 1500, gum acacia, and/or polyvinylpyrrolidone K-30 in the range of 1 - 20 %.
The glidant is selected from pregelatinised starch, talc, tribasic calcium phosphate, magnesium trisilicate, and/or colloidal silicon dioxide in the range of 0.5 - 10 %.
The antiadherent is selected from colloidal silicon dioxide, Bentonate clay in an amount of 0.5 - 5%.
The coating polymer is selected from gelatin, methyl cellulose, polydextrose, sodium cmc, hydroxy propyl cellulose, preferably hydroxy propyl methyl cellulose range from 1 -4%.
The coloring agent is selected from iron oxides, lake sunset yellow, lake tartrazine, and/or supra grade range from 0.1-1 %.
The solvent is selected from corn oil, water, acetone, methanol, ethanol propylene glycol, polyethylene glycol and / or isopropyl alcohol, dichloromethane in the range of 20 -50%.
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Pharmaceutical composition is in the oral dosage form preferably a coated or uncoated
tablet.
The said oral dosage can be administered at the optimal daily dosage of one tablet 2 times
a day depending on the severity of Anemia.
According to the present invention, the composition is formulated as film coated tablets, coated product in capsule or small minute tablet in capsules or soft gelatin capsule. Most preferably, the composition is in the form of tablets optionally coated within layer of film forming polymer or pharmaceutical excipient.
Thus, the present invention provides the composition useful for the treatment of mild & borderline anemia without any side effects such as gastrointestinal irritation, nausea, vomiting.
The composition can be prepared by wet granulation process, dry compression or slugging process.
The process of preparation of the composition comprises the following steps:
i) sifting Ferrous ascorbate, Sodium starch glycollate, folic acid,
Microcrystalline cellulose 102, Vitamin B12, PVP K-30 through suitable sieve and
transferring to Blender;
ii) adding sifted colloidal silicon dioxide, talc and Magnesium Stearate in cone blender
and blending for suitable time;
iii) compressing the lubricated blends to tablets;
iv) dispersing coating polymer in non-aqueous solvents or mixture thereof and stirring to
obtain a homogenized dispersion followed by adding flavor under constant stirring;
v) coating the compressed tablets with the dispersion followed by air drying.
The present investigation is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present investigation includes the following examples and further can be modified and altered within the technical concept of the present investigation.
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EXAMPLES:
Example 1:

Ingredients Quantity %
TABLET CORE
1. Ferrous Ascorbate 73.68
2. Sodium Starch GlycoUate 4.34
3. Microcrystalline Cellulose pH 102 16.29
4. Polyvinylpyrrolidone K-30 1.95
5. Colloidal Silicon Dioxide 0.65
6. Magnesium Stearate 0.98
7. Talc 0.98
8. Isopropyl Alcohol -
9. Folic Acid 3.11
10. Vitamin Bi2 0.008
11. D.M.Water -
COATING SOLUTION
12. Coating Polymer 2.5
13. Aqueous / Nonaqueous solvent (Mixture) Q.S
14. Flavorant ** / Without flavor 0.29
** Addition of flavor is tentative, can be added or not.
* THE SOLVENTS BEING VOLATILE ARE COMPLETELY LOST DURING
* DRYING & DO NOT CONTRIBUTE TO ADDITIONAL WEIGHT OF THE
TABLET.
The process for preparation of ferrous ascorbate tablet is as follows:
Step 1:
Sift 73.68 mg of Ferrous ascorbate, 4.34 mg of Sodium starch glycoUate, 3.11 mg of
folic acid, 16.29 mg of Microcrystalline cellulose 102 , 0.008 mg of Vitamin B12
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1.95 mg of PVP K-30 through suitable sieve, and transferred to Blender.
Step 2:
Then, sifted 0.65 mg of colloidal silicon dioxide, 0.98 mg of talc and 0.98 mg of
Magnesium Stearate are added in cone blender and blended for suitable time.
Step 3:
Compress the Lubricated blends to tablets.
Step 4:
Disperse 2.5 mg of Coating polymer in sufficient quantity of nonaqueous solvent or their mixture and stirred to obtain a homogenized dispersion. Add flavor to this homogenized dispersion solution under constant stirring.
Step 5:
The compressed tablets are coated with the prepared dispersion followed by air drying.
Step 6:
Dry the tablets in dehumidified room or dryer and pack into the suitable packing material.
Example 2:

Ingredients mg
1. Ferrous Ascorbate 72.5
2. Sodium Starch Glycollate 3.8
3. Microcrystalline Cellulose pH 102 14.92
4. Polyvinylpyrrolidone K-30 2.16
5. Folic Acid 3.1
6. Colloidal Silicon Dioxide 0.6
7. Talcum 0.857
8. Magnesium Stearate 0.857
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9. Vitamin B12 0.008
Coating Solution
10. Hydroxy propyl methyl cellulose based ready-mix 2.5
11. Isopropyl alcohol and dichloromethane mixture * Q.S
12. Flavorant** / Without flavor Q.S
* THE SOLVENTS BEING VOLATILE ARE COMPLETELY LOST DURING DRYING & DO NOT CONTRIBUTE TO ADDITIONAL WEIGHT OF THE TABLET.
** Addition of flavor is tentative, can be added or not.
Example 3: Formulation:
Table 3:

Ingredients mg
I] 1. Ferrous Ascorbate 93
2. Microcrystalline Cellulose pH 102 5
3. Ethyl Cellulose 2
4. Colour 0.04
5. Isopropyl Alcohol Q.S
6. Dichloromethane Q.S
II] 1. Folic Acid 26.3
2. Starch 63.7
3. Ethyl Cellulose 10
4. Isopropyl Alcohol Q.S
5. Dichloromethane Q.S
Ill] 1. Vitamin B12 0.1
2. Starch 86
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3. Ethyl Cellulose 14
4. Dichloromethane Q.S
5. Isopropyl Alcohol Q.S
Enteric coated beads of Ferrous Ascorbate, Folic acid and Vitamin B12 are prepared separately as given in Table 3. The enteric coated beads are filled in hard gelatin capsule
Example 4:
Table 4:

Ingredients %
I] 1. Ferrous Ascorbate 65.6
2. Sodium Starch Glycollate 5.6
3. PVP K-30 2.8
4. Microcrystalline Cellulose pH 102 22.3
5. Magnesium Stearate 1.4
6. Aerosil 0.8
7. Talcum 1.4
II] 1. Folic Acid 5
2. Vitamin B12 0.001
3. Microcrystalline Cellulose pH 102 79.2
4. PVP K-30 9.9
5. Magnesium Stearate 2.9
6. Aerosil 2.9
Small tablets of Ferrous Ascorbate, Folic acid and Vitamin B12 are prepared individually by following the method as given in Example 1. The ingredients and quantities required are illustrated in Table 4.
Small tablets of Ferrous Ascorbate, Folic acid and Vitamin B12 are filled into the hard gelatin capsules.
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Example 5:

Ingredients mg
1. Ferrous Ascorbate 33
2. Folic Acid 5
3. Vitamin B12 15
A formulation comprising Ferrous Ascorbate (33 mg), Vitamin B12 (15 mg), and Folic Acid (5 mg) is prepared as soft gelatin capsules using various oil bases including Wheat germ oil & Flax seed oil base.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. Synergistic pharmaceutical composition comprising lower than 100 mg of pharmaceutically acceptable salt of ferrous, folic acid, Vitamin B12 and pharmaceutically acceptable excipients useful in the treatment of mild and borderline iron deficiency anemia and prophylaxis of anemia
2. Synergistic pharmaceutical composition according to claim 1 wherein pharmaceutically acceptable salt of ferrous is preferably present in an amount of 5-50 mg, Folic acid is present in an amount of 0.1 - 10 mg and Vitamin Bi2 is present in an amount of 0.01 - 500 meg.
3. Synergistic pharmaceutical composition according to claim 1 wherein pharmaceutically acceptable salt of ferrous is ferrous ascorbate.
4. Pharmaceutical composition according to claim 1 wherein pharmaceutically acceptable excipients are disintegrants, binding agents, gelling agents, dispersion agents, lubricants, solvents, colorants or film coating polymers.
5. Pharmaceutical composition as claimed in claim 1, wherein the diluent is selected from dicalcium phosphate, lactose, starch, cellulose, magnesium carbonate, maltodextrin, and / or microcrystalline cellulose in range of 1-75 %.
6. Pharmaceutical composition as claimed in claim 1, wherein the disintegrants are crospovidone, carmellose sodium, sodium cmc, carboxy methyl cellulose, cellulose, and / or sodium starch glycollate in range of 1 - 30%.
7. Pharmaceutical composition as claimed in claim 1 , wherein lubricant is selected from zinc stearate, magnesium oxide, magnesium aluminium silicate, and/or magnesium stearate in the range of 0.5 - 5.0 %.
8. Pharmaceutical composition as claimed in claim 1, wherein binder is selected from HPMC, hydroxy propyl cellulose, starch paste, starch 1500, gum acacia, and/or polyvinylpyrrolidone K-30 in the range of 1 - 20 %.
9. Pharmaceutical composition as claimed in claim 1, wherein glidant is selected from pregelatinised starch, talc, tribasic calcium phosphate, magnesium trisilicate, and/or colloidal silicon dioxide in the range of 0.5 - 10 %.
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10. Pharmaceutical composition as claimed in claim 1, wherein antiadherent is selected from colloidal silicon dioxide, Bentonate clay as before from 0.5 - 5%.
11. Pharmaceutical composition as claimed in claim 1, wherein coating polymer is selected from gelatin, methyl cellulose, polydextrose, sodium cmc, hydroxy propyl cellulose, preferably hydroxy propyl methyl cellulose range from 1-4 %.
12. Pharmaceutical composition as claimed in claim 1, wherein coloring agent is selected from iron oxides, lake sunset yellow, lake tartrazine, and/or supra grade range from 0.1 - 1 %.
13. Pharmaceutical composition as claimed in claim 1, wherein solvents is selected from corn oil, water, acetone, methanol, ethanol propylene glycol, polyethylene glycol and / or isopropyl alcohol, dichloromethane range from 20 - 50%.
14. Pharmaceutical composition as claimed in claim 1 is in the solid dosage form preferably in a coated or uncoated tablet form.
15. A tablet form as claimed in claim 13 can be prepared by wet granulation
process, dry compression or slugging process.
Dated this 8th day of June 2007

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Abstract:
Synergistic pharmaceutical composition useful for the treatment of mild & borderline iron deficiency anemia as well as prophylaxis of anemia comprising lower than 100 mg of pharmaceutically acceptable salt of ferrous preferably ferrous ascorbate, Vitamin B12 and folic acid without any side effects such as, gastrointestinal irritation, nausea, vomiting.
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