Title of Invention	A SYNERGISTIC PHARMACEUTICAL COMPOSITION FOR ENHANCING HAEMOGLOBIN SYNTHESIS AND ZINC ASSIMILATION
Abstract	This invention relates to a syner~istic pharmaoeutical composition for enhancing haemoglobin synthesis and zinc assimilation. The compo.sition consists of L Histidine Hydrochloride, Llysin Hydrochloride, Glycine, Vitamins, Ferrous fumerate and Zinc sulphate. Pharmaceutically acceptable adjuvants or carriers m~y also be added.blending 3 amino acids that go in the makin~ of haemoQlobin synthesis, B Qroup of vitamins, vitamin C, a source of zinc and a soure of iron ~ith kno~n pharmaceutically acceptable adjuvants and for excipients.

Title of Invention

A SYNERGISTIC PHARMACEUTICAL COMPOSITION FOR ENHANCING HAEMOGLOBIN SYNTHESIS AND ZINC ASSIMILATION

Abstract

This invention relates to a syner~istic pharmaoeutical composition for enhancing haemoglobin synthesis and zinc assimilation. The compo.sition consists of L Histidine Hydrochloride, Llysin Hydrochloride, Glycine, Vitamins, Ferrous fumerate and Zinc sulphate. Pharmaceutically acceptable adjuvants or carriers m~y also be added.blending 3 amino acids that go in the makin~ of haemoQlobin synthesis, B Qroup of vitamins, vitamin C, a source of zinc and a soure of iron ~ith kno~n pharmaceutically acceptable adjuvants and for excipients.

Full Text	This invention relates to synergistic pharmaceutical composition for enhancing haemoglobin synthesis and Zinc assimilation. This pharmaceutical composition consists of vitamins of the Group B, Vitamin C, three essential amino acids, necessary for haemoglobin synthesis metabolism and Zinc and iron salts which compliment and assist in haemoglobin synthesis thereby promoting growth and reducing the rest of immunodeficiency. Vitamins are heterogenous organic compounds essential in small quantities for maintaining normal health, promoting growth and reducing the risk of infection. Human metabolic activity does not result in the synthesis of vitamins and as such they are to form a part of dietary intake regularly. Vitamins are either water soluble or oil soluble. Oil soluble vitamins are retained by the human system for a relatively longer period than the water soluble vitamins which are eliminated from the system easily. The need arises, therefore, to supplement the vitamins required by the system regularly. Most important water soluble vitamins belong to the vitamin 'B' group and vitamin 'C. Deficiency of vitamin B group is known to cause weight loss, Pellagra, Neuromuscular disorders, Beri beri, anaemia and the like. Vitamin C is yet another water soluble vitamin which needs to be supplemented almost daily. Scurvy and anaemia may result if vitamin C is deficient in dietary intake. Further it has also been established that a combination of vitamin C and iron enhances iron assimilation by the system. Proteins are complex nitrogen containing compounds formed mainly by amino acid residues joined by peptide linkage. Complex proteins like glycoproteins, nucleoproteins, lipoproteins, chromoproteins and the like have residues of carbohydrates, fats and nucleo acids conjugated with amino acid residues. Haemoglobin, the oxygen carrying protein present in red blood cells is a conjugate protein of four haemo groups which are organo metallic compounds containing iron. It is observed that the diminution of the amount of total haemoglobin circulating in the blood stream results in anaemia. Absence of iron in food intake or improper assimilation of iron by the system causes anaemia. Growing children, women, nursing mothers and convalescents require more haemoglobin and their diets should be supplimented by iron containing compounds. Haemoglobin deficiency and resultant anaemia are more common in the developing and under-developed countries due to imbalanced intake of vitamins and minerals. Out of the twenty three amino acids generaly found in human metabolism, as building blocks for proteins, only eight are not produced by the system during metabolic activity. It has already been established that these eight amino acids should find a place in the daily intake of food for maintaining proper growth and vitality. Out of these eight vital amino acids, three are found essential in haemoglobin synthesis metabolically. They are glycine, histidine and lysine. It has also been established that a composition of these three amino acids and an iron source increases the metabolic production of haemoglobin. From the above description it is clear that a combination of the three amino acids, vitamin B complex, vitamin C and a source of iron facilitates haemoglobin synthesis and easy assimilation of iron. Zinc is another essential trace element which plays a vital role in physiological processes. Many enzymes required for human metabolic activity are metallo enzymes having one or more inorganic elements as their constituents. Zinc is found to be an important trace element that forms a part of certain vital metallo enzymes involved in the metabolic pathways of synthesising carbohydrates, lipids and proteins. Zinc containing enzymes are also found to be beneficial in cell mediated immunity in convalescing patients. It is found that breast fed infants consume about 5 mg of zinc per day. During pregnancy and lactation increased intake of zinc is recommended. Zinc also is found to play a role in reducing hair fall and the process of ageing in humans. We have now found that a combination of the three amino acids that go in the making of haemoglobin, B group of vitamins, vitamin C, a source of iron and a source of zinc enhances haemoglobin synthesis and increases assimilation of thhe trace elements, iron and 2inc, during metabolic activity. We have also found that such a composition exhibits properties fundamentally different from the compounding ingredients and shows reinforced properties as the different components compliment each other in enhancing haemoglobin synthesis and in the increased assimilation of essential minerals like zinc and iron. The composition is found to be a synergestic dietary supplement resulting in augmenting immunity, promoting growth and health. This invention provides a synergistic pharmaceutical composition for enhancing haemoglobin synthesis and zinc assimilation which comprises a blend of the compounds listed hereinunder in the range specified thereagainst with known adjuvants and/or excipients. Ferrous Fumerate - 115 to 185 mg L Histidine HCL - 3 to 5 mg L Lysine Hydrochloride - 19 to 31 mg Glycine - 7.5 to 12.5 mg Vitamin B± mononitrate - 3.75 to 6.25 mg Riboflavin (vitamin B2) - 2.25 to 3.75 mg Vitamin Bg Hydrochloride - 1.2 to 1.8 mg Vitamin B12 - 1.9 to 3.1 meg Folic acid - 0.38 to 0.62 mg Ascorbic acid (Vitamin C) - 30 to 58 mg Zinc Sulphate - 35 to 65 mg Conventional additives, colourants, and excipients may be added depending upon the nature of the composition to be prepared. For instance, if a liquid composition is required pharmaceutically acceptable liquid carriers are added to the compounding ingredients which are subsequently dissolved or emulsified. Flavouring and colouring agents may also be added to the composition. Tablets and capsules can be prepared by mixing the above ingredients with pharmaceutically acceptable carriers which are directly tabletted or spheronised either together or in the desired groups which are then encapsulated in shells made of pharmaceutically acceptable biologically degradable materials. In a preferred embodiment compatible components of the composition are grouped together, spheronised, dried and encapsulated together in the desired range. A composition may contain a plurality of granules, the total content of which is within the range specified herein above. For example, a single capsule may contain pink, orange, yellow, blue and brown granules of the composition specified herein below: 1. Pink Granules: Vitamin B-^ mononitrate - 6 mg Vitamin Bg hydrochloride - 1.576 mg Lactose - 0.5 mg Maize starch - 2.75 mg Colourant Erythrocin - 0.01 mg Microcrystalline cellulose - 2.0 mg Distilled water - 0.01 ml The above ingredients are blended to form a uniform mass, extruded and then spheronised to form granules. The granules are then dried at 45° in a fluidised bed to a moisture content of 1.1 or below and are stored in a cool place till required. 2. Orange Granules: Riboflavin (Vitamin B2) - 3.3 mg Folic acid - 0.65 mg Vitamin B12 - 0.0025 mg Lactose - 6 mg Maize starch - 11 mg Micro crystalline cellulose - 4 mg Polyethylene glycol - 0.4 mg Sodium carboxy methyl cellulose- 0.3 mg Methhyl cellulose - 0.75 mg Distilled water - 0.1 ml All the ingredients are mixed and processed as stated in the case of pink granules, and are stored in a cool place till required. 3. Yellow Granules: L Histidine Hydrochloride - 4 mg Glycine - 10 mg L Lysine monohydrochhloride - 25 mg Lactose - 10 mg Maize starch - 16 mg Micro crystalline cellulose - 10 mg Methyl cellulose - 3 mg Colour Tartrazine - 0.3 mg Distilled water - 0.01 ml The above components are granulated and stored as stated under the pink granules. 4. Blue Granules: Ascorbic acid - 56 mg Stearic acid - 1.6 mg Industrial methylated spirit - 0.008 ml Lactose - 16 mg Maize starch - 5 mg Micro crystalline cellulose - 4 mg Sodium Carboxy methyl cellulose- 4 mg Polyethyline glycol 6000 - 4.8 mg Methyl cellulose - 1.4 mg Colour Indigo Carmine - 0.4 mg Distilled water - 0.01 ml All the ingredients are blended and granulated as mentioned under the pink granules and are stored in a cool place till required. 5. Brown Granules: Ferrous Numerate - 181 mg Maize starch - 27 mg Micro crystalline cellulose - 4.8 mg Sodium Carboxy methhyl cellulose- 1 mg Sucrose - 33 mg Distilled water - 0.01 ml Methyl cellulose - 3 mg Acetone - 0.039 ml Methyline chloride - 0.039 ml Castor oil - 0.38 mg All te above ingredients are homogenised and processed as stated under the pink granules. 6. Zinc Granules: Zinc Sulpate - 50 mg Lactose - 197 mg Starch - 45 mg Micro crystalline cellulose - 75.5 mg Methyl Cellulose - 5 mg Distilled water - As required All the above ingredients are homogenised to a uniform mass, wich is extruded, spheronised to form granules. The granules are dried at 45°C in a fluidised bed drier to a moisture content of less than 1%. The dried granules may be stored in a cool, dry place till required. Required quantities of all the above 6 granules are blended and then encapsulated in pharmaceuticals acceptable capsules. Required overage doeses of vitamins are to be included while preparing the composition. Obvious modifications and alterations known to persons skilled in the art are within the scope of this invention and the appended claims. Synergistic Hematinic Composition The present invention is the novel composition, as there is no such composition in the prior art. The present invention (Composition 1) relates to a synergistic composition of a pharmaceutically acceptable ferrous salt; an effective amount of amino acids, an effective amount of vitamins along with Zinc. The composition also contains an effective amount of iron absorption enhancer, such as ascorbic acid, and a pharmaceutically acceptable carrier, binder, or excipient, formulated into a suitable pharmaceutical formulation, especially capsule but not limiting to the same. During pregnancy the daily requirement of iron and zinc increases.The standard therapy for both iron and zinc deficiencies is the administration of iron and zinc supplementation. The co-administration of iron and zinc is restricted due to the fact that prenatal supplemental iron may adversley affect the maternal zinc status and vice versa. Inhibition of zinc absorption due to iron supplementation may adversely influence the maternal zinc status and alter the net zinc transfer to the fetus. This study was undertaken to compare the effectiveness of the present invention in improving the iron and zinc levels and thereby to treat these deficiencies. The efficiency of the present invention (Composition 1) is compared with similar other two compositions. A baseline and periodic observations were recorded for the following parameters during the two month study period. 1. Hemoglobin level. 2. Zinc level. 3. RBC Count. 4. Packed cell Volume. 5. Peripheral Smear. The results are shown in table 1. From the above table, the group (2) who received composition 1, the mean hemoglobin level thai was 10.5 gm/dl at the baseline, had been increased to 12.9 gm/dl after 2 months of therapy. In the groups (3) and (4) the mean hemoglobin level that was at 10.4 gm/dl at baseline were increased to 10.8 gm/dl and 10.9 gm/dl respectively after treatment. The control group showed no similar response. The changes observed with the group (2), treated with the composition 1 was significant (p=0.02) when compared with other groups. In Group (3) the RBC count at baseline, 3.57 millions/cu mm increased to 3.68 millions/cu mm and the packed cell volume was increased from 33.6 % to 34.7 % after therapy. In the case of group (4) the RBC count increased from 3.46 millions/cu mm to 3.70 millions/cu mm and the packed cell volume increased from 33.4 % to 35.1 % after two month treatment. Whereas in Group (2), the RBC count 3.46 millions/cu mm at baseline was increased to 4.11 millions/cu mm and the packed cell volume that was 33.4 % at baseline was elevated to 37.6 %. The group 1 subjects showed no significant improvement in all the parameters studied. The changes observed with the group (2) are significant at (p= 0.02) for RBC count and (p=0.002) for packed cell volume when compared with other two groups. The peripheral smear showed microcytic hypochromic cells in all groups at baseline. However, after therapy only the group 2 patients who received formulation comprising the composition 1 got back their normocytic normochromic cells. The group 3 and group 4 subjects showed 3 n.g/dl of zinc level increase in serum and approximated to group l.The group 2 subjects who received the formulation according to the present invention (Composition 1) showed surprisingly a 20 ng/dl increase of serum zinc level (significant at p=0.017). Conclusion : These results supports that the present invention comprising of ferrous fumerate, amino acids, vitamins and zinc is both clinically as well statistically significant in increasing the Hemoglobin level, Zinc level, RBC count and Packed cell volume. Further it is the only composition that does not have any inhibition of zinc absorption due to iron supplementation and vice versa. Example 2 The previous studies states that Zinc is absorbed through the intestinal tract into the body. In this process zinc in the form of a chelate with a low molecular weight carrier substance is transported from the intestinal lumen through the brush border membrane into the intestinal cells, temporarily stored in the form of zinc thioneine and then released into the blood stream when necessary to deliver zinc to the living tissues. It has not been well elucidated yet what molecules are carriers for zinc absorption. The elemental iron and a wide variety of iron supplements decreases this zinc absorption, as iron competes with zinc for absorption when taken together. The following study was performed to demonstrate the bioavailability of zinc from the compositions according to the present invention. Method Wistar rats of 8 weeks age were used in this study (n=12). The rats were fasted for 24 hours before they were given the compositions. The test composition was administered to the duodenum of ether-anesthetized rat as a solution or suspension in physiological saline. The dose of the composition was 10 mg/kg body weight as zinc in each case. Blood samples were collected before administration, 1,3,5 and 7 hours after the administration. Plasma levels of zinc were determined using Zn Test Wako Kit. The absorbed amount of zinc was determined from the area under the curve (AUC) of blood level of zinc vs. time curve up to 7 hours. The results were shown in table 2. As shown in table 2 the bioavailability of zinc from composition 1 was much better than that of other two compositions. The present study clearly states that the new invention under composition 1 unexpectedly shows significantly higher bioavailability of zinc inspite of adminsistering it along with iron as evident from the group 3 and group 4 results. Conclusion: From the above result it is evident that only the present invention (Composition 1) has unusual superior bioavailability of zinc when taken together with iron. Example 3 Treatment of anemia in addition to identifying the source of iron deficiency typically involves administering iron supplements. These ferrous supplements are most efficient on an empty stomach and is often not tolerated for many peoples due to gastrointestinal side effects and this fact limits the amount of iron supplements that can be prescribed. Inorder to evaluate the tolerability of the compositions stated in the present invention this study was performed. Method Albino rats housed individually in stainless steel cages were fed a low-iron diet and de-ionized distilled water ad lib for 24 days. The low-iron diet contained not more than about 3 mg of iron per kg of diet. Following the 24 day depletion period, blood was drawn from the tail vein of each rat for hemoglobin analysis. Anemic rats were selected and used for further study. The rats were housed individually in cages. They were divided into four groups (n = 12) and were treated as follows. Group 1 - received placebo and served as control. Group 2 - received Composition 1. (Animal dose: lOmg Fe/kg of body weight) Group 3 - received Composition 2. (Animal dose: lOmg Fe/kg of body weight) Group 4 - received Composition 3. (Animal dose: lOmg Fe/kg of body weight) After 15 days the blood was drawn from the tail vein for hemoglobin analysis. The hemoglobin response to the compositions were stated in the table 3. The group 3 and group 4 animals exhibited gross internal changes different from group 1 namely fat depletion, thyroid nodules, reddened mandibular lymph nodes, reddened stomach mucosa, small thymus, foci on the thymus and dark fecal matter. In contrats the gross internal findings exhibited by group 2 animals were only reddened thymus and dark fecal matter indicating that the present invention is free from gastrointestinal side effects and hence well tolerated. Conclusion: From the above results, it is clear that only the present invention (Composition 1) is free from gastro intestinal side effects and well tolerated. We Claim: 1. A synergistic pharmaceutical composition for enhancing haemoglobin synthesis and zinc assimilation comprising a blend of compounds listed hereinunder in the range specified thereagainst with known adjuvants and/or excipients. Ferrous Fumerate - 115 to 185 mg L Histidine HCL - 3 to 5 mg L Lysine Hydrochloride - 19 to 31 mg Glycine - 7.5 to 12.5 mg Vitamin B1 mononitrate - 3.75 to 6.25 mg Riboflavin (vitamin B2) - 2.25 to 3.75 mg Vitamin Bg Hydrochloride - 1.2 to 1.8 mg Vitamin B12 ~ 1.9 to 3.1 meg Folic acid - 0.38 to 0.62 mg Ascorbic acid (Vitamin C) - 30 to 56 mg Zinc Sulphate - 35 to 65 mg 2. The composition as claimed in dim 1, wherein the blend is in the form of an emulsion suspension or solution in known pharmaceutically acceptable adjuvants or carriers. 3. The composition as claimed in claim 1 wherein the composition is in the form of tablets. 4 The composition as claimed in claim 1 wherein the blends are in the form of granules encapsulated in pharmaceuticals acceptable casing. 5 The composition as claimed in claims 1 and 4 wherein blends of spheronised compatible compounds are encapsulated. 6. The composition as claimed in claims 1 to 5 having colourants added thereto. 7 The composition as claimed in claims 1 to 6 wherein different granules have different colours. 8 A synergistic pharmaceutical composition for enhancing haemoglobin synthesis and zinc assimilation substantially as herein described.

Full Text

This invention relates to synergistic pharmaceutical composition for enhancing haemoglobin synthesis and Zinc assimilation. This pharmaceutical composition consists of vitamins of the Group B, Vitamin C, three essential amino acids, necessary for haemoglobin synthesis metabolism and Zinc and iron salts which compliment and assist in haemoglobin synthesis thereby promoting growth and reducing the rest of immunodeficiency.
Vitamins are heterogenous organic compounds essential in small quantities for maintaining normal health, promoting growth and reducing the risk of infection. Human metabolic activity does not result in the synthesis of vitamins and as such they are to form a part of dietary intake regularly. Vitamins are either water soluble or oil soluble. Oil soluble vitamins are retained by the human system for a relatively longer period than the water soluble vitamins which are eliminated from the system easily. The need arises, therefore, to supplement the vitamins required by the system regularly. Most important water soluble vitamins belong to the vitamin 'B' group and vitamin 'C. Deficiency of vitamin B group is known to cause weight loss, Pellagra, Neuromuscular disorders, Beri beri, anaemia and the like. Vitamin C is yet another water soluble vitamin which needs to be supplemented almost daily. Scurvy and anaemia may result if vitamin C is deficient in dietary intake. Further it has also

been established that a combination of vitamin C and iron enhances iron assimilation by the system.
Proteins are complex nitrogen containing compounds formed mainly by amino acid residues joined by peptide linkage. Complex proteins like glycoproteins, nucleoproteins, lipoproteins, chromoproteins and the like have residues of carbohydrates, fats and nucleo acids conjugated with amino acid residues. Haemoglobin, the oxygen carrying protein present in red blood cells is a conjugate protein of four haemo groups which are organo metallic compounds containing iron. It is observed that the diminution of the amount of total haemoglobin circulating in the blood stream results in anaemia. Absence of iron in food intake or improper assimilation of iron by the system causes anaemia. Growing children, women, nursing mothers and convalescents require more haemoglobin and their diets should be supplimented by iron containing compounds. Haemoglobin deficiency and resultant anaemia are more common in the developing and under-developed countries due to imbalanced intake of vitamins and minerals. Out of the twenty three amino acids generaly found in human metabolism, as building blocks for proteins, only eight are not produced by the system during metabolic activity. It has already been established that these eight amino acids should find a place in the daily intake of food for maintaining proper growth and vitality. Out of these eight

vital amino acids, three are found essential in haemoglobin synthesis metabolically. They are glycine, histidine and lysine. It has also been established that a composition of these three amino acids and an iron source increases the metabolic production of haemoglobin.
From the above description it is clear that a combination of the three amino acids, vitamin B complex, vitamin C and a source of iron facilitates haemoglobin synthesis and easy assimilation of iron.
Zinc is another essential trace element which plays a vital role in physiological processes. Many enzymes required for human metabolic activity are metallo enzymes having one or more inorganic elements as their constituents. Zinc is found to be an important trace element that forms a part of certain vital metallo enzymes involved in the metabolic pathways of synthesising carbohydrates, lipids and proteins. Zinc containing enzymes are also found to be beneficial in cell mediated immunity in convalescing patients. It is found that breast fed infants consume about 5 mg of zinc per day. During pregnancy and lactation increased intake of zinc is recommended. Zinc also is found to play a role in reducing hair fall and the process of ageing in humans. We have now found that a combination of the three amino acids that go in the making of haemoglobin, B group

of vitamins, vitamin C, a source of iron and a source of zinc enhances haemoglobin synthesis and increases assimilation of thhe trace elements, iron and 2inc, during metabolic activity. We have also found that such a composition exhibits properties fundamentally different from the compounding ingredients and shows reinforced properties as the different components compliment each other in enhancing haemoglobin synthesis and in the increased assimilation of essential minerals like zinc and iron. The composition is found to be a synergestic dietary supplement resulting in augmenting immunity, promoting growth and health.
This invention provides a synergistic pharmaceutical composition for enhancing haemoglobin synthesis and zinc assimilation which comprises a blend of the compounds listed hereinunder in the range specified thereagainst with known adjuvants and/or excipients.
Ferrous Fumerate - 115 to 185 mg
L Histidine HCL - 3 to 5 mg
L Lysine Hydrochloride - 19 to 31 mg
Glycine - 7.5 to 12.5 mg
Vitamin B± mononitrate - 3.75 to 6.25 mg
Riboflavin (vitamin B2) - 2.25 to 3.75 mg
Vitamin Bg Hydrochloride - 1.2 to 1.8 mg
Vitamin B12 - 1.9 to 3.1 meg

Folic acid - 0.38 to 0.62 mg
Ascorbic acid (Vitamin C) - 30 to 58 mg
Zinc Sulphate - 35 to 65 mg
Conventional additives, colourants, and excipients may be added depending upon the nature of the composition to be prepared. For instance, if a liquid composition is required pharmaceutically acceptable liquid carriers are added to the compounding ingredients which are subsequently dissolved or emulsified. Flavouring and colouring agents may also be added to the composition. Tablets and capsules can be prepared by mixing the above ingredients with pharmaceutically acceptable carriers which are directly tabletted or spheronised either together or in the desired groups which are then encapsulated in shells made of pharmaceutically acceptable biologically degradable materials.
In a preferred embodiment compatible components of the composition are grouped together, spheronised, dried and encapsulated together in the desired range. A composition may contain a plurality of granules, the total content of which is within the range specified herein above. For example, a single capsule may contain pink, orange, yellow, blue and brown granules of the composition specified herein below:
1. Pink Granules:
Vitamin B-^ mononitrate - 6 mg Vitamin Bg hydrochloride - 1.576 mg

Lactose - 0.5 mg
Maize starch - 2.75 mg
Colourant Erythrocin - 0.01 mg
Microcrystalline cellulose - 2.0 mg
Distilled water - 0.01 ml
The above ingredients are blended to form a uniform mass, extruded and then spheronised to form granules. The granules are then dried at 45° in a fluidised bed to a moisture content of 1.1 or below and are stored in a cool place till required.
2. Orange Granules:
Riboflavin (Vitamin B2) - 3.3 mg
Folic acid - 0.65 mg
Vitamin B12 - 0.0025 mg
Lactose - 6 mg
Maize starch - 11 mg
Micro crystalline cellulose - 4 mg
Polyethylene glycol - 0.4 mg
Sodium carboxy methyl cellulose- 0.3 mg
Methhyl cellulose - 0.75 mg
Distilled water - 0.1 ml
All the ingredients are mixed and processed as stated in the case of pink granules, and are stored in a cool place till required.

3.

Yellow Granules:

L Histidine Hydrochloride - 4 mg
Glycine - 10 mg
L Lysine monohydrochhloride - 25 mg
Lactose - 10 mg
Maize starch - 16 mg
Micro crystalline cellulose - 10 mg
Methyl cellulose - 3 mg
Colour Tartrazine - 0.3 mg
Distilled water - 0.01 ml
The above components are granulated and stored as stated under
the pink granules.
4. Blue Granules:
Ascorbic acid - 56 mg
Stearic acid - 1.6 mg
Industrial methylated spirit - 0.008 ml
Lactose - 16 mg
Maize starch - 5 mg
Micro crystalline cellulose - 4 mg
Sodium Carboxy methyl cellulose- 4 mg
Polyethyline glycol 6000 - 4.8 mg
Methyl cellulose - 1.4 mg
Colour Indigo Carmine - 0.4 mg
Distilled water - 0.01 ml

All the ingredients are blended and granulated as mentioned under the pink granules and are stored in a cool place till required.
5. Brown Granules:
Ferrous Numerate - 181 mg
Maize starch - 27 mg
Micro crystalline cellulose - 4.8 mg
Sodium Carboxy methhyl cellulose- 1 mg
Sucrose - 33 mg
Distilled water - 0.01 ml
Methyl cellulose - 3 mg
Acetone - 0.039 ml
Methyline chloride - 0.039 ml
Castor oil - 0.38 mg
All te above ingredients are homogenised and processed as stated
under the pink granules.
6. Zinc Granules:
Zinc Sulpate - 50 mg
Lactose - 197 mg
Starch - 45 mg
Micro crystalline cellulose - 75.5 mg
Methyl Cellulose - 5 mg
Distilled water - As required

All the above ingredients are homogenised to a uniform mass, wich is extruded, spheronised to form granules. The granules are dried at 45°C in a fluidised bed drier to a moisture content of less than 1%. The dried granules may be stored in a cool, dry place till required.
Required quantities of all the above 6 granules are blended and then encapsulated in pharmaceuticals acceptable capsules. Required overage doeses of vitamins are to be included while preparing the composition.
Obvious modifications and alterations known to persons skilled in the art are within the scope of this invention and the appended claims.

Synergistic Hematinic Composition
The present invention is the novel composition, as there is no such composition in the prior art.
The present invention (Composition 1) relates to a synergistic composition of a pharmaceutically acceptable ferrous salt; an effective amount of amino acids, an effective amount of vitamins along with Zinc. The composition also contains an effective amount of iron absorption enhancer, such as ascorbic acid, and a pharmaceutically acceptable carrier, binder, or excipient, formulated into a suitable pharmaceutical formulation, especially capsule but not limiting to the same.
During pregnancy the daily requirement of iron and zinc increases.The standard therapy for both iron and zinc deficiencies is the administration of iron and zinc supplementation. The co-administration of iron and zinc is restricted due to the fact that prenatal supplemental iron may adversley affect the maternal zinc status and vice versa. Inhibition of zinc absorption due to iron supplementation may adversely influence the maternal zinc status and alter the net zinc transfer to the fetus.
This study was undertaken to compare the effectiveness of the present invention in improving the iron and zinc levels and thereby to treat these deficiencies. The efficiency of the present invention (Composition 1) is compared with similar other two compositions.

A baseline and periodic observations were recorded for the following parameters during the two month study period.
1. Hemoglobin level.
2. Zinc level.
3. RBC Count.
4. Packed cell Volume.
5. Peripheral Smear.
The results are shown in table 1.

From the above table, the group (2) who received composition 1, the mean hemoglobin level thai was 10.5 gm/dl at the baseline, had been increased to 12.9 gm/dl after 2 months of therapy. In the groups (3) and (4) the mean hemoglobin level that was at 10.4 gm/dl at baseline were increased to 10.8 gm/dl and 10.9 gm/dl respectively after treatment. The control group showed no similar response.
The changes observed with the group (2), treated with the composition 1 was significant (p=0.02) when compared with other groups.
In Group (3) the RBC count at baseline, 3.57 millions/cu mm increased to 3.68 millions/cu mm and the packed cell volume was increased from 33.6 % to 34.7 % after therapy.
In the case of group (4) the RBC count increased from 3.46 millions/cu mm to 3.70 millions/cu mm and the packed cell volume increased from 33.4 % to 35.1 % after two month treatment.

Whereas in Group (2), the RBC count 3.46 millions/cu mm at baseline was increased to 4.11 millions/cu mm and the packed cell volume that was 33.4 % at baseline was elevated to 37.6 %.
The group 1 subjects showed no significant improvement in all the parameters studied. The changes observed with the group (2) are significant at (p= 0.02) for RBC count and (p=0.002) for packed cell volume when compared with other two groups.
The peripheral smear showed microcytic hypochromic cells in all groups at baseline. However, after therapy only the group 2 patients who received formulation comprising the composition 1 got back their normocytic normochromic cells.
The group 3 and group 4 subjects showed 3 n.g/dl of zinc level increase in serum and approximated to group l.The group 2 subjects who received the formulation according to the present invention (Composition 1) showed surprisingly a 20 ng/dl increase of serum zinc level (significant at p=0.017).
Conclusion : These results supports that the present invention comprising of ferrous fumerate, amino acids, vitamins and zinc is both clinically as well statistically significant in increasing the Hemoglobin level, Zinc level, RBC count and Packed cell volume. Further it is the only composition that does not have any inhibition of zinc absorption due to iron supplementation and vice versa.
Example 2
The previous studies states that Zinc is absorbed through the intestinal tract into the body. In this process zinc in the form of a chelate with a low molecular weight carrier substance is transported from the intestinal lumen through the brush border membrane into the intestinal cells, temporarily stored in the form of zinc thioneine and then released into the blood stream when necessary to deliver zinc to the living tissues. It has not been well elucidated yet what molecules are carriers for zinc absorption. The elemental iron and a wide variety of iron supplements decreases this zinc absorption, as iron competes with zinc for absorption when taken together.
The following study was performed to demonstrate the bioavailability of zinc from the compositions according to the present invention.

Method
Wistar rats of 8 weeks age were used in this study (n=12). The rats were fasted for 24 hours before they were given the compositions. The test composition was administered to the duodenum of ether-anesthetized rat as a solution or suspension in physiological saline. The dose of the composition was 10 mg/kg body weight as zinc in each case. Blood samples were collected before administration, 1,3,5 and
7 hours after the administration. Plasma levels of zinc were determined using Zn Test Wako Kit. The absorbed amount of zinc was determined from the area under the curve (AUC) of blood level of zinc vs. time curve up to 7 hours.
The results were shown in table 2.

As shown in table 2 the bioavailability of zinc from composition 1 was much better than that of other two compositions.
The present study clearly states that the new invention under composition 1 unexpectedly shows significantly higher bioavailability of zinc inspite of adminsistering it along with iron as evident from the group 3 and group 4 results.
Conclusion: From the above result it is evident that only the present invention (Composition 1) has unusual superior bioavailability of zinc when taken together with iron.

Example 3
Treatment of anemia in addition to identifying the source of iron deficiency typically involves administering iron supplements. These ferrous supplements are most efficient on an empty stomach and is often not tolerated for many peoples due to gastrointestinal side effects and this fact limits the amount of iron supplements that can be prescribed.
Inorder to evaluate the tolerability of the compositions stated in the present invention this study was performed.
Method
Albino rats housed individually in stainless steel cages were fed a low-iron diet and de-ionized distilled water ad lib for 24 days. The low-iron diet contained not more than about 3 mg of iron per kg of diet. Following the 24 day depletion period, blood was drawn from the tail vein of each rat for hemoglobin analysis. Anemic rats were selected and used for further study.
The rats were housed individually in cages. They were divided into four groups (n = 12) and were treated as follows.
Group 1 - received placebo and served as control.
Group 2 - received Composition 1.
(Animal dose: lOmg Fe/kg of body weight)
Group 3 - received Composition 2.
(Animal dose: lOmg Fe/kg of body weight)
Group 4 - received Composition 3.
(Animal dose: lOmg Fe/kg of body weight)
After 15 days the blood was drawn from the tail vein for hemoglobin analysis. The hemoglobin response to the compositions were stated in the table 3.

The group 3 and group 4 animals exhibited gross internal changes different from group 1 namely fat depletion, thyroid nodules, reddened mandibular lymph nodes, reddened stomach mucosa, small thymus, foci on the thymus and dark fecal matter.
In contrats the gross internal findings exhibited by group 2 animals were only reddened thymus and dark fecal matter indicating that the present invention is free from gastrointestinal side effects and hence well tolerated.
Conclusion: From the above results, it is clear that only the present invention (Composition 1) is free from gastro intestinal side effects and well tolerated.

We Claim:
1. A synergistic pharmaceutical composition for enhancing
haemoglobin synthesis and zinc assimilation comprising a blend of
compounds listed hereinunder in the range specified thereagainst
with known adjuvants and/or excipients.
Ferrous Fumerate - 115 to 185 mg
L Histidine HCL - 3 to 5 mg
L Lysine Hydrochloride - 19 to 31 mg
Glycine - 7.5 to 12.5 mg
Vitamin B1 mononitrate - 3.75 to 6.25 mg
Riboflavin (vitamin B2) - 2.25 to 3.75 mg
Vitamin Bg Hydrochloride - 1.2 to 1.8 mg
Vitamin B12 ~ 1.9 to 3.1 meg
Folic acid - 0.38 to 0.62 mg
Ascorbic acid (Vitamin C) - 30 to 56 mg
Zinc Sulphate - 35 to 65 mg
2. The composition as claimed in dim 1, wherein the blend
is in the form of an emulsion suspension or solution in known
pharmaceutically acceptable adjuvants or carriers.
3. The composition as claimed in claim 1 wherein the
composition is in the form of tablets.

4 The composition as claimed in claim 1 wherein the blends are in the form of granules encapsulated in pharmaceuticals acceptable casing.
5 The composition as claimed in claims 1 and 4 wherein blends of spheronised compatible compounds are encapsulated.
6. The composition as claimed in claims 1 to 5 having colourants added thereto.
7 The composition as claimed in claims 1 to 6 wherein
different granules have different colours.
8 A synergistic pharmaceutical composition for enhancing
haemoglobin synthesis and zinc assimilation substantially as
herein described.

Documents:

1371-mas-96 abstract-duplicate.pdf

1371-mas-96 abstract.pdf

1371-mas-96 claims-duplicate.pdf

1371-mas-96 claims.pdf

1371-mas-96 correspondence-others.pdf

1371-mas-96 correspondence-po.pdf

1371-mas-96 description (complete)-duplicate.pdf

1371-mas-96 description (complete).pdf

1371-mas-96 form-1.pdf

1371-mas-96 form-19.pdf

1371-mas-96 form-26.pdf

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Patent Number

224286

Indian Patent Application Number

1371/MAS/1996

PG Journal Number

47/2008

Publication Date

21-Nov-2008

Grant Date

10-Oct-2008

Date of Filing

02-Aug-1996

Name of Patentee

TABLETS (INDIA) LIMITED

Applicant Address

179 TH ROAD, MADRAS 600 081,

Inventors:

#	Inventor's Name	Inventor's Address
1	MV SIVARAMAKRISHNAN	D-16 RK FLATS, NO.1 JEEVANANDAM STREET, WEST KK NAGER, MADRAS 600 078,
2	R. THIRUVENGADAM	E-9 GRIHALAKSHMI APARTMENT, 640/643 TH ROAD, MADRAS 600 081,

PCT International Classification Number

CO7G13/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA