FORM2
THE PATENTS ACT,970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel 3)
1. TITLE OF THE INVENTION:
"CALCIUM CITRATE MALATE SUSPENSION" 2. APPLICANT (S):
(a) NAME: FDC Limited
(b) NATIONALITY": Indian company incorporated under the Companies
Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

Field of the invention:
The present invention relates to a palatable liquid suspension formulation of calcium supplements for oral administration, comprising micronised calcium citrate malate, stabilized vitamin D3, thixotropic gel-forming agent(s), suspending agent(s) and other pharmaceutically acceptable excipients. The invention further relates to a process for preparation of the suspension having excellent suspendability.
Background of the invention:
Calcium is essential for maintenance of the nutritional integrity of nervous, muscular and skeletal system, cell membranes and capillary permeability. Calcium citrate malate is described as a metastable complex of calcium citrate and calcium malate, or as a mixture of calcium salts comprising the calcium salt of citric acid and malic acid.
There are many types of calcium supplements available which include calcium carbonate, calcium phosphate, calcium lactate, calcium gluconate, calcium malate, calcium citrate and calcium citrate malate. Bioavailability of any calcium source depends on its water-solubility and method of dissolution. Calcium citrate malate is comparitively more water soluble then other calcium supplements. Most of the calcium supplements provide intracellular absorption of calcium ions. Calcium citrate malate when dissolved, produce calcium ions and calcium complex, the calcium ions are actively absorbed through the intestinal cells to provide intracellular absorption of calcium ions, and the calcium complex passes between the intestinal cells to provide paracellular absorption. Thus calcium citrate malate provide two different calcium delivery vehicles and each of them uses a different path into the bloodstream such as intracellular and paracellular absorption. Hence calcium citrate malate is more bioavailble.
The effectiveness of calcium source depends upon elemental calcium, absorbable calcium and solubility at neutral pH. Elemental calcium is the amount of calcium available to the body for absorption, and absorbable calcium refers to the percentage of elemental calcium that can be absorbed by the body. It is known that calcium carbonate provides about 40% elemental calcium and about 26% of it is absorbable. Calcium citrate provides about 22%

elemental calcium and about 24% of it is absorbable. Calcium citrate malate provides about 20% elemental calcium and about 40% of it is absorbable. Calcium citrate malate is the most effective source of calcium, as its solubility at neutral pH and percentage of absorbable calcium is more compared to other calcium supplements.
Vitamin D is required for normal bone formation. Insufficiency of vitamin D is developed when sunlight exposure and dietary intake are inadequate. The vitamin D insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss and increased risk of skeletal fracture. In severe cases, vitamin D deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.
Vitamin D3 is a form of Vitamin D, also called as cholecalciferol and secosteroid. Vitamin D3 is a natural precursor of the calcium-regulating hormone calcitriol (1,25 dihydroxyvitamin D3). It is a white, crystalline and odorless powder. It is practically insoluble in water, freely soluble in usual organic solvents and slightly soluble in vegetable oils. The principal action of vitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion.
Calcium citrate malate the most bioavailable form of calcium, is shown to be effective in prevention of osteoporosis by building greater peak bone mass and retarding the rate of bone loss. The addition of vitamin D3 will improve the effect of calcium citrate malate on bone density and reduce fracture risk.
US 6509326 discloses nutritional mineral supplements that employ specific calcium salts of mixtures of citric and malic acids, and vitamin D. Estrogen can also be used in conjunction with any of these supplements. These nutritional mineral supplements can be added to foods and beverages, and are useful for increasing bone growth and treating age-related bone loss. The supplement is administered in the form of liquid dosage form such as aqueous solutions, emulsions, suspensions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.

US 5612026 discloses drink mix compositions useful for reducing serum cholesterol levels containing an anion exchange resin, xanthan gum, and an edible water-soluble salt at a level that reduces gelation rate of the drink mix compositions in an aqueous solution. The preferred form of compositions is a dry powder in bulk or unit dose form which readily mixes and disperses in a liquid, wherein calcium citrate malate is used as the edible water-soluble salt to reduce gelation rate.
US 5422101 discloses psyllium husk-containing drink mix compositions comprising psyllium husk, an anion exchange resin like cholestyramine or colestipol, and edible water-soluble salts including calcium citrate malate at a level sufficient to reduce the gelation rate of the psyllium husk and anion exchange resin-containing composition when dispersed in an aqueous solution.
US 5128374 teaches the method of building bone in humans and animals for the treatment of osteoporosis and related disorders, by administtration of certain calcium salts. Calcium citrate malate is preferably administered in an oral dosage form, containing pharmaceutically acceptable carriers and excipients.
US Patent application 20070065542 discloses a method of enhancing calcium bioavailability of a calcium citrate-containing tablet under physiological conditions by preparing solid preformed calcium citrate, adding citric acid to the calcium citrate, in a molar ratio between 0.1 and 0.6 mol of citric acid per mol of calcium citrate to provide a calcium citrate-citric acid mixture for forming the tablet.
None of the aforementioned prior art discloses a palatable liquid suspension formulation of calcium supplements for oral administration, which comprises micronised calcium citrate malate, stabilized vitamin D3, thixotropic gel-forming gum(s), suspending agent(s) and other pharmaceutically acceptable excipients.
The suspension of the present invention is developed to increase the convenience and ease of administration of calcium citrate malate to patients, particularly elderly and pediatric patients, who have difficulty in swallowing tablets.

Oral suspension available in the market generally has high viscosity, and may contain high amount of dispersed solid. However, if the dispersion is not proper, the suspension will not give dose accuracy. Further if the suspension has coarse material of active agent, it will not disperse properly and will not be palatable. The present invention describes calcium citrate malate suspension having excellent suspendability, wherein formulation contains micronised calcium citrate malate, which disperses uniformly to give dose accuracy and improves palatability of the suspension.
The mixture of thixotropic and suspending agents gives uniform, physically stable suspension with no caking and good sedimentation volume. Thixotropic agent being gel forming when stationary, prevents any setting of drug particles, and at the same time shear thing property of thixotropic agents facilitates pourability of suspension at the time of administration. The suspending agent gives structure to the product, thus preventing sedimentation even when viscosity of product is low after shaking (shear). In this way the combination of thixotropic agent and suspending agent has synergistic effect in giving suspension product with excellent physical properties. The invention further discloses process for preparation of suspension.
Object of the invention:
It is the main objective of present invention to provide a palatable liquid suspension formulation of calcium citrate malate along with stabilized vitamin D3, thixotropic gel-forming agent(s), suspending agent(s) and other pharmaceutically acceptable excipients, for oral administration.
Another objective of the present invention is to provide a process for preparation of liquid suspension formulation of calcium citrate malate having excellent suspendability,
Yet another objective of the present invention is to provide the convenience and ease of administration of calcium citrate malate to patients who have difficulty in swallowing tablets.

Summary of the invention:
In accordance with the above objectives the present invention provides a palatable liquid suspension formulation of calcium supplements for oral administration, comprising micronised calcium citrate malate, stabilized vitamin D3, thixotropic gel-forming agent(s), suspending agent(s) and other pharmaceutically acceptable excipients. The invention further discloses a process for preparation of the suspension having excellent suspendability.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention provides a palatable liquid suspension formulation of calcium supplements for oral administration, comprising
A) Micronised calcium citrate malate,
B) Stabilized vitamin D3,
C) Thixotropic gel-forming agent(s),
D) Suspending agent(s) and
E) Other pharmaceutically acceptable excipients.
Calcium citrate malate is a white, odorless powder. It is one of the most absorbable calcium available, and is composed of calcium and two organic acids, citric acid and malic acid, both of which help to increase calcium absorption. Calcium Citrate Malate is micronised and particles thus obtained are less than or equal to 100 microns. The amount of calcium citrate malate in the formulation is ranging from 2 % to 25 % w/v of equivalent calcium by weight of total formulation.
Vitamin D3 is a white, crystalline, odorless powder. It is used to increase intestinal absorption of calcium ion and regulate serum calcium and renal calcium. Pure vitamin D3 crystals or vitamin D3 resin is very susceptible to degradation upon exposure high

temperature, high moisture or contact with mineral elements. To reduce rate of degradation when exposure to heat or during prolonged storage, and to exhibits excellent storage stability of the formulation the present inventor used stabilized vitamin D3. Vitamin D3 is stabilized using natural or synthetic antioxidants. The amount of vitamin D3 in the formulation is ranging from 0.00005 % to 0.075 % w/v by weight of total formulation.
The present invention demonstrates the application of thixotropic agent(s) to control the fluidity or plasticity of the formulation. Thixotropic agent offers the shear thinning property to the system, which is thick or viscous under normal conditions, but flow under shear that is when shaken, agitated or otherwise stressed. The thixotropic agent is selected from a group consisting of but not limited to xanthan gum, locust bean gum, guar gum, bentonite, acacia, sodium alginate and carageenan. The concentration of thixotropic agent(s) in the present formulation is ranging from 0.01 % to 10 % w/v of the total weight of the formulation.
Suspending agent(s) increase apparent viscosity and prevent rapid sedimentation of the dispersed particles. Thus suspending agent improves pourability and spreadability of the formulation. The suspending agent is selected from a group consisting of but not limited to starch, carbomer. colloidal anhydrous silica, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose and polyvinyl alcohol, in the range of 0.1 % to 5 % w/v of total formulation.
The mixture of thixotropic and suspending agent gives uniform, physically stable suspension with no caking and good sedimentation volume.
Other pharmaceutically acceptable excipients in the present invention are selected from sweeteners, vehicle, preservatives, buffer, colors and flavors.
Sweeteners make the suspension palatable. The sweetener is selected from a group consisting of but not limited to Sucrose, Acesulfame Potassium, Aspartame, Sodium Cyclamate and Sucralose.

Vehicle is selected from a group consisting of but not limited to Sorbitol, Propylene Glycol, Glycerin and Water.
Taste enhancer is selected from a group consisting of but not limited to Citric Acid and Monosodium Glutamate.
The following examples, which include preferred embodiments, will serve to Illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLES:
Example 1:

Sr.
No. Ingredients % w/v
1 Calcium Citrate Malate 2.5
2 Stabilised vitamin D3 0.0005
3 Sodium methylparaben 0.2
4 Sodium propylparaben 0.02
5 Sodium alginate 0.32
6 Hydroxylethylcellulose 0.2
7 Sucrose 40.0
8 Sorbitol solution 6.0
9 Citric acid monohydrate 0.5
10 Mango flavor 0.8
11 Ponceau 4R 0.02
12 Purified water Q.S
Sodium Methylparaben, Sodium Propylparaben and Citric Acid Monohydrate are dissolved in purified water. Sucrose is dissolved into the above solution and dispersed Hydroxylethylcellulose and dispersed Sodium Alginate in purified water was added to the above liquid, followed by addition of Sorbitol, Calcium Citrate Malate and Vitamin D3 and homogenized for 30 minutes.
Added Ponceau 4 R and Mango supreme to above suspension and stirred for 15 minutes.

Example 2:

Sr.
No. Ingredients %
w/v
1 Calcium Citrate Malate 15
2 Stabilised vitamin D3 0.005
3 Sodium methylparaben 0.1
4 Sodium propylparaben 0.01
5 Sodium alginate 0.4
6 Guar gum 0.3
7 Sucrose 40.0
8 Sorbitol solution 10
9 Citric acid monohydrate 0.5
10 Orange flavor 0.8
11 Quinoline Yellow 0.02
12 Purified water Q.S
Sodium Methylparaben, Sodium Propylparaben and Citric Acid Monohydrate are dissolved in purified water. Sucrose is dissolved into the above solution. Dispersed Guar gum and dispersed Sodium Alginate in purified water was added to the above liquid, followed by addition of Sorbitol, Calcium Citrate Malate and Vitamin D3 and homogenized for 30 minutes. Added Quinoline yellow and Orange flavor to the above suspension and stirred for 15 minutes.
Example 3:

Sr.
No. Ingredients %
w/v
1 Calcium Citrate Malate 11.7
2 Stabilised vitamin D3 0.04
3 Sodium methylparaben 0.2
4 Sodium propylparaben 0.02
5 Xanthan gum 0.32
6 Colloidal silicon dioxide 0.2
7 Sucrose 32.0
8 Sorbitol Solution 6.0
9 Acesulfame potassium 0.36
10 Citric acid monohydrate 0.32
11 Mango flavor 0.8
12 Pineapple flavor 0.1
13 Quinoline yellow 0.02
14 Purified water Q.S

Sodium Methylparaben, Sodium Propylparaben, Citric Acid Monohydrate and Acesulfame Potassium are dissolved in purified water. Sucrose is dissolved into the above solution. Dispersed Xanthan gum and dispersed Colloidal silicon dioxide in purified water was added to the above liquid, followed by addition of Sorbitol, Calcium Citrate Malate and Vitamin D3 and homogenize for 30 minutes. Added Quinoline yellow and Pineapple supreme flavor and Mango supreme to the above suspension and stirred for 15 minutes.
Example 4:

Sr.
No. Ingredients %
w/v
I Calcium Citrate Malate 25
2 Stabilised vitamin D3 0.07
3 Bronopol 0.1
4 Bentonite 0.4
5 MicrocrystalHne cellulose 0.2
6 Sucrose 25.0
7 Sorbitol Solution 9.0
8 Aspartame 0.4
9 Citric acid monohydrate 0.12
10 Peppermint flavor 0.8
11 Purified water Q.S
Bronopol, Citric Acid Monohydrate and Aspartame are dissolved in purified water. Sucrose is dissolved into the above solution. Dispersed Bentonite and dispersed MicrocrystalHne Cellulose in purified water was added to the above liquid, followed by addition of Sorbitol, Calcium Citrate Malate and Vitamin D3 and homogenized for 30 minutes. Added Peppermint flavor to the above suspension and stirred for 15 minutes.
Values of sedimentation volume of calcium citrate malate suspension

Example Sedimentation volume (ml)

0 week 1 week 2week 3 week 4week
1 100 98 97 96 94
2 100 100 99.5 99 98
3 100 100 100 100 100
4 100 99 97 95 93

Quantitative expression of sedimentation over one month
Sedimentation volume v/s time of calcium citrate malate suspension

The sedimentation volume is the ratio of the equilibrium volume of the sediment to the total volume of the suspension.
The above graph shows that no sediment is visible even though the system is a flocculated suspension. Furthermore, the suspension is ideal since there is no visible, clear supernatant.

We Claim:
administration, comprising
A) Micronised calcium citrate malate having pariticle size of less than or equal to 100 microns of total formulation,
B) Stabilized vitamin D3,
C) Thixotropic gel-forming agent(s),
D) Suspending agent(s) and
E) Other pharmaceutically acceptable excipients,
2. The palatable liquid suspension formulation of calcium supplements for oral administration as claimed in claim 1, wherein the micronised calcium citrate malate is in an amount of 2 % to 25 % w/v of equivalent calcium by weight of
3. The palatable liquid suspension formulation of calcium supplements for oral administration as claimed in claim 1, wherein vitamin D3 is in an amount of 0.00005 % to 0.075 % w/v by weight of total formulation.
4. The palatable liquid suspension formulation of calcium supplements for oral administration as claimed in claim 1, wherein the thixotropic agent is selected from a group consisting of xanthan gum, locust bean gum, guar gum, bentonite, acacia, sodium alginate and carageenan, in an amount of 0.01% to 10% w/v of the total weight of the formulation.
5. The palatable liquid suspension formulation of calcium supplements for oral administration as claimed in claim 1, wherein suspending agent(s) are selected from a group consisting of starch, carbomer, colloidal anhydrous silica, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose and polyvinyl alcohol, in an amount of 0.1% to 5 % w/v of total formulation.

6. The palatable liquid suspension formulation of calcium supplements for oral administration as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from sweeteners, vehicle, preservatives, buffer, colors and flavors.