FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NOVEL FLOATING MOUTH-DISPERSING GRANULES OF CALCIUM
CARBONATE"
2. APPLICANT:
(a)NAME:FDC LTD.
(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 particularly describes the invention and manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to mouth-dispersing granules of calcium carbonate which do not require water for oral administration. The invention further relates to floating, gastroretentive mouth-dispersing granules of calcium carbonate. The mouth-dispersing granules of calcium carbonate of the present invention can be used as an antacid, a calcium supplement and for treatment of gastroesophageal reflux disease (GERD).
BACKGROUND AND PRIOR ART OF THE INVENTION:
Calcium is an essential mineral for development of bones in children, pregnant women and fractures of accidental and physiological origin. Calcium in dietary supplements is sufficient for metabolism and growth. However, in certain pathological conditions, body relies on calcium obtained from other sources such as pharmaceutical dosage forms and rernineralization. Calcium is present in the form of calcium salts such as calcium carbonate, calcium citrate and calcium citrate malate, in the pharmaceutical dosage forms. Calcium carbonate is natural, safe and economical amongst all the other calcium salts, and hence commonly used in pharmaceutical dosage forms as active as well as inactive ingredient.
Calcium carbonate is used in dietary supplements when the amount of calcium taken in the diet is not enough; and is also used as an antacid to relieve heartburn, acid indigestion and stomach upset. Calcium carbonate is one of the widely accepted antacid which can offer quick relief from acidity.
Conventional solid oral dosage forms such as tablets and capsules are widely used for administration of calcium. Many patients such as children, old-aged persons and patients who are busy or traveling with little or no access to water, find it very difficult to swallow such tablets and capsules. Hence, conventional solid oral dosage forms of calcium act as poor patient-compliant dosage forms.
An article titled "Preparation of alginate beads for floating drug delivery system: effects of CO2 gas-forming agents" by Choi et al, published in International Journal of Pharmaceutics 239 (2002) 81-91, discloses preparation of a floating controlled drug delivery system from a sodium alginate solution containing CaCO3 or NaHCO3 as gas-

forming agents. The article discloses the floating controlled drug delivery system in the form of floating beads, used for delivery of drugs such as riboflavin. However, the article does not teach mouth-dispersing formulation of calcium carbonate as active ingredient.
US Patent No. 4140760 discloses a pharmaceutical formulation for suppression of gastric reflux, comprising sodium alginate, sodium bicarbonate and calcium carbonate; wherein the composition may be presented in the form of dry powders, which can be further mixed with water to provide a palatable liquid preparation. However, the said patent does not teach drug formulations which can be consumed without the use of water.
US Patent no. 4414198 discloses a rapid water-disintegrable tablet comprising an intimate mixture of metal salt of alginic acid and a water soluble carbonate radical, such as calcium carbonate. However, the said patent does not disclose calcium carbonate granules which can be consumed without the use of water.
US Patent No. 5888540 discloses a soft gelatin capsule with a fill comprising a hydrogel material including alginic acid or metal alginates (e.g. sodium alginate); a gas generating agent such as calcium carbonate along with a bicarbonate; and an oil-based vehicle. The soft gelatin capsule, upon contact with an acidic aqueous medium, breaks up, disperses or dissolves, and the fill reacts to form a foam.
Though, there is ample literature available on calcium carbonate tablets, prior art failed to recognize the need of mouth dispersing gastroretentive granules of calcium carbonate that retains to stomach mucosa providing sustained availability of calcium for uptake. The major challenges faced while formulating mouth-dissolving dosage form include palability, mechanical strength, hygroscopicity and aqueous solubility of drug.
The present inventors have found that mouth-dispersing and floating granules of calcium carbonate, improve patient compliance and convenience as well as calcium bioavailability, while overcoming the difficulty of swallowing conventional solid oral dosage forms such as calcium tablets and capsules. Also found that mouth-dispersing and floating granules of calcium carbonate of the present invention overcomes the problems

involved in formulating the dosage forms such as mechanical strength, hygroscopicity and aqueous solubility of drug.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide gastroretentive mouth-dispersing granules of calcium carbonate, which offer high level of patient compliance, better bioavailability, improved palatability and reduced dose-related side effects.
Further object of the present invention is to provide floating gastroretentive mouth-dispersing granules of calcium carbonate, which offer cost effective, stable dosage form having pleasant mouth feel.
SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention provides mouth-dispersing granules of calcium carbonate comprising calcium carbonate as active ingredient, a raft-forming agent, superdisintegrant(s), sweetener(s), organic acid(s) and other pharmaceutically acceptable excipients; wherein the mouth-dispersing granules of calcium carbonate do not require water for oral administration. The invention further provides floating, gastroretentive mouth-dispersing granules of calcium carbonate.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail so that various aspects thereof may be more fully understood and appreciated.
The present invention describes mouth-dispersing granules of calcium carbonate which do not require water for oral administration. The invention further describes floating, gastroretentive mouth-dispersing granules of calcium carbonate.
Calcium carbonate is used in dietary supplements, and is one of the widely accepted antacid which may offer quick relief from acidity. However, poor solubility and gastric emptying hinders the acid neutralizing effect of calcium carbonate.

The long term administration of calcium requires patient friendly dosage forms, and mouth-dispersing granules as dosage form are easy to take without water, serving to be a patient friendly dosage form.
The absorption of calcium from the gastrointestinal tract (GIT) is negatively dependent on calcium intake. If calcium intake is high, calcium-binding protein mediated down regulation process, reduces the extent of calcium absorption. Moreover, the poor solubility and dissolution of calcium carbonate results into poor bioavailability of calcium carbonate. Hence, there is a need to develop gastroretentive floating formulation of calcium, which prevents the super-saturation of calcium in GIT and at the same time the dosage form should be retained in the stomach (absorption window of calcium) where calcium carbonate has highest solubility.
Gastroretentive dosage forms increase the extent of ionization and solubilization of calcium carbonate in stomach. The controlled release of solubilized calcium from dosage form provides better absorption of calcium in the intestine (absorption window of calcium). As acidic conditions favor absorption of calcium carbonate from the stomach, the slow release gastroretentive dosage form retaining calcium in acidic pH favors the absorption of calcium in proximal part of the GIT. The gastroretentive drug delivery system of the current invention retains the drug in acidic pH and hence favors the absorption of calcium in proximal part of GIT. To formulate a successful stomach specific or gastroretentive dosage form, several techniques are currently used such as floating dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying agents. Among these, the floating dosage forms have been extensively explored and reported in literature. The floating dosage forms have a bulk density less than gastric fluids, and hence remain buoyant in the stomach contents without getting affected by gastric emptying rate, for a prolonged period of time. While the system is floating on the gastric contents, drug is released slowly at the desired rate from the system; and after the release of the drug, the residual system is emptied from the stomach. This results in an increased gastroretention time and a better control of the fluctuations in plasma drug concentration.

Calcium carbonate has excellent physiochemical properties such as low bulk density, pH dependent solubility, low dose and better stability. These properties are found to be ideal for development of floating drug delivery system, wherein the dosage forms remain in the stomach for a prolonged period of time. Calcium carbonate, in contact with gastric acid produces carbon dioxide that improves the floating behavior of dosage form, when the gas is entrapped in gel network, and the acidic condition favors the absorption of calcium carbonate from stomach.
The floating, gastroretentive mouth-dispersing granules of calcium carbonate of the present invention, comprise calcium carbonate as active ingredient, a raft-forming agent, superdisintegrant(s), sweetener(s), organic acid(s) and other pharmaceutically acceptable excipients.
The floating, gastroretentive mouth-dispersing granules of calcium carbonate of the present invention can potentially achieve better bioavailability, while providing patients with most convenient mode of administration and preventing them from dosage-related side effects.
When mouth-dispersing granules of calcium carbonate are placed on the tongue, they rapidly dissolve or disintegrate in the saliva within few seconds, to release calcium carbonate. But, the raft-forming agent provides a strong floating gel that retains calcium carbonate and prevents it from getting released in the mouth. This strong floating gel is formed in the stomach and on coming in contact with the gastric fluid, releases calcium in the absorption window (i.e. proximal part of gastrointestinal tract) in a controlled manner, which prevents supersaturation of calcium at the absorption site and provides adequate gastric retention time for absorption of calcium from gastrointestinal tract (GIT), thus offering superior calcium bioavailability. As a result, the mouth-dispersing granules of calcium carbonate of the present invention, serves as floating extended-release dosage form, which retains calcium carbonate in stomach for a longer period of time.
The mouth-dispersing granules of calcium carbonate of present invention disperse in patient's mouth within few seconds without the need of water or chewing, while overcoming the difficulty of swallowing conventional oral dosage forms such as calcium

tablets and capsules. The mouth-dispersing granules of calcium carbonate get dissolved/disintegrated in the saliva within few seconds, and turn into smooth suspension/solution for easy swallowing, thus proving to be beneficial to children, old-aged patients, bed-ridden patients, busy patients and traveling patients, who find it difficult to swallow the calcium tablets/capsules.
Calcium carbonate used in the present invention as active ingredient is in an amount of 10 to 90% w/w of the total formulation.
The raft-forming agent provides a strong floating gel that retains calcium carbonate and also provides excellent mouth feel, and hence does not offer grittiness during disintegration and/or dissolution of the calcium carbonate granules in the mouth. The raft-forming agent used in the present invention is selected from but not limited to alginic acid and its salts such as sodium alginate, potassium alginate, calcium alginate, magnesium alginate and manganese alginate, and present in an amount of 2 to 50% w/w of the total formulation.
The superdisintegrant used in the present invention leads to explosion of calcium carbonate granules, and hence aids in rapid disintegration of the granules, which offers smaller particle size and higher surface area for dissolution of calcium carbonate granules in the mouth. The superdisintegrant(s) used in the present invention are selected from but not limited to crospovidone, croscarmellose sodium or sodium starch glycollate, and present in an amount of 0.5 to 20% w/w of the total formulation.
The sweeteners used in the present invention aid to provide a palatable taste. It also helps in faster dissolution. The sweeteners used in the present invention are in a combination of artificial sweetener and natural sweetener. The natural sweetener(s) are selected from but not limited to sugars such as sucrose, fructose, dextrose and glucose, and sweet polyols like glycerin, sorbitol and mannitol, and used in an amount of 2 to 50% w/w of the total formulation. The artificial sweetener(s) are selected from but not limited to aspartame, sucralose, acesulfame potassium, lactilol, cyclamates and saccharin, and are present in an amount of 0.02 to 10% w/w of the total formulation

The organic acid used in the present invention increases salivation, and hence offers high volume of saliva for dissolution of calcium carbonate granules. The pharmaceutically acceptable organic acid alone or in combination with alkaline salts, used in the present invention is selected from but not limited to citric acid, tartaric acid, maleic acid and their salts either alone or in combination, and is present in an amount of 0.5 to 20% of the total formulation.
The other pharmaceutically acceptable excipients used in the present invention include but are not limited to binder(s), glidant(s), antioxidant(s), stabilizer(s), flavoring agent(s) and colorant(s).
The mouth-dispersing calcium carbonate granules of the present invention are available within sachets/packets with proper dosing amounts.
The mouth-dispersing granules of calcium carbonate of the present invention can be used as an antacid, a calcium supplement and for treatment of gastroesophageal reflux disease (GERD).
The present invention is exemplified by the following examples which are provided for illustration only and should not be construed to limit the scope of the invention.
Examples:
Calcium carbonate floating mouth-dispersing granules Example 1:

Sr
No. Ingredients Quantity (mg/2gm)
1 Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Mannitol 607
5 Sodium Chloride 20
6 Crospovidone 40
7 Citric acid 100
8 Quinoline yellow 2
9 Trusil lemon 25
10 Colloidal silicon dioxide 4

Preparations & dissolution profiles are remaining
Process:
Accurately weighed calcium carbonate, sodium alginate, Sucralose, mannitol, sodium
chloride, crospovidone and citric acid are passed through 40# sieve, added colour and
mixed the above ingredients uniformly. Granulated this blend with water, dried and finaly
pass the dried granules through 40# sieve. Added flavor and lubricated with colloidal
silicon dioxide.

In vitro dissolution profile for calcium carb onate floating mouth-dispersing gr anules:
Time (hrs) Drug dissolution (%)

0.25 50


0.5 74


1.0 88


1.5 92


2.0 98


Stability Data:

Storage Condition Assay of Calcium
RT 99.40%
50oC/75%RH 1M 100.50%
40°C/75%RH 1M 99.60%

3M 99.0%

6M 99.23%
30oC/65%RH 3M 99.29%

6M 99.42%

9M 99.70%
Example 2:
Sr
No. Ingredients Quantity
(mg/2gm)
1 Calcium Carbonate 1000

2 Sodium alginate 400

3 Acesulfame potassium 2

4 Mannitol 407

5 Sodium Chloride 20

6 Crospovidone 40

7 Citric acid 100

8 Quinoline yellow 2

9 Trusil lemon 25

10 Colloidal silicon dioxide 4



Process:
Accurately weighed calcium carbonate, sodium alginate, Acesulfame potassium, mannitol, sodium chloride, crospovidone and citric acid Are passedthrough 30# sieved, added colour andmixed the above ingredients uniformly. Granulated this blend with water.dried and finaiy passed the dry granules through 30# sieve. Added flavor and lubricated with colloidal silicon dioxide.

Example 3:
Sr
No. Ingredients Quantity (mg/2gm)
I Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Mannitol 607
5 Sodium Chloride 20
6 Crospovidone 40
7 Citric acid 100
8 Quinoline yellow 2
9 Trusil lime 25
10 Colloidal silicon dioxide 4
Stabili ty Data:
Storage Condition Assay of Calcium
RT 99.42%
50oC/75%RH 1M 99.10%
40°C/75%RH IM 100.22%

3M 99.80%

6M 99.49%
30oC/65%RH 3M 99.32%

6M 99.19%

9M 99.28%
Process:
Accurately weighed calcium carbonate, sodium alginate, Sucralose, mannitol, sodium chloride, crospovidone and citric acid are Passed through 30# sieve, added colour, andmixed the above ingredients uniformly. Granulated this blend with water, dried and finaly passed the dry granules through 30# sieve. Added flavor and lubricated with colloidal silicon dioxide.

Example 4:
Sr
No. Ingredients Quantity
(mg/2gm)
I Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Mannitol 617
5 Sodium Chloride 20
6 Croscarmellose sodium 30
7 Citric acid 100
8 Quinoline yellow 2
9 Alfanso Mango flavor 25
10 Colloidal silicon dioxide 4
Accurately weighed calcium carbonate, sodium alginate, Sucralose, mannitol, sodium chloride, croscarmellose sodium and citric acid are passed through 30# sieve, added colour, mixed above ingredients uniformly. Granulated this blend with water, .dried and finally passed the dry granules through 30# sieve. Added flavor and lubricated with colloidal silicon dioxide.

Example 5:
Sr
No. Ingredients Quantity (mg/2gm)
1 Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Mannitol 607
5 Sodium Chloride 20
6 Crospovidone 40
7 Citric acid 100
8 Sunset yellow Supra 2
9 Orange flavor 25
10 Colloidal silicon dioxide 4
Process:
Accurately weighed calcium carbonate, sodium alginate, sucralose, mannitol, sodium chloride, crospovidone and citric acid are passed through 30# sieve, added colour and mixed the above ingredients uniformly. Granulated this blend with water, dried and finaly passed the dry granules through 30# sieve. Added flavor and lubricated with colloidal silicon dioxide.

Example 6:
Sr
No. Ingredients Quantity
(mg/2gm)
1 Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Sucrose 597
5 Sodium Chloride 30
6 Crospovidone 40
7 Citric acid 100
8 Quinoline yellow 2
9 Trusil lemon 25
10 Colloidal silicon dioxide 4
Process:
Accurately weighed calcium carbonate, sodium alginate, sucralose, sucrose, sodium
chloride, crospovidone and citric acid are pass these ingredients through 30# sieve and
mix the above ingredients uniformely. Granulate this blend with water, dried and finally
pass the dry granules through 30# sieve. Added flavor and lubricate with colloidal silicon
dioxide.

Example 7:
Sr
No. Ingredients Quantity
(mg/2gm)
1 Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Mannitol 607
5 Sodium Chloride 20
6 Sodium Starch glycolate 40
7 Citric acid 100
8 Quinoline yellow 2
9 Trusil lemon 25
10 Colloidal silicon dioxide 4
Process:
Accurately weighed calcium carbonate, sodium alginate, Sucralose, mannitol, sodium chloride, sodium starch glycolate and citric acid are passed through 30# sieve, added colour, mixed the above ingredients uniformly. Granulated this blend with

water,.driedand finally passed the dry granules through 30# sieve. Added flavor and lubricated with colloidal silicon dioxide.

Example 8:
Sr
No. Ingredients Quantity (mg/2gm)
1 Calcium Carbonate 1000
2 Sodium alginate 200
3 Sucralose 2
4 Mannitol 607
5 Sodium Chloride 20
6 Crospovidone 40
7 Citric acid 100
8 Quinoline yellow 2
9 Trusil lemon 25
10 Menthol 4
10 Colloidal silicon dioxide 4
Process:
Accurately weighed calcium carbonate, sodium alginate, Sucralose, mannitol, sodium chloride, crospovidone and citric acid are passed through 30# sieve, added colour, mixed the above ingredients uniformly. Dissolved menthol in water and useed this water for Granulation, dried the granules and finally passed the dry granules through 30# sieve. Added flavor and lubricated with colloidal silicon dioxide.
The moisture uptake study and invitro study in stimulated gastric fluid conditions are provided below in table 1 and Particle Size Distribution by sieve analysis is provided in table 2.

Table 1
Examples 1 3 5 8
Duration 3 months 3 months 3 months 3 months
Moisture uptake Studies 40 °C/75% RH in Open Petri dish % LOD 4.2% 4.4% 4.0% 3.8%
In-vitro study in stimulated gastric fluid floating lag time <60secs <30secs <45secs <60secs

floating time >4hrs >4hrs >4hrs >4hrs

Table 2
Particle Size Distribution by sieve analysis:

Sieve Size Examples [Percentage retained ]

1 3 5 8
140#(105μ) 41.31% 41.8% 42.19% 41.78%
100#(149μ) 5.96 % 5.39% 6.21 % 6.11 %
80#(177μ) 17.34% 17.68% 17.40% 17.26%
60#(250 μ) 33.56% 33.51 % 32.89 % 32.58 %
40#(400μ) 1.2% 1.28% 1.31 % 1.33%
Procedure:
1) A representative weighed granules (30gm) is poured into the top sieve which has the largest screen openings. Each lower sieve in the column has smaller openings than the one above. At the base is a round pan called the receiver.
2) The column is typically placed in a mechanical shaker. The shaker shakes the column, usually for some fixed amount of time.
3) After the shaking is complete the material on each sieve is weighed. The weight of the sample of each sieve is then divided by the total weight to give a percentage retained on each sieve.

We claim:
1. Floating, gastroretentive mouth-dispersing granules of calcium carbonate comprising calcium carbonate as active ingredient, a raft-forming agent, superdisintegrant(s), sweetener(s), organic acid(s) and other pharmaceutically acceptable excipients.
2. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 1, wherein calcium carbonate is used in an amount of 10% to 90% w/w of the total formulation.
3. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 1, wherein the raft-forming agent used is selected from alginic acid and its salts such as sodium alginate, potassium alginate, calcium alginate, magnesium alginate and manganese alginate, and is present in an amount of 2 to 50% w/w of the total formulation.
4. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 1, wherein the superdisintegrant(s) used are selected from crospovidone, croscarmellose sodium or sodium starch glycollate, and are present in an amount of 0.5 to 20% w/w of the total formulation.
5. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 1, wherein the sweeteners comprises a combination of artificial sweetener(s) and natural sweetener(s).
6. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 5, wherein the natural sweetener(s) are selected from sugars such as sucrose, fructose, dextrose and glucose, and sweet polyols like glycerin, sorbitol and mannitol, and are present in an amount of 2 to 50% w/w of the total formulation.

7. The floating, gastroretentive mouth-dispersing granules of calcium carbonate
according to claim 5, wherein the artificial sweetener(s) are selected from
aspartame, sucralose, acesulfame potassium, lactilol, cyclamates and saccharin,
and present in an amount of 0.02 to 10% w/w of the total formulation
8. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 1, wherein the organic acid(s) are used alone or in combination with alkaline salts.
9. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 8, wherein the organic acid(s) are selected from citric acid, tartaric acid, maleic acid and their salts, and are present in an amount of 0.5 to 20% of the total formulation.
10. The floating, gastroretentive mouth-dispersing granules of calcium carbonate according to claim 1, wherein the other pharmaceutically acceptable excipients comprise binder(s), glidant(s), antioxidants), stabilizer(s), flavoring agent(s) and colorant(s).
11. The floating, gastroretentive mouth-dispersing granules of calcium carbonate
according to claim 1, wherein said granules are provided , within sachets/packets
with proper dosing amounts.