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:
"A NOVEL SOLID ORAL DOSAGE FORM OF PARACETAMOL"
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 the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to gastroretentive dosage form of paracetamol comprising a system of hydrophilic swellable floating matrix in combination with a bioadhesive system.
BACKGROUND OF THE INVENTION:
Paracetamol chemically known as N-acetyl-para-aminophenol or 4-hydroxy acetanilide, shows analgesic and antipyretic effect; and is widely used in prescription and non-prescription medicines, often in combination with other therapeutically active compounds.
Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 10 to 60 minutes after oral administration. The elimination half-life varies from about 1 to 3 hours. Paracetamol is metabolized extensively in the liver and excreted in the urine mainly as inactive glucuronide and sulfate conjugates. The metabolites of paracetamol include a minor hydroxylated intermediate which has hepatotoxic activity. This intermediate metabolite is detoxified by conjugation with glutathione. If there is an over dose of paracetamol, the intermediate metabolite can accumulate in the liver and can cause irreversible liver damage.
Paracetamol is an antipyretic compound having analgesic activity. Paracetamol is safer than non-steroidal anti-inflammatory drugs (NSAIDs), particularly for renal failure patients, gastrointestinal bleeding; and has no drug dependency when compared with opiates. However, short half life (1.9 -2.5 h), high dose of 500/650 mg, high dosing frequency i.e. four times in a day (QID) administration and hepatotoxicity, are the factors limiting the use of paracetamol in the treatment of pain.
Dosage forms with a prolonged gastric residence time i.e. gastroretentive dosage forms, provide better bioavailability with new and important therapeutic options. Gastric retention provides advantages such as delivery of narrow absorption window drugs in stomach and small intestine, highly acid soluble drugs, drugs that are

unstable in intestine and colon, and high-dose poorly soluble drugs. Also, longer residence time in the stomach could be advantageous for local action in the upper part of the small intestine, for example in treatment of various gastrointestinal (GI) diseases such as gastric ulcer, acidity and H.Pylori infection. Furthermore, improved bioavailability can be expected for drugs that are readily absorbed upon release in the upper part of GI tract. These drugs can be delivered ideally as a gastroretentive sustained release formulation.
WO2010080580 describes matrix-forming, sustained-release pharmaceutical formulations comprising four primary components: (i) drug substance; (ii) water-swellable, pH independent polymer; (iii) anionic, pH dependent polymer; and (iv) a pharmaceutically-acceptable polymer selected from cationic polymer(s) and hydrocolloid(s). The application describes the formulation of matrix using pH dependent polymers and pH independent polymers. The anionic polymer used in matrix tablets may retard the drug release for longer period of time, especially in acidic condition of stomach. The said prior art discloses the formulation with pH dependent polymer, which often results the variability in the pharmacokinetic profile due to the presence of food and other medication in GIT.
US Patent No. 7674480 describes a controlled release gastroretentive oral formulation of therapeutic agents like methylphenidate. The formulation comprises immediate or controlled release of the active ingredient. Tablets of this type can be adhered to the mucosal wall of the stomach because the proposed formulation consists of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and cross linked polyacrylic acid as bioadhesive polymers. The patent is based on the bioadhesion system and does not disclose combination with floating matrix system which provides superior gastroretention than the invention described in the said patent.
EP Patent No. 305051 describes a sustained release oral pharmaceutical containing acetaminophen. A bilayer tablet with an immediate-release layer and a sustained-release layer was also formulated. The patent does not describe gastroretentive or

monolithic unilayer system, which has many pharmaceutical process related advantages.
WO2001080834 describes pharmaceutical composition comprising an immediate-release phase and a sustained-release phase of paracetamol matrix bilayer tablet, which has a unique in vitro dissolution profile resulting in advantageous pharmacokinetic properties. However, application does not teach gastroretentive dosage form of paracetamol; moreover bilayer tablets can exhibit certain disadvantages and are not easy for large scale manufacturing.
WO2009114648 describes gastroretentive controlled release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic, wherein the controlled-release portion was compressed with the immediate-release portion to form a bilayer tablet. The application describes combination of two therapeutic categories such as non opiate and opiate analgesics in a bilayer tablet, containing controlled-release portion and an immediate-release portion.
None of the aforementioned prior art, discloses gastroretentive dosage form of paracetamol comprising a system of hydrophilic swellable floating matrix in combination with bioadhesive system, new dose and dosage regimen. Controlled release dosage forms are designed not only to reduce the Cmax, but also to reduce fluctuations in plasma drug concentration. Gastroretentive dosage forms of paracetamol of the present invention are designed to achieve desired drug release profile which provide safe and effective dosage.
SUMMARY OF THE INVENTION:
The present invention relates to gastroretentive dosage form of paracetamol comprising a system of hydrophilic swellable floating matrix in combination with a bioadhesive system, wherein said combination of drug delivery system consists of hydrogel(s), superdisintegrant(s), microenvironmental pH modifier(s) and pharmaceutical^ acceptable excipients. The present invention further discloses a process for preparation of said dosage forms.

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 solid oral pharmaceutical composition comprising gastroretentive dosage form of paracetamol. The gastroretentive drug delivery system releases paracetamol at a predetermined rate, and also eliminates the undesired peak plasma concentration, thus reducing or eliminating unwanted side effects. The unique features of the formulation are enhanced bioavailability, reduced side effects and stable formulation. Moreover, the proposed dosage form offers better patient compliance by reducing the dosing frequency as well as adverse drug reaction profile. The propose dosage form can be administered twice daily, when compared with thrice daily administration of conventional controlled release dosage form of paracetamol. The present invention describes solid oral gastroretentive formulation of paracetamol comprising a system of hydrophilic swellable floating matrix in combination with a bioadhesive system, wherein said combination of drug delivery system consists of hydrogel(s), superdisintegrant(s), microenvironmental pH modifier(s) and pharmaceutically acceptable excipients.
Paracetamol has an analgesic and antipyretic properties. Paracetamol, the active ingredient of the formulation of present invention, is present in the range of 10% to 80% by weight of total formulation.
Hydrogel is a network of polymer chains that are water-insoluble, and sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are highly absorbent natural or synthetic polymers, which can accommodate upto over 99% water. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content.
Hydrogels are one of the upcoming classes of polymer-based controlled-release drug delivery systems. Besides exhibiting controlled drug release, hydrogels also show stimuli-responsive changes in their structural network, and hence the drug release.

Due to large variations in physiological pH at various body sites in normal as well as pathological conditions, pH-responsive polymeric networks have been extensively studied. Hydrogels (a class of polymeric systems) are used in controlled drug delivery, and their application in stimuli-responsive, especially pH-responsive, drug release profile. Hydrogels used in the present invention are selected from the group consisting of cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC), methyl cellulose (MC), Carboxymethyl cellulose (CMC), Sodium carboxymethyl cellulose (NaCMC) and calcium carboxylmethyl cellulose (CaCMC).
The role of superdisintegrant(s) is to absorb high quantity of gastric fluids and offer aqueous environment for matrix system. Gastric fluid absorbed by superdisintegrants, lead to faster gellation of hydrophillic polymer to form a viscous gel layer. The resulting gel layer maintains the integrity of the tablet dosage form, and acts as a barrier for drug release and hence prevents the breakdown of matrix in GIT and prevents dose dumping of the dosage form. The superdisintegrants used in the present invention are selected from a group consisting of but not limited to crospovidone, croscarmellose sodium and sodium starch glycollate, in the range of 0.5% to 15% by weight of total formulation.
The micro environmental pH modifier(s) are used to suppress the drug ionisation and hence, offer better absorption in the GIT. The microenvironmental pH modifiers used in the present invention in the formulation are selected from a group consisting of carbonates, bicarbonates, phosphates, borates preferably carbonates and bicarbonates more preferably sodium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, aluminium carbonate and zinc carbonate, in the range of 0.5% to 55% by weight of the total composition.
The pharmaceutically acceptable excipients include buffers, diluents, lubricants and glidants.
The diluent used in the present invention is at least one component selected from a group consisting of but not limited to a monosaccharide, a disaccharide, sugars

including lactose, sucrose, glucose, lactulose and dextrose, polyols including mannitol, xylitol, erythritol, dulcitol, ribitol, lactitol and sorbitol, cellulose derivatives including micro crystalline cellulose, semisynthetic cellulose, and inorganic compounds such as calcium carbonate, magnesium carbonate, calcium phosphate, dibasic calcium phosphate and calcium sulfate, in the range of 0.5 to 80% by weight of the total composition.
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 Quantity
(mg)
1 Paracetamol 650
2 Hypromellose K15 M 137
3 Sodium Starch Glycollate 40
4 Sodium Bicarbonate 40
5 Lactose 40
6 Magnesium stearate 9
7 Colloidal Silicon Dioxide 9
Paracetamol, Hypromellose K 15 M, Sodium Starch Glycollate, Sodium Bicarbonate and Lactose, are weighed and sifted through 30 mesh.
Mixed all the above ingredients uniformly and granulated with isopropyl alcohol: water (70:30).
Dried the granules and sifted through 30 mesh.

Lubricated the above granules with Magnesium Stearate and Colloidal Silicon Dioxide compressed the granules with tablet punch.
Example 2:

Sr.
No. Ingredients Quantity
(mg)
1 Paracetamol 650
2 Hypromellose K 15 M 80
3 Hypromellose K 100 LV 30
4 Croscarmellose Sodium 35
5 Sodium Bicarbonate 30
6 Microcrystalline Cellulose 40
7 Magnesium stearate 7
8 Colloidal Silicon Dioxide 7
Paracetamol, Hypromellose K 15 M, Hypromellose K 100 LV, Croscarmellose Sodium, Sodium Bicarbonate, Microcrystalline Cellulose are weighed, and sifted through 30 mesh.
Mixed the above ingredients uniformly and granulated with isopropyl alcohol: water (70:30). Driedthe granules and sifted through 30 mesh.
Lubricated the above granules with Magnesium Stearate and Colloidal Silicon Dioxide and compressed the granules with tablet punch.
Drug Release Profile:

Sr. No. Time Points % Drug release
1 30 min. 59
2 l Hr 64
3 2 Hr 72
4 4 Hr 80
5 6 Hr 88
6 8 hr 95

Example 3:

Sr.
No. Ingredients Quantity
(mg)
1 Paracetamol 650
2 Hydroxypropyl Cellulose 60
3 Croscarmellose Sodium 25
4 Sodium Bicarbonate 30
5 Microcrystalline Cellulose 40
6 Magnesium stearate 7
7 Colloidal Silicon Dioxide 7
Paracetamol, Hydroxypropyl Cellulose, Croscarmellose Sodium, Sodium Bicarbonate, Microcrystalline Cellulose are weighed, and sifted through 30 mesh.
Mixedthe above ingredients uniformly, and granulated with isopropyl alcohol: water
(70:30)
Dried the granules, and sifted through 30 mesh.
Lubricated the above granules with Magnesium Stearate and Colloidal Silicon Dioxide and compressed the granules with tablet punch.
Example 4:

Sr. No, Ingredients Quantity (mg)
1 Paracetamol 650
2 Hydroxethyl Cellulose 40
3 Hypromellose K 100 LV 30
4 Sodium Starch Glycollate 35
5 Sodium Bicarbonate 40
6 Lactose 30
7 Magnesium stearate 7
8 Colloidal Silicon Dioxide 7

Paracetamol, Hydroxyethyl Cellulose, Hypromellose K 100 LV, Sodium Starch Glycollate, Sodium Bicarbonate and Lactose are weighed and sifted through 30 mesh.
Mixed the above ingredients uniformly and granulated with isopropyl alcohol: water
(70:30)
Dried the granules and sifted through 30 mesh.
Lubricated the above granules with Magnesium Stearate and Colloidal Silicon Dioxide and compressed the granules with tablet punch.
Drug Release Profile:

Sr. No. Time Points % Drug release
1 30 min. 35
2 l Hr 46
3 2 Hr 53
4 4 Hr 65
5 6 hr 72
6 8 hr 84
Example 5:

Sr. No Ingredients Quantity
(mg)
1 Paracetamol 650
2 Hydroxy Propyl Methyl Cellulose K 4M 100
3 Hydroxy Ethyl cellulose 50
4 Sodium Bicarbonate 40
5 Sodium starch Glycollate 40
6 Lactose 42
7 Magnesium stearate 9
8 Colloidal silicon Dioxide 9

Paracetamol, Hydroxy Propyl Methyl Cellulose K 4M, Hydroxy Ethyl cellulose are weighed and sifted through 30 mesh.
Mixed all the above ingredients uniformly and granulated with isopropyl alcohol: water (50:50).
Dried the granules and sifted through 30 mesh.
Lubricated with Sodium Starch Glycollate, Sodium Bicarbonate, Lactose, Magnesium Stearate and Colloidal Silicon Dioxide and compressed the granules with tablet punch.
Drug Release Profile:

Sr.
No Time Points % Drug Release
1 30 min. 50
2 l Hr 58
3 2 Hr 66
4 4 Hr 77
5 6 Hr 86
6 8 Hr 92
Example 6:

Sr.
No Ingredients Quantity
(mg)
1 Paracetamol 650
2 Hydroxy Propyl Methyl Cellulose K 4 M 137
3 Sodium Bicarbonate 40
4 Sodium starch Glycollate 40
5 Lactose 40
6 Magnesium stearate 9
7 Colloidal silicon Dioxide 9

Weighed Paracetamol, Hydroxy Propyl Methyl Cellulose K 4M, and sifted through 30 mesh.
Mixed all the above ingredients uniformly and granulated with isopropyl alcohol: water (50:50).
Dried the granules and sifted through 30 mesh.
Lubricated with Sodium Starch Glycollate, Sodium Bicarbonate, Lactose, Magnesium Stearate and Colloidal Silicon Dioxide andcompressed the granules with tablet punch.
Drug release Profile:

Sr. No Time Points % Drug Release
1 30 min. 38
2 l Hr 43
3 2 Hr 51
4 4 Hr 63
5 6 Hr 72
6 8 Hr 89

We claim:
1. A solid oral gastroretentive dosage form of paracetamol comprising a system of hydrophilic swellable floating matrix in combination with a bioadhesive system, wherein said system consists of hydrogel(s), superdisintegrant(s), microenvironmental pH modifier(s) and pharmaceutically acceptable excipients.
2. The gastroretentive dosage form of paracetamol according to claim 1, wherein the paracetamol is present in the range of 10% to 80% by weight of total formulation.
3. The gastroretentive dosage form of paracetamol according to claim 1, wherein the hydrogel(s) are selected from a group consisting of cellulose derivatives including hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and calcium carboxylmethyl cellulose, present in the range of 10-50%.
4. The gastroretentive dosage form of paracetamol according to claim 1, wherein the superdisintegrant(s) are selected from a group consisting of crospovidone, croscarmellose sodium and sodium starch glycollate, present in the range of 0.5% to 15%o by weight of total formulation.
5. The gastroretentive dosage form of paracetamol according to claim 1, wherein the microenvironmental pH modifier(s) are selected from a group consisting of carbonates, bicarbonates, phosphates and borates, preferably carbonates and bicarbonates, present in the range of 0.2% to 20% by weight of the total composition.
6. The gastroretentive dosage form of paracetamol according to claim 5, wherein the microenvironmental pH modifiers are preferably selected from sodium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, aluminium carbonate or zinc carbonate.

7. The gastroretentive dosage form of paracetamol according to claim 1, wherein the pharmaceutically acceptable excipients comprises one or more buffers, diluents, lubricants and glidants.
8. A process for preparation of gastroretentive dosage form of paracetamol as claimed in claim 1, comprising mixing paracetamol, hydrogels, superdisintegrants and microenvironmental pH modifiers, uniformly; granulating the resulting mixture with isopropyl alcohol and water; drying the granules and sifting the granules through the mesh; lubricating the granules with magnesium stearate and colloidal silicon dioxide, and compressing the granules in desired shape.