Title of Invention	A PROCESS FOR THE PREPARATION OF A DELAYED RELEASE MULTI-LAYERED ORAL PHARMACEUTICAL FORMULATION IN THE FORM OF A TABLET
Abstract	The invention discloses a benzimidazole delayed release multi layered tablet formulation wherein the active compound is mixed with pharmaceutical aduvant/s and then layered in between a multi tier tablet structure.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) The Patent Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) "A PROCESS FOR THE PREPARATION OF A DELAYED RELEASE MULTI-LAYERED ORAL PHARMACEUTICAL FORMULATION IN THE FORM OF A TABLET" We, CADILA HEALTHCARE LTD., a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India. The following specification particularly describes the nature of the invention and the manner in which it is to be performed: 1 ORIGINAL 1025/MUM/2003 Field of Invention The present invention relates to a process for the preparation of a delayed release multi-layered oral pharmaceutical formulation in the form of a tablet. Background of the invention The present invention relates to formulations containing a benzimidazole. These compounds are used to treat gastroesophageal reflux disease (GERD). Benzimidazoles reduce gastric acid production by irreversibly inhibiting the H+/K+ ATPase of the parietal cell-the final common pathway for gastric acid secretion (Fellenius et a!., 1981; Wallmark et al., 1985; Frylund et al., 1988). Because these drugs maintain gastric pH control throughout the dosing interval and have a very good safety profile, it is a logical choice for stress ulcer prophylaxis. Benzimidazoles are prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, GERD, severe erosive esophagitis, poorly responsive systematic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These conditions are caused by an imbalance between acid and pepsin production, called aggressive factors, and mucous, bicarbonate, and prostaglandin production, called defensive factors. Rabeprazole is an orally active, potent, irreversible inhibitor of H+ K+ ATPase. Hence, they are classitied as proton pump" mnibitors. The proton pump is tne tinal step in acid production and the compounds of this class combine covalently with the associated H+ K+ ATPase to get a profound and prolonged inhibition of gastric acid secretion. The Cmax of Rabeprazole is about 4 to 5 hours in humans and the serum half-life is about 50 minutes to 1.5 hours depending on dose. It gives acid inhibitory effect for about 24 hours. Rabeprazole sodium, is a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-metiiyl-2-pyridinyl]-me1nyl]sulfinyl]-lH-benzimidazole sodium salt. It has an empirical formula of C18H2oN3NaO3S and a molecular weight of 381.43. Rabeprazole sodium, is a salt of weak acid and is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform and ethylacetate and 2 insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions, US patent 6605303 discloses an extended release once-a-day formulation wherein the benzimidazole moiety core is put in a hydrophilic or hydrophobic matrix. US patent 6299904 discloses a buccal release tablet containing benzimidazole. Benzimidazoles are however susceptible to degradation/transformation in acid reacting and neutral media. A fully bioavailable dosage form of rabeprazole must release the active drug rapidly in the proximal part of the gastrointestinal canal. An oral dosage form of rabeprazole must be protected from contact with the acid reacting, gastric juice in order to reach the small intestine without degradation where pH is near to pH 6.8 and where rapid absorption can occur. Ordinary enteric coatings, however, are made of acidic compounds. If covered with such a conventional enteric coating, rabeprazole rapidly decomposes by direct or indirect contact with it, with the result that the preparations become badly discolored and loss in rabeprazole content decreased with the passage of time. The current practice known in the art is to put a separating / barrier layer in between the drug core and the enteric coat as to prevent the interaction among the acidic polymer and the drug. Object of the invention The object of the present invention is to provide an oral pharmaceutical formulation of proton pump inhibitors that is protected against gastric acid so that the drug can reach the small intestine without degradation. Another object of the invention is to provide an oral pharmaceutical formulation of proton pump inhibitors without a separating layer between the drug core .and the enteric coat. Another object of the invention is to provide a process for the preparation on an oral pharmaceutical formulation of proton pump inhibitors without a separating layer between the drug core and the enteric coat Summary of the invention These and other objects of the invention are achieved by a multi-layered delayed release benzimidiazole oral pharmaceutical formulation comprising of at least one active layer of a proton pump inhibitor active drug or one of their single enantiomers or their alkaline salts or jtheir single enantiomers with pharmaceutically acceptable 3 adjuvants encased between a plurality of supporting layers of pharmaceutically acceptable adjuvants/ fillers, the formulation being further coated with enteric coating polymers without a barrier coat between the formulation and the enteric coat. In a preferred embodiment of the invention the proton pump inhibitor used is Rabeprazole sodium. In a preferred embodiment of the invention the pharmaceutically acceptable adjuvants are selected from a group consisting of diluents, binders, lubricants, colorant and disintegrants. In another embodiment of the invention the diluents are selected from a group consisting of lactose, microcrystalline cellulose, dicalcium phosphate, sodium chloride, mannitol, starch, sugars or combination thereof. In yet another embodiment of the invention the binders are selected froma. group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulase, hydroxypropyl methylcellulose, methylcellulose carboxymethyl cellulose, ethyl cellulose for combination thereof. In a further embodiment of the invention the glidant and lubricant are selected from a group consisting of colloidal silicone dioxide, talc, sodium laurel sulphate, calcium stearate, sodium steryl fumarate, magnesium stearate or combination thereof.. In still another embodiment of the invention the disintegrant/s is selected from a group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose or combination thereof. In a preferred embodiment of the invention the enteric coating polymers are selected from a group consisting of Eudragit, ethyl cellulose, cellulose acetate phthalate or combination thereof. The instant invention also discloses a process to prepare a multi-layered delayed release benzimidiazole oral pharmaceutical formulation comprising of the following steps: a) mixing the proton pump inhibitor with pharmaceutically acceptable adjuvants, b) mixing pharmaceutically acceptable adjuvants for encasing layers; c) making tablets from above two blends by direct compression method; d) coating the tablets so formed with enteric coating polymers. Detailed description of the invention 4 The novelty of the present invention lies in the fact that the separating layer is altogether avoided and the final formulation is given a direct enteric coat without resort to the separating layer. The present invention discloses a multi-layered delayed release benzimidiazole oral pharmaceutical formulation comprising of at least one active layer of a proton pump inhibitor active drug or one of their single enantiomers or their alkaline salts or their single enantiomers with pharmaceutically acceptable adjuvants encased between a plurality of supporting layers of pharmaceutically acceptable adjuvants/ fillers the formulation being further coated with enteric coating polymers without a barrier coat between the formulation and the enteric coat. In its preferred embodiment, the invention discloses an delayed release multi layered oral pharmaceutical tablet formulation prepared by direct compression method containing at least one active layer consisting of a Rabeprazole sodium with pharmaceutically acceptable adjuvants / fillers encased between supporting layers of pharmaceutically acceptable adjuvants, further coating the tablet formulation with enteric coating polymers wherein the pharmaceutically acceptable adjuvants used in all the layers are the same such that there no barrier coat between the formulation and the enteric coat. It is to be noted that though the examples cover Rabeprazole in particular, other benzimidiazoles like omeprazole, pantoprazole, esomeprazole, lansoprazole can be formulated in similar manner to achieve substantially same results. The tabletting as per this invention is done by direct compression. The powder blend for tabletting is prepared by mixing the active ingredients with adjuvant/s for preparation of layer containing active pharmaceutical ingredient. Other layers are prepared from the powder blend prepared using adjuvant/s. The powder blend is compressed to get multi-layer tablet. Tablets are coated with enteric coating polymers such as Eudragit, ethyl cellulose, cellulose acetate phthalate, either singly or in combination. The pharmaceutical adjuvant(s) include diluent like, lactose, macrocrystalline cellulose, dicalcium phosphate, sodium chloride, mannitol, starch, sugars or combination thereof. Binders like polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, ethyl cellulose or combination thereof may also be added. 5 The glidant and lubricant that may be used include colloidal silicone dioxide, talc, sodium laurel sulphate, calcium stearate, sodium steryl fumarate, magnesium stearate or combination thereof. Disintegrant/s like sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose or combination thereof may be added. The following are non-limiting examples of the formulation according to the present invention. Examples Example 1 A. Preparation of active layer % w/w Rabeprazole sodium 20 Mannitol 41 Dicalcium phosphate 30 Talc 05 Sodium starch Glycolate 03 Sodium laurel sulphate 01 Rabeprazole sodium, mannitol and dicalcium phosphate are mixed for 5 min. The powder blend is mixed with sodium starch glycolate for 3 min and with Talc for additional 2 min. B. Preparation of encasing/additional/supporting layer % w/w Mannitol 50 Dicalcium phosphate 40 Talc 05 Sodium starch glycolate 04 Magnesium stearate 01 Mannitol and dicalcium phosphate are mixed for 5 min. The powder blend is mixed with sodium starch glycolate for 3 min, with talc for 2 min and finally with magnesium stearate for 1 min. Multi-layer tablets are compressed in such a way that the top and 6 bottom layers consist of powder blend of part B and the middle layer(s) consists of powder blend of part A. The multi-layer tablets are coated with Eudragit L100 - 55. Example 2 A. Preparation of active layer % w/w Rabeperazole sodium 20 Microcrystalline cellulose 40 Dicalcium phosphate 30 Talc 05 Sodium starch Glycolate 03 Sodium laurel sulphate 01 Rabeprazole sodium, lactose and microcrystalline cellulose are mixed for 5 min. The powder blend is mixed with sodium starch glycolate for 3 min and with Talc for additional 2 min. B. Preparation of additional/supporting layer % w/w Dicalcium phosphate 50 Microcrystalline cellulose 40 Talc 03 Sodium starch glycolate 06 Sodium laurel sulphate 01 Microcrystalline cellulose and dicalcium phosphate are mixed for 5 min. The powder blend is mixed with sodium starch glycolate for 3 min, with talc for 2 min and finally with sodium laurel sulphate for 1 min. Multi-layer tablets are compressed in such a way that the top and bottom layers consist of powder blend of part 2B and the middle layer(s) consists of powder blend of part 2A. The multi-layer tablets are coated with Eudragit NE 30D-55. 7 Example 3 A. Preparation of active layer % w/w Rabeprazole sodium 20 Mannitol 42 Microcrystalline cellulose 30 Talc 03 Sodium starch Glycolate 03 Sodium steryl fumarate 02 Rabeprazole sodium, mannitol and microcrystalline cellulose are mixed for 5 min. The powder blend is mixed with sodium starch glycolate and sodium laurel sulphate for 3 min, with Talc for additional 2 min and sodium steryl fumarate for 2 min. B. Preparation of encasing/ additional/supporting layer % w/w Mannitol 50 Microcrystalline cellulose 40 Talc 05 Sodium starch glycolate 04 Sodium steryl fumarate 01 Mannitol and microcrystalline cellulose are mixed for 5 min. The powder blend is mixed with sodium starch glycolate for 3 min, with talc for 2 min and finally with magnesium stearate for 1 min. Multi-layer tablets are compressed in such a way that the top and bottom layers consist of powder blend of part B and the middle layer(s) consists of powder blend of part A. The multi-layer tablets are coated with Eudragit L100-55. 8 We claim: 1. A process for the preparation of a delayed release multi-layered oral pharmaceutical formulation in the form of a tablet which comprises: (i) preparing an active layer of a proton pump inhibitor, or its enantiomer/s or alkaline salt/s and at least one pharmaceutical adjuvants; (ii) preparing a plurality of supporting layers of said adjuvants; (iii) preparing a tablet with (i) and (ii) above characterized in that the said tablet is prepared by direct compression method such that the top and bottom layers consists of said adjuvants, said middle layer consists of said active layer of proton pump inhibitor and adjuvant(s), said multilayer tablet is coated with enteric coating polymers without use of additional barrier layer. 2. A process as claimed in claim 1 wherein said proton pump inhibitor used is Rabeprazole sodium. 3. A process as claimed in claim 1 wherein said pharmaceutically acceptable adjuvants are selected from a group consisting of diluents, binders, lubricants, colorant and disintegrants. 4. A process as claimed in my preceding claims wherein diluents are selected from a group consisting of lactose, microcrystalline cellulose, dicalcium phosphate, sodium chloride, mannitol, starch, sugars or combination thereof. 5 A process as claimed in any preceding claim wherein the binders are selected from a group consisting of polyvinylpyrrolidone, polyethylene glycol, droxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, ethyl cellulose or combination thereof. 6. A process as claimed in any preceding claim wherein the glidant and the lubricant are selected from a group consisting of colloidal silicone dioxide, talc, sodium laurel sulphate, calcium stearate, sodium steryl fumarate, magnesium stearate or combination thereof. 7. A process as claimed in any preceding claim wherein the disintegrant/s is selected from a group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose or combination thereof. 9 8. A process as claimed in any preceding claim wherein the enteric coating polymers are selected from a group consisting of Eudragit, ethyl cellulose, cellulose acetate phthalate or combination thereof. Dated this the 4th day of November 2004 (H. SUBRAMANIAM) of SUBRAMANIAM, NATARAJ & ASSOCIATES Attorney for the applicants 10

Documents:

1025-mum-2003-abstract(31-10-2007).doc

1025-mum-2003-abstract(31-10-2007).pdf

1025-mum-2003-abstract(complete)-(5-11-2004).pdf

1025-mum-2003-abstract(granted)-(20-12-2007).pdf

1025-mum-2003-abstract(provisional)-(15-7-2005).pdf

1025-mum-2003-cancelled page(31-10-2007).pdf

1025-mum-2003-cancelled pages(21-5-2008).pdf

1025-mum-2003-cancelled pages(5-11-2004).pdf

1025-mum-2003-claims(complete)-(5-11-2004).pdf

1025-mum-2003-claims(granted)-(20-12-2007).pdf

1025-mum-2003-claims(granted)-(31-10-2007).doc

1025-mum-2003-claims(granted)-(31-10-2007).pdf

1025-mum-2003-claims(retyped)-(26-10-2007).pdf

1025-mum-2003-correspondence(21-5-2008).pdf

1025-mum-2003-correspondence(31-10-2007).pdf

1025-mum-2003-correspondence(ipo)-(14-1-2008).pdf

1025-mum-2003-correspondence(ipo)-(24-10-2007).pdf

1025-mum-2003-description(complete)-(5-11-2004).pdf

1025-mum-2003-description(granted)-(20-12-2007).pdf

1025-mum-2003-description(provisional)-(15-7-2005).pdf

1025-mum-2003-form 1(30-09-2003).pdf

1025-mum-2003-form 1(30-10-2003).pdf

1025-mum-2003-form 1(31-10-2007).pdf

1025-mum-2003-form 18(29-12-2005).pdf

1025-mum-2003-form 2(complete)-(5-11-2004).pdf

1025-mum-2003-form 2(granted)-(20-12-2007).pdf

1025-mum-2003-form 2(granted)-(31-10-2007).doc

1025-mum-2003-form 2(granted)-(31-10-2007).pdf

1025-mum-2003-form 2(provisional)-(15-7-2005).pdf

1025-mum-2003-form 2(title page)-(complete)-(5-11-2004).pdf

1025-mum-2003-form 2(title page)-(granted)-(20-12-2007).pdf

1025-mum-2003-form 2(title page)-(provisional)-(15-7-2005).pdf

1025-mum-2003-form 3(07-07-2007).pdf

1025-mum-2003-form 3(30-09-2003).pdf

1025-MUM-2003-FORM 3(7-9-2007).pdf

1025-mum-2003-form 4(05-11-2004).pdf

1025-mum-2003-form 5(05-11-2004).pdf

1025-mum-2003-form 5(07-09-2007).pdf

1025-mum-2003-form 5(7-9-2007).pdf

1025-mum-2003-form-pct-isa-210(30-9-2003).pdf

1025-mum-2003-general power of authoritey(30-09-2003).pdf

1025-MUM-2003-GENERAL POWER OF AUTHORITY(30-9-2003).pdf

1025-mum-2003-specification(amanded)-(21-5-2008).pdf

1025-mum-2003-specification(amanded)-(31-10-2007).pdf

1025-mum-2003-specification(amended)-(31-10-2007).pdf

1025-mum-2003-specification(amended)-(7-9-2007).pdf

1025-mum-2003-wo international publication report(21-5-2008).pdf

1025-mum-2003-wo international publication report(30-9-2003).pdf