COMPLETE AFTER PROVISIONAL
LEFT ON 11/09/06



FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [ See Sections 10 and rule 13 ]
Title: MODIFIED RELEASE DOSAGE FORM OF ACID LABILE BENZIMIDAZOLE COMPOUND
Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10th Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
The following specification particularly describes the invention and the manner in which it is to be performed.

1 1 SEP Z0Q6

Field of the invention
The present invention relates to oral pharmaceutical dosage forms for acid labile benzimidazole compound preferably pantoprazole. This dosage form is in the form of capsule or tablets containing the said benzimidazole.
Background
The compound, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] sulphinyl]-lH-benzimidazole is a benzimidazole compound suitable for inhibiting the gastric secretion in mammals. In particular, it is suitable for the prevention and treatment of disorders related with the secretion of gastric acid, for example, gastric ulcer, duodenal ulcer, reflux esophagitis, Zollinger-Ellison syndrome, etc. Other benzimidazole compounds with anti-ulcer activity are omeprazole, lansoprazole and rabeprazole.
Pantoprazole, just as is the case with other benzimidazole compounds that have therapeutic interest, is an acid labile compound. This causes numerous problems when it comes to developing a pharmaceutical formulation for oral administration due to the fact that when said compound comes into contact with the stomach content, which is a strongly acidic environment, degradation occurs.
To avoid contact between acid labile compounds and gastric juice after oral administration of said compounds, solid pharmaceutical formulations have been developed that comprise a nucleus that contains the acid labile compound and an external layer that constitutes a gastro-resistant coating that may be separated by one or more intermediate layers.
Pace 2 of36

Prior art
WO2005009410 discloses a pharmaceutical dosage form comprising a pharmaceutical
active and a disintegrant, a swellable coating surrounding the core, an enteric coating surrounding the swellable coating. The swellable coating comprises one or more hydrocolloid-formers selected from zein, crospovidone, and a hydroxypropyl cellulose.*
US6068856 discloses a delayed and controlled release oral pharmaceutical composition comprising pantoprazole, an alkaline pellet or tablet core, at least one intermediate layer controlling release of active ingredient and an outer enteric layer, which is soluble in the small intestine.
WO2005110488 disclosed an inclusion complex comprising benzimidazole with improved storage stability wherein a water-soluble polymer is added when a benzimidazole derivative is being included into cyclodextrin.
WO2005051362 discloses oral benzimidazole pharmaceutical composition, the composition comprising a core comprising a benzimidazole compound and one or more pharmaceutically acceptable excipients, a separating layer surrounding the core comprising a water-insoluble and non-disintegrating polymer, an enteric coating surrounding the separating layer. The water insoluble and substantially non-disintegrating polymer comprises one or more of cellulose acetate, ethylcellulose, hydroxyethylcellulose and zein.
Objects of the invention
First object of the present invention is to provide orally administrable acid stable antiulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof.
Page 3 of 36

Another object of present invention is to develop the pharmaceutically stable oral formulation for Pantoprazole.
One more object of the present invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products capable of being used clinically.
This pharmaceutical invention further aims to develop the pharmaceutical formulations for oral use, which avoid contact between acid labile compounds and gastric juice after oral administration of said compounds.
Still one more object of the present invention is to provide solid pharmaceutical formulations comprise a dosage form containing the benzimidazole derivative or its pharmaceutically acceptable salts in a gelatin capsule or compressed as tablet and an external layer that constitutes a gastro-resistant coating that may be separated by one or more intermediate layers for uniform coating of the capsule or a layer of excipients. e.g.: Tablet in Tablet.
Summary of the Invention
In accordance with the present invention, there is provided a method of treating gastric acid disorders by orally administering to a patient a pharmaceutical composition(s) and/or dosage form(s) of benzimidazole, preferably Pantoprazole disclosed herein.
Page 4 of 36

Detailed Description of the Invention
The present invention provides a solid pharmaceutical formulation as enteric coated dosage form that contains an acid labile benzimidazole compound preferably Pantoprazole as an active ingredient, suitable for oral administration, hereinafter the pharmaceutical formulation of the invention, that comprises a capsule or tablet as dosage form that contain the active ingredient, one or more intermediate layers and an external enteric coating over the capsule or tablet.
Modified release in the present invention means release of active ingredient from the dosage form in gastrointestinal tract below stomach.
In a preferred embodiment, the subject formulation comprises:
Core covered by intermediate coating further coated by enteric coating wherein Core comprises of active pharmaceutical ingredient, filler, diluent, alkalizer, disintegrant, binder, lubricant etc. The intermediate - seal coat comprising luster clear and water or seal coating material comprising sugar with gelatin, glident, stabilizer, solvent etc. The enteric coat comprising enteric coating polymer, plastisizer, opacifier, glident, solvent etc.
The active pharmaceutical ingredient can be 5 - 50% and selected from the group of benzimidazole. The preferred benzimidazole compound is pantoprazole or its pharmaceutically acceptable salt in the range of 9-90 mg per weight of core of dosage form.
Diluent, ranges from 10 - 90%, can be selected from the group comprising of but not limited to mannitol, sorbitol, xylitol, lactose, dicalcium phosphate, calcium sufate, kaolin,sodium chloride, starch, sucrose, bentonite or combination thereof
Page 5 of 36

Filler, ranges from 10% to 90%, can be selected from the group comprising of but not limited to mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose, carbonates and bicarbonates, phosphates, oxides or hydroxides of metal, starch or combination thereof.
Pharmaceutically acceptable alkalizers, ranges from 3-15%, can be selected from the group comprising of but not limited to carbonate, bicarbonate, hydroxides or halides of alkali or alkaline earth metals or salts of glycine and alkali metal carbonates.
Binder, ranges from 0.1 to 25% can be selected from the group comprising of but not limited to starch, povidone, and modified starch, natural or synthetic gums.
Disintegrant ranges selected from 1-30%, can be selected from the group comprising of but not limited to cross linked polymer, cross linked cellulose or starch or combination thereof.
Lubricant, ranges from 0.5-15%, can be selected from the group comprising of but not limited to talc, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumerate etc.
The formulation of the present invention is preferably based on a granules or pellets formed from a methods optionally wet granulation, dry granulation (slugging) or pelletization or direct compression technology which comprises an acid-labile compound as an active ingredient and pharmaceutically acceptable excipients wherein an acid labile compound is a substituted benzimidazole such as Pantoprazole.
The granules or pellets are to be filled in capsule or compressed into tablets or these granules or pellets are coated by intermediate layer and enteric coat and then filled
Page 6 of 36

into the capsule. For capsules, the shell can be of gelatin or hydroxy propyl methylcellulose.
The intermediate layer or coat can be of film polymer or sugar coat or of luster clear. The sugar coat comprises sugar, gelatin, glident(s), stabilizer, solvent, etc. The enteric coat comprises enteric coating polymer, plasticizer, opacifier, glident, solvent etc.
Solvents is used as per the quantity required can be selected from the group comprising of but not limited to isopropanolol, purified water, mixture of purified water and isopropanolol, mixture of isopropanolol and dichloromethane etc.
Stabilizers ranges from 1 - 15% can be selected from the group comprising of but not limited to alkali metal oxides like magnesium oxide,sodium oxide,alkali metal hydroxides like sodium hydroxide, magnesiumhydroxide, carbonates like mono sodium glycine carbonate, di sodium glycine carbonate,sodium carbonate anhydrous,amines,aminoacids and salts etc.
Glidents, ranges from 0.5 - 15 %, can be selected from the group comprising of but not limited to talc,sodium stearyl fumerate, magnesium stearate, stearic acid, calcium stearate etc.
Plasticizer, ranges from 0.5 -25%, can be selected from the group comprising of but not limited to triethyl citrate, acetylated triethyl citrate, methyl citrate, propylene glycol, polyethylene glycol, triacetin etc.
Opacifiers, ranges from 1 - 10%, can be selected from the group comprising of but not limited to titanium dioxide, talc and all colorants etc.
Page 7 of 36

The film polymers which can be used for the intermediate layer are selected from the group comprising but not limited to hydroxy propyl methyl cellulose, hydroxy propylcellulose, polyvinylpyrrolidone, methacrylate co-polymers, sodium alginate, guar gum and/or sodium carboxymethyl cellulose or zein. The outer layer of tablet consists of mannitol, sorbitol and or the alkaline excipients.
Aqueous dispersions of suitable polymers which are resistant to gastric juice, are selected from the group comprising but not limited to a methacrylic acid/methyl methacrylate copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate if desired with the addition of a plasticizer, optionally surface active agent and/or anti-adherent are advantageously used.
Types of the dosage forms:
In a preferred embodiment, the subject formulation comprises:
A) an oral dosage form preferably capsule filled with granules comprising of
1) a therapeutically effective amount of an active ingredient, e.g., an acid-labile
compound such as a substituted benzimidazole preferably pantoprazole
2) a filler
3) a pharmaceutically acceptable alkaline agent
4) a binder
5) a disintegrant, and
6) a lubricant
7) a single and/or multiple layer of coating on capsule, the coating comprising an intermediate/precoating agent and enteric coating agent.
B) Orally administrable benzimidazole, preferably pantoprazole tablet, which is
resistant to gastric juice where core components comprises of pantoprazole, sodium
carbonate, povidone, calcium stearate and mannitol (same as to that of innovator), an
inert water insoluble zein coating as intermediate layer which is protective coat
Page 8 of 36

surrounding the core, outer layer which is resistant to gastric juice with Eudragit polymer.
C) Tablet dosage form comprising core of therapeu'tically active ingredient, e.g., an
acid-labile compound such as a substituted benzimidazole preferably pantoprazole, an
outer inert alkaline ingredients layer, a single or multiple layer of coating comprising
atleast one layer of enteric coating polymer.
D) Dosage form comprising granules or pellets of benzimidazole comprising
benzimidazole or its pharmaceutically acceptable salt and pharmaceutically acceptable
excipients, coated with intermediate coat and finally coated with the enteric coat, are
either compressed into the table or filled into the capsule.
E) Tablet of benzimidazole comprising benzimidazole or its pharmaceutically
acceptable salt and pharmaceutically acceptable excipients, covered by an outer tablet
of pharmaceutically acceptable excipients and finally coated with the enteric coat.
Advantages of the invention
The stabilized pharmaceutical compositions of the present invention shows number of advantages as follows:
1) The present invention provides a solution to avoid contact between acid labile compounds and gastric juice after oral administration of said compounds.
2) Minimum number of excipients is required for filling in capsule as compared to tablet dosage form
3) They exhibit an extended shelf life under normal storage conditions.
4) They exhibit minimal, if any, degradation over a significant period of time.
5) They exhibit good stability when developed as enteric-coated capsule dosage form.
6) When developed as tablet in tablet dosage form, intermediate coating layer will not be required for stability.
Page 9 of 36

Process for preparation of dosage form:
1. Active pharmaceutical ingredient, diluent, alkelizer, disintegrant, lubricant are mixed and compressed to prepare a core. Core can also be prepared by active pharmaceutical ingredient layered on inert core.
2-a While using luster clear for intermediate coating the luster clear is dispersed
in the solvent preferably water. This solution is sprayed on the tablet in suitable apparatus.
2-bWhile using sugar coating as an intermediate coating the coating solution is prepared, wherein gelatin is soaked in solvent preferably water and sugar is dissolved in solvent preferably water. These solutions are mixed and glident homogenized in water is added with stirring and then stabilizer is added. This total clear is sieved and sprayed onto the tablet.
3. Enteric coating is done
Throughout this specification and the appended claims it is to be understood that the words "comprise" and include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Examples :
The present invention has been described by way of example only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.
The above said invention can be illustrated by but not limited to following examples.
Page 10 of 36

Enteric Coated Capsule filled with granules
Example: 1 (Wet Granulation)
Composition:

Sr.No. Ingredients Category %w/w
1) Pantoprazole as Sodium salt Active 16.0
2) Mannitol Diluent 47.04
3) Sodium Carbonate Anhydrous Alkalizer/diluent 8.0
4) Crospovidone Disintegrant 24.0
5) Povidone K-90 Binder 2.40
6) Purified water Solvent q.s.
7) Calcium Stearate Lubricant 2.56
Total 100.0
Process for preparation:
Pantoprazole as Sodium salt is mixed with mannitol, some of sodium carbonate anhydrous and crospovidone. The remainder of sodium carbonate anhydrous are added to clear aqueous solution of povidone K-90 and the pH is brought to >10 with sodium carbonate anhydrous. Granules are obtained with this solution in a rapid mixer granulator. The remainder of crospovidone, and calcium stearate are added to the dry granules and granules are filled suitable size of capsule preferably size "4".
Page 11 of 36

Example: 2 (Dry Granulation) (Slugging) Composition:

Sr. No. Ingredients %w/w
1) Pantoprazole as Sodium salt 16.0
2) Mannitol 47.04
3) Sodium Carbonate Anhydrous 8.0
4) Crospovidone 24.0
5) Povidone K-90 2.40
6) Calcium Stearate 2.56
Total 100.0
Process for preparation:
Pantoprazole as sodium salt is mixed with mannitol, sodium carbonate anhydrous and povidone K-90, some of crospovidone and calcium stearate. Slugs are obtained by slugging this blend in a roller compactor. Granules are obtained by sieving and/or nilling slugs in sifter cum mill. The remainder of calcium stearate are added to the p-anules and granules are filled in suitable size of capsule preferably size "4".
Example: 3 Directly compressible blend to be filled in capsule
Composition:

Sr. No. Ingredients %w/w
1) Pantoprazole as Sodium salt 16.0
2) Mannitol directly compressible grade 47.04
3) Sodium Carbonate Anhydrous 8.0
Page 12 of 36

4) Crospovidone 24.0
5) Povidone K-90 2.40
6) Calcium Stearate 2.56
Total 100.0
Process for preparation:
All the ingredients are mixed in blender and obtained blend is to be filled in suitable
size of capsule preferably size "4".
Example: 4
Composition:

Sr. No. Ingredients % w/w
1) Pantoprazole as Sodium salt 16.0
2) Mannitol directly compressible grade 48.44
3) Sodium Carbonate Anhydrous 8.0
4) Crospovidone 24.0
5) Calcium Stearate 3.56
Total 100.0
Process for preparation:
All the ingredients are mixed in blender and obtained blend is to be filled in suitable size of capsule preferably size "4".
Page 13 of 36

Pre-Coating (Intermediate coating)
Example: 5
Composition:

Sr.No. Ingredients %w/w
1) Hydroxy Propyl cellulose 100.0
2) Purified Water q.s.
Total 100.0
Process of coating:
Two third of water is heated to 90°C. Hydroxy propyl cellulose is added to the water with gentle agitation and mixed for 60 min. Finally the remaining water is added and cooled down below 35°C. Capsules are coated with an adequate layer thickness of the solution in a suitable apparatus.
Example: 6
Composition:

Sr. No. Ingredients %w/w
1) Hydroxypropylmethyl cellulose 90.0
2) Povidone 10.0
3) Purified Water q.s.
Total 100.0
Page 14 of 36

Process of coating:
Two third of water is heated to 60°C. Hydroxy propyl methyl cellulose and povidone are added to the water with gentle agitation and mixed for 30 min. Finally the remaining water is added and cooled down below 35°C. Capsules are coated with an adequate layer thickness of the solution in a suitable apparatus.
Enteric Coating (Coating with a layer which is resistant to gastric juice)
Example: 7
Composition:

Sr. No. Ingredients %w/w
1) Eudragit L 30 D 55 73.32*
2) Triethyl Citrate 7.35
3) Talcum 18.33
4) Polysorbate 80 1.0
5) Purified Water q.s.
Total 100.0
* Based on dry weight
Process of coating:
Eudragit L 30 D 55 is diluted with water and triethyl citrate and polysorbate 80 are added while gentle stirring. Milled dispersion of talcum was added with gentle stirring. The dispersion is sieved before processing and sprayed in suitable apparatuses, onto the precoated capsules.
Page IS of 36

Example: 8
Composition:

Sr. No. Ingredients %w/w
1) Hydroxy propyl methyl cellulose phthalate 84.0
2) Triethyl Citrate 8.0
3) Talcum 8.0
4) Acetone q.s.
5) Isopropyl alcohol q.s.
Total 100.0
Process of coating:
Hydroxy propyl methylcellulose phthalate is dissolved in mixture of acetone and isopropyl alcohol (1:1) with stirring and triethyl citrate is added. Milled dispersion of talcum was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatuses, onto the precoated capsules.
Plg»16of36

Example: 9
Composition:

Sr. No. Ingredients %w/w
1) Cellulose acetate phthalate 80.0
2) Triethyl Citrate 10.0
3) Talcum 10.0
4) Acetone q.s.
5) Methylene chloride q.s.
Total 100.0
5rocess of coating:
Cellulose acetate phthalate is dissolved in mixture of acetone and methylene chloride (1:1) with stirring and triethyl citrate is added. Milled dispersion of talcum was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the precoated capsules.
Examples of Tablets
Example: 10 (Wet Granulation)
Step A: Core Tablets
Composition:

Sr. No. Ingredients Category % w/w
1) Pantoprazole as Sodium salt Active 16.0
2) Mannitol Diluent 47.04
3) Sodium Carbonate Anhydrous Alkalizer/diluent 8.0
4) Crospovidone Disintegrant 24.0
P«gel7ofJ6

5) PovidoneK-90/Hydroxypropyl cellulose Binder 2.40
6) Purified water Solvent q.s.
7) Calcium Stearate Lubricant 2.56
Total 100.0
Process for preparation:
Pantoprazole as Sodium salt is mixed with mannitol, some of sodium carbonate anhydrous and crospovidone. The remainder of sodium carbonate anhydrous are added to clear aqueous solution of povidoneK-90/hydroxypropyl cellulose and the pH is brought to >10 with mannitol. Granules are obtained with this solution in a rapid mixer granulator. The remainder of crospovidone, and calcium stearate are added to the dry granules and compressed using suitable punches.
Step B: Sub-Coating (Coating with Zein) Composition:

Sr. No. Ingredients % w/w
1) Zein 2.0
2) Isopropyl alcohol 90.0
3) Purified water 8.0
Total 100.0
Process of coating:
Zein dissolved in a Isopropyl alcohol with stirring followed by adding in purified water mixed to get clear solution. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the core tablets.
Page 18 of 36

Step C: Enteric-coating Composition:

Sr. No. Ingredients %w/w
1) Methacrylic acid copolymer 55.0
2) Triethyl citrate 2.0
3) Titanium dioxide 8.0
4) Talc 5.0
5) Isopropyl alcohol 30.0
Total 100.0
Process of coating:
Methacrylic acid copolymer is dissolved in isopropyl alcohol with stirring and triethyl citrate is added. Milled dispersion of titanium dioxide and talc was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable
apparatus, onto the subcoated tablets.
Page 19 of 36

Example: 11 (Tablet in Tablet)
Direct compression Step A: Inner Core
Composition:

Sr.No. Ingredients Category %wM
1) Pantoprazole as Sodium salt Active 16.0
2) Mannitol(Direct compressible grade) Diluent 27.04
3) Sodium Carbonate Anhydrous Alkalizer/diluent 4.0
4) Crospovidone Disintegrant 6.0
5) Calcium Stearate Lubricant 1.56
Total 54.6
Process for preparation:
Pantoprazole as sodium salt is mixed with mannitol, sodium carbonate anhydrous, crospovidone and compressed the inner core tablets using suitable punches.
Page 20 of 36

StepB: Surrounding core: Composition:

Sr. No. Ingredients Category %w/w
1) Mannitol(Direct compressible grade) Diluent 33.84
2) Sodium Carbonate Anhydrous Alkalizer/diluent 4.0
3) Crospovidone Disintegrant 6.0
4) Calcium Stearate Lubricant 1.56
Total (inner-core+sorrounding core) 100.0
Process of coating:
Mannitol is mixed with sodium carbonate anhydrous, crospovidone, calcium stearate and blend is prepared. The compressed inner cores are placed in blend of surrounding cores and compression done using suitable punches.
Step C: Enteric-coating Composition:

Sr. No. Ingredients % w/w
1) Methacrylic acid copolymer 55.0
2) Triethyl citrate 2.0
3) Titanium dioxide 8.0
4) Talc 5.0
5) Isopropyl alcohol 30.0
Total 100.0
Pige 21 of 36

Process of coating:
Methacrylic acid copolymer is dissolved in isopropyl alcohol with stirring and triethyl citrate is added. Milled dispersion of titanium dioxide and talc was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Example: 12
Step A: Core Tablets

Sr. No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
2) Sorbitol(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkalizer/diluent 14.4
4) Crospovidone Disintegrant 9.0
5) Calcium Stearate Lubricant 4.6
Total 180.0
1) is mixed with 2), 3), 4) and further mixed with 5) compressed the core tablets using suitable punches.
Page 22 of 36

Step B: Surrounding core (Seal coating-Intermediate)

Sr. No. Ingredients Category mg/tab
1) Lustre clear(Mixture of MicrocrystallineCellulose + Carrageenan) Seal coating polymer 7.20
2) Purified Water Solvent -
Total 7.20
1) is dispersed in 2) with stirring and dispersion prepared, sprayed in suitable apparatus, onto the tablets.
StepC: Enteric-coating

Sr. No. Ingredients Category mg/tab
1) Methacrylic acid copolymer Enteric coating polymer 15.84
2) Triethyl citrate Plasticizer 1.59
3) Titanium dioxide Opacifier 0.32
4) Talc Glident 0.06
5) Purified Water Solvent -
Total 17.81
1) is dissolved in 5) with stirring and 2) is added. Milled dispersion of 3) and 4) was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Page 23 of 36

Example: 13
Step A: Core Tablets

Sr. No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
2) Lactose(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkalizer/diluent 14.4
4) Sodium Starch Glycollate Disintegrant 9.0
5) Calcium Stearate Lubricant 4.6
Total 180.0
1) is mixed with 2), 3), 4) and further mixed with 5) compressed the core tablets using suitable punches.
Step B: Surrounding core (Seal coating-Intermediate)

Sr. No. Ingredients Category mg/tab
1) Lustre clear(Mixture of MicrocrystallineCellulose + Carrageenan) Seal coating polymer 7.20
2) Purified Water Solvent -
Total 7.20
1) is dispersed in 2) with stirring and dispersion prepared, sprayed in suitable apparatus, onto the tablets.
Page 24 of 36

StepC: Enteric-coating

Sr. No. Ingredients Category mg/tab
1) Methacrylic acid copolymer Enteric coating polymer 15.84
2) Triethyl citrate Plasticizer 1.59
3) Titanium dioxide Opacifier 0.32
4) Talc Glident 0.06
5) Purified Water Solvent -
Total 17.81
is dissolved in 5) with stirring and 2) is added. Milled dispersion of 3) and 4) was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Example: 14
Step A: Core Tablets

Sr.No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
2) Lactose(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkalizer/diluent 14.4
4) Crospovidone Disintegrant 9.0
5) Calcium Stearate Lubricant 4.6
Total 180.0
Page 25 of 36

1) is mixed with 2), 3), 4) and further mixed with 5) compressed the core tablets using suitable punches.
Step B: Surrounding core (Seal coating-Intermediate)

Sr.No. Ingredients Category mg/tab
1) Lustre clear(Mixture of MicrocrystallineCellulose + Carrageenan) Seal coating polymer 7.20
2) Purified Water Solvent -
Total 7.20
1) is dispersed in 2) with stirring and dispersion prepared, sprayed in suitable apparatus, onto the tablets.
Step C: Enteric-coating

Sr.No. Ingredients Category mg/tab
1) Methacrylic acid copolymer Enteric coating polymer 15.84
2) Triethyl citrate Plasticizer 1.59
3) Titanium dioxide Opacifier 0.32
4) Talc Glident 0.06
5) Purified Water Solvent -
Total 17.81
is dissolved in 5) with stirring and 2) is added. Milled dispersion of 3) and 4) was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
P«ge26of36

Example: 15
Step A: Core Tablets
Sr. No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
2) Mannitol(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkalizer/diluent 14.4
4) Sodium starch Glycollate Disintegrant 9.0
5) Calcium Stearate Lubricant 4.6
Total 180.0
1) is mixed with 2), 3), 4) and further mixed with 5) compressed the core tablets using suitable punches.
Step B: Surrounding core (Seal coating-Intermediate)

Sr.No. Ingredients Category mg/tab
1) Sucrose Seal coating polymer 9.80
2) Gelatin Seal coating polymer 0.20
3) Talc Glident 1.00
4) Titanium dioxide Glident 1.00
5) Sodium Carbonate anhydrous Stabilizer 0.50
6) Purified Water Solvent -
Total 12.50
Plge27of36

2) is soaked in part qty of 6) and 1) is dissolved in part qty of 6) .Mix the solutions and add 3) 4) is homogenized in part qty of 6) with stirring and 5) is added. Dispersion of above total mix is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Step C: Enteric-coating

Sr.No. Ingredients Category mg/tab
1) Methacrylic acid copolymer Enteric coating polymer 15.84
2) Triethyl citrate Plasticizer 1.59
3) Titanium dioxide Opacifier 0.32
4) Talc Glident 0.06
5) Purified Water Solvent -
Total 17.81
1) is dissolved in 5) with stirring and 2) is added. Milled dispersion of 3) and 4) was added with gentle stirring.. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Page 28 of 36

Example: 16
Step A: Core Tablets

Sr.No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
2) Sorbitol(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkalizer/diluent 14.4
4) Sodium starch Glycollate Disintegrant 9.0
5) Calcium Stearate Lubricant 4.6
Total 180.0
1) is mixed with 2), 3), 4) and further mixed with 5) compressed the core tablets using
suitable punches.
Step B: Surrounding core (Seal coating-Intermediate)

Sr. No. Ingredients Category mg/tab
1) Sucrose Seal coating polymer 9.80
2) Gelatin Seal coating polymer 0.20
3) Talc Glident 1.00
4) Titanium dioxide Glident 1.00
5) Sodium Carbonate anhydrous Stabilizer 0.50
6) Purified Water Solvent -
Total 12.50
Page 29 of 36

2) is soaked in part qty of 6) and 1) ii dissolved in part qty of 6) .Mix the solutions and add 3) 4) is homogenized in part qty of 6) with stirring and 5) is added. Dispersion of above total mix is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Step C: Enteric-coating

Sr. No. Ingredients Category mg/tab
1) Methacrylic acid copolymer Enteric coating polymer 15.84
2) Triethyl citrate Plasticizer 1.59
3) Titanium dioxide Opacifier 0.32
4) Talc Glident 0.06
5) Purified Water Solvent -
Total 17.81
1) is dissolved in 5) with stirring and 2) is added. Milled dispersion of 3) and 4) was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Page 30 of 36

Example: 17
Step A: Core Tablets

Sr. No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
2) Lactose(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkalizer/diluent 14.4
4) Sodium starch Glycollate Disintegrant 9.0
5) Calcium Stearate Lubricant 4.6
Total 180.0
1) is mixed with 2), 3), 4) and further mixed with 5) compressed the core tablets using suitable punches.
Step B: Surrounding core (Seal coating-Intermediate)

Sr.No. Ingredients Category mg/tab
1) Sucrose Seal coating polymer 9.80
2) Gelatin Seal coating polymer 0.20
3) Talc Glident 1.00
4) Titanium dioxide Glident 1.00
5) Sodium Carbonate anhydrous Stabilizer 0.50
6) Purified Water Solvent -
Total 12.50
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2) is soaked in part qty of 6) and 1) is dissolved in part qty of 6) .Mix the solutions and add 3) 4) is homogenized in part qty of 6) with stirring and 5) is added. Dispersion of above total mix is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
Step C: Enteric-coating

Sr. No. Ingredients Category mg/tab
1) Methacrylic acid copolymer Enteric coating polymer 15.84
2) Triethyl citrate Plasticizer 1.59
3) Titanium dioxide Opacifier 0.32
4) Talc Glident 0.06
5) Purified Water Solvent -
Total 17.81
1) is dissolved in 5) with stirring and 2) is added. Milled dispersion of 3) and 4) was added with gentle stirring. The dispersion is sieved before processing if required and sprayed in suitable apparatus, onto the tablets.
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We Claim,
1. Modified release dosage form of benzimidazole comprises core of benzimidazole or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients, coated with intermediate coat, finally coated with enteric coat.
2. Modified release enteric-coated capsule of benzimidazole comprises capsule coated with intermediate coat finally coated with enteric coat, filled with benzimidazole or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients.
3. Modified release dosage form of benzimidazole comprises inner tablet and outer tablet wherein the inner tablet is of benzimidazole covered by the outer tablet of pharmaceutically acceptable excipients.
4. Modified release dosage form of benzimidazole as claimed in claim 1 to 3, wherein benzimidazole is in the form of pellets or granules or tablets.
5. Modified release dosage form of benzimidazole as claimed in claim 1 & 4, wherein pellets or granules are either compressed into tablets or filled in a capsule.
6. Modified release dosage form of benzimidazole as claimed in claim 1 to 5 wherein preferred benzimidazole is pantoprazole or its pharmaceutically acceptable salts.
7. Modified release tablet or capsule of benzimidazole as claimed in claim 1 to 3, wherein benzimidazole is optionally coated on inert core.
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8. Modified release dosage form of benzimidazole as claimed in claim 1 to 3, wherein intermediate layer comprises the sugar, dissolve in suitable solvent, in combination with gelatin, glident 0.5-15%, stabilizer 1-15% or zein or combination thereof.
9. Modified release dosage form of benzimidazole as claimed in claim 1 to 4, wherein benzimidazole active ingredient is in the range of 5-50% weight of granules or pellets or core tablet of the dosage form.
10. Modified release dosage form of benzimidazole as claimed in claim 1 to 3, wherein excipients are diluents 10 - 90%, fillers 10-90%, disintegrant 1- 30%, alkalizer 3-15%, binder 0.1-25%, lubricant 0.5- 15% or optionally surface active agent combination thereof.
11. Modified release dosage form of benzimidazole as claimed in claim 10, wherein diluents can be dicalcium phosphate, calcium sulfate, lactose, mannitol, inositol, cellulose, kaolin, sodium chlioride, starch, powdered sugar, sorbitol, sucrose, bentonite, microcrystalline cellulose or combination thereof.
12. Modified release dosage form of benzimidazole as claimed in claim 10, wherein fillers can be mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose, carbonates, bicarbonates, phosphates, oxides or hydroxides of metals, starch or combination thereof.
13. Modified release dosage form of benzimidazole as claimed in claim 10, wherein disintegrant can be cross linked polymer, cross linked cellulose or starch or combination thereof
P«ge 34 of 36

14. Modified release dosage form of benzimidazole as claimed in claim 10, wherein alkalizer can be carbonates, bicarbonates, hydroxide or halides of alkali or alkaline earth metal group or salts of glycine and alkali carbonates or combination thereof.
15. Modified release dosage form of benzimidazole as claimed in claim 10, wherein binders can be starch, povidone, modified starch, synthetic or natural starch or combination thereof.
16. Modified release dosage form of benzimidazole as claimed in claim 10, wherein lubricants can be talc, magnesium stearate, calcium stearate, stearic acid or combination thereof.
17. Modified release dosage form of benzimidazole as claimed in claim 8, wherein stabilizers can be oxides and hydroxides of alkali or alkaline earth metals or salts of glycine and alkali carbonates or combination thereof.
18. Modified release dosage form of benzimidazole as claimed in claim 8, wherein glidents can be talc, magnesium stearate, calcium stearate, stearic acid or combination thereof.
19. Modified release dosage form of benzimidazole as claimed in claim 1 to 3, wherein enteric coating comprises cellulose polymer, dissolve in solvent, in combination with plasticizers, opacifier or glident or combination thereof.
20. Modified release dosage form of benzimidazole as claimed in claim 17, wherein cellulose polymers are acrylate and/or methacrylate copolymers, or resins or combination thereof,
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21. Modified release dosage form of benzimidazole as claimed in claim 17, wherein plasticizers, in the range of 0.5-25 %, can be triethyl citrate derivatives, glycol derivatives like propylene glycol, polyethylene glycol or combination thereof.
22. Modified release dosage form of benzimidazole as claimed in claim 1 to 3, wherein granules or pellets are prepared either by wet granulation or dry granulation method.
23. Modified release dosage form of benzimidazole as claimed in claim 1 to 3, wherein dosage form can be once a day or twice a day.
24. Modified release dosage form of benzimidazole as herein described with foregoing description and examples.
Ketana Laljibhai Babaria
For and on behalf of the applicant
Dated this 09th Day of September 2006

To,
The Controller of patent The Patent Office at Mumbai
Page 36 of 36

Abstract
The present invention relates to oral pharmaceutical dosage forms for acid labile benzimidazole compound preferably pantoprazole. This dosage form is in the form of capsule or tablets containing the said benzimidazole.
H 1 SEP Z006