FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
See Sections 10 and rule 13

TITLE: MODIFIED RELEASE DOSAGE FORM OF BENZIMIDAZOLE
Applicant: (a) Astrone Research Limited
(b) Natinality: Indian
(c) 10th Floor, Premier House
Bodakdev, Opp. Gurudwara
Sarkhej - Gandhinagar Highway Ahmedabad 380054
The Following specification describes the invention:

Modified Release Dosage Form of Benzimidazole
Field of the invention
The invention relates to oral pharmaceutical dosage forms for acid labile benzimidazole compound preferably pantoprazole. This dosage form is in the form of tablets or capsule 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 en vironment, 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.
Page 2 of 17

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, hydroxyethyl- cellulose and zein.
Objects of the invention
First object of the invention is to provide orally administrable acid stable antiulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof.
Another object of invention is to develop the pharmaceutically stable oral formulation for Pantoprazole.

Still another object of the present invention is to prepare an oral dosage form of benzimidazole comprising sugar coating or luster clear as an intermediate layer.
One more object of the 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.
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. An oral dosage form of benzimidazole comprises sugar coating or luster clear as an intermediate layer.
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. The pharmaceutical formulation of the present invention that comprises a capsule or tablet as dosage form that comprising the active ingredient, one or more intermediate layers and' an external enteric coating over the tablet or capsule.

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 - seal coating further coated by enteric coating comprising.
Core comprises of active pharmaceutical ingredient, diluent, alkelizer,
disintegrent, 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.
Diluent ranges from 20 - 70% can be selected from the group comprising of but not limited to mannitol sorbitol, xylitol, lactose and the like.
Pharmaceutically acceptable alkelizer ranges from 3 - 15% can be selected from the group comprising of but not limited to carbonate or bicarbonate, metal oxides or hydroxides, mono sodium glycine carbonate or disodium glycine carbonate but not limited to sodium or calcium carbonates or bicarbonate.
Disintegrant ranges from 2 - 10% can be selected from the group comprising of but not limited to starch, crospovidone, croscarmellose sodium etc.
Lubricant ranges from 0.5 - 5% can be selected from the group comprising of but
not limited to talc, magnesium stearate, stearic acid, calcium stearate, sodium
stearyl fumerate etc.

Plasticizer ranges from 1 - 5% 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.
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 - 5% 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.
Opacifiers ranges from 1— 3% can be selected from the group comprising of but not limited to titanium dioxide,talc and all colorants etc.
Glidants ranges from 0.5 - 5 can be selected from the group comprising of but not limited tp talc,sodium stearyl fumerate, magnesium stearate, stearic acid, calcium stearate etc.
The formulation of the present invention is preferably based on direct compression technology or granules formed from a methods optionally wet granulation, dry granulation (slugging) or pellet based technology which comprises an acid-labile compound as an active ingredient, e.g., a substituted benzimidazole such as pantoprazole.
The granules or pellets are directly filled in capsule or compressed into tablets or
these granules or pellets are coated by intermediate layer and enteric coat and then

filled into the capsule.

The intermediate layer or coat can be sugar coat or of luster clear. The sugar coat comprises sugar, gelatin, glident(s), stabilizer, solvent, 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 composition of luster clear is carrageenan (10-25%), microcrystalline
cellulose', (30 - 60%) arid polyethylene glycol (25 –50%) in Pharmaceutical
solvent.
Process for preparation of dosage form:
1. Active pharmaceutical ingredient, diluent, alkelizer, disintegrent, 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. - b While 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.
EXAMPLE:1
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 Alkaliser/diluent 14.4
4) Crospovidpne 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 8 of 17

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) P.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 Glidant 0.06
5) P.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 9 of 17

EXAMPLE: 2
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 Alkaliser/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 clears(Mixture of MicrocrystallineCellulose + Carrageenan) Seal coating polymer 7.20
2) P.Water Solvent -
Total 7.20

1) is dispersed in 2) with stirring and dispersion prepared, sprayed in suitable apparatus, onto the tablets.
Pagel0ofl7

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 Glidant 0.06
5) P.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: 3
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 Alkaliser/diluent 14.4
4) CrospovMone 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.
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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) P.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 Glidant 0.06
P 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.
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EXAMPLE; 4
Step A; Core Tablets
Sr. No. Ingredients Category mg/tab
1) Pantoprazole as Sodium salt Active 45.64
Mannitol(Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkaliser/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 Glidant 1.00
4) Titanium dioxide Glidant 1.00
5) Sodium Carbonate anhydrous Stabilizer 0.50
6) P.Water Solvent -
Total 12.50
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
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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 Glidant 0.06
5) P.Water Solvent -
Z 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.
EXAMPLE: 5
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 Alkaliser/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.
Page 14 of 17
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 Glidant 1.00
4) Titanium dioxide Glidant 1.00
5) Sodium Carbonate anhydrous Stabilizer 0.50
6) P.Water Solvent -
Total 12.50
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 Glidant 0.06
5) P.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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EXAMPLE : 6
Step A: Core Tablets

Sr. No. Ingredients Category mg/tab
1) Pantoprazqle as Sodium salt Active 45.64
2) Lactose (Direct compressible grade) Diluent 106.36
3) Sodium Carbonate Anhydrous Alkaliser/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 Glidant 1.00
4) Titanium dioxide Glidant 1.00
5) Sodium Carbonate anhydrous Stabilizer 0.50
6) P.Water Solvent -
Total 12.50
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
Page l6 of l7

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 Glidant 0.06
5) P.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.
Dated this 12th day of January 2006.