FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
DELAYED RELEASE DOSAGE FORM OF PANTOPRAZOLE COMPRISING
PRE-GELATINIZED STARCH AS BINDER
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides delayed release dosage form comprising of a
core containing pantoprazole or salt thereof in admixture with pre-gelatinized
starch as binder, filler and, optionally, other pharmaceutically acceptable
excipient and an inorganic base, an inert water-soluble intermediate layer
surrounding the core and an outer enteric coat.
The following specification particularly describes the invention and the manner
in which it is to be performed.
The present invention provides delayed release dosage form comprising of a
core containing pantoprazole or salt thereof in admixture with pre-gelatinized
starch as binder, filler and, optionally, other pharmaceutically acceptable
excipient and an inorganic base, an inert water-soluble intermediate layer
surroundingthe core and an outer enteric coat.

Pantoprazole is a compound that inhibits gastric acid secretion. Pantoprazole is
chemically, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulflnyl]-1H-
benzimidazole. Pantoprazole is indicated for short-term treatment of erosive
esophagitis associated with Gastroesophageal Reflux Disease (GERD),
maintenance of healing of erosive esophagitis, and pathological hypersecretory
conditions Including Zollinger-Ellison Syndrome.

US Patent No 4,758,579 (the '579 Patent) disclose processes and
pharmaceutical compositions of pantoprazole or a salt thereof.
US Patent No 5,997,903 (the '903 Patent) disclose a preparation of Pantoprazole
in pellet or tablet form for oral administration consisting of a core in which
pantoprazole or its physiologically tolerated salt is in admixture with another
tablet auxiliary, an inert water-soluble intermediate layer surrounding the core
and an outer layer which is resistant to gastric juice, the binder is
polyvinylpyrrolidone and/or hydroxypropyl methylcellulose. The specification and
the file history of the '903 Patent suggests that the applicants have condemned
the use of lactose, carboxy methylcellulose and hydroxypropyl cellulose as
incompatible with pantoprazole.
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US patent No 6, 159, 499 (the '499 Patent) discloses a composition comprising a
core containing an acid-labile benzimidazole active principle which is not in the
form of an alkaline salt and comprises plurality of nuclei which then compressed
together, an intermediate layer surrounding the core; and an enteric layer
surrounding the intermediate layer.
US patent No 6, 068, 856 (the '856 Patent) 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.
US Patent No. 6,274,173 (the '173 Patent) discloses oral pharmaceutical
composition in pellet or tablet form with delayed and controlled release of active
ingredient, comprising an acid-labile irreversible proton pump inhibitor other than
pantoprazole, and wherein the composition comprises 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.
PCT Patent Application WO2004/066982 discloses stable oral benzimidazole
pharmaceutical composition comprising a core comprising a benzimidazole
compound, a separating layer surrounding the core and comprising a
substantially water- soluble material and an enteric coating surrounding the
separating layer without any pharmaceutically acceptable excipients.
The present inventors have now surprisingly found that pre-gelatinized starch
when used as a binder provides excellent binding in the preparation of
pantoprazole delayed release dosage form. Moreover, it was also observed that
pre-gelatinized starch is compatible with pantoprazole or salt thereof and other
pharmaceutically acceptable excipients used in the dosage form.
3

In one of the aspects of the present invention there is provided a delayed release
dosage form comprising of a core containing pantoprazole or salt thereof in
admixture with pre-gelatinized starch as binder, filler and, optionally, other
pharmaceutically acceptable excipient and an inorganic base, an inert water-
soluble intermediate layer surrounding the core and an outer enteric coat.
Pantoprazole can be present in the form of pantoprazole sodium sesquihydrate.
The intermediate layer also can be called as seal coat is formed from an inert
water-soluble film former. The pharmaceutically acceptable seal coat forming
polymers can be selected from a group comprising of one or more of suitable
cellulose ethers include one or more of hydroxypropyl methylcellulose,
hydroxypropyl cellulose and other suitable cellulose ethers. The film former has
been applied from a solution. The intermediate layer is surrounded by outer
enteric coat. The pharmaceutically acceptable enteric coating forming polymers
can be selected from methacrylic acid/methyl methacrylate copolymers such as
Eudragit L or cellulose derivatives such as carboxymethyl cellulose, cellulose
acetate phthalate, hydroxypropylmethyl cellulose phthalate and other suitable
polymers.
Pharmaceutically acceptable excipients can be filler, binder, lubricant, alkalizing
agent, disintegrant, glidant and the like. The binder is pre-gelatinized starch. The
lubricants may be one or more of magnesium stearate, calcium stearate,
polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl
fumarate and sodium benzoate. The glidants may be one or more of colloidal
silicon dioxide and talc.
The delayed release dosage form containing pantoprazole or salt thereof
includes solid oral dosage forms such as tablets, capsules, granules and pellets.
4

In yet another aspect of the present invention, there is provided a process for
preparation of delayed release dosage form comprising of a core containing
pantoprazole or salt thereof wherein the said process comprises of,
a) incorporating pantoprazole or salt thereof along with filler, binder and
optionally, other pharmaceutically acceptable excipient and an inorganic
base in a pellet or tablet core,
b) applying thereto an inert water-soluble intermediate layer surrounding the
core,
c) subsequently applying an outer enteric coat,
wherein, the binder is pre-gelatinized starch.
The delayed release dosage form should not release more than 10%
pantoprazole in first two hours, when measured in a USP Type II apparatus at 75
rpm and using 0.1 N hydrochloric acid at 37°C ±0.5. Further, the delayed release
dosage form may have dissolution of about 100 % in next one hour when
measured in a USP Type II apparatus at 100 rpm and replacing 0.1 N
hydrochloric acid with pH 6.8 phosphate buffer at 37°C ±0.5.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
. invention.
EXAMPLES
The composition of the batches is provided in Table 1.
Table 2 provides the dissolution data for the pantoprazole DR tablets prepared
as per the Formula given in Table 1. For determination of drug release rate, USP
Type 2 Apparatus (rpm 75) was used wherein 0.1 N hydrochloric acid in 750 ml
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was used as a medium (2 hrs), followed by 1000 ml of 6.8 pH phosphate buffer
(1 hr).
Table 1 - Examples of Pantoprazole delayed release tablets (40 mg) prepared
by using pre-gelatinized starch as a binder

Example 1 Example 2
Sr.no
Ingredient Mg/tab Mg/tab
CORE

1 Pantoprazole sodium 48.76 48.76
2 Mannitol 84.19 84.19
3 Pregelatinized starch
(starch 1500) 18.0 18.0
4 Colloidal silicon dioxide
(Aerosil) 1.8 1.8
5 Sodium carbonate
anhydrous 9.0 9.0
6 Calcium stearate 1.35 1.35
7 Talc 0.9 0.9
8 Pregelatinized starch
(Starch 1500) 9.0 9.0
9 Sodium starch glycolate 7.0 7.0
10 Water q.s q.s
Tablet Weight (mg) 180.0 180.0
SEAL COAT Mg/
Tab Mg/
Tab
1 Opadry
(HPMC & Macrogol
based) 5.4 5.4
2 Water q.s q.s
Tablet Weight (mg) 185.4 185.4
ENTERIC COAT
1 Eudragit L30-D55 12.5 -
2 Eudragit L100-D55 - 12.5
3 Talc 1.25 1.25
4 Tri ethyl citrate 1.00 1.00
5 Sodium hydroxide - q.s
6 Water q.s q.s
Tablet Weight (mg) 200.15 200.15
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Pantoprazole, mannitol, starch 1500 and aerosil were sifted through ASTM mesh
# 40 and mixed thoroughly using suitable blender.
Sodium carbonate was dissolved in purified water, and used as a granulating
fluid for carrying out granulation of above mix. Wet dough was passed through
ASTM mesh #12 and the wet granules were dried, at 60° C to achieve an LOD of
1.5-3%. Dried granules are sized through ASTM mesh # 30 to get uniform size
granules. The granules thus obtained were mixed with aerosil, starch 1500, talc,
sodium starch glycolate and calcium stearate, which were passed ASTM mesh #
60 and compressed into tablets. Tablets were coated with 10% w/w aqueous
solution of Opadry, this forms seal coat around the core. Further 30%w/w
aqueous solution of Eudragit L 30-D55 along with sodium hydroxide, tri ethyl
citrate and talc was used to give enteric coat to the seal coated tablets.
Table 2 -Dissolution data of the tablets prepared as per the present invention

Duration Protonix® Example 1 Example 2
0.1 N HCI
2hrs 0.0 0.0 0.0
6.8 phosphate
buffer
10 min 1.0 0.0 0.0
20 min 20.0 24.0 14.0
30 min 75.0 82.0 53.0
45 min 100.0 98.0 96.0
60 min 100.0 99.0 96.0
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WE CLAIM:
1. A delayed release dosage form comprising of a core containing
pantoprazole or salt thereof in admixture with pre-gelatinized starch as
binder, filler and, optionally, other pharmaceutically acceptable excipient
and an inorganic base, an inert water-soluble intermediate layer
surrounding the core and an outer enteric coat.
2. The delayed release dosage form according to claim 1, wherein
pantoprazole is in the form of pantoprazole sodium sesquihydrate.
3. The delayed release dosage form according to claim 1, wherein the
intermediate layer forming polymers are selected from a group comprising
of one or more of suitable cellulose ethers include one or more of
hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable
cellulose ethers.
4. The delayed release dosage form according to claim 1, wherein the
intermediate layer is surrounded by outer enteric coat.
5. The delayed release dosage form according to claim 1, wherein the
pharmaceutically acceptable enteric coating forming polymers are
selected from methacrylic acid/methyl methacrylate copolymers and
cellulose derivatives.
6. The delayed release dosage form according to claim 1, wherein
pharmaceutically acceptable excipient is one or more of filler, lubricant,
alkalizing agent, disintegrant or glidant.
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7. The delayed release dosage form according to claim 1, wherein lubricant
is one or more of magnesium stearate, calcium stearate, polyethylene
glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate
or sodium benzoate.
8. The delayed release dosage form according to claim 1 in the form of
tablets, capsules, granules or pellets.
9. A process for preparation of delayed release dosage form comprising of a
core containing pantoprazole or salt thereof wherein the said process
comprises of,
a) incorporating pantoprazole or salt thereof along with filler, binder
and optionally, other pharmaceutically acceptable excipient and an
inorganic base in a pellet or tablet core,
b) applying thereto an inert water-soluble intermediate layer
surrounding the core,
c) subsequently applying an outer enteric coat,
wherein, the binder is pre-gelatinized starch.
10. A process according to claim 9, wherein pantoprazole is in the form of
pantoprazole sodium sesquihydrate.
Dated this 28TH day of February, 2006

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