Technical Field of the Invention
The present invention relates to a stabilized delayed release pharmaceutical composition of rabeprazole or pharmaceutically acceptable salts thereof.
Background of the Invention
2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl-1 H-benzimidazole hereinafter referred to as rabeprazole belongs to the class of H+-K+-ATPase inhibitors. Its effect on suppressing gastric acid secretion, and an appropriate duration of action, makes it useful for treatment of various digestive ulcers.
Rabeprazole, however, is prone to rapid decomposition and discoloration in the presence of moisture in the acidic conditions. In respect to these stability problems, it is obvious that the active substance administered orally must be protected from contact with the acidic reacting gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is alkaline and where rapid absorption of the pharmaceutically active substance can occur. Conventional stabilizing measures of coating acid sensitive compounds with enteric polymers are unsuitable for rabeprazole because the acidic functional groups of the enteric polymer react with rabeprazole, leading to its decomposition. Thus, the coating of a core comprising an acid-unstable compound with such an enteric coating might cause the decomposition of said drug. However, an intermediate coating may stabilize the drug from such decomposition.
A number of research endeavors have been directed towards preparing stabilized dosage forms of various benzimidazoles.
US 5,035,899 discloses a method of stabilizing a pharmaceutical composition comprising an acid unstable compound. The pharmaceutical composition comprises a core comprising the drug; seal coat layer and an enteric layer. The seal coat layer includes a water insoluble film forming material and slightly water soluble material such as magnesium oxide.
US 2002/0039597 discloses a chemically stable pharmaceutical preparation of benzimidazole type compound wherein the preparation is stabilized by incorporating in the core at least one substance selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropyl cellulose and crospovidone. This application provides a dosage form wherein the granules of the drug are coated with seal coating and enteric coating and thereafter the granules are compressed to provide a tablet.
Now, we have developed an alternative stabilized, delayed release pharmaceutical composition of Rabeprazole or pharmaceutically acceptable salt thereof.
Summary of the Invention
In one of the aspects, there is provided a stabilized delayed release pharmaceutical composition of Rabeprazole comprising:

a. a tablet core comprising Rabeprazole or pharmaceutically acceptable salts thereof, sodium
carbonate and crospovidone,
b. seal coating comprising ethyl cellulose and crospovidone, and
c. an enteric coating.
In another aspect, there is provided a process for the preparation of a stabilized delayed release pharmaceutical composition comprising the steps of:
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate;
ii) blending crospovidone and pharmaceutically acceptable intragranular inert excipients;
iii) mixing the two blends;
iv) optionally granulating the blend of step iii);
v) blending the granules of step iv) or blend of step iii) with pharmaceutically acceptable inert
excipients;
vi) lubricating the blend;
vii) compressing the lubricated blend into suitable sized tablet core.
viii) seal coating and enteric coating the tablet core.
In another aspect, there is provided a method for the treatment of erosive or ulcerative gastroesophageal reflux disease (GERD), daytime and nighttime heartburn and other symptoms associated with GERD, duodenal ulcers, pathological hypersecretory conditions, including Zollinger-Ellison Syndrome and for the maintenance of healing and reduction in relapse rates of heartburn symptoms in patients with GERD, comprising administering a stabilized delayed release pharmaceutical composition of Rabeprazole comprising:
a. a tablet core comprising Rabeprazole or pharmaceutically acceptable salts thereof,sodium
carbonate and crospovidone,
b. seal coating comprising ethyl cellulose and crospovidone, and
c. an enteric coating.
Detailed Description of the Invention
The term 'rabeprazole' as used herein includes any polymorphic form of Rabeprazole. The pharmaceutically acceptable salts thereof include salts of rabeprazole with alkali metals such as sodium, potassium, calcium magnesium and the like. In particular, rabeprazole sodium or rabeprazole potassium may be used.
Rabeprazole is used for the treatment of erosive or ulcerative gastroesophageal reflux disease (GERD), daytime and nighttime heartburn and other symptoms associated with GERD, duodenal ulcers, pathological hypersecretory conditions, including Zollinger-Ellison Syndrome and for the maintenance of healing and reduction in relapse rates of heartburn symptoms in patients with GERD.
The term 'stabilized' as used herein means the composition has Rabeprazole content of at least 90 % of the initial value when subjected to the stability conditions of 40°C and 75 % relative humidity for 3 months.

The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, pill and the like. In case of capsule, the tablet core is coated with seal coating and enteric coating and is filled into capsule.
The tablet core comprises rabeprazole or pharmaceutically acceptable salts thereof, sodium carbonate, crospovidone and other pharmaceutically acceptable inert excipients. The tablet core may be prepared by wet granulation, dry granulation or direct compression. The wet granulation may be carried out using granulating fluid or binder solution. The granulating fluid or binder solution comprises non-aqueous solvent selected from ethanol, methanol, isopropyl alcohol, or mixture thereof.
Sodium carbonate is a water soluble alkanizing agent. Milled or unmilled sodium carbonate with different particle size ranges or surface areas may be used. The surface area of sodium carbonate may be less than 1 m2/g. The concentration of sodium carbonate may vary from 0.1 to 15 % by weight of the total composition.
Crospovidone in the core and seal coat would ensure immediate release of Rabeprazole once the enteric coating layer is dissolved. It is used as a disintegrating agent and its concentration may vary from 0.1 to 40% by weight of the total composition. Its concentration in the core may vary from 10 to 40 % of the weight of the core tablet, whereas its concentration in the seal coating may vary from 30 to 80 % of the weight of the seal coat. The commercially available grades of crospovidone like Polyplasdone XL, Kollidon, and Peristone may be used.
Enteric coating layer is applied to prevent the degradation of Rabeprazole in the stomach. The enteric coat layer includes an enteric polymer which prevents the release of drug in acidic condition and releases the drug in alkaline environment. Examples of enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl phthalate, hydroxypropyl methylcellulose phthalate (HPMC phthalate), hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers such as Eudragit L 100-55, Eudragit L30 D-557 Eudragit L 100, Eudragit S 100; and mixtures thereof. In particular, the enteric polymer is HPMC phthalate in a concentration range of about 50% to about 90% by weight of the total weight of the enteric coat layer.
To avoid the direct contact of enteric polymers with Rabeprazole, an intermediate layer called seal coat is applied between tablet core and the enteric coat. However, it does not delay the release of the drug from the core. Seal coat is the layer of film coating and comprises ethyl cellulose and crospovidone. Ethyl cellulose is a film coating agent used in pharmaceutical preparations. Commercially available grades of ethyl cellulose like ethocel standard premium with different viscosities can be used. The concentration of ethyl cellulose may vary from 10 to 60 % by weight of the seal coat. It may further comprise other film forming agents. Examples of these agents include Hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxy methylcellulose, hydroxymethylcellulose, hydroxymethylcellulose. The seal coat may further comprise slightly water-soluble substance selected from the group consisting of magnesium oxide, silicic anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, calcium stearate, magnesium stearate and sucrose fatty

acid esters. Different methods like spray coating in conventional pan, fluidized bed processor, dip coating can be used for coating.
The pharmaceutical composition may further comprise one or more pharmaceutically acceptable inert excipients. The term 'pharmaceutically acceptable inert excipients' as used herein includes binders, disintegrants, lubricants, glidants, diluents, plasticizers, opacifiers, coloring agents and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, gelatin, pregelatinized starch, ethyl cellulose, polyvinyl alcohol and the like.
The pharmaceutical composition may comprise additional disintegrant in addition to crospovidone. Examples of these include starch, croscarmellose, sodium starch glycolate and the like.
Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
Examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose, sugar compressible, sugar confectioners, and the like.
Examples of plasticizers include acetylated triacetin, triethyl citrate, tributyl citrate, glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene glycol, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctyl phthalate, dibutyl sebacate, and the like.
Examples of opacifiers include titanium dioxide and the like.
Examples of coloring agents include Iron oxide, Ferric oxide yellow, Lake of Tartrazine, Allura red, Lake of Quinoline yellow, Lake of Erythrosine.
According to one of the embodiments, the tablet core is prepared by wet granulation process, the process comprising the steps of
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate and
crospovidone;
ii) granulating the above blend with a granulating fluid;
iii) optionally blending the granules with pharmaceutically acceptable inert extragranular excipients;
iv) lubricating the granules/blend;
v) compressing the lubricated granules/blend into suitable sized tablet core.

According to yet another embodiment, the tablet core is prepared by wet granulation process, the process comprising the steps of
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate and a
part of crospovidone;
ii) granulating the above blend with a granulating fluid;
iii) blending the remaining crospovidone with other pharmaceutically acceptable inert excipients;
iv) blending the granules of step ii) with the blend of step iii);
v) lubricating the blend of step iv);
vi) compressing the lubricated granules into suitable sized tablet core.
According to another embodiment, the tablet core is prepared by wet granulation process, the process comprising the steps of
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate;
ii) blending crospovidone and pharmaceutically acceptable intragranular inert excipients;
iii) mixing the two blends;
iv) granulating the blend of step iii) with a binder solution;
v) optionally blending the granules of step iv) or blend of step iii) with pharmaceutically acceptable
inert excipients;
vi) lubricating the blend;
vii) compressing the lubricated blend into suitable sized tablet core.
According to another embodiment, the tablet core is prepared by dry granulation process, the process comprising the steps of
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate and crospovidone;
ii) granulating the above blend using slugging or roller compaction;
iii) optionally blending with pharmaceutically acceptable inert extragranular excipients;
iv) lubricating the granules/blend;
v) compressing the lubricated granules into suitable sized tablet core.
According to yet another embodiment, the tablet core is prepared by direct compression process, the process comprising the steps of
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate, crospovidone and pharmaceutically acceptable inert excipients;
ii) lubricating the blend;
iii) compressing the blend into suitable sized tablet core.
The tablet cores obtained are then coated with seal coating and enteric coating thereon by conventional process.
The solvents that can be used for the coating are selected from the group consisting of water, ethanol, methanol, isopropyl alcohol, acetone or mixture thereof.

The following examples are representative of the invention, but are not to be construed as limiting the scope of the claims
Example:

(Table Removed)
Process:
1 Rabeprazole sodium and sodium carbonate were blended together.
2 Crospovidone and mannitol were blended.
3. Blends of step 1 and 2 were mixed.
4 HPC-L was dissolved in ethanol and blend of step 3 was granulated with this solution.
5. The granules were dried and blended with the extragranular excipients.
6. The blend of above step was lubricated and compressed into suitable sized tablet core.
Seal coating
7 Ethyl cellulose was dissolved in ethanol.
8 Crospovidone and magnesium stearate were added to this solution and stirred.
9 Core tablets of step 6 were coated using the dispersion of step 8 in coating pan.
Enteric coating
10. Titanium dioxide, talc, and ferric oxide were dispersed in water and homogenized.
11. HPMC phthalate was dissolved in the mixture of ethanol and water using mechanical stirrer and
diacetylated monoglyceride was dispersed therein.
12. The dispersion of step 10 was added to the solution of step 11.
13. The seal coated tablets of step 9 were coated with the dispersion of step 12.
The tablets were packaged in HDPE bottle with silica gel and HDPE bottle with molecular sieve.
Stability data:
The packaged tablets of the above example were subjected to the stability studies of 40° C and 75 % relative humidity for 3 months. The results are as given in Table 1.
Table 1. Stability data of above example:

(Table Removed)
The compositions were stable during the course of stability studies.

WE CLAIM:
1 A stabilized delayed release pharmaceutical composition of Rabeprazole comprising:
a. a tablet core comprising Rabeprazole or pharmaceutically acceptable salt thereof, sodium
carbonate and crospovidone,
b. seal coating comprising ethyl cellulose and crospovidone, and
c. an enteric coating.
2 The pharmaceutical composition according to claim 1, wherein the composition has Rabeprazole
content of at least 90 % of the initial value when subjected to the stability conditions of 40°C and 75
% relative humidity for 3 months.
3. The pharmaceutical composition according to claim 1, wherein the enteric layer comprises one or
more enteric polymers selected from the group consisting of cellulose acetate phthalate,
hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl
phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate;
methacrylic acid copolymers.
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition
further comprise pharmaceutically acceptable inert excipients selected from the group consisting of
binders, disintegrants, lubricants, glidants, diluents, plasticizers, opacifiers and coloring agents.
5. The pharmaceutical composition according to claim 1, wherein it is prepared by the process
comprising the steps of:
i) blending Rabeprazole or pharmaceutically acceptable salt thereof with sodium carbonate;
ii) blending crospovidone and pharmaceutically acceptable intragranular inert excipients;
iii) mixing the two blends;
iv) optionally granulating the blend of step iii);
v) blending the granules of step iv) or blend of step iii) with pharmaceutically acceptable inert
excipients;
vi) lubricating the blend;
vii) compressing the lubricated blend into suitable sized tablet core.
viii) seal coating and enteric coating the tablet core.
6 The pharmaceutical composition according to claim 5, wherein the granulation is carried out by wet
granulation or dry process.
7 The pharmaceutical composition according to claim 6, wherein the wet granulation is carried out by a
binder solution or a granulating fluid.

8. The pharmaceutical composition according to claim 7, wherein the binder solution or granulating fluid
comprises non-aqueous solvent selected from the group consisting of ethanol, methanol, isopropyl
alcohol or mixture thereof.
9. The pharmaceutical composition according to claim 1 for the treatment of erosive or ulcerative
gastroesophageal reflux disease (GERD), daytime and nighttime heartburn and other symptoms
associated with GERD, duodenal ulcers, pathological hypersecretory conditions, including Zollinger-
Ellison Syndrome and for the maintenance of healing and reduction in relapse rates of heartburn
symptoms in patients with GERD,
10.A stabilized delayed release pharmaceutical composition of Rabeprazole or pharmaceutically
acceptable salt thereof as described herein.