FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
“PHARMACEUTICAL COMPOSITIONS OF RABEPRAZOLE”
We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India,
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION:
The present invention relates to an improved pharmaceutical composition comprising rabeprazole and/or a pharmaceutically acceptable salt thereof, particularly rabeprazole sodium for oral use, and to a method of manufacture of such composition.
BACKGROUND OF THE INVENTION:
Rabeprazole, chemically 2(4-(3-methoxypropoxy)-3-methylpyridin-2-yl)methyl sulfinyl)-1H-benzimidazole, has been disclosed in European granted patent EP 268956 presenting the proton pump inhibition activity thereof, a synthesis and a formulation. Rabeprazole may be used for treatment or prevention of peptic ulcers.
Rabeprazole is commercially available as delayed release tablets and capsules under the trade names - Aciphex and Aciphex sprinkle, respectively in USA.
Stability of rabeprazole sodium itself is poor. In particular, it is rapidly decomposed and colored under moist conditions or in an acidic to neutral aqueous solution. When rabeprazole sodium is to be formulated into a preparation for oral administration, therefore, they should be coated with an enteric coating to thereby prevent the decomposition of the same with gastric acid. However an enteric coating is an acidic material which is insoluble in water under acidic conditions and soluble in water under neutral to alkaline conditions. Thus the coating of a core comprising an acid-unstable compound, e.g., a benzimidazole derivative with such an enteric coating might generally cause the decomposition of said acid-unstable compound. Such decomposition occurs even during the enteric coating stage by a common method, for example, with the use of a fluidized bed coater, which results in the coloration of the surface of the core. Further the storage stability of the coated core as well as the stability in an acidic solution of the same might be lowered thereby.
In order to avoid these difficulties, Japanese Patent Laid-Open No. 258316/1987 and No. 258320/1987 disclose each a method comprising intermediately coating the

core containing an acid-unstable compound with a material soluble in water or decomposable in water and then further coating the same with an enteric coating. However these methods cannot sufficiently stabilize an acid-unstable compound and therefore further improvement is required.
US granted patent No. 5,035,899 discloses a peroral preparation of an acid-unstable compound characterized in that a core containing an acid-unstable compound is coated with a hardly water-soluble film-forming material containing a suspended, hardly water-soluble fine material, and further coated with an enteric coating.
US patent application No. 20080145421 discloses a pharmaceutical composition characterized that a core substance is coated with a principal ingredient layer comprising a benzimidazole compound and ethyl cellulose.
European patent application EP 1004305 disclose a composition of rabeprazole sodium with specially selected excipient such as potassium carbonate, sodium hydroxide, potassium hydroxide and other fillers such as aminoalkyl methaacrylate copolymer E.
WO 2005/011637 describes a pharmaceutical composition characterized by having, on a core substance, a layer (1) containing crospovidone, a layer (2) containing sodium hydroxide which is adjacent to the layer containing crospovidone, and a layer (3) containing a benzimidazole compound or a pharmacologically acceptable salt thereof which is adjacent to the layer containing sodium hydroxide.
Considering the importance gained for the composition containing rabeprazole, its enantiomers or salts thereof, for the treatment of duodenal ulcers, there is a need for the development of pharmaceutical composition containing said derivatives having stability for an extended period during which period the composition does not get discoloured and / or degraded.

SUMMARY OF THE INVENTION:
One embodiment discloses a delayed release pharmaceutical composition comprising rabeprazole and at least one pharmaceutically acceptable excipient, wherein the composition comprising:
i) a core comprising rabeprazole (optionally comprises alkalizer); ii) optionally a separating layer coated on the core;
iii) atleast one enteric layer comprising of enteric polymer (s) and plasticizer either coated on the core or on the separating layer to obtain enteric coated pellets.
Plasticizers in the enteric layers is up to 15%, preferably up to 12.5%, more preferably up to 10% by weight of enteric polymer.
Another embodiment discloses a delayed release pharmaceutical composition comprising rabeprazole and at least one pharmaceutically acceptable excipient, wherein the composition comprising:
i) a core comprising rabeprazole and carrageenan (optionally comprises alkalizer); ii) optionally a separating layer coated on the core;
iii) atleast one enteric layer comprising of enteric polymer (s) and plasticizer either coated on the core or on the separating layer to obtain enteric coated pellets
Another embodiment discloses a process for the preparation of delayed release pharmaceutical composition comprising rabeprazole or is salts thereof and at least one pharmaceutically excipient; wherein the process comprises: i) preparing a core comprising rabeprazole (optionally mixing with alkalizer); ii) optionally coating the core with a separating layer; and
iii) coating the product of step (a) or (b) with atleast one enteric layer comprising enteric polymer(s) and plasticizer.
iv) filling the enteric coated cores in hard gelatin or HPMC capsules or mixing the with atleast one tablet excipient selected from filler, binder, disintegrant, lubricating agent, sweetener and flavor, followed by compression.

Rabeprazole or salts thereof may be available in multiple unit dosage forms like enteric coated granules or enteric coated pellets or enteric coated mini-tablets inside the capsule, enteric coated granules or enteric coated pellets compressed into tablets and single unit dosage form like single unit enteric-coated tablets.
Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients. The pharmaceutical acceptable excipients may include alkalizer, diluent, disintegrant, binder, lubricant, glidant, plasticizer, anti-tacking agent, opacifying agent, and the like.
The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.
DETAIL DESCRIPTION OF THE INVENTION:
The term "delayed release pharmaceutical composition" as described herein is intended to include compositions which provide a maximum release of rabeprazole in the less acidic environment of the intestine relative to the more acidic environment of the stomach.
The term "rabeprazole" as described herein is intended to include rabeprazole free base or pharmaceutically acceptable salts thereof, racemic mixture, individual enantiomer or mixtures thereof. The preferred salt is rabeprazole sodium. The particle size of rabeprazole as used herein may vary from 1 µm to 200 µm.
The term "core" as described herein is intended to include anything below the separating coat or when the separating coat is absent, anything below the enteric coat. Thus the core may contain inert core covered with rabeprazole, core containing rabeprazole, or mixtures thereof. The inert core may comprise inert non-pareils which are conventionally used in pharmaceutical industry and are readily available. The inert non-pareils may be of any pharmaceutically acceptable excipient such as starch, sugar,

microcrystalline cellulose, vegetable gums, waxes, and the like. Preferably, the inert non-pareils are of microcrystalline cellulose. The size of the inert non-pareils may vary from 0.1 mm to 2 mm. The core may also be prepared by techniques such as granulation or extrusion-spheronization. For example, the core may be prepared by mixing at least one pharmaceutically acceptable excipient and rabeprazole, moistening the mixture with water and/or an organic solvent, granulating and subsequently drying to obtain granules which may be used as the core. Alternatively, such granules may be compressed into a mini-tablet, which may be used as the core. The core may also be prepared by mixing at least one pharmaceutically acceptable excipient and rabeprazole, wetting with water or an organic solvent and mixing in a high shear granulator to form a homogeneous wet mass, extruding the wet mass to form extrudates which are subsequently spheronized to form spheres which may be used as the core. The core may be present in an amount ranging from 10% to 90% by weight of the composition. Preferably, the core comprises rabeprazole, alkalizer and further comprises at least one pharmaceutically excipient.
The delayed release compositions may comprise a separating layer between the core and the enteric layer. The separating layer preferably performs one or more of the following functions: providing a smooth base for the application of the enteric layer, prolonging the formulation's resistance to the acidic environment of the stomach, improving stability of the formulation by inhibiting interaction between the rabeprazole and the enteric layer. The separating layer may comprise at least one film forming polymer such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone; and the like. The separating layer may be prepared by dissolving an appropriate amount of film forming polymer into a suitable solvent system such as water, organic solvent such as alcohol, methylene chloride, and the like; or mixtures thereof, and spraying the solution or suspension on core using a suitable apparatus. The separating coat may be present in an amount ranging from 0.5% to 30% by weight of the composition.

The "enteric layer" as described herein may comprise a suitable polymer selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac and the like. The polymer may be used either alone or in combination with other polymers. The enteric layer may be applied by dispersing or suspending the enteric polymer in a suitable medium, such as water or aqueous acidic or alkaline solutions, or in organic solvents such as methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methylene chloride, ethylene chloride, ethyl acetate, or mixtures thereof, and the resultant solution or suspension may be sprayed directly on the core or separating coat, followed by drying to obtain delayed release composition. The enteric coat may be present in an amount ranging from 0.5% to 70% by weight of the composition. The enteric coating polymer may be present in an amount ranging from 5-50% by weight, more preferably 10-30% by weight of the composition. Plasticizers in the enteric layers is up to 15%, preferably up to 12.5%, more preferably up to 10% by weight of enteric polymer.
Preferably, the delayed release pharmaceutical composition of rabeprazole comprises carrageenan in an amount of 0.1 % to 50%, more preferably, 2 % to 30%.
The pharmaceutical compositions as described herein may additionally comprise at least one pharmaceutically acceptable excipient selected from alkalizer, diluent, disintegrant, binder, lubricant, glidant, plasticizer, anti-tacking agent, opacifying agent, and the like.
Alkalizer may be selected from sodium carbonate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium oxide, sodium hydroxide and mixtures thereof. Preferably, the alkalizer is magnesium oxide. The alkalizer may be present in an amount of 1% to 50% by weight of the composition, preferably 5% to 35%.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate,

tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof. Diluent may generally be added to increase the bulk volume of the powder to facilitate granulation or compression. Diluent, such as a sugar, may also be added as a component of the coat, such as in the separating coat, to impart sticking and acid-resistance properties to the coating layer. The diluent may be present in an amount ranging from 1% to 80% by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof. The disintegrant may be present in an amount ranging from 1% to 20% by weight of the composition.
Binder may be selected from carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. Binder may be used as a component of the coat to ensure proper adhesion of the subsequent coats. The binder may be present in an amount ranging from 0.1% to 25% by weight of the composition.
Lubricant may be selected from metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof. Glidant may be selected from talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1% to 10% by weight of the composition.

Plasticizer may be used in a coat to increase the flexibility and strength of the layer and may be selected from propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. The plasticizer may be present in an amount ranging from 0.1% to 20% by weight of the composition.
Anti-tacking agent may be used in a coat to aid bulk build-up and form a smooth surface and may be selected from talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-tacking agent may be present in an amount ranging from 0.1% to 20% by weight of the composition.
Opacifying agent may be used in a coat to prevent photo-degradation and may be selected from titanium dioxide, iron oxides, and the like. The opacifying agent may be present in an amount ranging from 0.1% to 10% by weight of the composition.
The pharmaceutical compositions as described herein may be prepared by different techniques. For example, when an inert core is used, non-pareils may be coated with a seal coat comprising a film forming polymer, e.g. hydroxypropyl cellulose, and excipients like alkalizer, plasticizer, anti-tacking agent and opacifying agent. The components of the seal coat may be dissolved or dispersed in an appropriate solvent and the dispersion may be coated on the core in a conventional coating pan or fluidized bed equipment (such as a Wurster or Glatt) and the coated cores may then be dried. A coat of rabeprazole may then be applied to such coated cores using similar process as above, wherein rabeprazole may be built up on the coated cores by spraying a suspension or dispersion comprising rabeprazole and excipients such as alkalizer, binder, plasticizer, antitacking agent and opacifying agent. Alternatively, the rabeprazole coat may also be applied by powder-coating, wherein the coated cores as described above are maintained in a sticky state, a mixture of rabeprazole and powdered excipients such as alkalizer, binder, plasticizer, anti -tacking agent and opacifying agent are added continuously or periodically so as to adhere to the sticky cores. When the entire rabeprazole coat has been applied, the drug coated cores are

dried. The drug-coated cores may optionally be coated with a separating coat or may directly be coated with the enteric coat. The enteric coat may be applied by dispersing or suspending the enteric polymer in a suitable medium which may additionally comprise excipients such as plasticizer, anti-tacking agent and opacifying agent, and the resultant dispersion may be sprayed on the drug-coated cores, followed by drying to obtain enteric coated pellets. The enteric coated pellets may be filled into capsules of suitable size or provided as any suitable composition such as tablet or sachet.
The compositions may also be prepared by providing a core prepared by techniques such as granulation. For example, pharmaceutically acceptable excipients such as alkalizer, diluent, disintegrant, binder, glidant, and rabeprazole may be mixed; the mixture may be moistened with water or an organic solvent such as alcohol or methylene chloride or mixtures thereof, granulated and subsequently dried to obtain granules which may be used as the core. The core may be optionally coated with a separating coat or directly coated with the enteric coat by processes as described herein to obtain pellets which may be filled into capsules of suitable size or provided as any suitable composition such as tablet or sachet. Alternatively, the uncoated granules may be lubricated and compressed into a tablet, which may be used as the core. The tablet may be optionally coated with a separating coat and subsequently coated with the enteric coat.
The compositions may also be prepared by providing a core prepared by techniques such as extrusion-spheronization wherein at least one pharmaceutically acceptable excipient and optionally rabeprazole are mixed and wetted with water or organic solvent in a high shear granulator to form a homogeneous wet mass, the wet mass is extruded to form extrudates which are subsequently spheronized to form spheres, which may be used as the core. The core may be optionally coated with a separating coat and subsequently coated with the enteric coat by processes as described herein to obtain pellets which may be filled into capsules of suitable size or provided as any suitable composition such as tablet or sachet. Alternatively, the

uncoated cores may be compressed into a tablet, which may be used as the core. The tablet may be optionally coated with a separating coat and subsequently coated with the enteric coat.
Preferably, the pharmaceutical composition of rabeprazole is enteric coated pellets filled capsule.
Capsules considered are soft gelatin, hard gelatin, HPMC, polysaccharide or starch capsules as plugged, welded or glued capsules, of different size, colour, and water content. Preferably, HPMC capsules.
The patient can use a capsule by opening it, sprinkling the contents of the capsule onto soft food, such as apple sauce, and ingesting the coated particles along with the food.
In one embodiment, stable pharmaceutical composition of rabeprazole may be prepared by
a) providing inert non-pareils;
b) coating the inert non-pareils with a suspension or solution containing rabeprazole and at least one pharmaceutically acceptable excipient selected from the group consisting of alkalizer, diluent, disintegrant, glidant and binder;
c) coating the drug-coated cores with a separating coat;
d) coating the product obtained above with an enteric coat;
e) optionally mixing the enteric-coated pellets with at least one pharmaceutically
acceptable excipient; and
f) filling the enteric-coated pellets into capsules.
In another embodiment, stable pharmaceutical composition of rabeprazole may be prepared by
a) preparing a core by mixing rabeprazole and at least one pharmaceutically acceptable excipient selected from the group consisting of alkalizer, diluent, disintegrant, glidant and binder;

b) granulating the mixture with a solvent or a binder solution,
c) drying the granules;
d) optionally coating the granules with a separating coat;
e) coating the product obtained above with an enteric coat;
f) optionally mixing the enteric-coated granules with at least one pharmaceutically acceptable excipient; and
g) filling the enteric-coated granules into capsules or compressing into tablets.
In another embodiment, stable pharmaceutical composition of rabeprazole may be prepared by
a) preparing a core by mixing at least one pharmaceutically acceptable excipient selected from the group consisting of diluent, disintegrant, glidant and binder;
b) granulating the mixture with a solvent,
c) drying the granules;
d) coating the granules with a suspension or solution containing rabeprazole and at least one pharmaceutically excipient selected from the group consisting of alkalizer, diluent, disintegrant, glidant and binder;
e) optionally coating the granules with a separating coat;
f) coating the product obtained above with an enteric coat;
g) optionally mixing the enteric-coated granules with at least one pharmaceutically
acceptable excipient; and
h) filling the enteric-coated granules into capsules or compressing into tablets.
In another embodiment, stable pharmaceutical composition of rabeprazole may be prepared by
a) preparing a core by mixing rabeprazole and at least one pharmaceutically
acceptable excipient selected from the group consisting of diluent, disintegrant, glidant
and binder;
b) granulating the mixture with a solvent,

c) Subjecting the wet granules to extrusion process using suitable size screen and collecting the extrudates in a suitable container.
d) Loading the wet extrudates in spheronizer, collecting the spheres in suitable container.
e) optionally coating the granules with a separating coat;
f) coating the product obtained above with an enteric coat;
g) optionally mixing the enteric-coated granules with at least one pharmaceutically
acceptable excipient; and
h) filling the enteric-coated granules into capsules.
In another embodiment, stable pharmaceutical composition of rabeprazole may be prepared by
a) preparing a core by mixing rabeprazole and at least one pharmaceutically
acceptable excipient selected from the group consisting of alkalizer, diluent,
disintegrant, glidant and binder;
b) granulating the mixture with a solvent or a binder solution,
c) drying the granules;
d) mixing the granules with at least one pharmaceutically acceptable excipient; and compressing into mini-tablets.

d) optionally coating the mini-tablets with a separating coat;
e) coating the product obtained above with an enteric coat;
f) filling the enteric-coated mini-tablets into capsules.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. 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.

Example 1
Table 1

Sr. No. Name of Ingredient Qty Mg/Capsule
1 Rabeprazole sodium 10.00
2 Low substituted hydroxy propyl cellulose 5.600
3 Magnesium oxide 26.00
4 Carragenan 4.000
5 Microcrystalline cellulose 100.0
6 Isopropyl alcohol q.s
Separating Layer
7 Ethyl cellulose 4.100
8 Magnesium oxide 9.760
9 Diacetylated mono glyceride 0.410
10 Talc 1.000
11 Isopropyl alcohol q.s
Enteric coating
12 Hypromellose phthalate 65.00
13 Diacetylated mono glyceride 6.250
14 Talc 7.500
15 Titanium dioxide 0.380
16 Isopropyl alcohol q.s
Total 240.00

Process:
A. Preparation of Rabeprazole granules:
i) Mixing rabeprazole sodium with magnesium oxide, low substituted hydroxy propyl cellulose, microcrystalline cellulose in rapid mixer granulator.
ii) Granulating the above mixture by using granulating solution prepared by dispersing carrageenan in isopropyl alcohol.
iii) Subjecting the wet granules to extrusion process and collect the extrudates.
iv) Spheronizing the extrudates to achieve suitable size spheres.
B. Separating Layer
Spraying a dispersion of ethyl cellulose, magnesium oxide, diacetylated mono glyceride and talc in isopropyl alcohol onto granules of step (A) using wurster process.
C. Enteric layer
Spraying a dispersion of hypromellose phthalate, diacetylated mono glyceride talc and titanium dioxide in isopropyl alcohol onto granules of step (B) using wurster process.
D. Final Dosage form
Filling the enteric coated granules into HPMC/gelatin capsules.
Example 2
Table 2

Sr. No. Name of Ingredient Qty Mg/Capsule
1 Rabeprazole sodium 10.00
2 Low substituted hydroxy propyl cellulose 4.600
3 Magnesium oxide 25.00

4 Povidone 4.000
5 Microcrystalline cellulose 100.0
6 Isopropyl alcohol q.s
7 Colloidal silicon dioxide 1.000
8 Magnesium stearate 1.000
Separating layer
9 Ethyl cellulose 4.100
10 Magnesium oxide 9.760
11 Diacetylated mono glyceride 0.410
12 Talc 1.000
13 Isopropyl alcohol q.s
Enteric layer
14 Hypromellose phthalate 65.00
15 Diacetylated mono glyceride 6.250
16 Talc 7.500
17 Titanium dioxide 0.380
18 Isopropyl alcohol q.s
Total 240.00
Process:
A. Preparation of Rabeprazole mini-tablets:
i) Mixing rabeprazole sodium with magnesium oxide, low substituted hydroxy propyl cellulose, microcrystalline cellulose in rapid mixer granulator.

ii) Granulating the above mixture by using granulating solution prepared by dissolving povidone in isopropyl alcohol and drying the granules.
iii) Mixing the dried granules with colloidal silicon dioxide and magnesium stearate followed by compressing into mini-tablets.
B. Separating layer
Spraying a dispersion of ethyl cellulose, magnesium oxide, diacetylated mono glyceride and talc in isopropyl alcohol using wurster process.
C. Enteric layer
Spraying a dispersion of hypromellose phthalate, diacetylated mono glyceride talc and titanium dioxide in isopropyl alcohol using wurster process.
D. Final Dosage form
Filling the enteric coated mini-tablets into HPMC/gelatin capsules.
Example 3
Table 3

Sr. No. Name of Ingredient Qty Mg/Capsule
Seal coating of pellets
1 Non-pareil seeds 100.00
2 Magnesium oxide 2.000
3 Hydroxypropyl cellulose 4.000
4 Isopropyl alcohol q.s
Drug layer
5 Rabeprazole soidum 10.00

6 Magnesium oxide 25.00
7 Hydroxypropyl cellulose 5.000
8 Isopropyl alcohol q.s
Separating layer
9 Ethyl cellulose 4.100
10 Magnesium oxide 9.760
11 Diacetylated mono glyceride 0.410
13 Isopropyl alcohol q.s
Enteric layer
14 Hypromellose phthalate 65.00
15 Diacetylated mono glyceride 6.850
16 Talc 7.500
17 Titanium dioxide 0.380
18 Isopropyl alcohol+Methylene chloride q.s
Total 240.00
Process:
A. Seal coating of non-pareil seeds
i) Spraying a dispersion of magnesium oxide and hydroxypropyl cellulose in isopropyl alcohol onto inert pellets using wurster process.
B. Drug Layer

i) Spraying the drug dispersion containing rabeprazole sodium, hydroxy propyl cellulose and magnesium oxide in isopropyl alcohol onto seal coated pellets using wurster process.
C. Separating Layer
Spraying a dispersion of ethyl cellulose, magnesium oxide and diacetylated mono glyceride in isopropyl alcohol onto drug layered pellets using wurster process.
D. Enteric layer
Spraying a dispersion of hypromellose phthalate, diacetylated mono glyceride talc and titanium dioxide in isopropyl alcohol onto step (c) pellets using wurster process.
E. Final Dosage form
Filling the enteric coated pellets into HPMC/gelatin capsules.
Example 4
Table 4

Sr. No. Name of Ingredient Qty Mg/Capsule
1 Rabeprazole sodium 10.00
2 Low substituted hydroxy propyl cellulose 5.600
3 Magnesium oxide 26.00
4 Carrageenan 4.000
5 Microcrystalline cellulose 100.0
6 Isopropyl alcohol q.s
Separating Layer
7 Ethyl cellulose 4.100

8 Magnesium oxide 9.760
9 Diacetylated mono glyceride 0.410
10 Talc 1.000
11 Isopropyl alcohol q.s
Enteric coating
12 Hypromellose phthalate 65.00
13 Diacetylated mono glyceride 6.250
14 Talc 7.500
15 Titanium dioxide 0.380
16 Isopropyl alcohol q.s
Total 240.00
Process:
A. Preparation of Rabeprazole granules:
i) Mixing rabeprazole sodium with magnesium oxide, low substituted hydroxy propyl cellulose, microcrystalline cellulose in rapid mixer granulator.
ii) Granulating the above mixture by using granulating solution prepared by dispersing carrageenan in isopropyl alcohol followed by drying.
B. Separating Layer
Spraying a dispersion of ethyl cellulose, magnesium oxide, diacetylated mono glyceride and talc in isopropyl alcohol onto granules of step (A) using wurster process.
C. Enteric layer

Spraying a dispersion of hypromellose phthalate, diacetylated mono glyceride talc and titanium dioxide in isopropyl alcohol onto granules of step (B) using wurster process.
D. Final Dosage form
Filling the enteric coated granules into HPMC/gelatin capsules.
Example 5
Table 5

Sr. No. Name of Ingredient Qty Mg/Capsule
Seal coating of pellets
1 MCC Spheres 100.00
2 Magnesium oxide 2.000
3 Hydroxypropyl cellulose 4.000
4 Isopropyl alcohol q.s
Drug layer
5 Rabeprazole sodium 10.00
6 Magnesium oxide 20.00
7 Carrageenan 10.000
8 Isopropyl alcohol q.s
Separating layer
9 Ethyl cellulose 4.100
10 Magnesium oxide 9.760
11 Diacetylated mono glyceride 0.410
13 Isopropyl alcohol q.s

Enteric layer
14 Hypromellose phthalate 65.00
15 Diacetylated mono glyceride 6.850
16 Talc 7.500
17 Titanium dioxide 0.380
18 Isopropyl alcohol+Methylene chloride q.s
Total 240.00
Process:
A. Seal coating of MCC Spheres
i) Spraying a dispersion of magnesium oxide and hydroxypropyl cellulose in isopropyl alcohol onto inert pellets using wurster process.
B. Drug Layer
i) Spraying the drug dispersion containing rabeprazole sodium, carrageenan and magnesium oxide in isopropyl alcohol onto seal coated pellets using wurster process.
C. Separating Layer
Spraying a dispersion of ethyl cellulose, magnesium oxide and diacetylated mono glyceride in isopropyl alcohol onto drug layered pellets using wurster process.
D. Enteric layer
Spraying a dispersion of hypromellose phthalate, diacetylated mono glyceride talc and titanium dioxide in isopropyl alcohol onto step (c) pellets using wurster process.
E. Final Dosage form
Filling the enteric coated pellets into HPMC/gelatin capsules.

Example 6
Table 6

Sr. No. Name of Ingredient Qty Mg/Capsule
Seal coating of pellets
1 MCC Spheres 100.00
2 Sodium hydroxide 0.500
3 Hydroxypropyl cellulose 4.000
4 Purified water q.s
Drug layer
5 Rabeprazole sodium 10.00
6 Sodium Hydroxide 2.760
7 Carrageenan 10.000
8 Isopropyl alcohol q.s
Separating layer
9 Ethyl cellulose 4.100
10 Magnesium oxide 8.500
11 Diacetylated mono glyceride 0.410
13 Isopropyl alcohol q.s
Enteric layer
14 Hypromellose phthalate 65.00
15 Diacetylated mono glyceride 6.850
16 Talc 7.500

17 Titanium dioxide 0.380
18 Isopropyl alcohol+Methylene chloride q.s
Total 220.00
Process:
A. Seal coating of MCC Spheres
i) Spraying a dispersion of sodium hydroxide and hydroxypropyl cellulose in purified water onto inert pellets using wurster process.
B. Drug Layer
i) Spraying the drug dispersion containing rabeprazole sodium, carrageenan and magnesium oxide in isopropyl alcohol onto seal coated pellets using wurster process.
C. Separating Layer
Spraying a dispersion of ethyl cellulose, magnesium oxide and diacetylated mono glyceride in isopropyl alcohol onto drug layered pellets using wurster process.
D. Enteric layer
Spraying a dispersion of hypromellose phthalate, diacetylated mono glyceride talc and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride onto step (c) pellets using wurster process.
E. Final Dosage form
Filling the enteric coated pellets into HPMC/gelatin capsules.

We claim:
1. A multiple unit composition comprising of enteric coated pellets and at least one
pharmaceutically excipient, wherein each pellet comprises:
i) a core comprising rabeprazole;
ii) optionally a separating layer coated on the core;
iii) an enteric layer comprising atleast one enteric polymer and plasticizer either coated on the core or on the separating layer to obtain enteric coated pellets, such that the last enteric layer is formed from a solution comprising of enteric polymer and plasticizer in solvent(s).
2. A multiple unit composition as claimed in claim 1, wherein the core is inert core covered with rabeprazole, core containing rabeprazole, or mixtures thereof.
3. A multiple unit composition as claimed in claim 2, wherein the process for preparing inert core covered with rabeprazole comprises inert core coated with a solution/dispersion comprising of rabeprazole alone or in combination with atleast one pharmaceutically acceptable excipient in solvent(s).
4. A multiple unit composition as claimed in claim 2, wherein the process for preparing core containing rabeprazole comprises granulation or extrusion-spheronization.
5. A multiple unit composition as claimed in claim 1, wherein the enteric layer is from 10% to 70% by weight of the total composition.
6. A multiple unit composition as claimed in claim 1, wherein the enteric polymer is cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or mixtures thereof.

7. A multiple unit composition as claimed in claim 1, where in the amount of plasticizer is from 1 to 20% by weight of the total composition.
8. A multiple unit composition as claimed in claim 1, wherein the plasticizer is propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate; or mixtures thereof.
9. A multiple unit composition as claimed in claim 1, wherein the enteric coated units are filled into capsule.
10. A multiple unit composition as claimed in claim 9, wherein the contents of the capsule can be sprinkled onto soft food and ingesting the coated particles along with the food.