FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
C complete specification
[See section 10 and rule 13]
TITLE
"STABILIZED PHARMACEUTICAL COMPOSITION CONTAINING
RABEPRAZOLE SODIUM WITH IMPROVED BIOAVAILABILITY"
Applicant: TORRENT PHARMACEUTICALS LIMITED, Torrent House, Off Ashram
Road, Near Dinesh hall, Ahmedabad - 380 009, Gujarat, India.
The following specification particularly describes the invention and the marmer in which
it is to be performed.

STABILIZED PHARMACEUTICAL COMPOSITION CONTAINING
RABEPRAZOLE SODIUM WITH IMPROVED BIOAVAILABILITY
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical composition comprising
rabeprazole in a form of pellets either alone or in combination with one or
more prokinetic agent in a sustained released form, wherein the said
formulation provides enhanced bioavailability of rabeprazole in comparison to
tablet formulation of rabeprazole.
The instant invention also relates to use of the said composition in the
prevention and treatment of acid related gastrointestinal disorders, particutarly
disorders associated with gastroesophageal reflux.
Furthermore, the present invention refers to a method for the manufacture of
said pharmaceutical composition.
BACKGROUND OF THE INVENTION
Gastro esophageal reflux disease (GERD) is among the most common
disorders seen by gastroenterologists and general practitioners. Therapeutic
agents effective in the treatment of GERD include gastric acid suppressing
agents, such as H2 receptor antagonists, proton pump inhïbitors, other agents
of interest are antacids/alginates and prokinetic agents. These agents can be
distinguished by their mechanisms of action, safety profile, pharmacokinetics
and indications.
Antacids and alginates are widely used option. They have a shorter duration of
action and are seen as an inexpensive and safe option. However, they do not
provïde a long-term symptom resolutiofi of GERD.
H2 receptor antagonists are widely prescribed for GERD. They are
l

advanlageous and offer more potent and a longer duration of action on gastric
acidity.
Proton pump inhibitors, such as rabeprazole, are rapidly replacing H2 receptor
antagonists, for the treatment of GERD. Proton pump inhibitors are known to
offer significant advantages over H2 receptor antagonists in terms of symptom
resolution, healing and prevention of relapse for GERD.
Rabeprazole is a substituted benzimidazole derivative, chemically known as 2-
[[[4-(3-memoxypropoxy)-3-methyI-2-pyridinyl]-methyl]sulfinyl]-lH-
benzimidazote as disclosed in US5045552 and EP268956B1. Rabeprazole
belongs to a class of proton-pump inhibitors, that inhibits gastric acid secretion
by inhibiting the enzyme H+, K+ ATPase at the secretory surface of the
gastric parietal cell and is useful for the prevention and treatment of ulcers,
gastro esophageal reflux disease (GERD or heartburn) and other conditions
involving excessive acid secretion. The stability of rabeprazole sodium is a
function of pH; it is rapidly degraded in acid media and is more stable under
alkaline conditions.
Rabeprazole is unstable and prone to rapid decomposition and discoloration in
the presence of moisture at neutral to acidic conditions. Various approaches in
the art have been disclosed to préparé a stabilized formulation of rabeprazole.
WO2004014345 describes the pharmaceutical preparations of pellets
containing a benzimidazole compounds with an inert core to which a layer
containing an active ingrediënt is applied. To the said layer of active
ingrediënt further layer is applied, preferably one or more inert layers
(separating layers), which is optional. Further, the pellet has an outer layer
comprising an enteric coat, that is, an enteric layer. The described
pharmaceutical preparation achieves excellent storage stability, which is
achieved by combining the benzimidazole compound in mixture with
microcrystalline cellulose in the form of a layer containing an active
ingrediënt on an inert core (a neutral pellet).
2

WO97I2580 and WO9712581 describe and oral dosage forms of substituted
benzimidazoles obtained by compression of pellets containing benzimidazole,
thereby producing micro-tablets that are subsequently coated and placed inside
hard gelatine capsules.
EP993830, US5626875 discloses a stable oral pharmaceutical preparation of
benzimidazole compound comprising a nucleus formed by an inert core, the
acid labile benzimidazole, an inert water soluble polymer and pharmaceutical
acceptable excipients with the exclusion of alkaline reacting excipients; an
inert coating disposed on said nucleus, formed by a water soluble polymer and
other pharmaceutically acceptable excipients, with the exclusion of alkaline
reacting excipients;
and an outer layer on the previous coating comprising an enteric coating.
US6228400 discloses the pharmaceutical formulations containining an inert
core, a drug emulsion layer of a free base of omeprazole or lansoprazole with
a nonionic surfactant and water over inert core, a protective coating and an
enteric coating
WO03077829 describes an oral pharmaceutical composition of an acid labile
drugs characterized in a core containing acid labile drug, sub coat, a separating
layer, seal coat is a layer which separate the sub coat with enteric coat and the
enteric coating layer.
WO2002026210 and US 2003211147 describes a delayed-release,
pharmaceutical capsule dosage form, which comprises one or several enteric-
coated, compressed cores encapsulated by a capsule shell, wherein the enteric
coated compressed core consists essentially of a mixture of a pharmaceutically
acceptable carrier and benzimidazole proton pump inhibitors. The invention
also claims that the bioavailability of the benzimidazole compound is
enhanced relstfïve to a pellet or granule-containing formulations.
3

US 6379705 describe pellet pharmaceutical preparations containing
substituted benzimidazoles. The preparations comprise a spherical inert core
which is coated with an active layer containing at least one substituted
benzimidazole or its salt in the micronized form, which is coated in turn with
an insulating layer consisting of a water soluble polymer and coated lastly
with a gastroresistant or enteric layer. The pellets produced are placed in hard
gelatin capsules for oral administration.
WO9852564 describes pharmaceutical composition, which is a solid pellet
comprising an inert core, a benzimidazole in or on the core and a moisture
resistant coating comprising at least one hydrophobic material and an enteric
coating around the moisture resistant coating.
Despite different approaches discloses in the art, there exist a need to develop
a stable pellet formulation of rabeprazole, which provides comparable or
higher bioavailability to marketed formulation of rabeprazole.
Prokinetic agents are those medications that work by increasing the movement
of materials through the Gï tract. Motility of the GI tract is mediated via
smooth muscle cell response to neurotransmitters. The neuronal regulation of
gastric motility involves stimulation by cholinergic neurons, inhibition
(generally) by adrenergic neurons and complex modulatory influence of
enteric nervous system, in which dopamine and seretonin play a role. Thus
antagonists of D2 and 5HTs receptors as well as agonists of 5HT4 receptors
can stimulate gastric motility frequently in ways that depend on cholinergic
transmission. Prokinetic agents of the first generation, e.g. bethanecol,
stimulates cholinergic receptors and of the second generation, e.g.
domperidone and metoctopramrde, blocks effects of endogenous dopamine in
the gut. The action of the third generation prokinetic agents, such as
substituted benzamides, e.g. cisapride and mosapride derives primarily, but
not exciusively, from facilitating acetylcholine release from neurones of the
myenteric plexus via stimulation of 5-HT4 receptors. The efficacy of orally
administered prokinetic agents in patients with GERD and reflux oesophagitis
has been studied and a superior effect in alleviating gastro esophageal
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symptoms and healing low grade oesophagitis (non circumferential erosion)
has been shown in most studies.
Mosapride, chemically known as 4-AMINO-5-CHLORO-2-ETHOXY-N-
[4- (4-FLUOROPHENYL) METHYL]-2- MORPHOLINYL] METHYLj-
BENZAMIDE, is disclosed in EP243959 and US4870074 as gastrointestinal
prokinetic agent. Mosapride is 5-HT4 agonist intended fpr oral treatment of
gastrointestinal motility disorders. It is known to exert its action by facilitating
acetylcholine release from the enteric cholinergic neurons. With respect to the
therapeutic actions, mosapride enhances gastric emptying and also improves
total acid clearance time. Conditions or symptoms relieved by the promotion
of gastric emptying include bul are not limited to gastric stasis, flatulence,
dyspepsia, peptic ulcer and reflux oesophagitis. Mosapride, a prokinetic agent
is also used in the present invention.

Mosapride has a bioavailability of 8% and has elimination half-Iife of 1.4 to
2.0 hrs (Sakashita M, et al, Arzneimittelforschung. 1993 Aug;43(8):867-72).
Hence, conventïonal release formulation cannot maintain required plasma
concentration for long time and is therefore given 3-4 times a day (Drugs of
the future, 1993, 513-515). It is a safe drug. Most of the studies have reported
no serious side effects of mosapride even at higher dose (Drugs Res., 1993,
867-872; J Pharmacol Expt ther, 1997, 220-227). Mosapride is a seiective 5-
HT4 receptor agonist and does not interact with other receptor types. It has a
very favorable tolerability profüe, with only minor adverse effects such as
headache. Unlike other prokinetic agents, mosapride does not cause
extrapyramidal symptoms or endocrine disorders. Although, there were rare
reports of mosapride associated with QT interval prolongation, the reported
incidences occurred when mosapride was used with other pro-arrhythmic
drugs.
Considering the above aspects, a sustained release formulation of mosapride
would be of great use. The potential advantages of sustained-release mosapride
over conventional mosapride are as follows;
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• Increased patiënt compliance because of less frequent drug
administration.
• The sustained therapeutic plasma levels with this formulation would be
maintained for 24 hours.
This would make the drug administration meal independent and would also
prevent the regurgitation (GERD) even during sleep.
Patients with mild symptoms of Gastro esophageal reflux disease and limited
mucosal damage respond best to H2-receptor antagonist, prokinetic agents or
proton pump inhibitors. But in case of severe symptoms, severe mucosal
damage or both are almost always treated with proton pump inhibitors for
profound and long-term control of gastric acid secretion. However, due to the
wide diversity of symptoms and disease severity produced by acid reflux has
fed to the need for more individuatized treatment strategies
Proton pump inhibitors and prokinetic agents are frequently co-prescribed in
the management of GERD. A prokinetic agent prevents reflux while proton
pump inhibitors reduce acid secretion. Thus the combination provides
complementary actions in abatïng the symptomatology and in controlling the
disease. Moreover, there is no adverse drug interaction reported between both
the drugs.
A combination therapy of a prokinetic agent and a gastric acid lowering
compound has been found rational and more effective than mono therapy apart
from full dose of proton pump inhibitors in different studies. Administration of
cisapride and ranitidine was shown to further lower the exposure of the
oesophagus to acid(s) (Inauen W et al. Gut 1993; 34: 1025-1031). Such a
therapy was also shown to improve healing rates (de Boer WA et al. Aliment
Pharmacol Ther 1994; 8: 147-157). WO 95/01S03 describes a pharmaceutical
composition of famotidine, cisapride and optionally simethicone in the
treatment of gastrointestinal distress.
6

Further, Vyneri et al (N. Engl. J Med 1995; 333: 1106-1110) found that
omeprazole alone or in combination with cisapride was more effective than
ranitidïne alone or cisapride alone and that omeprazole combined with
cisapride was more effective than ranitidine plus cisapride. Such combination
therapies might be considered for patients whose predominant symptom is
regurgitation; those whose symptoms occur mainly at night; those with
respiratory problems such as posterior laryngitis, asthma, chronic bronchitis,
or recurrent aspiration; those with cough and hoarseness related to reflux
disease.
Thus, a combination therapy compristng an acid suppressing agent and a
prokinetic agent is attractive, rational and effective. An acid suppressing agent
plus a prokinetic agent could be an alternative to each of them separately in
case of faïlure. However, because of the large number of tab Iets/pi lis that must
be taken each day in such a therapy, the compliance of such a treatment may
be a problem. It is well known that patiënt compliance is a main factor in
receiving good results in medical treatments. Administration of two, three or
even more different tablets to the patiënt is not convenient or satisfactory to
achieve the most optimal results.
The combination of a proton pump inhibitor and a prokinetic agent, where the
proton pump inhibitor is as delayed release and the prokinetic agent is, as
sustained release wiil provide following advantages over the available dosage
forms:
• Combination of a proton pump inhibitor and a prokinetic agent has
synergistic effect.
• Similar duration of action of proton pump inhibitor and sustained
release prokinetic agent.
• Ease of administration and better compüance because of single daily
administration.
• Effective in controlling nocturnal esophageal reflux due to prolonged
duration of action.
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• No overlap in adverse drug reactions. The combinaiion wil! have the
lowest possible daily therapeutic dose of the respective drugs, which
makes it less vulnerable to cause any sorts of side effects.
• No Adverse drug interaction.
US6132771 describes a multiple unit tablet dosage form comprising a proton
pump inhibitor in the form of enteric coated pellets and one or more prokinetic
agents in a fixed formulation.
Currently, there is no commercially available stable formulation of
rabeprazole pellets either alone or in combination with a prokinetic agent in a
single dosage form, which provides an effective approach for the treatment of
GERD and increases patiënt compliance as well as provides comparable or
superior bioavailability with respect to the marketed formulations of
rabeprazole. Thus, there is a need to préparé a pharmaceutical composition,
which fulfils the aforesaid objectives. The said combination can be either in
the form of rabeprazole in a delayed release form either alone or with the
prokinetic agent in an immediate release and / or sustained release form.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical
composition comprising rabeprazole and one or more prokinetic agent.
Another object of the present invention is to provide a stable pharmaceutical
composition comprising rabeprazole in a form of an enteric coated pellet and
one or more prokinetic agent in a sustained release form.
Another object of the present invention is to provide a stable pharmaceutical
composition comprising rabeprazole in a form of an enteric coated pellet and
mosapride in a form of sustained release tablet.
8

Still another object of the instant invention is to provide a stable
pharmaceutical composition comprising rabeprazole in an enteric coated pellet
form.
A still further object of the present invention is to provide a process for the
preparation of said pharmaceutical composition.
Another object of the invention is to préparé a pharmaceutical composition,
which is useful for the treatment and prevention of acid related gastrointestinal
disorders particularly gastroesophageal reflux disorders.
Another object of the invention is to préparé a fixed dose oral pharmaceutical
composition containing rabeprazole and mosapride, admïnistrable to a
mammal in need thereof.
SUMMARY OF THE INVENTION
The present invention relates to stable pharmaceutical composition comprising
rabeprazole in a form of pellets either alone or in combination with one or
more prokinetic agent in a sustained released form, wherein the said
formulation provides enhanced bioavailabïlity of rabeprazole in comparison to
tablet formulation of rabeprazole.
Further, the present invention relates to a stable pharmaceutical composition
comprising rabeprazole sodium in the form of enteric coated pellets in
combination with mosapride citrate dihydrate in the form of sustained release
tablet, wherein the bioavailability of rabeprazole is increased by about 1.5 to
2.5 fold with respect to the marketed tablet formulation.
The present invention provides a use of the said formulation for the treatment
and preventton of acid related gastrointestinal disorders, preferably
gastroesophageal reflux disorders.
9

The present invention also discloses the process for the preparation of said
pharmaceutical preparation.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to stable pharmaceutical composition comprising
rabeprazole either alone or in combination with one or more prokinetic agent
and pharmaceutically acceptable excipients. In the instant invention,
rabeprazole is present in a form of enteric coated pellets and the prokinetic
agent in a sustained release form.
[n a preferred embodiment, the present invention discloses a pharmaceutical
composition of rabeprazole sodium in a form of enteric coated pellets in
combination with mosapride citrate dihydrate, in a form of sustained release
tablet.
In another embodiment, the present invention discloses a pharmaceutical
composition of rabeprazole sodium in a form of enteric coated pellets,
In the present invention, we have surprisingly found that the bioavailability of
rabeprazole is enhanced in comparïson to the marketed tablet formulation of
rabeprazole, when rabeprazole sodium is formulated in a form of enteric
coated pellets, either alone or in combination with mosapride citrate dihydrate
in a form of sustained release tablet. It has been found that the bioavailability
of rabeprazole in enteric coated pellet form is enhanced by around 1.5 to 2.5
fold. Considering this substantial increase in bioavailability, the dose of
rabeprazole sodium can be reduced by about 40 to 60%, preferably by about
50 %, when formulated either alone or in combination with a prokinetic agent.
The preparation of enteric coated pellets of rabeprazole and sustained release
tablet of one or more prokinetic agent is described in the instant invention.
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The formulation disciosed in the present invention is not a mere admixture but
has propenies different from the sum total of the proporties of its ingredients.
The term "rabeprazole" as used herein includes rabeprazole, a
pharmaceutically acceptable salt of rabeprazole, a single enantiomer of
rabeprazole or a pharmaceutically acceptable salt of the single enantiomer.
The term "prokinetic agent" as used herein includes prokinetic agent or its
pharmaceutically acceptable salt.
The term "mosapride:' as used herein includes mosapride or its
pharmaceutically acceptable salt.
The term "sustained release" as used herein in relation to the composition
according to the invention means release, which is not immediate release and
is taken to encompass controlled release, sustained release, prolonged release
timed release, retarded release, extended release, delayed release etc.
The term "inert core" as used herein in relation to the composition according
to the invention means ethyl cellulose or any inert material coated sugar
globules or microcrystalline cellulose spheres or any other inert material
spheres.
The pharmaceutical composition of the present invention typically comprises
from 5mg to lOOmg of rabeprazole. The formulation of this invention
preferably comprises lOmg to 40mg rabeprazole.
The amount of prokinetic agent in the pharmaceutical formulation is from l mg
to 50mg. In a preferred embodiment, the amount of prokinetic agent is 2mg to
20mg.
The amount of mosapride in the pharmaceutical formulation is from l to 50
mg. In a preferred embodiment, the amount of mosapride is 2 to 20 mg.
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The pharmaceutical composition of the present invention may be administered
either twice daily or once daily.
The pharmaceutical composition of the instant invention comprises
rabeprazole sodium, optionally with one or more prokinetic agent and
pharmaceutically acceptable excipients selected from the group comprising of
pH modulator, stabilizing agent, diluent, binder or film forming polymer,
enteric polymer, disintegrant, anti-sticking agent, plasticizer, rate controlling
agent, glidant, coloring agent, aqueous or non-aqueous solvent and other
pharmaceutical ly acceptable excipient or adjuvant.
The prokinetic agent in the instant invention can be selected from the group
comprising of first, second and third generation prokinetic agents like
cisapride, dazopride, mosapride, exepanol, lintopride, motilin, idremcinal,
mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851,
zacopride, ecabapide, prucalopride, fedotozine, cinitapride, itopride,
polycarbophil, tegaserod, INKP-100, diacol, metoclopramide, domperidone,
etc.
The pH modulator can be selected from the group comprising of magnesium
oxide, dibasic calcium phosphate anhydrous, tribasic calcium phosphate,
precipitated calcium carbonate and cellulose derivatives including powdered
cellulose and other materials known to one of ordinary skill in the art. The pH
modulator in the dosage form ranges from l % to 30 % by weight.
Stabilizing agents can be selected from the group comprising of calcium
carbonate, dibasic calcium phosphate dihydrate, calcium sulphate anhydrous,
calcium sulphate dihydrate, magnesium oxide, magnesium carbonate,
magnesium silicate, potassium bicarbonate, potassium hydroxide, dibasic
potassium phosphate, sodium hydroxide, sodium bicarbonate, sodium
carbonate, dibasic sodium phosphate, tribasic sodium phosphate, magnesium
lactate, magnesium gluconate, aluminium hydroxide, sodium citrate, sodium
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tartarate, sodium polyphosphate, potassium polyphosphate, sodium acetate,
calcium acetate, potassium metaphosphate, calcium glycerophosphate,
calcium lactate, calcium bicarbonate and other materials known to one of
ordinary skill in the art. Stabilizing agents in the dosage form ranges from l %
to 30 % by weight
pH modulator and stabilizing agents and its amount in the present formulation
is selected in such a way that the pH of the formulation is maintained at a level
so as the minimal degradation of rabeprazole is achieved.
Diluents can be selected from the group comprising of calcium carbonate,
calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,
microcrystalline cellulose, silicified microcry stal line cellulose, cellulose
powdered and its derivatives, dextrates, dextrins, dextrose excipients, fructose,
kaolin, lactitol, lactose, mannitol, sorbitol, starch and its derivatives, sucrose,
sugar compressible, sugar confectioners and other materials known to one of
ordinary skill in the art. Diluents in the dosage form ranges from 10% to 50%
by weight
Binder or film forming polymer can be selected from the group comprising of
polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, acacia, algïnate
derivatives, hydroxy propyl cellulose, carboxymethylcellulose sodium,
compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose,
pregelatinized starch and other materials known to one of ordinary skill in the
art. Binders in the dosage form ranges from l % to 10 % by weight.
The enteric coating polymers can be selected from the group comprising of
Eudragit L12.5 P, Eudragit L 12.5, Eudragit L 100, Eudragit L 100-55,
Eudragit L30D55, Eudragit S12.5 P, Eudragit S 12.5, Eudragit S 100,
Hydroxypropyl Methylcellulose Phthalate, Poïyvinyl acetate phthalate,
Cellulose acetate phthalate, shellac and other materials known to one of
ordinary skill in the art. Enteric coating polymers in the dosage form ranges
from 5 % to 20 % by weight.
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Disintegrants can be selected from the group comprising of starch, sodium
starch glycolate, croscarmellose sodium, crospovidone, alginate derivatives,
carboxy methyl cellulose sodium, guar gum and other materials known to one
of ordinary skill in the art. Disintegrants in the dosage form ranges from 0.5 %
to 15 % by weight.
Anti-sticking agent can be selected from the group comprising of stearate
derivatives like magnesium stearate, calcium stearate, zinc stearate,
polyethylene glycol (various grades), talc, hydrogenated castor oil, silica,
colloidal silica, cornstarch, calcium stlicate, magnesium silicate, silicon hydro
gel and other materials known to one of ordinary skill in the art. Anti-sticking
agents in the dosage form ranges from 0.1 % to 5 % by weight.
Plasticizers can be selected from the group comprising of dibutyl sebacate,
polyethylene glycol and polypropylene glycol, dibutyl phthalate, diethyl
phthalate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl
tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or
glycol esters of fatty acids, refmed mineral oils, oleic acid, castor oil, corn oil,
camphor, glycerol and sorbitol polyethylene glycols, propylene glycol,
glycerols, glycerides, fractionated coconut oil and castor oil, ester of a citric
acid, phthalic acid or sebacic acid, or a mixture thereof. An ester selected
from the group consisting of phthalate esters, phosphate esters, citrate esters,
fatty acid esters and tartarate esters, glycerine or glycol derivatives, or sorbitol
and other materials known to one of ordinary skill in the art. Plasticizer in the
dosage form ranges from l % to 20 % by weight.
The rate controlling agents can be selected from the group comprising of
cellulosic polymers such as ethylcellulose, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, methylcellulose, carboxy methyl cellulose, hydroxyl
methylcellulose and hydroxyethylcellulose, waxes, hydroxypropylmethyl
cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate
and methacrylic acid polymers such as Eudragit RL and RS,
polymethacrylates, sodium carboxymethylcellulose, calcium
carboxymethylcellulose, acrylic acid polymer, polyethylene glycol,
14

polyethylene oxide, carrageenan, cellulose acetate, zein, carbohydrate gums,
polyuronic acid salts, cellulose ethers and acrylic acid polymers. The
carbohydrate gums may be one or more of xanthan gum, tragacanth gum, gum
karaya, guar gum, acacïa, gdlan and locust bean gum. The polyuronic acid
salts may be one or more of alkali metal salts of alginic acid and pectic acid
and other materials known to one of ordinary skill in the art. The rate
controlling agent in the dosage form ranges from 10 % to 50 % by weight.
Aqueous or non-aqueous solvents can be selected from the group comprises
ethanol, methanol, iso-propanol, water and other known to one of ordinary
skill in the art.
Glidants can be selected from the group comprising of colloidal siïicon
dioxide, cornstarch, talc, calcium silicate, magnesium silicate and other
materials known to one of ordinary skill in the art. Glidants in the dosage form
ranges from 0.1% to 10 % by weight.
Other pharmaceutical solvents are selected from the group comprising of
acetone, dichloromethane, Isopropyl alcohol, Methanol, water etc.
Coloring agent is selected from the group comprising of iron oxides and its
derivatives like red oxide of iron, yellow oxide of iron etc. lake and dye colors
and colors which are pharmaceutically acceptable.
The preparatie n of pharmaceutical composition of the present invention
comprises of two phases:
Phase-1: Preparation of rabeprazole sodium enteric coated pellets comprising
ethyl cellulose or any other inert material coated sugar globules or
microcrystalline cellulose spheres or any other inert material spheres of 10
mesh to 100 mesh size, preferably 20 mesh to 30 mesh size. These globules
are further coated by addition of an alkali agent to make the drug stable on it.
These globules are further coated by a material containing active
pharmaceutical ingrediënt and alkali material as stabilizer. This stabilizer is
15

used here to maintain the pH of the said layer at not less than 9, preferably
10.5. Further the said globules are coated with barrier coating comprising inert
polymers. Then, the same barrier coated globules are coated with an enteric
polymer.
Phase-2: Preparation of sustained release portion of prokinetic agent
comprising an immediate release portion and sustained release portion of
prokinetic agent.
Phase-1: Prepration of rabeprazole sodium enteric coated pellets
comprising the folio» ing steps:
1. Ethyl cellulose or any inert material coated sugar giobules or
microcrystalline cellulose spheres or any other inert material spheres of
10 mesh to 100 mesh size preferably 20 mesh to 30 mesh size is taken
as an inert core. Inert coating of inert material coated sugar globules is
done by spraying the spraying solution on to the ethyl cellulose coated
sugar globules on a Wurster spray (Glatt). The spraying solution is
prepared by following method:
Binder or film forming polymer(s) is dissolved in water. Anti-sticking
and pH modulator are milled together in the presence of a sufficient
quantity of water in a colloidal mill. The above milled dispersion is
added to the binder or film forming polymer(s) solution and stirred to
get a clear homogeneous suspension and the same is passëd through
SieveNo.100
2. Seal coated sugar globules prepared in step l are fiirther coated by the
suspension containing active ingrediënt i.e. rabeprazole sodium in
dissolved / disperse form. The coating of active ingrediënt is done by
spraying the coating solution comprising active ingrediënt on to the
inert material coated sugar globules (prepared in step 1) by Wurster
spray (Glatt). The coating solution comprising active ingrediënt is
prepared by the following method.
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Binder or film forming polymer(s) is dissolved in water. The pH
modulator is milled with a sufficient quantity of water in a colloidal
mill to get suspension. The pH modulator and rabeprazole sodium are
dissolved / disperse in a sufficient quantity of water. The above
prepared solution of binder or film forming polymer(s) and suspension
of pH modulator vis added to the solution of rabeprazole sodium in
water and stirred to get a clear suspension and passed through Sieve
No.100
3. Further, barrier coating is applied to the globules prepared in step 2
above by Wurster spray (Glatt). The barrier or film forming polymer(s)
coating suspension is prepared by following method:
Binder or film forming polymer(s) is dissolved in water. The pH
modulator and anti-sticking agent are milled with a sufficient quantity
of water in a colloidal mill. This prepared suspension of pH modulator
is added to the solution of binder or film forming polymer(s) in water
and stirred to get a homogenous suspension and passed through Sieve
No. 100.
4. Further, the coated globules prepared in step 3 are coated by an enteric
coating polymer(s) and excipients. The coating is applied by Wurster
spray (Glatt). The suspension for enteric coating is prepared by the
following method.
The plasticizer is dissolved in water. The anti-sticking agent is mlled
with a sufficient quantity of water in a co lloidal mill. The solution of
plasticizer and anti-sticking agent dispersion is added to the enteric
coating polymer solution or suspension and stirred gently to get a
homogeneous suspension and passed through Sieve No.100 to form
pellets.
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5. The pellets prepared by steps l to 4 are filled in capsule, compressed
into tablets, added in dry suspension or ready for use suspension,
sachets, or formulated as dispersible tablets.
Phase-2: Preparation of prokinetic agent sustained release composition
by following steps:
The sustained release composition of prokinetic agent comprises
immediate release (IR) portion and sustained release (SR) portion or
only sustained release portion.
(A) Immediate release portion of prokinetic agent tablet is prepared bv
following steps:
1. The prokinetic agent mosapride or its salt is passed through Mesh No.100,
red oxide of iron and yellow oxide of iron are passed through Mesh
No.150. Diluents are passed through Mesh No. 40.
2. The sifted material is blended together.
3. Binder is dissolved in purified water and is used as the granulating solution
to préparé granules of the above blend till the mass of required consistency
is obtained.
4. The wet mass obtained in step 3 above is passed through mesh No. 08 and
the wet granules dried in a tray dryer at 70°C till the loss on drying is
1.59%.
5. The dried granules are passed through mesh No. 20 and blended with a
compression mixture comprising of glidant colloidal silicon dioxide,
disintegrating agent and lubricant, previously sieved through mesh No. 60.
6. The granules prepared in step 5 can be used as such or compressed into a
tablet or mini tablets or pellets.
18

(B) Sustained release portion of prokinetic agent tablet is orepared bv
fotlowing steps:
1. The prokinetic agent mosapride is passed through Mesh No. 100.
Diluent lactose and rate controlling polymer are passed through Mesh
No. 40.
2. The sifted materials of step l are blended together.

3. Binder is dissolved in non-aqueous solvent and is used as the
granulating solution to préparé granules of the above blend till mass
of required consistency is obtained.
4. The wet mass is passed through Mesh No. 08.
5. The wet granules are dried in a tray dryer at 70°C till the loss on drying
is 1.81%.
6. The dried granules are passed through Mesh No. 20 and blended with a
compression mixture comprising of glidant and lubricant, previously
sieved through Mesh No. 60.
7. The granutes prepared in step 6 can be compressed into a tablet or mini
tablets or pellets.
Rabeprazole pellets obtained by phase I can be formulated in different ways
but not limited to pellets fïlled in capsule, pellets compressed into tablets,
pellets in dry suspension or ready for use suspension, sachets and dispersible
tablets.
Rabeprazole pellets obtained by phase I, preparation of fraction A of phase -
II and preparation of fraction B of phase - II can be combined into a final
formulation in different ways but not limited to pellets fïlled in capsule or
pellets compressed into tablets or mini tablets fïlled in capsule and along with
bi-layer tablet prepared from fraction A and B (IR and SR respectïvely) fïlled
into capsule.
Throughout this specification and the appended claims it is to be understood
that the words "comprise" and "include" and variations such as "comprises",
19

"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.
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.
PREPARATORY EXAMPLE OF THE DOSAGE FORM
Example -1
P re pa ratio D of Rabeprazole and Mosapride SR capsules
The effective amount of active ingrediënt according to this invention
comprises of:
Rabeprazole Sodium 20mg
(as enteric coated pellets)
Mosapride Citrate dihydrate eq. to
Mosapride Citrate anhydrous 15mg
(in sustained release form)
Color: Red oxide of Iron and Yellow Oxide of ïron
Prepration of Rabeprazole sodium enteric coated pellets:
The ingredients used in the preparation of Rabeprazole enteric coated pellets
containing Rabeprazole Sodium in the instant invention by Wurster spraying
(Glatt process) are given below along with the method of preparation of said
pellets.
A) Formula for seal coating of sugar globules.
* loss to be considered during process.
Table l
20

Ingredïents Quantity
Per batch/grams Percentage by
weight
Sugar globules (seal coated) 1000 96.955
Magnesium oxide light 15 1.45
Hydroxy propyl methyl cellulose 6 cps 15 1.45
Talc 1.5 0.145
Purified water 630 -
21

Procedure
1.45%w/w hydroxypropylmethylcellulose 6 cps was dissolved in water.
Milled together 0.145%w/w talc and 1.45%w/w magnesium oxide with
sufficient quantity of water in a colloidal mill. Added the milled dispersion of
above to the HPMC solution and stirred to get a clear solution and passed
through Sieve No.100.
The above solution was sprayed on to the ethyl cellulose coated sugar globules
on a Wurster spray (Glatt)
B) Formula for drug coating on seal coated sugar globules:
Table2

Ingredients Quantity
Per batch/grams Percentage by
weight
Sugar globules (seal coated) Step A 800 60.859
Rabeprazole sodium 350 26.626
Magnesium oxide light 70 5.325
Hydroxy propyl methyl cellulose 6CPS 87.5 6.656
Sodium hydroxide 7.0 0.534
Purified water 3500
Procedure
6.656 % w/w hydroxypropylmethylcellulose 6 cps was dissolved in water.
Milled 5.325% w/w magnesium oxide with sufficient quantity of water in a
colloidal mill. 0.534% w/w Sodium hydroxide and 26.626 % w/w Rabeprazole
sodium were dissolved in sufficient quantity of water. Added the above
solution of HPMC and magnesium oxide to the solution of rabeprazole in
water and stirred to get homogeneous suspension and passed through Sieve
No. 100.
The above suspension was sprayed on to the seal coated sugar globules by
Wurster spray (Glatt).
22

C) Formula for Barrier coating:
Table 3

Ingredients Quantity
Per batch/grams Percentage by
Weight
Drug coated pellets 1200 86.957
Hydroxy propyl methyl cellulose 6CPS 150 10.869
Magnesium oxide light 15 1.087
Magnesium stearate 15 1.087
Purified water 3600 -
Procedure
10.869 % w/w Hydroxypropyl methylcellulose 6 cps was dissolved in water.
Milled 1.0869% w/w magnesium oxide and 1.087 % w/w magnesium stearate
with sufficient quantity of water in a colloidal mill. Added the suspension of
magnesium oxide and Magnesium stearate into the solution of HPMC in water
and stirred to get a homogenous suspension and passed through sieve 100#.
The above suspension was sprayed on to the seal coated sugar globules by
Wurster spray (Glatt).
D) Formula for enteric coating:
Table 4

Ingredients Quantity
Per batch/grams Percentage by
weight
Barrier coated pellets 1300 66.663
Eudragit L 30 D 55 1667.0 25.645
Talc 100 5.128
Polyethylene glycolöOOO 50 2.564
Purified water 1400 -
23

Procedure
2.564 % w/w Polyethylene glycol 6000 was dissolved in water. Milled 5.128
% w/w Talc with sufficient quantity of water in a colloidal mill. Added the
solution of Polyethylene glycol 6000 and talc dispersion to 25.645 % w/w
Eudragit L30 D 55, stirred gently and passed through Sieve No. 100.
The above suspension was sprayed on to the seal coated sugar globules by
Wurster spray (Glatt).
The final pellets were filled in hard geJatin capsules.
Assay : 102.5%
Related Impurities : Single max 0.62
Total imp 1.62
Karl Fischer Coëfficiënt : 5.26
Dissolution Profile of Rabeprazole sodium of the instant invention at pH 1.2
simulated gastric fluid
The dissolution of pellets prepared accordïng to the instant inventïon was
determined in a paddie apparatus. The rotation speed was set at 50 ± 2 revolutions
per minute, the dissolution medium being 0.1 N HC1 maintained at a fixed
temperature of 37°C (pH 1.2 simulated gastric fluid). The total volume of the
dissolution fluid was 250 ml. The data obtained is presented in Table 5.
Table 5

Product containing 20 mg of Rabeprazole sodium % DRUG RELEASE
S.NO. DOSAGE FORM 2hr
1 Rabeprazole sodium enteric coated
Pellets 15.02%w/w 6.7
(Limit NMT 10 % in 2 hours)

24

Dissolution Profïle of Rabeprazole sodium of the instant invention at pH 10
The dissolution of pellets prepared according to the instant invention was
determined in a basket apparatus. The rotation speed was set at 100 ± 2
revolutions per minute, the dissolution medium being pH 10 buffer maintained at
a fixed temperature of 37°C The total volume of the dissolution fluid was 900 ml.
The data obtained is presented in Table 6.
Table 6

Product containing 20 mg of Rabeprazole sodium % DRUG RELEASE
S NO... DOSAGE FORM 45 min
1 Rabeprazole sodium enteric coated
Pellets 15.02 % w/w 96.1

The dissolution rate of the pellets prepared in the instant invention was found to
be less than 10 % in 2 hours in simulated gastric fluid (pH 1.2) and more than 70
% in 45 minutes at pH 10. Thus, the dissolution of the delayed release pellets of
rabeprazole prepared according to the instant invention is acceptable.
Preparation of Mosapride citrate Sustained release tablets
The ingredients used in the preparation of Mosapride citrate sustained release
tablets containing Mosapride citrate in the instant invention is given below
along with method of preparation of said tablets by wet granulation.
25

A) Formula for preparation of IR fraction:
Table 7

Ingredients Quantity
In mg /tab Percentage by
weight
Mosapride citrate dihydrate eq. to Mosapride citrate
anhydrous 4.5mg 4.764 3.285

Lactose 85.0 . 58.621
Microcrystalline cellulose 43.336 29.886
Red oxide of iron 0.03 0.021
Yellow oxide of iron 0.12 0.083
Polyvinyl pyrrolïdone K 30 4.5 3. 103
Croscarmellose sodium 5.0 3.45
Colloidal silicon dioxide 0.75 0.517
Magnesium stearate 1.50 1.034
Tolal 145 mg 100 % w/w
*Potency of the Mosapride citrate adjusted to 100 % & quantity of lactose IP should be
reduced to keep input constant.
Procedure
Mosapride citrate 3.285% w/w was passed through Mesh No. 100. 0.021% w/w
red oxide of iron and 0.083% w/w yellow oxide of iron were passed through Mesh
No. 150. Lactose 58.621% w/w and microcrystalline cellulose 29.886% w/w were
passed through Mesh No. 40. The sifted materials were blended together. 3.103%
w/w of polyvinylpyrrolidone K30 was dissolved in 400 ml of purified water and
was used as the granulating solution to préparé granutes of the above blend till the
mass of required consistency was obtained. It required 500 ml of extra purified
water. The wet mass was passed through Mesh No. 08 and the wet granules dried
in a tray dryer at 70°C till the loss on drying was l .59 %. The dried granules were
passed through Mesh No.20 and blended with a compression mixture comprising
of 0.517% w/w of colloidal silicon dioxide, 3.45% w/w of croscarmellose sodium
and 1.034% w/w of magnesium stearate, previously sieved through Mesh No. 60.
26

B) Formula for preparation of Sustained Release fraction:
Table S

Ingredients Quantity
In mg /tab Percentage by
weight
Mosapride citrate dihydrate equivalent, to Mosapride citrate 11.117 ' 13.897

Lactose 38.383 47.978
Hydroxypropyl methyl cellulose K4M 25.0 31.250
Polyvinyl pyrrolidone K 30 4.0 5.000
ColloidaJ silicon dioxide 0.5 0.625
Magnesium stearate 1.0 1.250
Total 80 mg 100 % w/w
* Potency of the Mosapride citrate adjusted to 100 % & quantity of lactose IP should be
reduced to keep input constant.
Procedure
Mosapride citrate 13.897% w/w was passed through Mesh No. 100. Lactose
47.978% w/w and hydroxypropylmethylcellulose K4M were passed through Mesh
No. 40. The sifted materials were blended together. 5.0% w/w of
poJyvinylpyrrolidone K30 was dissolved in 1000 ml of isopropyl aJcohol and was
used as the granulating solution to préparé granules of the above blend till the
mass of required consistency was obtained. The wet mass was passed through
Mesh No. 08 and the wet granules dried in a tray dryer at 70°C till the loss on
drying was 1.81%. The dried granules were passed through Mesh No. 20 and
blended with a compression mixture comprising of 0.625% w/w of colloidal
silicon dioxide and 1.25% w/w of magnesium stearate, previously sieved through
Mesh No.60.
The final blend thus obtained comprising of two layers of fraction A and B (IR
and SR respectïvely) were compressed into 225 mg bilayered tablets on a tablet
compression machine using 10*5 mm capsule shaped punches.
27

Assay ; 99.03
Karl Fischer Coëfficiënt : 5.68
OrganicVolatile Impurities (IPA) : 1557ppm
Dissolution Profile of Mosapride citrate of the instant invention at pH 1.2
(simulated gastric fluidt
The dissolution of tablets prepared according to the instant invention was
determined in a Paddie apparatus. The rotation speed was set at 50 ± 2 revolutions
per minute, the dissolution medium being 0.1 N HC1 maintained at a fixed
temperature of 37 °C (pH 1.2 simulated gastric fluid). The total volume of the
dissolution fluid was 900 ml. The data obtained is presented in Table 9.
Table 9

PRODUCT CONTAINING
15 MG UNCOATED TABLET % DRUG RELEASE AT DIFFERENT TIME INTERVALS

Hours
SLNO DOSAGE FORM 1 2 4 6 8 10 12
1. Mosapride citrate sustained release
tablets 38.4 48.5 64.1 76.3 87.3 92.1 100.5
Thus, the dissolution rate of the mosapride citrate sustained release tablets
prepared in the instant invention was found to be acceptable.
The final pellets of the rabeprazole and mosapride tablet are than filled in hard
gelatin capsules.
28

Example II
Six month stability profile of Rabeprazole and mosapride citrate SR
capsules
Table 10

Condiüon/ Assay (%) RI % Dissolution % Dissolution
Period Rabeprazole Mosapride.(hr)
GF IF
Rabe. Mosa. single total 2hrs 45min 1 6 12
Initial 102.5 99.03 0.62 1.62 6.7 96.1 38.4 76.3 100.5
40°C 75%RH 97.2 102 - - 5.0 95.4 38.7 73.8
1M
40ÜC 75%RH 97.7 100.2 ~ -- 5.8 97.9 40.1 79.8 101.6
3M
40"C 75%RH 94.32 99.21 0.47 2.07 8.4 95.7 39.5 77.8 104.2
6M
30°C 65%RH 99.1 99.5 ~ - 2.7 101.5 40.4 80.1 103.3
3M
30°C 65%RH 95.91 100.13 0.26 1.24 4.9 97.4 39.4 78.1 103.8
6M
29

Example III
Six month stability profile of Rabeprazole pellets fïlled in Capsules and
rabeprazole tablets.
Table 11

Rabeprazole Pellets Rabeprazole Tablets (Velozf
Condition/
Period Assay (%) W Assay (%) Rl
Rabeprazole Single total Rabeprazole single total
Initia! 100.03 0.62 1.62 97.07 - -
40°C 75%RH
1M 100.3 0.49 1.08 96.1 0.4 1.1
40°C 75%RH
3M 96.7 0.59 1.23 96.7 0.69 1.76
40"C 75%RH
6M 94.35 0.21 1.17 94.3 1.14 4.66
30°C 65%RH
3M 97.9 0.67 1.76
30°C 65%RH
6M 94.90 0.33 1.35
$ Veloz - Rabeprazole enteric coated tablet - Manufactured by Torrent Pharmaceuticals Ltd.
Above data confirms that pellets are more stable than tablet formulations
Example-IV
Bioequivalence study
We have conducted two Pharmacokinetic studies on Rabeprazole 20 mg in
healthy human Volunteers.
The first study (Study 1) was a bioavailability study conducted comparing
Rabeprazole as enteric coated pellets in the Fixed Dose Combination (FDC) of
Rabeprazole 20mg + Mosapride SR 15 mg capsule formulation, with co-
administration of VELOZ (Rabeprazole Tablet formulation; Torrent
30

Pharmaceuticals Limited, India) and MOSID OD (Mosapride SR 15 mg
Tablet formuJation; Torrent Pharmaceuticals Limited, India).
The second study (Study II) was a bioequivalence study conducted at Torrent
Research Centre with 12 volunteers comparing test formulation (Rabeprazole
20mg Tablet of Torrent Pharmaceuticals Ltd) with Reference formulation
"PARIET" (Rabeprazole sodium 20mg tablet of EISAI Pharma UK).
We compared Pharmacokinetic Parameters of Rabeprazole 20 mg from both
these studies,
Since the sampling time points were different in two studies we rook only
those time points that were common to both the studies for the calculation of
Pharmacokinetic Parameters. For the statistical calculation plasma
concentrations derived at Pre-dose and 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0,
8.0 and 10.0 hours were considered. Original time points for Study l was Pre-
dose and 1.0, 1.5, 2.0, 2.5, 3,0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0 hours
after study drug administration and for Study 2 Pre-dose and 0.5, 0.75, 1.0,
^1.25, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0 and 12.0, hours
after study drug administration. This was done to take care of sampling time
points variatïons in the two studies that were likely to affect the mean
concentrations for Cmax, AUC(o.t) and AUC(o-α).
The derived Cmax and AUC for Rabeprazole in the two studies are given in the
table 12 below.
Table 12

Study Group Formulation WIM
(ng/ml) AUCV(0-t)(ng/ml*hr) AUC(0-α)(ng/ml *hr)
I A Rabeprazole
Peflet* + Mosapride
citratedihydrate(15
mg) in capsule 937.685+219.35 1698.486 +565.52 1749.330+589.05

B Rabeprazole*
(Veloz tablet)
+ Mosapride citrate
dihydrate( 15 mg)
(MOSID OD tablet) 355.749 ±331.05 877.901+609.77 975.748+608.43
II C Rabeprazole*
(Veloz tablet) 511.076±231.13 928.193±598.20 1035.218+641.62

D Rabeprazole*
(Pariet tablet) 354.238+191.84 624.239+362.58 902.564+334.57
31

* Enteric coated
AUC (0^o) - Area under the curve from zero to infmity.
Cmax - The peak plasma concentration achieved after the administration of the
drug.
With the tablet formulation of Rabeprazole (Group B, C, & D) the observed
Cmax was within the range of 354.238 +J91.84 to 511.076 +.231.13 whereas
with the Rabeprazole capsules containing pellets (Group A) the Cmax was
937.685 +219.35. Similarly, for AUC(0-α) with the tablet formulation of
Rabeprazole (Group B, C, & D) the observed AUC was within the range of
902.564 +334.57 to 1035.218 + 641.62 whereas for the Rabeprazole capsules
containing pellets (Group A) the AUC was 1749.330 +.589.05.
For AUC, there was no significant difference between Groups B, C & D. The
observed AUC for Group A was signifïcantly higher (p<0.001) as compared to
Group B, C & D.
The Cmax was also signifïcantly higher (pO.OOl) for Group A as compared to
Group B, C & D.
Mosapride was administered either as FDC or co-administered with
Rabeprazole in the first study.
Thus, it can be concluded that the bioavailability of rabeprazole in pellet form
is signifïcantly higher as compared to that of Rabeprazole tablet (Veloz and
Pariet)
32

CLAIMS
1. A stabilized pharmaceutical composition comprising rabeprazole,
optionally with one or more prokinetic agent and one or more
pharmaceutically acceptable excipients, wherein the said composition
provides enhanced bioavailability of rabeprazole relative to a tablet
formulation of rabeprazole.
2. A pharmaceutical composition as claimed in claim l, wherein the one
or more pharmaceutically acceptable excipients comprise pH
modulators, stabilizing agents, binders or film forming polymers,
enteric polymers, diluents, disintegrants, anti-sticking agents,
plasticizers, rate controlling agents, glidants, coloring agents, solvents.
3. A pharmaceutical composition as claimed in claim l, wherein
rabeprazole is in the form of rabeprazole sodium.
4. A pharmaceutical composition as claimed in claim l, wherein
rabeprazole sodium is in the form of enteric coated pellets.
5. A pharmaceutical composition as claimed in claim l, wherein
prokinetic agent is in a sustained release form,
6. A pharmaceutical composition as claimed in claim l, wherein the
bioavailability of rabeprazole is increased up to 1.5 to 2.5 fold.
7. A pharmaceutical composition as claimed in claim l, wherein
prokinetic agent is selected from the group comprising of cisapride,
dazopride, mosapride, exepanol, lintopride, motilin, idremcinal,
mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851,
zacopride, ecabapide, prucalopride, fedotozine, cinitapride, itopride,
polycarbophil, tegaserod, INKP-100, diacol, metoclopramïde,
domperidone or pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition as claimecl in claim 7, wherein
preferred salt of mosapride is mosapride citrate dihydrate.
9. A pharmaceutical composition as claimed in claim l, wherein the
amount of the rabeprazole is in the range of 5mg. to lOOmg, preferably
in the range of l0mg. to 40mg. and the amount of the prokinetic agent
is in the range of Img to 50mg, preferably in the range of 2mg. to
20mg..
33

10. A pharmaceutical composition as claimed in claim l, wherein the
amount of the rabeprazole is in the range of 5mg. to lOOmg, preferably
in the range of lOmg. to 40mg. and the amount of the mosapride is in
the range of 1mg. to 50mg, preferably in the range of 2mg. to 20 mg..
11. A pharmaceutical composition as claimed in claim 2, wherein pH
modulator is selected from the group comprising of magnesium oxide,
dibasic calcium phosphate anhydrous, tribasic calcium phosphate,
precipitated calcium carbonate and cellulose derivatives including
powdered cellulose.
12. A pharmaceutical composition as claimed in claim 2, wherein
stabilizing agent is selected from the group comprising of calcium
carbonate, diabasic calcium phosphate dihydrate, calcium sulphate
anhydrous, calcium sulphate dihydrate, magnesium oxide, magnesium
carbonate, magnesium silicate, potassium bicarbonate, potassium
hydroxide, dibasic potassium phosphate, sodium hydroxide, sodium
bicarbonate, sodium carbonate, dibasic sodium phosphate, tribasic
sodium phosphate, magnesium lactate, magnesium gluconate,
aluminium hydroxide, sodium citrate, sodium tartarate, sodium
polyphosphate, potassium polyphosphate, sodium acetate, calcium
acetate, potassium metaphosphate, calcium glycerophosphate, calcium
lactate and calcium bicarbonate.
13. A pharmaceutical composition as claimed in claim 2, wherein enteric
polymer is selected from the group comprising of Eudragit L12.5 P,
Eudragit L 12.5, Eudragit L 100, Eudragit L 100-55, Eudragit L30D55,
Eudragit S12.5 P, Eudragit S 12.5, Eudragit S 100, Hydroxypropyl
Methylcellulose Phthalate, Polyvinyl acetate phthalate, Cellulose
acetate phthalate and shellac.
14. A pharmaceutical composition as claimed in claim 2, wherein diluent
is selected from the group comprising of calcium carbonate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,
microcrystalline cellulose, silicified microcry stal line cellulose,
cellulose powders and its derivatives, dextrates, dextrins, dextrose,
fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch and its
derivatives, sucrose, sugar compressible and sugar confectioners.
34

15. A pharmaceutical composition as claimed in claim 2, wherein binder
or film forming polymer is selected from the group comprising of
polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, acacia, alginic
acid, hydroxy propyl cellulose, carboxymethylcellulose sodium,
compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl
cellulose and pregelatinized starch.
16. A pharmaceutical composition as claimed in claim 2, wherein
disintegrant is selected from the group comprising of starch, sodium
starch glycolate, croscarmellose sodium, crospovidone, alginic acid,
carboxy methylcellulose sodium and guar gum.
17. A pharmaceutical composition as claimed in claim 2, wherein anti-
sticking agent is selected from the group comprising of magnesium
stearate, calcium stearate, zinc stearate, polyethylene glycol, talc,
hydrogenated castor oil, silica, colloidal silica, corn starch, calcium
silicate, magnesium silicate- and silicon hydro gel.
18. A pharmaceutical composition as claimed in claim 2, wherein
plasticizer is selected from the group comprising of dibutyl sebacate,
polyethylene glycol and polypropylene glycol, dibutyl phthalate,
diethyl phthalate, triethyl citrate, tributyl citrate, acetylated
monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate,
benzyl benzoate, butyl and/or glycol esters of fatty acids, refined
mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and
sorbitol polyethylene glycols, propylene glycol, glycerols, glycerides,
fractionated coconut oil, castor oil, phthalic acid, sebacic acid, or a
mixture thereof.
19. A pharmaceutical composition as claimed in claim 2, wherein rate
controlling agent is selected from the group comprising of cellulosic
polymers such as ethylcellulose, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, methylcellulose, carboxy methyl cellulose,
hydroxyl methylcellulose and hydroxyethylcellulose, waxes,
hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate,
cellulose acetate trimellitate and methacrylic acid polymers such as
Eudragit RL and RS, polyrnethacrylates, sodium
carboxymethylcellulose, calcium carboxymethylcellulose, acrylic acid
35

polymer, polyethylene glycol, polyethylene oxide, carrageenan,
cellulose acetate, zein, carbohydrate gums, polyuronic acid salts,
cellulose ethers and acrylic acid polymers, xanthan gum, tragacanth
gum, gum karaya, guar gum, acacia, gellan, locust bean gum, alginic
acid and pectic acid
20. A pharmaceutical composition as claimed in claim 2, wherein Aqueous
or non aqueous solvent is selected from the group comprising of
ethanol, methanol, iso-propanol and water.
21. A pharmaceutical composition as claimed in claim 2, wherein glidant
is selected from the group comprising of colloidal silicon dioxide, corn
starch, talc, calcium silicate and magnesium silicate.
22. A pharmaceutical composition as claimed in claim 2, wherein
pharmaceutical solvents are selected from the group comprising of
methanol, acetone and purified water.
23. A pharmaceutical composition as claimed in claim 2, wherein coloring
agent is selected form the group comprising of iron oxides and its
derivatives like red oxide of iron, yellow oxide of iron, lake and dye
colors and the colors which are pharmaceutically acceptable.
24. Process for the preparation of stable pharmaceutical composition
comprises rabeprazole sodium enteric coated pellets, wherein an inert
core is coated with rabeprazole sodium and enteric coating,
characterized in that the inert core, drug coating and enteric coating is
separated by an alkaline layers and the bioavailability of rabeprazole is
enhanced relative to a tablet formulation of rabeprazole.
25. A process as claimed in claim 24, wherein enteric coated pellets of
rabeprazole are filled in a capsule or sachet or compressed into tablets
or formulated into a dry suspension or ready for use suspension or
dispersible tablets.
26. A process as claimed in claim 25 may further comprise one or more
prokinetic agent in a sustained release form.
27. A process as claimed in claim 26, wherein preparation of sustained
release formulation of prokinetic agent comprising the steps of
preparing immediate release portion and sustained release portion and
36

subsequently compressing into the bilayred tablet or filled in the
capsule.
37
28. A process as claimed in claim 26, wherein prokinetic agent is
mosapride citrate dihydrate.
29. A Process for the preparation of pharmaceutical composition as
claimed in claim 26, wherein enteric coated pellets of rabeprazole
prepared are encapsulated either alone or with the sustained release
prokinetic agent.
30. A pharmaceutical composition as claimed in claim l is useful for
prevention and treatment of acid related gastrointestinal disorders,
preferably gastroesophageal reflux disorders.
31. A pharmaceutical composition substantially as herein described with
reference to the foregoing examples.
32. A process for the preparation of the pharmaceutical composition
substantially as described with reference to the foregoing examples.
33. A method of achieving a plasma concentration wherein upon
administration to a patiënt of a total dose of about 20mg of
pharmaceutical composition as claimed in claim l produces AUC«:
vafue of at least 1382 ng/ml*hr of rabeprazole.