FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10 and rule 13)
" CHRONOTHERAPEUTIC PHARMACEUTICAL COMPOSITION FOR GASTROESOPHAGEAL REFLUX
DISEASE"


an Indian company incorporated under the Companies Act, 1913,having registered office
at
Piramal Healthcare Ltd
Piramal Tower, Ganpatraokadam Marg,
Lower Parel, Mumbai-400013
Maharashtra, India
PIRAMAL HEALTHCARE LTD.
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION


FIELD OF INVENTION
The present invention generally relates to chronotherapeutic pharmaceutical composition comprising atleast one therapeutically effective amount of active ingredient preferably two therapeutically effective amounts of active ingredients to treat conditions related to gastric acid secretion. The present invention further relates to methods of preparing such pharmaceutical compositions. The present invention preferably is in tablet dosage form comprising at least one active ingredient of class proton pump inhibitor and /or second active ingredient of class histamine H2 receptor antagonist.
BACKGROUND OF THE INVENTION
Oral controlled release has been the most popular drug delivery system for obvious advantages of oral route of drug administration. It ensures sustained action of drug release over a prolonged period of time maintaining plasma concentations in the therapeutic window.
Certain disease conditions demand release of drug after a lag time.The drug should not be released for the first 2 to 6 hours. After this lag time the drug should be released either in pulses or an extended release manner so as to achieve the desired therapeutic action.
The conditions ,which demand such release pattern include :
a)PhysiologicaI functions that follow circadian rhythm and cause a rise and fall in
hormones like renin,aldosterone and Cortisol etc.
b)Diseases that display chronopharmacological dependence like gastrosophageal reflux
disease(GERD),brochial asthma, myocardial infarction,angina pectoris, rheumatic
arthritis.hypertension etc.
These types of drug delivery systems,which release bioactive agents at a rhythm that
ideally matches the biological requirement of a given disease therapy are called
chronotherapeutic drug delivery systems.they include time-controlled and site-specific
drug delivery systems.
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Doctors generally did not take into account the natural circadian variation in the body's physiological functions. Researchers have now found that the timing for the taking of a medicine can affect the way the human body responds to the medicine. The science of treating the human body taking into account the natural circadian variation is Chronotherapeutics. Chronotherapeutics relies on the practice of delivering the correct amount of medication to the correct site of action at the most appropriate time period for the particular disease or condition.
The major objective of chronotherapy for indications such as gastric acid secretion, asthma and cardiovascular diseases is to deliver the drug in higher concentrations during the time of greatest need and in lesser concentrations when the need is less. Our circadian rhythm is based on sleep-activity cycle and is influenced by our genetic makeup and thereby affects our bodies' function throughout day and night (24-hour period).
Gastroesophageal reflux disease (GERD), Gastro-oesophageal reflux disease (GORD), Gastric reflux disease, or Acid reflux disease is defined as chronic symptoms or mucosal damage produced by the abnormal reflux in the esophagus. This is commonly due to transient or permanent changes in the barrier between the esophagus and the stomach. This can be due to incompetence of the lower esophageal sphincter, transient lower esophageal sphincter relaxation, impaired expulsion of gastric reflux from the esophagus, or a hiatus hernia.
GERD episodes typically occur during the early daytime hours, but some GERD sufferers also experience reflux during the night, even when being treated with proton pump inhibitors. These nighttime episodes of reflux are referred to as nocturnal acid breakthrough ("NAB").For patients taking proton pump inhibitors, NAB is defined as a nocturnal gastric pH less than 4 for greater than 1 hour.Although acid lowering agents like H2 receptor antagonists and proton pump inhibitors greatly reduce the symptoms of GERD,some patients continue to experience nocturnal acid breakthrough.
Symptoms associated with GERD vary in severity throughout a 24-hour period. Studies have shown that gastric acid secretion, especially the midnight GERD follows a circadian
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rhythm and in such case administration of a different kind of unit dosage form which delivers the drug in higher concentrations during the time of greatest need, e.g. around dinner and close to midnight and lesser concentration at other times is needed.
NAB shall be interpreted by physiology of acid secretion, which follows circadian rhythm. Normally intragastric pH is elevated after taking food due to buffer effect of the food. However food stimulates acid release causing pH drop later. For much of 24 hrs pH will be below 2. Gastric acid secretion is most pronounced in the evening and early night, resulting in a surge of gastric acidity around 2 am, with acid secretion decreasing towards the morning.
Most individuals are recumbent during nighttime and do not swallow as frequently as during daytime. Without the assistance of gravity and with decreased salivary buffering, esophageal acid clearance depends primarily on esophageal peristalsis. Therefore, nocturnal acid breakthrough is of particular importance in patients with complicated GERD, Barrett's esophagus, and esophageal motility abnormalities. The importance of these previously mentioned mechanisms is supported by clinical studies. Fouad et al (Aliment Pharmacol Ther. 1999) found that at least 50% of patients with Barrett's esophagus and scleroderma with GERD had increased overnight esophageal acid exposure during nocturnal acid breakthrough and gastric pH may decrease to a level that is potentially damaging to the esophageal mucosa during NAB. In a similar study, Katz and colleagues (Aliment Pharmacol Ther. 1998) found that patients with decreased lower esophageal sphincter pressure and ineffective esophageal motility who had nocturnal acid breakthrough were 8 times more likely to reflux during gastric acid breakthrough compared with those individuals without nocturnal acid breakthrough. Therefore put these patients at risk due to the prolonged esophageal acid clearance seen in patients with ineffective motility.
The goals of treatment for patients with GERD are to eliminate symptoms, heal mucosal lesions, maintain symptomatic and endoscopic remission and, whenever possible, prevent complications. The healing rate of erosive esophagitis at 8 weeks is directly related to the
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duration of suppression of intragastric acidity to pH > 4 over a 24-h period (Bell NJY, et al. Digestion 1992).
Ladas et al. (Am J Gastroenterol 2000) showed that the time intragastric pH < 4 has predictive value for recurrence of esophagitis for patients on omeprazole (20 mg/day) maintenance therapy after esophagitis has been healed; further suggesting the importance of pH control in maintenance of GERD healing. Proton pump inhibitor given in a single daily dose provides sufficient acid suppression to effectively treat most patients, however, intragastric pH control is poorer overnight than in daytime.
Over the last 30 years, several technical advancements in bioerodible polymers, formulation stability and greater in-depth understanding of pharmacokinetics have resulted new techniques of drug delivery. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapy and/or targeting delivery of a medicinal agent to a specific organ or tissue. It is for this reason controlled or targeted drug deliveiy systems have been, and continue to be, receiving more and more attention. However, recently chronotherapeutic drug deliver)' system has drawn the attention in both academic and industrial circles. Till now. the emphasis has been on drug delivery device that maintains constant drug levels throughout the day. But in chronopharmaceutical drug delivery, emphasis is placed on drug delivery system that takes account of bodily functions, such as cardiovascular diseases and asthma etc., during the day and night.
It is now considered desirable by those skilled in the art to provide the oral controlled release compositions that is adaptable to deliver the drug(s) such that the release rates and drug plasma profiles can be matched to physiological and chronotherapeutic requirements.
There are numerous treatments available for GERD, US patent no. 5,036,057 describes treating GERD with a local anaesthetic in a dosage form designed to float on the gastrointestinal fluids in the stomach. Other treatments include administering proton
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pump inhibitors, histamine H2-receptor blockers and antacids as described by Scott, et al.in American Family Physician March 1999.
WO2004035090 assigned to Orexo discloses once daily preparations comprising acid susceptible proton pump inhibitor and a H2 receptor antagonist and atleast one pharmaceutically acceptable excipient which results in a delayed release and/or extended release of the acid susceptible proton pump inhibitor whereas H2 receptor antagonist is included in such a way that it is rapidly released from the dosage form, which may not cover the need of proton pump inhibitor and H2 receptor antagonist at the time of need(between 10.00pm to 6.00am)
Peghini PL, et al (Gastroenterology. 1998 Dec) shows that bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related.
The present invention includes proton pump inhibitor (PPI) as delayed- immediate release form and Histamine (H2) receptor antagonist (H2RA) as delayed-sustained release form.
The dosage form shall be taken in the morning, wherein delayed-immediate release PPI will be released immediately after a delay of 2 - 3 hours covers morning GERD symptoms. Delayed-sustained release H2RA will be released in a sustained fashion for 10 - 22 hours after a delay of 2- 6 hours thus covers the nocturnal acid breakthrough symptoms (NAB), which normally occur during period from 10pm to 6ams so that NAB can be effectively controlled.
Inspite of existing prior arts mentioned above there is still need for an invention that is better in controlling NAB by delivering H2RA at a delayed followed by sustained release manner at the time of need (between 10.00pm and 6.00am).
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Although the chronotherapeutic drug delivery technology can be used for any of drugs from PPI and H2RA class,for the present invention rabeprazole and ranitidine were selected for illustration purpose.
Rabeprazole sodium chemically known as "2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-l//-benzimidazole sodium salt" and represented by formula I:

O HjC 0-CH;. ^-CH,
CH:

Formula I
Rabeprazole is an antiulcer drug in the class of proton pump inhibitors.Rabeprazole decreases the amount of acid produced in the stomach.lt is used to treat symptoms of GERD and other conditions involving excessive stomach acid such as Zollinger-Ellison syndrome. Rabeprazole is also used to promote healing of erosive esophagitis (damage to esophagus caused by stomach acid).
Ranitidine hydrochloride chemically known as "N[2-[[[5- [(dimethylamino)methyl]-2-
furanyl]methyl]thio]ethyl]-N'-methy 1-2-nitro-1,1 -ethenediamine, HC1" and represented
by formula II: ,

Formula II
Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in the treatment of peptic ulcer disease (PUD) and GERD.
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SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, chronotherapeutic drug delivery system is provided for oral administration, said dosage form comprising of:
a) A first layer of delayed-immediate release active ingredient.
b) A second layer of same or another active ingredient which release after a lag time of 2-6 hours followed by extended release for 10-22 hours to release the drug as per body's circadian rhythm.
In accordance with second embodiment of the present invention, chronotherapeutic drug delivery system is provided for oral administration, said dosage form comprising of:
a) A first layer of delayed-immediate release active ingredient, preferably of class proton pump inhibitor.
b) A second layer of same or another active ingredient, preferably of class histamine H2-receptor antagonist which release after a lag time of 2-6 hours followed by extended release for 10-22 hours to release the drug as per body's circadian rhythm.
In accordance with third embodiment of the present invention, chronotherapeutic drug delivery system is provided for oral administration, said dosage form comprising of:
a) A single layer tablet comprising two active ingredients, either or both or which is in pellets and/ or granule form before compression.
b) One of the active ingredient is delayed immediate release and second active ingredient release after a lag time of 2-6 hours followed by extended release for 10-22 hours to release the drug as per body's circadian rhythm.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to chronotherapeutic drug delivery system comprising of atleast two active ingredients and methods of making the same. The invention described herein may have single layer or bilayer in tablet dosage form, out of which one is immediate release layer and second layer release after a lag time of 2-6 hours followed by extended release for 10-22 hours to release the drug as per body's circadian rhythm.
The immediate release layer consists of RabeprazoJe sodium whereas Ranitidine hydrochloride comprising layer is developed into sustained release layer.
The formulation process of present invention may involve preparation of coated pellets of one active ingredient preferably from the class "proton pump inhibitor (PPI)" which is delayed immediate release, and further preparation of sustained release coated granules of another active ingredient preferably from class "H2 receptor antagonist (H2RA)".
The pellets of proton pump inhibitor are blended as immediate release layer, and the sustained release coated granules of H2RA are blended with sustained release polymer as sustained release layer and both the layers are compressed into bilayer tablet followed by enteric coating.
Further the formulation process of present invention may involve mixing coated pellets of proton pump inhibitor as immediate release layer, ancl mixing of H2RA along with sustained release polymers as sustained release layer and both the layers are compressed into bilayer tablet followed by enteric coating.
Still further the formulation process of present invention may involve mixing coated pellets of proton pump inhibitor with sustained release coated granules of H2RA receptor antagonist and compressed into single layer tablet followed by enteric coating.
The term "delayed immediate release" as used herein means the release of active ingredient is delayed for 2-3 hours (lag time) after which the drug is released immediately like any conventional tablet form. In this invention PPI is formulated as delayed immediate release form to protect PPI from acid environment in the stomach, wherein the
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PPI will be released like a conventional tablet once it reaches higher pH (>5.5) in intestine.
The term "delayed-sustained release" as used herein means the release of active ingredient is delayed for 2-6 hours (lag time) after which the drug is released in a sustained release manner for 10- 22 hours. In this invention H2RA is formulated as delayed-sustained release form, wherein delayed release followed by sustained release covers the nocturnal acid breakthrough symptoms (NAB), which normally occur during period from 10pm to 6am.
The term "active ingredient" as used herein is from class proton pump inhibitor (PPI) and histamine H2 receptor antagonist (H2RA).
The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient for example, fillers, diluents, carriers, alkalinizer, plasticizer, antiadherents, solvents and the like. The excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for pharmaceutical use.
The term "diluent" or "filler" as used herein means inert substances used as fillers to create the desired bulk, flow properties. Such compounds include, by way of example and without limitation, microcrystalline cellulose, mannitol, pregelatinized starch, dibasic calcium phosphate, kaolin, sucrose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, lactose, glucose and combinations thereof and other such materials known to those of ordinary skill in the art.
The term "binder" as used herein means agents used while making granules of the active ingredient by mixing it with diluent/filler. Such compounds include, by way of example and without limitation, hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone, pregelatinized starch, starch, hydroxyl propyl methyl cellulose (HPMC), crospovidone and hydroxy ethyl cellulose (HEC) and combinations thereof and other such materials known to those of ordinary skill in the art.
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The term "disintegrants" as used herein means agent added to a tablet or capsule blend to aid in the break up of the compacted mass when it is put into a fluid environment. Examples include but not limited to low-substituted hydroxy propyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxy propyl cellulose. In the present invention preferable disintegrant is crospovidone which is completely insoluble in water, rapidly disperses and swells in water, but does not gel even after prolonged exposure, have greatest rate of swelling compared to other disintegrants and greater surface area to volume ratio than other disintegrants.
The term "sustained release polymer (SR polymer)" as used herein means a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner. The release of the active agent may be constant over a long period. Such compounds include, by way of example and without limitation, hydroxypropyl cellulose (HPC), ethyl cellulose, hydroxyl propyl methyl cellulose (HPMC), hydroxy ethyl cellulose (HEC), sodium carboxymethyl cellulose (sodium CMC), ammonio methacrylate copolymer, carbomer, polyethylene oxide (PEO), xanthan gum and alginates and combinations thereof and other such materials known to those of ordinary skill in the art.
The term "glidant" as used herein means agents used in formulations to improve flow-properties. Such compounds include, by way of example and without limitation, silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
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The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention. The examples should not be read as limiting the scope of the present invention.
EXAMPLES:
The ingredients and the mg per unit dose formula of the composition of these examples are set forth in tables below:
Step (a): Preparation of Rabeprazole Coated Pellets
Seal coating of Microcrystalline cellulose spheres (MCC spheres):

Ingredients Mg/tab
MCC spheres 35.0
Ethyl cellulose 1.0
Magnesium oxide 1.0
Glycerin 0.17
Talc 0.33
Isopropyl alcohol 22.5
1.Coating dispersion was prepared as per above formula by dissolving ethyl cellulose and glycerin in isopropyl alcohol followed by dispersing talc in it.
2.The coating dispersion was sprayed on to microcrystalline cellulose spheres in the fluid bed coater to get seal coated microcrystalline cellulose spheres.
Drug loading on MCC seal coated spheres:

Mg/tab
Ingredients
37.5
Seal coated MCC spheres
20.5
Rabeprazole sodium
4.0
Magnesium oxide
1.0
Sodium hydroxide
3.0
Low- substituted hydroxy propyl cellulose
i.O
Hydroxypropyl cellulose
0.3
Polyethylene glycol 6000
3.2
Talc
105.0
Isopropyl alcohol
70.0
Water
ving hydroxypropyl
3.Coating dispersion was prepared as per above formula by disso
cellulose, sodium hydroxide, polyethylene glycol 6000 and Rabeprazole sodium in water,
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added with isopropyl alcohol, followed by dispersing the magnesium oxide, low-substituted hydroxy propyl cellulose and talc in it.
4.The dispersion was sprayed on to seal coated micro crystalline cellulose spheres in the fluid bed coater to get Rabeprazole loaded spheres.
Seal coating of drug loaded Non-Pareil Seeds:

Ingredients Mg/tab
Rabeprazole loaded spheres 72.5
Ethyl cellulose 3.0
Magnesium oxide 3.0
Glycerin 0.5
Talc 1.0
Isopropyl alcohol 67.5
5.Coating dispersion prepared as per above formula by dissolving ethyl cellulose and glycerin in isopropyl alcohol followed by dispersing the magnesium oxide and talc in it. d.Trie coating dispersion was sprayed on to Rabeprazole /oaded spheres in the fluid bed coater to get seal coated Rabeprazole pellets.
Protective coating on seal coated Rabeprazole pellets:

Ingredients Mg/tab
Seal coated Rabeprazole pellets 80.0
Hydroxy propyl cellulose 1.0
Low- substituted hydroxy propyl cellulose 1.0
Mannitol 5.0
Talc 3.0
Isopropyl alcohol 21.0
Water 49.0
7.Coating dispersion prepared as per above formula by dissolving hydroxy propyl cellulose and mannitol in water, added with isopropyl alcohol, followed by dispersing the talc and low- substituted hydroxy propyl cellulose in it.
8.The coating dispersion was sprayed on to seal coated Rabeprazole pellets in the fluid bed coater to get Rabeprazole coated pellets.
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Step (b): Preparation of Ranitidine SR Coated Granules I

Ingredients Mg/tab
Ranitidine Hydrochloride 336.0
Ethyl cellulose (lOcps) 64.1
Dibutyl phthalate 16.0
Talc 26.7
Isopropyl alcohol 961.5
1.Coating dispersion prepared as per above formula by dissolving ethyl cellulose and dibutyl phthalate in isopropyl alcohol followed by dispersing the talc in it.
2.The coating dispersion was sprayed on to Ranitidine hydrochloride in the fluid bed coater to get Ranitidine SR coated granules I.
Step (c): Preparation of Ranitidine SR Coated Granules II

Ingredients Mg/tab
Ranitidine Hydrochloride 336,0
Ethyl cellulose (50cps) 63.5
Dibutyl phthalate 16.0
Talc 26.5
Isopropyl alcohol 1900.0
1.Coating dispersion prepared as per above formula by dissolving ethyl cellulose and dibutyl phthalate in isopropyl alcohol followed by dispersing the talc in it. 2.The coating dispersion was sprayed on to Ranitidine hydrochloride in the fluid bed coater to get Ranitidine SR coated granules II.
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EXAMPLE I: (Bilayer tablets) Rabeprazole Layer

Ingredients Mg/tab
Rabeprazole coated pellets 82.0
Micro crystal line cellulose 136.0
Pregelatinized starch 20.0
Magnesium oxide 10.0
Calcium silicate 30.0
Crospovidone 10.0
Low- substituted hydroxy propyl cellulose 10.0
Magnesium stearate 2.0
Total 300.0
1. Rabeprazole coated pellets taken from step (a), mixed with microcrystalline cellulose, pregelatinized starch, magnesium oxide.
2. Calcium silicate was mixed with crospovidone and low- substituted hydroxy propyl cellulose.
3. Both the blends of step 1 & step 2 were mixed and lubricated with magnesium stearate, which forms Rabeprazole layer.
Ranitidine Layer

Ingredients Mg/tab
Ranitidine SR coated granules I 442.8
Microcrystalline cellulose 93.2
Polyethylene oxide 60.0
Magnesium stearate 4.0
Total weight of tablet 600.0
4.Ranitidine SR coated granules I taken from step (b), mixed with microcrystalline
cellulose, polyethylene oxide.
5.The blend was lubricated with magnesium stearate, which forms Ranitidine layer.
Bilayer Tablet
6.Rabeprazole layer of step 3 and Ranitidine layer of step 5 were compressed in to bilayer tablets.
Seal Coating Of Tablets:

Ingredient Mg/tab
Ethyl cellulose 12.5
Magnesium oxide 12.5
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Glycerin 2.5
Talc 2.5
Isopropyl alcohol 220.0
7.Coating dispersion prepared as per above formula by dissolving ethyl cellulose and glycerin in isopropyl alcohol followed by dispersing the magnesium oxide and talc in it. 8.The coating dispersion was sprayed on to bilayer tablets in the tablet coating pan to get seal coated tablets.
Enteric Coating of Tablets:

Ingredient Mg/tab
Ready to disperse coating composition of methacrylic acid copolymer. Type C 80.0
Simethicone 1.0
Water 319.0
9.Coating dispersion prepared as per above formula by dispersing ready to disperse coating composition of methacrylic acid copolymer, type Cand simethicone in water. lO.The coating dispersion was sprayed on to seal coated tablets in the tablet coating pan to get enteric-coated tablets.
EXAMPLE II :(Bilaver tablets) Rabeprazole Layer

Ingredients Mg/tab
Rabeprazole coated pellets 82.0
Microcrystalline cellulose 136.0
Pregelatinized starch 20.0
Magnesium oxide 10.0
Calcium silicate 30.0
Crospovidone 10.0
Low- substituted hydroxy propyl cellulose 10.0
Magnesium stearate 2.0
Total 300.0
1 .Rabeprazole coated pellets taken from step (a), mixed with microcrystalline cellulose, pregelatinized starch, magnesium oxide.
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2.Calcium silicate was mixed with crospovidone and low- substituted hydroxy propyl
cellulose.
3.Both the blends of step 1 & step 2 were mixed and lubricated with magnesium stearate,
which forms Rabeprazole layer.
Ranitidine Layer

Ingredients Mg/tab
Ranitidine hydrochloride 336.0
Microcrystalline cellulose 25.0
Ammonio methacrylate copolymer. Type A and B 180.0
Polyethylene oxide 50.0
Magnesium aluminometasilicate 6.0
Magnesium stearate 3.0
Total weight of layer 600.0
4.Ranitidine hydrochloride mixed with magnesium aluminometasilicate, microcrystalline
cellulose, ammonio methacrylate copolymer, type A and B and polyethylene oxide,
lubricated with half the quantity of magnesium stearate.
5.The blend was dry granulated by slugging and deslugging of slugs.
6.The deslugged granules were lubricated with remaining half quantity of magnesium
stearate. which forms Ranitidine layer.
Bilayer Tablet
7.Rabeprazole layer of step 3 and Ranitidine layer of step 6 were compressed in to bilayer tablets.
Seal Coating Of Tablets

Ingredient Mg/tab
Ethyl cellulose 12.5
Magnesium oxide 12.5
Glycerin 2.5
Talc 2.5
Isopropyl alcohol 220.0
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8.Coating dispersion prepared as per above formula by dissolving ethyl cellulose and glycerin in isopropyl alcohol followed by dispersing the magnesium oxide and talc in it. 9.The coating dispersion was sprayed on to bilayer tablets in the tablet coating pan to get seal coated tablets.
Enteric Coating of Tablets

Ingredient Mg/tab
Ready to disperse coating composition of methacryiic acid copolymer, Type C 80.0
Simethicone 1.0
Water 319.0
10.Coating dispersion prepared as per above formula by dispersing ready to disperse coating composition of methacryiic acid copolymer, type Cand simethicone in water. 11 .The coating dispersion was sprayed on to seal coated tablets in the tablet coating pan to get enteric-coated tablets.
EXAMPLE III: (Single Layer Tablets)

Ingredients Mg/tab
Rabeprazole coated pellets 82.0
Ranitidine SR coated granules II 442.0
Microcrystalline cellulose 390.0
Mannitol 200.0
Calcium silicate 60.0
Low- substituted hydroxy propyl cellulose 20.0
Magnesium stearate 6.0
Total 1200.0
1.Rabeprazole Coated Pellets taken from step (a), and Ranitidine SR coated granules II
taken from step (c), mixed with microcrystalline cellulose and mannitol.
2.Calcium silicate was mixed with low- substituted hydroxy propyl cellulose.
3.Both the blends of step 1 & step 2 were mixed and lubricated with magnesium stearate,
and the blend was compressed in to single layer tablets.
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Seal Coating Of Tablets:

Ingredient Mg/tab
Ethyl cellulose 15.0
Magnesium oxide 15.0
Glycerin 3.0
Talc 3.0
Isopropyi alcohol 264.0
4.Coating dispersion prepared as per above formula by dissolving ethyl cellulose and glycerin in isopropyi alcohol followed by dispersing the magnesium oxide and talc in it. 5.The coating dispersion was sprayed on to single layer tablets in the tablet coating pan to get seal coated tablets.
Enteric Coating of Tablets:

Ingredient Mg/tab
Ready to disperse coating composition of methacrylic acid copolymer. Type C 100.0
Simethicone 1.0
Water 399.0
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6.Coating dispersion prepared as per above formula by dispersing ready to disperse coating composition of methacrylic acid copolymer, type C and simethicone in water. 7.The coating dispersion was sprayed on to seal coated tablets in the tablet coating pan to get enteric-coated tablets.