COMPLETE AFTER PROVISIONAL LEFT ON 22/8/06
FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
"DELAYED RELEASE TABLETS FOR RABEPRAZOLE"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark Pharmaceuticals Limited
Glenmark House,
HDO - Corporate Bldg,
Wing -A, B, D, Sawant Marg,
Chakala, Andheri (East),
Mumbai - 400 099
INDIA
COMPLETE SPECIFICATION
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
22 AUG 2006


DELAYED RELEASE TABLETS FOR RABEPRAZOLE
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to enteric coated tablets containing the active pharmaceutical ingredient Rabeprazole sodium in the salt form ("Rabeprazole sodium") in a delayed release formulation and a process for the manufacturing of the said formulation.
2. Description of the Related Art
An important therapeutic area in the human health is the medicinal treatment of the acid disorders. Related therapies typically involve the delivery of an active pharmaceutical ingredient to the gastrointestinal cavity and its environs. In its normal state, the lining of the stomach secretes a fluid that is acidic in nature and helps in digestion of the food ingested. This acidity is also a protective mechanism that helps to protect the stomach from invasion by other organisms.
Gastrointestinal disorders require treatments for conditions such as gastrointestinal reflux disease; gastritis/peptic ulcers, constipation and indigestion. GERD (gastroesophageal reflux disease) or "acid reflux" or "reflux esophagitis" is a condition in which acid from the stomach regurgitates into the esophagus and the usual symptom is heartburn-the uncomfortable burning sensation behind the breastbone that most commonly occurs after a meal in some individuals.
The acid reflux experience with GERD can damage the lining of the esophagus, causing inflammation. Chewable antacid tablets are the first choice for the treatment for the mild to moderate conditions. Serious disorders, however, require a proper treatment course. [0005] In order to treat such disorders oral proton pump inhibitor drugs (i.e., H+/K+-ATPase inhibitors) have been used. Examples of these compounds which are commercially available
2

and/or have been tested clinically include omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole. Drugs of this class suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme system (proton pump) at the secretory surface of the gastric parietal cell.
AstraZeneca markets the Omeprazole delayed realease capsules has used the alkaline salt or an alkaline reacting compound in a core containing the acid labile drug, The Omeprazole delayed release capsules marketed by Astra, is decribed following two US patents.
US4786505 discloses pharmaceutical preparation containing omeprazole together with an alkaline reacting compound or an alkaline salt of omeprazole optionally together with an alkaline compound as the core material, one or more subcoating layers comprising inert reacting compounds which are soluble or rapidly disintegrating in water, or polymeric, water soluble filmforming compounds, optionally containing pH-buffering alkaline compounds and an enteric coating as well as a process for the preparation thereof and the use in the treatment of gastrointestinal diseases. Process for the preparation of an oral pharmaceutical preparation containing omeprazole, comprising
(a) preparing a core comprising an effective amount of a material selected from the group consisting of omeprazole plus an alkaline reacting compound, an alkaline omeprazole salt plus an alkaline reacting compound and an alkaline omeprazole salt alone;
(b) coating the core with one or more layers of an inert subcoating material selected from among tablet excipients and polymeric film-forming compounds to form a subcoated core; and
(c) coating the subcoated core with an enteric coating.
The subcoating layer comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose or polyvinylpyrrolidone along with alkaline salt of the acid labile compound such as the sodium, potassium, magnesium calcium or ammonium salt. The subcoat is coated with an enteric coating that comprises hydroxypropyl methylcellulose phthalate, cellulose acetate
3

phthalate, co-polymerized methacrylic acid/methacrylic acid methyl ester or polyvinyl acetate phthalate, optionally containing a plasticizer.
US4853230 discloses pharmaceutical preparation containing an acid labile compound together with an alkaline reacting compound or an alkaline salt of an acid labile compound optionally together with an alkaline compound as the core material, one or more subcoating layers comprising inert reacting compounds which are soluble or rapidly disintegrating in water, or polymeric, water soluble film forming compounds, optionally containing pH-buffering alkaline compounds and an enteric coating as well as a process for the preparation thereof and the use in the treatment of gastrointestinal diseases. Process for the preparation of an oral pharmaceutical formulation containing an acid labile compound in which cores containing the acid labile compound mixed with an alkaline reacting compound or compounds or an alkaline salt of the acid labile compound optionally mixed with an alkaline reacting compound or compounds are coated with one or more inert reacting subcoating layers whereaftera the subcoated cores are further coated with an enteric coating layer. The subcoating layer comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose or polyvinyl-pyrrolidone along with alkaline salt of the acid labile compound such as the sodium, potassium, magnesium calcium or ammonium salt. The subcoat is coated with an enteric coating that comprises hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, co-polymerized methacrylic acid/methacrylic acid methyl ester or polyvinyl acetate phthalate, optionally containing a plasticizer.
Rabeprazole is another proton pump inhibotor, having chemical name 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-l-H-benzimidazole. Aciphex is the brand name of delayed release tablets of Rabeprazole sodium in US launched by Eisai Co Ltd, Tokyo, Japan. Eisai has used a subcoating of ethyl cellulose which separates the Rabeprazole containing portion of the tablet from the enteric coating.
Rabeprazole is unstable at acidic pH for example even at a relatively mild acidic pH of 6, rabeprazole quickly cyclizes and as a result becomes inactive as a drug. This drug degradation
4

can be readily seen in vitro by placing the drug in water having the pH of about 6. The water quickly changes the color from clear to yellow, brown and then purple as the drug gets cyclized and becomes inactive. As a result of the instability of Rabeprazole it is sold in the tablet form with an enteric coating. The enteric coating prevents the tablet from disintegrating in the stomach, and thereby prevents the degradation of the acid labile drug before it can be absorbed from the proximal small intestine. US patent 5035899 assigned to Esai. describes the marketed formulation of rabeprazole.
US5035899 discloses a peroral preparation of an acid-unstable compound comprises (1) a core containing the acid-unstable compound, (2) a first layer, coated on the core, comprising a hardly water-soluble, film-forming material and fine particles of a hardly water-soluble substance, suspended in the material, and (3) a second layer, coated on the first layer, of enteric film. The acid-unstable compound is a benzimidazole compound. The core in tablet form may be obtained by mixing an acid-unstable compound with excipients such as mannitol or lactose and binders such as hydroxypropylcellulose or polyvinylpyrrolidone, granulating the obtained mixture by fluidized bed granulation or tumbling granulation and then tableting the granules. Examples of the hardly water-soluble fine material to be used as the intermediate coating layer in the present invention include magnesium oxide, silicic anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, calcium stearate, magnesium stearate and sucrose fatty acid esters. Namely, the film-forming material is dissolved in a solvent such as ethanol and then the fine material is thoroughly suspended therein with the use of, for example, Polytron. RTM. The obtained suspension may be sprayed onto the core in a conventional manner, for example, with the use of a fluidized bed coater to thereby form the aimed intermediate coating layer. Then the core thus coated with the intermediate coating layer is further coated with an enteric coating to thereby give a stabilized peroral preparation of an acid-unstable compound according to the present invention. Namely, the enteric material is dissolved or suspended in a solvent optionally together with a plasticizer, and the solution thus obtained is applied onto the intermediately coated core in a conventional manner with, for example, a fluidized bed coater. Examples of the enteric material to be used in the present invention include hydroxypropylmethylcellulose phthalate,
5

cellulose acetate phthalate, methacrylic acid/methyl methacrylate copolymer and polyvinyl acetate phthalate.
The formulations currently available in the market utilize a subcoat that comprises of a water soluble or rapidly disintegrating film forming compound or a subcoat that comprises of a hardly water-soluble, film-forming material whereas the present invention uses a subcoat that comprises of a combination of water soluble and water insoluble, film-forming material.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, an oral pharmaceutical composition in a solid dosage form is provided comprising (a) a core comprising a therapeutically effective amount of at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor; and (b) an enteric coating on at least a portion of the core, wherein the composition provides a delayed release of the at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor.
In accordance with a second embodiment of the present invention, an oral pharmaceutical composition in a delayed-release solid dosage form is provided comprising (a) a core comprising a therapeutically effective amount of at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor; (b) a subcoating over at least a portion of the core, the subcoating comprising at least one water-soluble film forming polymer and at least one water-insoluble film forming polymer; and (c) an enteric coating coated on the subcoating.
In accordance with a third embodiment of the present invention, a process for preparing an oral pharmaceutical composition in a delayed-release solid dosage form is provided, the process comprising (a) dissolving at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor and at least 20% by weight of the proton pump inhibitor of an alkalizer in an aqueous solvent; (b) spraying the solution in a fluidized bed granulator tp
6

provide a core; (c) applying a subcoating over at least a portion of the core, the subcoating comprising at least one water-soluble film forming polymer and at least one water-insoluble film forming polymer; and (c) applying an enteric coating over at least a portion of the subcoating.
In accordance with a fourth embodiment of the present invention, a method of inhibiting gastric acid secretion is provided comprising administering to a mammal in need of treatment, an effective amount of an oral pharmaceutical composition in a delayed-release solid dosage form comprising (a) a core comprising a therapeutically effective amount of at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor; (b) an optional subcoating over at least a portion of the core, the subcoating comprising at least one water-soluble film forming polymer and at least one water-insoluble film forming polymer; and (c) an enteric coating coated on the subcoating or core
In further embodiment of the present invention, the said formulation of the present invention uses Rabeprazole and other required pharmaceutically acceptable excipients selected form amongst but are not limited to the diluents, alkalizers, disintegrants, glidants and lubricants in the core.
The important aspect of the present invention is that the process for the manufacturing involves use of a subcoat that contains a combination of a water-soluble & water-insoluble film forming polymer that is applied to the core tablet of Rabeprazole. The core tablets are made by dissolving Rabeprazole and at least 20% by weight of Rabeprazole of an alkalizer in an aqueous solvent and spraying the solution obtained by top-spray in a fluidized bed granulator on a blend of a part of the diluent and a part of the disintegrant to adsorb the drug and the alkalizer onto the surface of excipients and/or form bridges between the excipient particles due to the evaporation of the solvent in which the drug and the water soluble polymer are dissolved. The blend prepared thus is mixed with other excipients and compressed into tablets which are subsequently given a subcoat followed by an enteric coatine.
7

The invention relates to conventional enteric coated tablets which releases the drug rapidly in the intestine as compared to the drug release in the compositions discussed in the prior art.
DEFINITIONS
The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
As used herein, the term "diluent" or "filler" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the
8

preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
As used herein, the term "glidant" is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
As used herein, the term "buffering agent" is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art
As used herein, the term "lubricant" is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
As used herein, the term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar,
9

guar, locust bean, karaya, pectin, tragacanth, 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.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to delayed release pharmaceutical compositions. Accordingly, in one embodiment of the present invention, the pharmaceutical compositions can be an oral pharmaceutical composition in a solid dosage form which includes at least (a) a core comprising a therapeutically effective amount of at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor; (b) an optional subcoating over at least a portion of the core, the subcoating comprising at least one water-soluble film forming polymer and at least one water-insoluble film forming polymer; and (c) an enteric coating coated on the subcoating or core.
The formulations of the present invention use Rabeprazole sodium and other required pharmaceutically acceptable excipients selected from amongst the diluents, alkalizers, pH-buffering compounds, disintegrants, glidants and lubricants in the core. The alkalizers are selected from the group comprising of Meglumine, Sodium borate, tri sodium phosphate & sodium hydroxide. The diluents are selected from the group comprising of lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, calcium sulphate, dextrates, dextrin, sucrose, sorbitol, calcium carbonate, magnesium carbonate, kaolin, maltodextrin, starches, pregelatinized starch and tricalcium phosphate. The pH-buffering compounds are selected from the group comprising of compounds usually used in antacid formulations such as, for instance, magnesium oxide, hydroxide or carbonate, aluminium or calcium hydroxide,
10

carbonate or silicate; composite aluminium/magnesium compounds such as, for instance Al203.6MgO.C02.12H20, (Mg6 Al2(OH)16C03.4H20), MgO.Al2O3.2SiO2.nH2O, aluminium hydroxide/sodium bicarbonate coprecipitate or similar compounds; or other pharmaceutical^ acceptable pH-buffering compounds such as, for instance the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids and salts thereof. The disintegrants are selected from the group comprising of crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropyl cellulose, starch and magnesium aluminium silicate. The glidants are selected from the group comprising of colloidal silicon dioxide and talc. The lubricants are selected from the group comprising of magnesium stearate, calcium stearate, hydrogenated vegetable oil, paraffin, polyethylene glycol, sodium benzoate, zinc stearate, stearic acid and talc.
Before applying enteric coating layer(s) onto the core material in the form of individual tablets, said tablets may optionally be covered with one or more seal coatings comprising pharmaceutical excipients optionally including alkaline compounds such as for instance pH-buffering compounds. This/these seal coating(s) separate(s) the core material from the outer layer(s), the outer layer(s) being enteric coating layer(s). The seal coating(s) can be applied to the core material by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the seal coating(s) can be applied to the core material by using powder coating technique. The seal coating used in the present invention is a combination of a water-soluble & water-insoluble film forming polymer. The water-soluble film forming polymer is at least one selected from the group consisting of alkylcellulose,hydroxyalkylcellulose, hydroxyalkylalkylcellulose, carboxyalkylcellulose, alkali metal salt of carboxyalkylcellulose,carboxyalkylalkylcellulose, carboxyalkylcellulose ester, starch, pectin, chitin derivatives, polysaccharides, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylate copolymer, aminoalkyl methacrylate copolymer; polyvinylacetaldiethylaminoacetate, sugar surfactant, polyvinylalcohol, polyvinylpyrrolidone, copolymer of polyvinyl pyrrolidone and vinyl acetate, polyalkylene
11

oxide, and copolymer of ethylene oxide and propylene oxide wherein the alkylcellulose is methylcellulose ; the hydroxyalkylcellulose is at least one selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxybutylcellulose; the hydroxyalkylalkylcellulose is at least one selected from the group consisting of hydroxyethylmethylcellulose and hydroxypropyl methylcellulose; the carboxyalkylcellulose is carboxy methylcellulose; the alkali metal salt of carboxyalkylcellulose is sodium carboxy methylcellulose; the carboxyalkylalkylcellulose is carboxymethylethylcellulose.
The water-insoluble film forming polymers are selected from ethyl cellulose, polyvinyl acetate but are not limited to these.
Additives such as plasticizers, pH-buffering compounds, colorants, opacifiers, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the seal coating(s). The plasticizers are selected from the group comprising of polyethylene glycol, triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, sorbitol and glycerol. The anti-tacking agents are selected from the group comprising of talc, colloidal silicon dioxide and magnesium stearate and paraffin. The fillers are selected from the group comprising of lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, calcium sulphate, dextrates, dextrin, sucrose, sorbitol, calcium carbonate, magnesium carbonate, kaolin, maltodextrin, starches, pregelatinized starch, tricalcium phosphate, talc and titanium dioxide. The coloring agents are selected from the group comprising of ferric oxides. The opacifier is titanium dioxide. When the optional seal coating(s) is applied to the core material it may constitute a variable thickness. The maximum thickness of the optional seal coating(s) is normally only limited by processing conditions. The seal coating(s) may serve as a diffusion barrier and may act as a pH-buffering zone. The pH-buffering properties of the seal coating(s) can be further strengthened by introducing into the layer(s) substances chosen from a group of compounds usually used in antacid formulations such as, for instance, magnesium oxide, hydroxide or carbonate, aluminium or
12

calcium hydroxide, carbonate or silicate; composite aluminium/magnesium compounds such as, for instance Al203.6MgO.C02.12H20, (Mg6 Al2(OH)i6C03.4H20), MgO.Al2O3.2SiO2.nH2O, aluminium hydroxide/sodium bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH-buffering compounds such as, for instance the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids and salts thereof. Talc or other compounds may be added to increase the thickness of the layer(s) and thereby strengthen the diffusion barrier. The optionally applied seal coating(s) is not essential for the invention.
One or more enteric coating layers are applied onto the core material or onto the core material covered with seal coating(s) by using a suitable coating technique. The enteric coating layer material may be dispersed or dissolved in either water or in suitable organic solvents. As enteric coating layer polymers one or more, separately or in combination, of the following can be used; e.g. solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating layer polymer(s). The enteric coating layers contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers. Additives such as dispersants, colorants, pigments, polymers e.g. poly (ethylacrylat, methylmethacrylaf), anti-tacking and anti-foaming agents may also be included into the enteric coating layer(s). Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acid susceptible core.
To protect drug substance to obtain an acceptable acid resistance of the tablet dosage form according to the invention, the maximum thickness of the applied enteric coating layer(s) is normally only limited by processing conditions.
13

The process for manufacturing involves dissolving Rabeprazole and at least 20% by weight of Rabeprazole of an alkalizer in an aqueous solvent and spraying this solution on a blend of a part of the diluent with or without a part of the alkalizing agent and with or without a part of the disintegrant in a fluidized bed granulator. The aqueous solvent used for spraying Rabeprazole and an alkalizer can be any aqueous solvent in which both Rabeprazole and the alkalizer are soluble. The blend obtained by spraying Rabeprazole and an alkalizer on a part of the diluent and disintegrant is then mixed with the remaining parts of the diluent, disintegrant and the lubricant. The resulting blend is then compressed into core tablets and the core tablets are then given one or more seal coatings followed by a final enteric coating.
The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims. The percent w/w formula composition of the example of the present invention is tabulated in
EXAMPLE 1

Ingredients mg/tab
Rabeprazole sodium 20
Meglumine 5
Purified water QS
Sodium starch glycolate 4
DCP 89
MgO 20
Sodium starch glycolate 6
Talc 3
Magnesium stearate 1.5
Total 148.5
Seal coating
HPMC E5 LV 2.5
Ethyl cellulose 2.5
Triethyl citrate 0.5
MDC QS
IPA QS
Enteric coating
14

Acryl-Eze 15
Purified water QS
Total 169
Detailed Description of the Manufacturing Process
1. Dissolved total quantity of the Meglumine (or other proposed alkalizer) in Purified water and then dissolved total quantity of drug in this solution. This solution was used as the granulation fluid.
2. DCP anhydrous, Magnesium oxide and Sodium starch glycolate was sifted through ASTM mesh # 40.
3. The pre granulation blend of step no. 2 was then transferred to the bowl of PLM / Glatt.
4. The blend of step no. 3 was mixed for 10 min in PLM at medium speed or fluidized in Glatt.
5. The solution of step no. 1 was added to the dry mixed blend of step no. 4 & adding was continued till the whole solution was completely added.
6. Once the granulating fluid is completely added, the granules were then dried in the same Fluid Bed Drier till the LOD of the dried granules was found to be less than 2.0%w/w.
7. The dried granules of step no. 6 were then passed through ASTM mesh #30.
8. The dried granules of step no. 7 was then mixed with sodium starch glycolate & Talc and blended in the Bin Blender for 10 minutes.
9. The blend of step no. 8 was then finally mixed with Magnesium Stearate in the same blender for 3 minutes.
10. The blend of step no. 10 was then ready for compression.
11. Lubricated blend was compressed using compression machine by controlling humidity (less than 30% RH)
12. Compressed core tablets were seal coated using GAC 250 coating machine using non aqueous solvents up to 5 mg per tablet weight gain.
13. These seal coated tablets were enteric coated using Acryl-eze (Methyl methacrylates) using GAC 250 coating machine using aqueous coating up to 15 mg per tablet weight gain.
15

DISSOLUTION PROFILE
The dissolution of the tablets is carried out using the above formulation disclosed in EXAMPLE (1) .Dissolution test is performed in USP type II apparatus , using 900 ml dissolution medium , at 50 RPM and using ph 6.8 phosphate buffer as dissolution medium.

Dissolution in USP II, 900 ml, 50 rpm
Batch No Innovator (2854) /017
Media pH 6.8 P04 buffer
Intial 2 hr in 0.1 N HC1, with zero percent release
Time points (minutes) followed by dissolution in pH 6.8 P04 buffer
5 0 0
10 0 0
30 85 83
45 63 64
60 52 55
16

Claims:
1. An oral pharmaceutical composition in a solid dosage form comprising (a) a core
comprising a therapeutically effective amount of at least one acid labile, substituted
benzimidazole H+/K+-ATPase proton pump inhibitor; and (b) an enteric coating on at least a
portion of the core, wherein the composition provides a delayed release of the at least one acid
labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor.
2. An oral pharmaceutical composition in a delayed-release solid dosage form comprising (a) a core comprising a therapeutically effective amount of at least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump inhibitor; (b) a subcoating over at least a portion of the core, the subcoating comprising at least one water-soluble film forming polymer and at least one water-insoluble film forming polymer; and (c) an enteric coating coated on the subcoating.
3. The composition of Features 1 and 2, wherein the at least one proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole, tenatoprazole, nepaprazole or an enantiomer, isomer, tautomer, ester, amide, derivative, prodrug, free base, or salt thereof.

4. The composition of Features 1-3, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of a carrier, a binder, a flavoring agent, a sweetening agent, a disintegrant, a flow aid, a lubricant, an adjuvant, a colorant, a diluent, a moistening agent, a preservative, an anti-foaming agent, an antioxidant, a chelating agent, an antifungal agent, an antibacterial agent, and mixtures thereof.
5. The composition of Features 1-4, wherein the solid dosage form is selected from the group consisting of a tablet, a chewabie tablet, a caplet, a capsule, a suspension tablet, a troche, a lozenge, and a powder.
17

6. The composition of claim 1-4, wherein the solid dosage form is a chewable tablet.
7. The composition of of claim 1-4, wherein the solid dosage form is a capsule.
8. A process for preparing an oral pharmaceutical composition in a delayed-release solid dosage form, the process comprising (a) dissolving at least one acid labile, substituted benzimidazole ITVK4"-ATPase proton pump inhibitor and at least 20% by weight of the proton pump inhibitor of an alkalizer in an aqueous solvent; (b) spraying the solution in a fluidized bed granulator to provide a core; (c) applying a subcoating over at least a portion of the core, the subcoating comprising at least one water-soluble film forming polymer and at least one water-insoluble film forming polymer; and (c) applying an enteric coating over at least a portion of the subcoating.
9. A method of inhibiting gastric acid secretion comprising administering to a
mammal in need of treatment, an effective amount of an oral
pharmaceutical composition in a delayed-release solid dosage form
comprising (a) a core comprising a therapeutically effective amount of at
least one acid labile, substituted benzimidazole H+/K+-ATPase proton pump
inhibitor; (b) an optional subcoating over at least a portion of the core, the
subcoating comprising at least one water-soluble film forming polymer and
at least one water-insoluble film forming polymer; and (c) an enteric
coating coated on the subcoating or core.
Dated this Twenty first (21st) day of August, 2006

18