FIELD OF THE INVENTION
This invention in general relates to a stable pharmaceutical composition comprising rabeprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. More particularly, the present invention discloses stable pharmaceutical compositions of rabeprazole based on multiparticulate system. The invention also provides a process for manufacturing such composition.

BACKGROUND OF THE INVENTION
Benzimidazole derivatives like rabeprazole and its derivatives are known to degrade in the acidic medium and thus are difficult to formulate for oral administration. Upon oral administration, the pharmaceutical composition comes in contact with gastric fluid in the stomach, which is highly acidic, leading to breakdown and loss of activity of the benzimidazole derivative.
Pharmaceutical compositions comprising acid labile drugs, like rabeprazole are protected from acidic gastric juices by an enteric coating. However most of the enteric coating materials are either themselves acidic in nature or contain acidic materials, which may react with the benzimidazole derivative and cause degradation.

Rabeprazole is a proton pump inhibitor that suppresses gastric acid production in the stomach. Rabeprazole sodium is one of the benzimidazoles developed for treating erosive or ulcerative Gastroesophageal Reflux Disease (GERD). Chemically it is 2- [[4-(3-methoxypropoxy)-3-methyl-pyridin-2-yl] methyl} sulfinyl]-1H-benzimidazole. Rabeprazole sodium is represented by the following formula:

Rabeprazole is approved for oral administration as Delayed release tablet and capsule dosage form in US under the tradename Aciphex® Tablets and Aciphex® Sprinkles, respectively. Aciphex® Sprinkles contains granules of rabeprazole sodium in a hard hypromellose capsule. The inactive ingredients of Aciphex Sprinkles are colloidal silicon dioxide, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium oxide, magnesium stearate, mannitol, talc, titanium dioxide, carrageenan, potassium chloride, FD&C Blue No. 2 Aluminum Lake (in the 5 mg capsule), FD&C Yellow, No. 6 (in the 10 mg capsule), and gray printing ink. The recommended dose is 20 mg for adults but dose may be further increased or decreased according to age and symptoms, however, the maximum daily dose should not exceed 120 mg.

US 5,045,552 assigned to Eisai Co., Ltd. discloses rabeprazole as product.

US 9,040,564 assigned to Eisai R&D Management Co., Ltd. discloses a pharmaceutical composition comprising a core coated with drug layer comprising rabeprazole or a pharmaceutically acceptable salt thereof and ethyl cellulose; which is further coated with one or more intermediate layers and enteric polymer layer over the intermediate layer.

WO 2010041276 A1 assigned to Jubilant Organosys Ltd. discloses a stabilized pharmaceutical composition of amorphous form of esomeprazole based on multiparticulate systems (MUPS).

US 8,865,212 B2 assigned to Jubilant Generics Limited discloses a enteric coated tablet formulation of an acid labile benzimidazole derivative consisting essentially of compressed core, wherein core is devoid of disintegrants.

Prior arts mentioned above attempted to provide formulations, which can ease in the treatment of GERD patients with an enhanced patient compliance. However, there is still a need to formulate a patient compliant enhanced formulation, which can be easily manufactured in a cost effective way, easy to scale-up and exhibit desired pharmaceutical technical attributes.

The present invention relates to a pharmaceutical composition based on multiparticulate systems (MUPS) comprising rabeprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a process for preparing the same, which is expected to exhibit desired pharmaceutical technical attributes.

Multiparticulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity of small discrete units. In these systems, the dosage of the drug substances is divided on a plurality of subunits, typically consisting of thousands of spherical particles with diameter of 0.05-2.00 mm. To deliver the recommended total dose, these subunits are filled into a sachet or encapsulated into capsules or compressed into a tablet. MUPS facilitate disintegration in the stomach, or to provide a convenient, fast disintegrating tablet that dissolves in water before swallowing which can aid compliance in older patients and children. MUPS provide advantage over unit dosage forms by avoiding dose dumping and increasing gastric emptying which reduces food effect.

Conventional compositions are not patient friendly. Disadvantage of conventional formulation is that it has to be swallowed with water. As a result, aged persons, children and the people on the move often experience difficulty in complying. Oral disintegrating tablet formulations and ready to use suspensions can be taken without water, so they may be easily taken by such aged persons, children or the people on travel. Orally disintegrating tablet formulation rapidly disintegrates in the buccal cavity dispersing the contents, has a pleasant taste and smooth mouthfeel (no grittiness), and completely release the drug in the gastrointestinal tract. This convenience leads to better compliance.

The inventors of the present invention worked on alternate dosage forms like MUPS based tablets, MUPS based capsules, MUPS based orally disintegrating tablets, MUPS based powder for oral suspension and MUPS based ready to use (RTU) suspension; which offer desired technical attributes and also decreases the food effect of the drug.

Also the oral pharmaceutical composition multiparticulates of this invention comprise of a tablet, capsule or a sachet. The commercial multiparticulate based formulation and formulations disclosed in the prior art exhibit food effect, however, the formulation of the present invention is expected to exhibit no food effect thus improving the bioavailability of the drug product.

The inventors of the present invention a multiparticulate system based pharmaceutical compositions which is expected to exhibit desirable pharmaceutical technical attributes prepared by a process which is simple, cost effective and reproducible.

SUMMARY OF THE INVENTION
It is an object of the present invention to develop a stable pharmaceutical composition based on multiparticulate systems (MUPs) of rabeprazole or their pharmaceutically acceptable salts thereof and a process for preparing the same.

Another object of the present invention is to provide a stable MUPs based pharmaceutical formulation of rabeprazole or its pharmaceutically acceptable salts thereof, wherein said formulation comprises an inert core, drug layer comprising rabeprazole or its pharmaceutically acceptable salts and a pH independent aminoalkyl methacrylate copolymer, wherein drug layer is essentially free of ethyl cellulose, coated with an intermediate layer comprising water soluble/water insoluble polymer and one or more pharmaceutically acceptable excipients, further coated with an outer enteric layer comprising various enteric polymers.

Another object of the present invention is to develop stable MUPs based pharmaceutical formulation of rabeprazole or its pharmaceutically acceptable salts thereof, wherein the composition exhibited desired technical attribute desirable technical attributes like stability, dissolution, assay and bioavailability.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising rabeprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention includes, but is not limited to, pellets, beads, minitabs, granules, tablets, capsules, orally disintegrating tablets, dispersible tablets, microcapsules, microspheres, powder for oral suspension and the like. Preferably, the pharmaceutical composition refers to orally disintegrating tablets, powder for oral suspension, RTU (ready to use) powder for oral suspension, powder for oral solution and capsules. More preferably, the pharmaceutical composition refers to an orally disintegrating tablets.

The term “core” used herein refers to a plurality of discrete or aggregated particles, pellets, beads, tablets, minitabs, particle form, spherules, granules, beadlets, microcapsules, millispheres, microspheres, capsules and the like, comprising a drug, at least one or more pharmaceutically acceptable excipients.

“Rabeprazole” as used herein refers to the free acid form, its salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. Preferably, the salt of rabeprazole used here is rabeprazole sodium.

The phrase “inert core,” as used herein, includes core that may be microcrystalline cellulose spheres, sugar spheres, non-pariel seeds, and water insoluble and non-swellable beads.

The phrase “MUPs based composition,” as used herein, means that the drug will not be released in the mouth after disintegration, but will be released in the GI tract. Also the MUPs based composition is in the form of a tablet, capsule, orally disintegrating tablets, mouth dissolving tablets, powder for oral suspension, ready to use (RTU) suspension, dispersible tablets for suspension, powder for oral solutionand the like. The term MUPS and multiparticulates are used interchangeably in the invention.

The pellets or spheres or granules can be dispensed in a pharmaceutically acceptable packaging like sachet, blisters or bottle pack.

The term "excipient" means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like as known in the art. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.

As used herein, the term "about" means ± approximately 10% of the indicated value.
The term “w/w” as used herein refers the total weight of the core composition.
The term “substantially free” or “essentially free” as used herein refers to the amount which is in range from 0-5% w/w by total weight of composition.

The term “sachet” as used herein refers to any suitable container, package or bag to contain the dry powder composition. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. Sachet can be three layered with sandwiched polyethylene terephthalate (PET)/aluminium/polyethylene layers or four layered or more with addition of more layers of PET/aluminium/polyethylene to provide robust protection to moisture sensitive drugs. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing. The sachet may be of any suitable size. The sachet is sealed using any appropriate method.

The present invention relates to a pharmaceutical composition based on Multiparticulate systems (MUPS) of rabeprazole or its pharmaceutically acceptable salts thereof and a process for preparing the same.

The present invention also relates to a pharmaceutical composition based on Multiparticulate systems (MUPS) comprising rabeprazole or its pharmaceutically acceptable salts thereof, prepared by extrusion spheronization or hot melt extrusion process.

It is a principal object of the present invention is to provide a novel and cost effective MUPS based pharmaceutical formulation of rabeprazole or its pharmaceutically acceptable salts thereof, having stability and bioavailability.

Further object of the present invention is to provide a stable MUPS based pharmaceutical formulation of rabeprazole or its pharmaceutically acceptable salts thereof, wherein said formulation comprises an inert core, drug layer over the inert core comprising rabeprazole or its pharmaceutically acceptable salts and a pH independent aminoalkyl methacrylate copolymer, wherein drug layer is essentially free of ethyl cellulose, a seal coat and an enteric coat over the seal coat.

Another object of the present invention is to provide a stable MUPS based pharmaceutical formulation of rabeprazole or its pharmaceutically acceptable salts thereof, wherein said formulation comprises a core comprising rabeprazole or its pharmaceutically acceptable salts or derivatives and a pH independent aminoalkyl methacrylate copolymer, a seal coat and an enteric coat over the seal coat.

The following embodiments further describe the objects of the present invention, however, the disclosed invention is not restricted to the particular embodiments hereinafter described and extends to cover the modifications obvious to one of ordinary skill in the art.

In one embodiment of the present invention relates to a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof comprising:
a) an inert core coated with a drug layer comprising rabeprazole or its pharmaceutically acceptable salts thereof and optionally an alkaline agent, wherein the drug layer is free of ethyl cellulose
b) intermediate layer comprising water soluble/water insoluble polymer and one or more pharmaceutically acceptable excipients
c) outer enteric layer comprising one or more enteric polymers
wherein the coated core is further mixed with one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention, the pharmaceutical composition is in the form of a capsule, a tablet, an orally disintegrating tablet, dispersible tablets for suspension, mouth dissolving tablets, a powder for oral suspension, powder for oral solution or ready to use (RTU) suspension.

Another embodiment of the present invention relates to a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof comprising:
a) an inert core comprising rabeprazole or its pharmaceutically acceptable salts thereof and an alkaline agent prepared using extrusion spheronization, coated with drug layer, wherein the drug layer is free of ethyl cellulose
b) intermediate layer: comprising a water soluble/water insoluble polymer optionally having other pharmaceutically acceptable excipients
c) outer enteric layer comprising an enteric polymer and
d) optionally mixing the enteric coated core with pharmaceutically acceptable excipients
wherein the pharmaceutical composition is in the form of a capsule, a tablet, an orally disintegrating tablet, dispersible tablet for suspension, a powder for oral suspension, powder for oral solution or ready to use (RTU) suspensions.

Another embodiment of the present invention relates to stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof based on MUPS comprising:
a) an inert core coated with a drug layer comprising rabeprazole or its pharmaceutically acceptable salts thereof, a pH independent aminoalkyl methacrylate copolymer and one or more pharmaceutical excipients.
b) optionally one water soluble seal coating layer
c) at least an enteric coating layer
d) optionally, mixing the coated core with one or more pharmaceutically acceptable excipients
wherein 0-5% drug is released in 0.1N HCL (750 mL) within 2 hours and at least 75% drug is released within 30 minutes in phosphate buffer (pH 6.8; 1000 ml) using a USP II apparatus at 100 rpm.

In another embodiment of the present invention relates to a stable MUPS based pharmaceutical composition, which is in the form of a capsule, a tablet, an orally disintegrating tablet, dispersible tablet for suspension, powder for oral suspension, powder for oral or ready to use (RTU) suspension.

In yet another embodiment of the present invention, relates to the pH independent aminoalkyl methacrylate copolymer selected from Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), Poly (methyl acrylate, methyl methacrylate, methacrylic acid), Poly (methacrylic acid, methyl methacrylate) dand Poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate).

In yet another embodiment of the present invention, relates to one or more pharmaceutical excipients selected from diluents, disintegrant, binders, alkaline agents, surfactants, cushioning agent, sweeteners, flavoring agent, lubricant and glidants.

In another embodiment of the present invention, relates to the process for preparing a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof based on MUPS, wherein the process comprises of:
a) coating the inert core with a drug layer comprising rabeprazole or its pharmaceutically acceptable salts thereof and a pH independent aminoalkyl methacrylate copolymer
b) optionally applying the intermediate coating of a water soluble/insoluble polymer on the drug coated core
c) coating the resultant product with one or more enteric layers and
d) drying the enteric coated product to obtain the pharmaceutical composition
e) optionally mixing the enteric coated core with pharmaceutical excipients
wherein the pharmaceutical composition is in the form of a capsule or a tablet or an orally disintegrating tablet or powder for oral solution or a powder for oral suspension or ready to use (RTU) suspension.

Another embodiment of the present invention, relates to a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof based on MUPS comprising
a) a core comprising rabeprazole or its pharmaceutically acceptable salts thereof and a pH independent aminoalkyl methacrylate copolymer prepared using extrusion spheronization,
b) optionally an intermediate layer comprising a water soluble/water insoluble polymer
c) an outer layer comprising an enteric polymer and
d) optionally mixing the enteric coated core with one or more pharmaceutically acceptable excipients
wherein the pharmaceutical composition is in the form of a capsule, a tablet, an orally disintegrating tablet, a powder for oral solution, a powder for oral suspension or ready to use (RTU) suspension.

Another embodiment of the present invention relates to a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof comprising:
a) a core comprising rabeprazole or its pharmaceutically acceptable salts thereof and an alkaline agent, wherein the drug layer is free of ethyl cellulose
b) intermediate layer comprising a water soluble/insoluble polymer optionally having other pharmaceutically acceptable excipients
c) outer layer comprising an enteric polymer and
d) mixing the enteric coated core with superdisintegrants, diluents, binders, lubricants, glidants and other pharmaceutically acceptable excipients for compressing the coated core into a tablet dosage form, which disintegrates in mouth in less than 60 seconds.

In another embodiment of the present invention relates to a stable MUPS based pharmaceutical composition comprising:
a) a core comprising rabeprazole or its pharmaceutically acceptable salts thereof and hot melt carrier, prepared by hot melt extrusion method
b) mixing the core with pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of a capsule, a tablet, an orally disintegrating tablet, as a powder for oral suspension or ready to use (RTU) suspension and solution.

Another embodiment of the present invention relates to a stable MUPS based pharmaceutical composition of rabeprazole comprising:
a) a core comprising rabeprazole or its pharmaceutically acceptable salts thereof, optionally an alkaline agent and hot melt carrier, prepared by hot melt extrusion method, wherein the weight ratio of the drug to the hot melt carrier is in the range from about 1: 1 to about 1: 50.
b) mixing the core with pharmaceutically acceptable excipients and
c) compressing into a tablet dosage form, which disintegrates in mouth in 60 seconds or less after administration.

In another embodiment of the present invention the hot melt carrier comprises at least one of the carriers selected from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, a hydroxypropyl methyl cellulose acetate succinate, a polyethylene glycol, a hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and an acrylic resin, wherein the weight ratio of the drug to the hot melt carrier is ranged from about 1: 1 to about 1: 50.

In another embodiment of the present invention, relates to a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof having a bulk density in the range from 0.72 g/ml to 0.82 g/ml and tapped density in the range from 0.76 g/ml to 0.84 g/ml.

In another embodiment of the present invention, a stable MUPS based pharmaceutical composition of rabeprazole and its pharmaceutically acceptable salts thereof, wherein the formulation exhibits a desired release profile, whereby negligible drug release exhibited in an acid stage and substantial drug release exhibited at buffer stage (pH 6.8).

In another embodiment, of the present invention relates to a stable MUPS based pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof, which are stable at 40 °C and 75% relative humidity at least for a period of about 3 months.

In further embodiment, the present invention includes method of using a pharmaceutical composition based on Multiparticulate systems (MUPS) of rabeprazole or its pharmaceutically acceptable salts thereof in the treatment of Ulcerative GERD, Maintenance of Healing of Erosive or Ulcerative GERD in Adults, Symptomatic GERD, Healing of Duodenal Ulcers, Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence, Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome and Symptomatic GERD.

In an another embodiment of the present invention, the multiparticulates of rabeprazole or its pharmaceutically acceptable salts thereof significantly decreased the food effect, prepared by extrusion spheronization and hot melt extrusion, thereby increasing the patient's medication flexibility and compliance.

Another embodiment of the present invention also provides a process for the preparation of a solid oral multiparticulate pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof of, comprising the steps of; (a) dry blending the drug and excipients, (b) wet granulation (aqueous or non-aqueous) of the mass, (c) extrusion through a screen of defined mesh size to compact the wet mass into cylindrical strands, (d) spheronization of cylindrical strands in a spheronizer to convert the cylindrical strands into spheres, (e) seal coating of the spheres, (f) enteric coating of the spheres over the seal coating, and (g) optionally coated with an outer seal coat over the enteric coating layer.

In another embodiment of the present invention, there is provided a process for the preparation of a multiparticulates of rabeprazole or its pharmaceutically acceptable esters thereof by using methods known in the art but not limited to blending, mixing, granulation, hot-melt extrusion, extrusion spheronization, spray drying, spray coating techniques. The formulation so formed may be administered directly or incorporated into/processed to pharmaceutical compositions for oral administration.

One embodiment of the invention encompasses the pharmaceutical composition based on Multiparticulate systems (MUPs) of rabeprazole or its pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient selected from at least one of diluent, binder, disintegrant, surfactant, alkaline agent, and glidant or the like.

Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during process is water.

In another embodiment of the invention, the pharmaceutical compositions comprising low amount of intermediate/enteric coating as compared to amount used in coatings comprises from 0.1% w/w to 5% w/w, preferably 0.1% w/w to 4% w/w of the composition.

Hot melt carriers may be selected from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, a hydroxypropyl methyl cellulose acetate succinate, a polyethylene glycol, a hydroxypropyl methyl cellulose, hydroxypropyl cellulose, an acrylic resin and mixtures thereof.

Diluents or fillers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. Diluent may constitute from about 10% w/w to about 95% w/w of the total composition.

Aminoalkyl methacrylate copolymer is selected from Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), Poly(methyl acrylate, methyl methacrylate, methacrylic acid), Poly(methacrylic acid, methyl methacrylate), and Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), Ammonio Methacrylate Copolymer (Type A), Ammonio Methacrylate Copolymer (Type B), Basic Butylated Methacrylate Copolymer, Methacrylic Acid–Ethyl Acrylate Copolymer (1 : 1), Methacrylic Acid–Ethyl Acrylate Copolymer (1 : 1), Dispersion 30 per cent Methacrylic Acid–Methyl Methacrylate Copolymer (1 : 1), Methacrylic Acid–Methyl Methacrylate Copolymer (1 : 2) and Polyacrylate Dispersion (30 per cent). Aminoalkyl methacrylate copolymers with various brand names like Eudragit® E 100, Eudragit® E 12,5, Eudragit® E PO, Eudragit® RL PO (Powder), Eudragit® RL 100, Eudragit® RL 30 D, Eudragit® RL 12,5 Eudragit® RS PO, Eudragit® RS 100, Eudragit® RS 30 D, Eudragit® RS 12,5 Eudragit® NE 30 D, Eudragit® NE 40 D and Eudragit® NM 30 D.

Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, acacia, microcrystalline cellulose, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, gelatin, glucose, guar gum, hydroxypropyl cellulose, maltose, methylcellulose, povidone, copovidone, starch, polyvinyl alcohol, or mixtures thereof. The binder may constitute from about 1% w/w to about 20% w/w of the total composition.

Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. The Glidant may constitute from about 0% w/w to about 30% w/w of the total composition.

Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available SEPITRAP® 80 or SEPITRAP® 4000 etc. The surfactant may constitute from about 1% w/w to about 5% w/w of the total composition.

The term disintegrant also includes superdisintegrant. The disintegrants used in the composition includes but not limited to, natural, modified or pre-gelatinized starch, carboxymethylcellulose, starch, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and the like or mixtures thereof in the range of about 0.1 to 20 % w/w. Effervescent disintegrating systems can also be employed. A disintegrant may be employed singularly or more than one disintegrants may also be employed. Higher concentrations of disintegrants may as well be employed.

Alkaline agent may be used generally to provide a microenvironment of pH above 7 around the active ingredient but it also gives effervescence effect when come into contact with gastric juice. Suitable alkaline agents include, but are not limited to, pharmacologically alkali metal, alkaline earth metal or metal salts of weak acids such as sodium carbonate which can be anhydrous or hydrous, calcium carbonate and magnesium carbonate and the pharmacologically hydroxides and oxides of alkaline earth and earth metals such as magnesium hydroxide and magnesium oxide. The alkaline agent may constitute from about 0% w/w to about 10% w/w of the total composition.

Various useful sweetening agents include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, neotame, aspartame, acesulfame K, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium, aspartame. Sugar or a sugar alcohol can also act as filler. Preferably sweetening agent used is sodium saccharin, sucralose, neotame. The amount of sweetening agent ranges from about 0.05% to about 85% by weight of the composition.

Various useful flavoring agents, include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, chocolate, pineapple, apricot; synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, mint and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. Preferably, wild cherry, walnut, chocolate, pineapple, apricot, anise, banana and orange. Flavoring agent is present in the concentration of 0.1 - 1.0 % w/w and is satisfactory. Although flavoring agent in lesser concentrations than 0.l%w/w or in higher concentrations than l%w/w can be used, use of flavoring agent concentration in the vicinity of 0.4 % w/w gives better composition. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavour/s used.

Suitable coloring agent are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents, natural coloring agents, natural juice concentrates, pigments such as iron oxide, titanium dioxide, and zinc oxide, and combinations thereof.
Suitable suspending agents are selected from the group comprising gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth; celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (Avicel® RC); polyvinylpyrrolidone; alginic acid; alginate; sodium alginate; bentonite; carbomers (carboxyvinyl polymers) such as those available under the trade name Carbopol®; cetostearyl alcohol; maltodextrin; polyvinyl alcohol; colloidal silicon dioxide, propylene carbonate; propylene glycol; sodium starch glycolate; starch; acrylic polymers etc. The suspending agents are present in an amount ranging from about 0% to about 20% w/w of the composition. In a particular embodiment, the dry powder compositions are free of suspending agents.
Various useful pH adjusting agent or buffering agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium.
Another embodiment of the present invention relates to the amount of rabeprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof present in the multiparticulates from about 1 mg to about 100 mg, preferably 1-50 mg, more preferably 1-20 mg.
Additional excipients such as film-forming polymers, plasticizers, antiadherents and opacifiers are used.
Various water-soluble polymers are used in the composition. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. If desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking agents, and the like.

Various water insoluble polymers/enteric polymers suitable for use in the present invention include, but are not limited to, all the pH independent polymers like various grades of Eudragit: Eudragit®RL PO, Eudragit®RL 100, Eudragit®RL 30D, Eudragit®RL 12, 5, Eudragit®NE 30 D, Eudragit®NE40 D, Eudragit®NM 30 D etc. Other water insoluble polymers/enteric polymers may be selected from cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), polyvinyl acetate phthalate methylcellulose acetate phthalate (MCAP) and methacrylic acid copolymers or its derivatives. Methacrylic acid copolymers or its derivatives are available under various trade names such as EUDRAGIT®, Acryl-EZE®, Eastacryl®, and Kollicoat® from Evonik Industries, Colorcon, Eastman Chemical and BASF Fine Chemicals respectively. Preferably, enteric coating polymers suitable for use in the present invention are Eudragit S100, Eudragit L100, Poly(methacrylic acid-co-methyl methacrylate), Cellulose acetate trimellitate (CAT), Poly(vinyl acetate phthalate) (PVAP), Hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS).

Aqueous and non-aqueous carriers/vehicles/solvents for ready to use suspensions or powder for oral suspensions of the present invention include but are not limited to water, alcohol, polyethylene glycol, propylene glycol or glycerin buffers, oil, or combinations thereof. Oils include peanut oil, soy bean oil, corn oil, sesame oil, cottonseed oil, acetylated glycerides, ethyl oleate, mineral oil, fatty acid esters, mono- or di- fatty acid esters of polyethylene glycols, or glyceryl mono-oleate. Particularly, the suspensions are aqueous based. By “aqueous carrier” is meant a suspension comprising water, or a combination of water and a water-miscible organic solvent or solvents. Water-miscible solvents include but are not limited to propylene glycol, polyethylene glycol and ethanol. By “non-aqueous carrier” is meant a suspension in which the carrier does not include water. The carrier can also include one more pharmaceutically acceptable excipients which can be in dissolved or dispersed form. The carrier is present in an amount from about 30 w/w% to about 95 w/w%.
The pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like. The glass or plastic bottle is provided with a child proof closure. The package can include a syringe (marked in mL) for ease of dosing.

In another embodiment the present invention includes a pharmaceutical composition based on Multiparticulate systems (MUPs) of rabeprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, form prepared by the above process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 42 NF 37, 2019 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2 value). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
f2 = 50 • log {[1 + (1/n)St=1n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation of rabeprazole pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.

EXAMPLES
The following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature.

Example 1: Multiparticulate systems (MUPs) of Rabeprazole
Table 1:
Composition Example
I II
S. No. Ingredients %w/w
Core
1. Rabeprazole sodium 5-50 10-60
2. Sodium Carbonate (Alkaline agent) 0.1-10 --
3. Aminoalkyl methacrylate copolymer 0.1-10 0.1-10
4. Microcrystalline Cellulose (diluent) 10-90 10-90
5. Polysorbate 80 (surfactant) 0.1-5 --
6. Sodium lauryl sulfate (surfactant) -- 0.1-5
7. Crospovidone (disintegrant) 1-5 1-5
8. Purified Water q.s q.s
Seal Coating
9. Hypromellose 2-10 --
10. Talc 0.5-5 --
11. Titanium dioxide -- --
12. Polysorbate 80 0.1-2 0.1-2
13. Purified water q.s q.s
Enteric Coating
14. Eudragit 0.5-5 0.5-5
15. Talc 0.5-2 0.5-2
16. Triethyl Citrate 0.5-2 0.5-2
17. Sodium lauryl sulfate -- 0.1-2
18. Purified Water/solvents q.s. q.s.
Preferred method of manufacture: Wet granulation/ Extrusion-spheronization

Example 2: Multiparticulate systems (MUPs) of Rabeprazole
Composition Example
I II
S. No. Ingredients %w/w
Inert Core
1. Microcrystalline cellulose sphere 1-50 --
2. Sugar spheres -- 1-50
Drug Layer
3. Rabeprazole sodium 0.1-70 0.1-70
4. Sodium Carbonate (Alkaline agent) 0.1-10 --
5. Aminoalkyl methacrylate copolymer 0.1-10 0.1-10
6. Polysorbate 80 (surfactant) 0.1-5 --
7. Sodium lauryl sulfate (surfactant) -- 0.1-5
8. Crospovidone (disintegrant) 1-20 1-20
9. Purified Water q.s q.s
Seal Coating
10. Hypromellose 2-10 --
11. Talc 0.5-5 --
12. Titanium dioxide -- --
13. Polysorbate 80 0.1-2 0.1-2
14. Purified water q.s q.s
Enteric Coating
15. Eudragit 0.5-5 0.5-5
16. Talc 0.5-2 0.5-2
17. Triethyl Citrate 0.5-2 0.5-2
18. Sodium lauryl sulfate -- 0.1-2
19. Purified Water/solvents q.s. q.s.
Preferred method of manufacture: Fluidized bed coating

Example 3: MUPs based Rabeprazole Orally disintegrating tablets
S. No Ingredients %w/w
1. MUPs of example 1 or 2 1-60 1-60
Extragranular excipients
2. Microcrystalline cellulose 5-30 5-30
3. Mannitol 5-30 5-30
4. Hydroxypropyl cellulose 2-10 2-10
5. Crospovidone 2-10 --
6. Banana flavor 0.0-1.0 --
7. Chocolate flavor -- 0.0-1.0
8. Sucralose 0.05-2.5 --
9. Sodium saccharin -- 0.05-2.5
10. Silicon dioxide 5-20 5-20
11. Magnesium stearate 0.1-2 0.1-2

Example 5: MUPs based Powder for oral suspension
S. No Ingredients %w/w
1. MUPs of example 1 or 2 1-60 1-60
Extragranular excipients
2. Mannitol 5-30 5-30
3. Cherry flavor 0.0-1.0 --
4. Chocolate flavor -- 0.0-1.0
5. Sucralose 0.05-2.5 --
6. Sodium saccharin -- 0.05-2.5
7. Silicon dioxide 0.5-20 0.5-20

We Claim:

1. A stable pharmaceutical composition of rabeprazole or its pharmaceutically acceptable salts thereof, based on multiparticulate systems comprising:
a) an inert core coated with a drug layer comprising rabeprazole or its pharmaceutically acceptable salts thereof, a pH independent aminoalkyl methacrylate copolymer and one or more pharmaceutical excipients.
b) optionally one water soluble seal coating layer
c) at least an enteric coating layer
d) optionally, mixing the coated core with pharmaceutically acceptable excipients,
wherein 0-5% drug is released in 0.1N HCL (750 mL) within 2 hours and at least 75% drug is released within 30 minutes in phosphate buffer (pH 6.8; 1000 ml) using a USP II apparatus at 100 rpm.

2. The pharmaceutical composition of claim 1 is in the form of a capsule, a tablet, an orally disintegrating tablet, powder for oral suspension or ready to use (RTU) suspension.

3. The pharmaceutical composition according to claim 1, wherein the pH independent aminoalkyl methacrylate copolymer is selected from Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), Poly(methyl acrylate, methyl methacrylate, methacrylic acid), Poly (methacrylic acid, methyl methacrylate) and Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate).

4. The pharmaceutical composition according to claim 1, wherein the one or more pharmaceutical excipients is selected from diluents, disintegrant, binders, alkaline agents, surfactants, cushioning agent, sweeteners, lubricant and glidants.

5. The pharmaceutical composition according to claim 1, wherein the water-soluble seal coating layer comprises a water soluble polymer.

6. The tablet formulation as claimed in claim 5, wherein the water-soluble polymer is hydroxypropyl methyl cellulose.

7. The pharmaceutical composition according to claim 1, wherein the drug layer is essentially free of ethyl cellulose.

8. The pharmaceutical composition according to claim 1, wherein bulk density is in the range from 0.72 g/ml to 0.82 g/ml and tapped density in the range from 0.76 g/ml to 0.84 g/ml.

9. A process for preparing the pharmaceutical oral multiparticulate composition of rabeprazole or its pharmaceutically acceptable salts thereof, wherein the process comprises of:
a) coating the inert core with a drug layer comprising rabeprazole or its pharmaceutically acceptable salts, esters and derivatives thereof and a pH independent aminoalkyl methacrylate copolymer;
b) optionally applying the intermediate coating of a water soluble/insoluble polymer on the drug coated core;
c) coating the resultant product with one or more enteric layers; and
d) drying the enteric coated product to obtain the pharmaceutical composition,
e) optionally mixing the enteric coated core with pharmaceutically acceptable excipients.

10. A pharmaceutical oral multiparticulate composition of rabeprazole or its pharmaceutically acceptable salts thereof comprising
a) core comprising rabeprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a pH independent aminoalkyl methacrylate copolymer prepared using extrusion spheronization,
b) optionally an intermediate layer comprising a water soluble/water insoluble polymer
c) outer enteric layer comprising an enteric polymer and
d) optionally mixing the enteric coated core with pharmaceutically acceptable excipients,
wherein the pharmaceutical composition is in the form of a capsule, a tablet, an orally disintegrating tablet, powder for oral suspension or ready to use (RTU) suspension.