WO2005051362A2

WO2005051362A2 - Oral benzimidazole compositions comprising an active core, an optional separating layer and an enteric coating

Info

Publication number: WO2005051362A2
Application number: PCT/IB2004/003865
Authority: WO
Inventors: Vivek Mahendrakumar Dubey; Visingiri Venkat Ram Mohan Rao; Abhijit Mukund Deshmukh; Sanjeev Kumar Sethi
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-11-28
Filing date: 2004-11-24
Publication date: 2005-06-09
Also published as: CA2547398A1; WO2005051362A3

Abstract

The present invention relates to stable oral benzimidazole compositions and processes for their preparation.

Description

STABLE ORAL BENZIMIDAZOLE COMPOSITIONS AND PROCESSES FOR THEIR PREPARATION Field of the Invention The present invention relates to stable oral benzimidazole compositions and processes for their preparation. Background of the Invention U.S. Patent Nos. 4,255,431, 4,628,098 and 4,758,579 disclose substituted pyridylsulfinyl benzimidazoles as potent inhibitors of gastric acid secretion. This class of compounds inhibits gastric acid secretion by inhibiting H⁺-K⁺ ATPase (proton-pump) activity. Drugs in this class are known to be highly unstable in an acidic environment. They are also unstable in the presence of moisture and organic solvents. Thus, the formulation in which the drugs are to be administered to a patient, and the process for manufacture of the formulation, must be designed to protect the drug from moisture as well as an acidic environment. Due to the rapid drug degradation that occurs in acidic gastric fluids, the formulations may be enteric coated. The stability problems associated with benzimidazole compounds are well recognized in the prior art, which teaches various approaches to preparing stable formulations containing benzimidazole compounds. One of the most common approaches utilized to stabilize benzimidazole compounds is the use of an alkaline core, a separating layer and an enteric coating. It is well-recognized in the art that use of an alkaline medium within the core protects benzimidazole compounds from acid degradation. Previous attempts to stabilize formulations of benzimidazole compounds were ineffective when using an alkaline core without a separating layer between the core and the enteric coating. Thus, the need for a separating layer between the core and enteric coating. An example of the use of a separating layer between the alkaline core and the enteric coating is described in U.S. Patent No.

4,786,505 and U.S. Patent No. 4,853,230. The separating layer disclosed is made of water- soluble polymeric substances. U.S. Patent No. 5,035,899 discloses a peroral preparation of a benzimidazole compound that is described as consisting essentially of a core, a slightly water soluble first coating layer, and a second coating layer. The core contains a pharmacologically effective, acid-unstable benzimidazole compound. The first coating layer is coated on the core and includes a slightly water-soluble, film-forming material selected from the group consisting of ethyl cellulose and polyvinyl acetate and fine particles of a slightly water-soluble substance selected from the group consisting of magnesium oxide, silicic anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, calcium stearate, magnesium stearate and sucrose fatty acid esters suspended in the first layer. The second coating layer is coated on the first layer and is made of an enteric polymer film. U.S. Patent No. 6,274,173 discloses a controlled release phaπnaceutical composition that includes an acid-labile proton-pump inhibitor other than pantoprazole, an alkaline pellet or tablet core, at least one water-insoluble intermediate layer which controls the release of the active ingredient, and an outer enteric layer which is soluble in the intestine. The subcoating is described as controlling the release of the active ingredient and thereby the active ingredient is released in a modified release manner, i.e., part of the active ingredient is released in immediate manner and part is released in controlled manner. U.S. Patent No. 5,877,192 discloses the use of the (-)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, in the treatment of gastric acid related diseases as a means to decrease individual variation in plasma levels when compared to omeprazole. The use of the (-)-enantiomer of omeprazole is used to increase the average plasma levels (AUC) of the substance when compared to those of racemic omeprazole; thereby imparting a higher dose efficiency. According to the prior art, formulating benzimidazole compounds with the alkaline core being directly coated with an enteric coating without a separating coat was tried with little success with respect to producing stable formulations of benzimidazole compounds. For example, WO 00/78284 discloses a formulation containing a benzimidazole compound without a separating layer. These formulations disclose the use of a neutralized enteric coating applied as a solution with a pH value of at least 6.5 and more preferably in a range of from about 7 to about 10. The enteric coating is applied directly to the benzimidazole derivative substrate. This solution, with the optional addition of a plasticizer, can be directly coated onto the substrate without any need for an intermediate layer. U.S. Patent No. 6,602,522 discloses a stable pharmaceutical composition for an orally administered acid-labile compound used as an active ingredient. The composition includes a tableted core and a single layer of coating on the tableted core, the coating including an enteric coating agent. The tableted core includes an uncoated granulation of a therapeutically effective amount of the active ingredient, an optional surface active agent, a pharmaceutically acceptable alkaline agent, at least one water-soluble binder, and at least one water-insoluble binder. The patent also discloses a tableted core with an alkaline medium and an enteric coating layered directly on the tableted core. Later efforts to stabilize benzimidazole compounds were based on the use of an acidic core with a separating layer made up of water-soluble polymers and other excipients. U.S. Patent No. 5,385,739 discloses a stable formulation of omeprazole microgranules containing a neutral core of sugar and starch and an active layer consisting of a dilution of omeprazole in mannitol, in substantially equal amounts. The active omeprazole layer contains about 10% by weight of carboxymethyl starch and about 5% by weight of a sodium lauryl sulfate surface-active compound. The dilution of omeprazole in mannitol is applied to the neutral core by means of hydroxypropyl methylcellulose as a high viscosity binder. U.S. Patent No. 5,626,875 discloses the use of an inert sugar/starch spherical core coated with a first layer made up of a mixture of the benzimidazole compound, a water- soluble inert polymer and non-alkaline reacting pharmaceutical acceptable excipients. The first layer is coated with a second isolation layer formed by water-soluble polymers and non- alkaline reacting pharmaceutically accepted excipients. A third layer consisting of an enteric coating is applied over the second layer. U.S. Patent Application No. 2003011S650 discloses a tableted oral pharmaceutical dosage foπn that is covered by an enteric coating and consists of a plurality of units that contain a benzimidazole compound labile in an acid medium as the active principle. The plurality of units contain: i) an inert core; ii) an active layer deposited on the inert core i) and made up of a benzimidazole compound labile in an acid medium, a non-alkaline water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients; and iii) an intermediate layer consisting of an inert non-alkaline coating foπned from a non-alkaline, water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients. The intermediate layer is disposed over the active layer ii) that covers the inert core i). U.S. Patent No. 5,626,875 and U.S. Patent Application No. 20030118650 thus use an intermediate layer made of a non-alkaline water-soluble inert polymer along with one or more pharmaceutically acceptable inert excipients. U.S. Patent No. 6,159,499 discloses a composition that is described as being substantially free of alkaline-reacting compounds. The composition includes (a) a core containing an acid-labile benzimidazole active principle; (b) an intermediate layer surrounding the core; and (c) an enteric layer surrounding the intermediate layer. The core includes a plurality of nuclei and the active principle mixed together and then compressed together. The active principle is described as not being in the form of an alkaline salt. This patent also discloses a process for preparing stable oral dosage foπn of benzimidazole compounds which are free from alkaline reacting compounds. The process includes the steps of (i) mixing a plurality of nuclei with an active principle; (ii) compressing the product of step (i) to foπn a core comprising the active principle; (iii) coating the core with an intermediate layer; and (iv) coating the product from step (iii) with an enteric layer. U.S. Patent No. 6,207, 19S discloses a stable drug composition that includes (a) a core containing an acid-labile omeprazole active principle; (b) an intermediate layer that includes at least one polymer; and (c) an enteric layer. The composition is described as being free of alkaline-reacting compounds. The core is made up of pharmaceutically inert nuclei and the active ingredient, both of which are compressed together. The omeprazole active principle is described as not being in the form of an alkaline salt. The polymer of the intermediate layer is described as being selected from sugars, polyethylene glycol, polyvinylpyrrolidone, poly (vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and mixtures thereof. WO 99/61022 discloses a stable oral pharmaceutical composition in the form of a mixture containing a substituted pyridyl sulfinyl benzimidazole having gastric acid secretion inhibitory activity and a carrier. The earner includes at least one polymer that is at least partially made up of vinylpyrrolidone monomeric units. Also disclosed is the use of a mixture of benzimidazole compounds with at least one polymer containing vinylpyrrolidone monomeric units, the mixture being free of any alkaline reacting compounds to stabilize benzimidazole compounds. The formulation is in the foπn of a premix which is not compressed to facilitate the manufacturing operations. U.S. Patent Application 2002128293 teaches a stable oral pharmaceutical composition containing omeprazole and a pharmaceutically acceptable earner that includes at least one water-insoluble polymer that is at least partially made up of vinylpyrrolidone. The application discloses cross-linked polyvinyl pyn-olidone as the water-insoluble polymer that acts as disintegrant. As described below, the inventors have developed a formulation that does not include such a vinylpyrrolidone polymer with disintegrating properties in the separating layer. There are various drawbacks associated with the prior art formulations with respect to the efficient stabilization of the composition, cost and ease of manufacturing, and environment concerns with the use of organic solvents. The present invention relates to the stable oral benzimidazole compositions which overcome the problems associated with prior art. Summary of the Invention In one general aspect there is provided a stable oral benzimidazole pharmaceutical composition. The composition includes a core comprising a benzimidazole compound and one or more pharmaceutically acceptable excipients;a separating layer suixounding the core comprising a water-insoluble and non-disintegrating polymer and, optionally, one or more water soluble excipients; and an enteric coating surrounding the separating layer. Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the benzimidazole compound may be one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole, and single enantiomers thereof. The one or more pharmaceutically acceptable excipients may be one or more of diluents, disintegrants, binders and lubricants. The water-soluble excipient includes one or more of a water-soluble polymer and a water-soluble excipient. The water-soluble polymer may be one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose and copolymer of vinylpyrrolidone and vinyl acetate. The water- soluble excipient may be one or more of lactose, mannitol, sorbitol, sucrose and glucose. The water insoluble and substantially non-disintegrating polymer may be one or more of cellulose acetate, ethylcellulose, hydroxyethylcellulose and zein. In another general aspect there is provided a stable oral benzimidazole phaπnaceutical composition. The composition includes; a core containing a benzimidazole compound and one or more pharmaceutically acceptable excipients; and an enteric coating surrounding and directly in contact with the core, said enteric coating having a pH less than 6.5, wherein the composition is devoid of a separating layer between the core and the enteric coating. Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the benzimidazole compound may be one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole and single enantiomer thereof. The one or more pharmaceutically acceptable excipients of the core may be selected from one or more of diluents, disintegrants, binders and lubricants. In another general aspect there is provided a process for the preparation of a stable oral benzimidazole phaπnaceutical composition. The process includes; dispersing a benzimidazole compound, and one or more pharmaceutically acceptable excipients in an aqueous medium to obtain a dispersion; spray drying the dispersion to form granules, compressing the granules to form a core; coating the core with a separating layer formed by a water insoluble and non-disintegrating polymer and optional pharmaceutically acceptable excipients; and coating the core with an enteric coating. Embodiments of the process may include one or more of the following features. For example, the benzimidazole compound may be selected from one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole and single enantiomers thereof. The one or more pharmaceutically acceptable excipients of the core may be selected from one or more of diluents, disintegrants, binders and lubricants. In another general aspect there is provided a method inhibiting gastric acid secretion. The method includes administering a pharmaceutical composition, wherein the composition includes; a core comprising a benzimidazole compound and one or more pharmaceutically acceptable excipients; a separating layer surrounding the core and comprising a water- insoluble and non-disintegrating polymer and, optionally, one or more water soluble excipients; and an enteric coating surrounding the separating layer. Embodiments of the method may include one or more of the following features. For example, the benzimidazole compound may be one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole and single enantiomers thereof. In another general aspect there is provided a method inhibiting gastric acid secretion. The method includes administering a phaπnaceutical composition that includes; a core containing a benzimidazole compound and one or more pharmaceutically acceptable excipients; and an enteric coating surrounding and directly in contact with the core, said enteric coating having pH less than 6.5, wherein the composition is devoid of a separating layer between the core and the enteric coating. Embodiments of the method may include one or more of the following features, For example, the benzimidazole compound may be one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole, and single enantiomers thereof. Detailed Description of the Invention In seeking to develop stable benzimidazole dosage foπns, the inventors have developed a number of stable dosage forms and processes for their preparation. For example, the inventors have developed a stable benzimidazole dosage foπn that includes a core, a separating layer, and an enteric coating. The core includes a benzimidazole compound and one or more pharmaceutically acceptable excipients. The separating layer is deposited or otherwise coated on the core and includes , a water-insoluble and substantially non- disintegrating polymer, and optionally one or more water soluble excipients. The enteric coating surrounds the separating layer. The inventors also have developed a stable benzimidazole dosage foπn that includes a core and an enteric coating that is deposited or otherwise coated directly on the core. The core contains a benzimidazole compound and one or more pharmaceutically acceptable excipients. The enteric coating is in direct contact with the core and has a pH less than 6.5. The dosage form is devoid of a separating layer between the core and the enteric coating. One process to formulate the stable benzimidazole formulation includes preparing a core and coating the core. To prepare the core, a benzimidazole compound, a water-soluble material and, optionally, one or more phaπnaceutically acceptable excipients are dispersed in purified water to obtain a dispersion. The dispersion is spray dried, mixed with optional phaπnaceutically acceptable excipients, and compressed to form cores. The core then is coated with a separating layer that is foπned from substantially water-soluble material and optional phaπnaceutically acceptable excipients. The coated core then is coated with an enteric coating. Alternatively, the cores may be enteric coated without including the separating layer. Suitable benzimidazole compounds include any substituted benzimidazole compound that is capable of inhibiting gastric acid secretion by any mechanism and thus having utility in treating various gastrointestinal disorders. The benzimidazole compounds may include, for example, one or more of omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole, pariprazole, single enantiomers thereof, phaπnaceutically acceptable salts, solvates, hydrates, or mixtures thereof. The benzimidazole compounds may be in the crystalline or amorphous salt form. The amount of benzimidazole compound may vary from about 1% to about 80%, and preferably from about 5% to about 35% based on the weight of the formulation. The core as used herein refers to any structure that is enclosed or surrounded by a separating coating or equivalent, or where the separating coating is absent, enclosed or surrounded by an enteric coating. The core may be in the form of a tablet, pellet, capsule, powder or mixture thereof. The term 'tablet' as used herein may include one or more of minitablets, micro tablets, or tablets. The term 'pellets' as used herein may include one or more of granules, beads, pellets, slugs or mixtures thereof. The core may be acidic, alkaline or neutral depending on the formulation. The core may contain one or more pharmaceutically acceptable excipients, including one or more of binders, diluents, disintegrants, lubricants/glidants and solubilizers/wetting agents. The benzimidazole compound in the core may be amorphous or crystalline. The benzimidazole compound may also be spray dried with water soluble polymers and incorporated in the core. The core may contain one or more pre-layers of water soluble polymers between the inert nucleus and drug containing layer. These one or more pre-layers are different from the separating layer (or subcoat). Suitable diluents include one or more of sugars, such as dextrose, glucose, and lactose; sugar alcohols such as sorbitol, xylitol, and mannitol; cellulose derivatives such as powdered cellulose and microcrystalline cellulose; starches such as corn starch, pregelatinized starch, and maize starch. The preferred range of diluents in the formulation depends on the type of foπnulations to be prepared as disclosed in the various examples contained herein. Suitable binders include one or more of cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and methylcellulose; gums such as xanthan gum, gum acacia, and tragacanth; water-soluble vinylpyιτolidone polymers such as polyvinylpyiTolidone and copolymers of vinylpyn-olidone and vinyl acetate; and sugars such as sorbitol, mannitol or such like. The prefeιτed range of binders in the foπnulation depends on the type of foπnulations to be prepared as disclosed in various examples contained herein. Suitable disintegrants may include one or more of sodium starch glycolate, croscarmellose sodium, com starch, and other suitable disintegrants. Suitable wetting agents include one or more of sodium lauryl sulphate, polysorbate 80, and equivalents. Suitable lubricants/glidants include one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and equivalents. The preferred ranges of disintegrants, wetting agents, and lubricants/glidants in the formulation depends on the type of formulations to be prepared as disclosed in various examples contained herein. The separating layer as used herein refers to the layer that separates the core from the enteric coating. The separating layer is made up of water insoluble and substantially non- disintegrating polymers, and may optionally include one or more water-soluble excipients. The water insoluble and substantially non-distintegrating polymers include one or more of cellulose esters, such as cellulose acetate, ethylcellulose, hydroxyethylcellulose; and proteins, such as zein. The water-soluble excipients may be selected from glucose, lactose, mannitol, sorbitol, sucrose, dextrose or equivalents. The substantially water-soluble polymers may be selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and vinyl acetate. Preferably, such polymers are hydroxypropylmethylcellulose, hydroxypropyl cellulose or polyvinylpyiTolidone. The range of the substantially water-soluble polymers in the formulation depends on the type of foπnulations prepared and will be apparent to one skilled in the art based on the various examples disclosed in the specification. The enteric coating may include one or more of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid methyl esters/methacrylic acid copolymers, such as compounds known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L 100 55 and marketed by Rohm Phaπna, and mixtures thereof. The enteric coating may also contain plasticizers such as triacetin, triethyl citrate, tributyl sebecate, diethyl phthalate, polyethylene glycol and inert excipients such as talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose, crospovidone and the like. Also provided is a method of inhibiting gastric acid secretion. The method includes administering to a patient in need thereof a pharmaceutical composition that includes: a) a core comprising a benzimidazole compound and at least one phaπnaceutically acceptable excipients, b) a separating layer surrounding the core, said separating layer comprising a substantially water-insoluble and substantially non-disintegrating polymer and, optionally, one or more water-soluble excipients, and c) an enteric coating suιτounding the separating layer. Also included is a method of inhibiting gastric acid secretion. The method includes administering to a patient in need thereof a pharmaceutical composition that includes: a) a core comprising a benzimidazole compound and at least one pharmaceutically acceptable excipient, b) an enteric coating surrounding and directly in contact with the core, wherein the composition is devoid of a separating layer between the core and the enteric coating. The following examples illustrate stable oral benzimidazole compositions and processes of making the compositions as disclosed in the various embodiments discussed throughout the specification. The example are merely provided to illustrate the composition and processes for their preparation and are not intended to be limiting. The obvious variations of these compositions are contemplated to be within the scope of the present invention and the appended claims.

Example 1

# evaporates during processing *Acryl EZE is a registered trademark of Colorcon and is a type of ready to disperse enteric coating formulation. Procedure:

PVP-K30/HPC-L/HPMC/Mannitol (one or mixtures there of) was dissolved in water, and to this ammonium hydroxide was added. To the above mixture omeprazole was added and dispersed. The dispersion was applied to the inert tablet using a conventional coating machine. The benzimidazole tablets thus prepared were coated with suitable polymer/excipient using a conventional coating machine. Finally, the tablets were enteric coated with the enteric layer formulation.

Example 2

# evaporates during processing *Acryl EZE™ is a registered trademark of Colorcon and is a type of ready-to-disperse enteric coating formulation. Procedure: HPMC/HPC-L was dissolved in water and applied on Non Pariel seeds. HPC-L/Mannitol was dissolved under stirring in purified water. To the above mixture ammonium hydroxide was added, with continuous stirring. Esomeprazole was dispersed in the mixture thus prepared under constant stirring. The non-pariel seeds were coated with the esomeprazole dispersion in a Fluid Bed Processor to form pellets. The pellets then were coated with suitable polymer/excipient and then enteric material using a Fluid Bed Processor. Example 3

# evaporates during processing *Acryl EZE™ is a registered trademark of Colorcon, is a type of ready to disperse enteric coating formulation. Procedure: PVP-K30/HPC-L/HPMC was dissolved in water and to this ammonium hydroxide was added. To the above mixture rabeprazole was added and dispersed. The dispersion was applied on inert tablet using conventional coating machine. Prepared benzimidazole tablets were coated with suitable polymer using conventional coating machine. The tablets then were enteric coated with Acryl EZE. Multiple tablets were filled in hard gelatin capsules. Example 4

Procedure: Drug layering 1. Hydroxypropyl methylcellulose was dissolved in water followed by dispersion of lansoprazole. 2. Non-pariel seeds were loaded in fluid bed processor followed by spraying the dispersion of step 1 to obtain drug-layered pellets. Separating layer 1. Hydroxypropyl methylcellulose was dissolved in water followed by dispersion of talc and titanium dioxide. 2. The drug-layered pellets were loaded in fluid bed processor followed by coating with the solution of step 1 above. Enteric coating Preparation of Hydroxypropyl methylcellulose phthalate coating dispersion: 1. Talc, Titanium dioxide and Polyethylene glycol 300 were dispersed in acetone. 2. Hydroxypropyl methylcellulose phthalate was dissolved in acetone 3. The dispersion of step 1 was added to the dispersion of step 2 followed by water addition and mixing. The bairier-coated pellets were coated with the above enteric coating dispersion and the enteric-coated pellets were filled in hard gelatin capsules.

Example 5

The procedure described above for Example 4 was followed for Example 5.

Example 6:

Procedure: Drug layering 1. Hydroxypropyl methylcellulose was dissolved in water followed by dispersion of lansoprazole. 2. Sugar spheres were loaded in fluid bed processor followed by spraying dispersion of step 1 to obtain drug-layered pellets. Separating layer 1. Hydroxypropyl methylcellulose was dissolved in water followed by dispersion of talc and titanium dioxide. 2. The drug-layered pellets were loaded in fluid bed processor followed by coating with solution of step 1 above. Enteric coating

Preparation of Hydroxypropyl methylcellulose phthalate coating dispersion: 1. Talc, Titanium dioxide and Polyethylene glycol 300 were dispersed in water. 2. The dispersion of step 1 above was added to the Methacrylic acid:Ethylacrylate copolymer dispersion and st red for 30 min. The barrier-coated pellets were coated with the above enteric coating dispersion and the enteric-coated pellets were filled into hard gelatin capsules.

Example 7

# Evaporates during processing Procedure: Hydroxypropyl cellulose was dissolved in water and sprayed on non-pariel seeds. Hydroxypropyl cellulose was dissolved under stirring in purified water and then ammonium hydroxide was added under continued stirring. Then omeprazole was dispersed in a prepared mixture under constant stirring. Non-pariel seeds were coated with omeprazole dispersion in a Fluid Bed Processor to obtain pellets. The pellets thus prepared were coated with mannitol followed by the enteric coating formulation using a Fluid Bed Processor. Finally, the pellets were blended with colloidal silicon dioxide and filled into hard gelatin capsules. Example 8

Procedure:

Hydroxypropyl cellulose and polyethylene glycol 6000 were dissolved in water. Talc was dispersed in the above solution and the resulting dispersion was sprayed on to non-pariel seeds. Hydroxypropyl cellulose was dissolved under stirring in purified water followed by the addition of ammonium hydroxide under continued stimng. Omeprazole was dispersed onto the above prepared mixture under constant stirring. The above dispersion then was sprayed onto non-pariel seeds in a fluid bed processor to obtain pellets. The pellets were coated with mannitol/HPC/HPMC followed by the enteric coating formulation using a fluid bed processor. Finally, the pellets were blended with colloidal silicon dioxide and filled into hard gelatin capsules.

Example 9

# Evaporates during processing * Acryl EZE ; TM . is a legisteied tiademark of Colorcon and is a type of ready-to-disperse enteric coating formulation. Procedure:

Mannitol and PVP-K30/HPC-L/HPMC were dissolved in water, and to this ammonium hydroxide was added. To the above mixture omeprazole was added and dispersed. The dispersion then was spray dried and the spray dried granules were mixed with Pearlitol, lubricated with sodium stearyl fumarate to form a blend, and the blend was compressed into tablets. The benzimidazole tablets thus prepared were coated with suitable polymer/excipient using a conventional coating machine. The tablets then were enteric coated with the enteric coating formulation.

Example 10: Enteric-coated minitablets containing pantoprazole.

Procedure: Coating of Drug 1. Pantoprazole and hydroxypropyl methylcellulose (for mixing) were mixed and granulated with purified water to obtain a wet mass. 2. The wet mass was passed through a 30-mesh screen. 3. Hydroxypropyl methylcellulose (for coating) was dissolved in purified water. 4. The screened mass of step 2 was loaded in a fluid bed processor and the solution of step 3 was sprayed onto it to obtain coated pantoprazole. Compression 1. The coated pantoprazole, mannitol, microcrystalline cellulose and crospovidone were mixed in a suitable blender. 2. Magnesium stearate and colloidal silicon dioxide were added to the blend of step 1. 3. The blend of step 2 was compressed into tablets. Enteric coating Preparation of Hydroxypropyl methylcellulose phthalate coating dispersion: 1. Talc, titanium dioxide and polyethylene glycol 300 were dispersed in acetone. 2. Hydroxypropyl methylcellulose phthalate was dissolved in acetone. 3. The dispersion of step (1) was added to dispersion of step (2) followed by water addition and mixing. The tablets thus produced were enteric coated with the enteric coating dispersion and suitable numbers of tablets as per desired dosage were optionally filled into hard gelatin capsule.

Example 11

Note: The core can be in the form of pellets also. *Plasdone S-630 is copolymer of N-vinyl-2-pyrrolidone and vinyl acetate Procedure:

Preparation of the core: 1. 50 mg of ingi-edient 2, 5 mg of ingredient 3, and ingredient 4 were taken in fluid bed granulator (rapid mixer granulator may also be used) to form a powder mix.

2. Ingredient 5 was dissolved in a sufficient quantity of purified water and 44.5 mg of esomeprazole magnesium was dispersed into it with stirring to form a dispersion.

3. 50 mg of ingi-edient 2 and 10 mg of ingredient 3 was dissolved in a sufficient quantity of water to form a solution.

4. The solution of step 3 was added to the dispersion of step 2 and continued stiπing was applied for about 15-30 minutes to form a dispersion.

5. The dispersion of step 4 was sprayed onto the powder mix of step 1 until granules of sufficient strength were formed. 6. The granules of step 5 were dried until the loss on drying of the granules was about 1.5-2 % w/w.

7. The granules of step 6 were sifted through a suitable mesh and the retentions milled.

8. The granules of step 7 were blended with ingredients 6 - 9 and compressed into mini tablets having a suitable diameter using a rotary tablet compression machine. Separating layer: 1. Ingredient 1 was dissolved in a sufficient quantity of isopropyl alcohol / water. 2. Ingredient 2 was added to the solution of step 1 and stirred for 15 - 30 minutes to form a coating solution. 3. The coating solution was sprayed onto the mini tablets placed in a suitable coating pan until a desirable weight build up was achieved. Enteric coating:

The core mini tablets were loaded in a perforated coating pan and solution A and B was sprayed simultaneously till a desirable weight build up was achieved. Although solutions A and B were sprayed simultaneously, solution A can be sprayed first followed by spraying of solution B.

Example 12

Note: Core could be in a form of pellets also. *Plasdone S-630 is copolymer of N-vinyl-2-pyrrolidone and vinyl acetate Procedure:

Preparation of the core: 1. Ingredients 1, 2, 4, and 5 were mixed in a rapid mixer granulator for sufficient time to form a powder mix. Although a rapid mixer granulator was used, a fluid bed coater may also be used. 2. Ingredient 3 was dissolved in a sufficient quantity of purified water and sprayed onto the powder mix of step 1 until granules of sufficient strength were formed. 3. The granules of step 2 were dried until the loss on drying of granules was about 1.5-2 % w/w.

4. The granules of step 3 were sifted through a suitable mesh and the retentions milled.

5. The granules of step 4 were blended with ingi-edient 6 - 9 and compressed into mini tablets having a suitable diameter using a rotary tablet compression machine. Separating layer:

Procedure as described in example 11 was followed.

Enteric coating:

Procedure as described in example 11 was followed.

Example 13

*Plasdone S-630 is copolymer of N-vinyl-2-pyrrolidone and vinyl acetate Procedure: Preparation of the core:

1. Ingredients 1, 2, 4, 5, and 6 were mixed in a rapid mixer granulator for sufficient time to form a powder mix. Although a rapid mixer granulator was used, a fluid bed coater may also be used.

2. Ingredient 3 was dissolved in a sufficient quantity of purified water and sprayed onto the powder mix of step 1 until granules of sufficient strength were formed.

3. The granules of step 2 were passed through an extruder and spheronizer to foπn pellets.

4. The pellets of step 3 were dried in a suitable dryer until the loss on drying of the pellets was about 1-1.5 % w/w.

Separating layer:

Procedure as described in example 11 was followed. Enteric coating:

Procedure as described in example 11 was followed.

Example 14

'^:Plasdone S-630 is copolymer of N-vinyl-2-pyrrolidone and vinyl acetate Procedure Preparation of core:

The core can be prepared by either of the two methods designated as Method A and Method B below. Method A:

1. 7 mg of esomeprazole magnesium, 50 mg of ingredient 2, 5 mg of ingredient 3, and ingi-edient 4 were taken in a Fluid Bed Granulator to form a powder mix. Although a fluid bed coater was used, a rapid mixer granulator may instead be used.

2. Ingi-edient 5 was dissolved in a sufficient quantity of purified water and 37.5 mg of esomeprazole magnesium was dispersed into it with stirring to form a dispersion.

3. 50 mg of ingi-edient 2 and 10 mg of ingredient 3 were dissolved in a sufficient quantity of water to form a solution.

4. The solution of step 3 was added to the dispersion of step 2 and continued stimng was applied for about 15 - 30 minutes to form a dispersion. 5. The dispersion of step 4 was sprayed onto the powder mix of step 1 until granules of sufficient strength were formed.

6. The granules of step 5 were dried until the loss on drying of granules was about 1.5-2 % w/w.

7. The granules of step 6 were sifted through suitable mesh and the retentions milled. 8. The granules of step 7 was blended with ingredient 6 - 9 and compressed into tablets of a suitable diameter using a rotary tablet compression machine.

Enteric coating:

Procedure as described in Example 11 was followed.

Method B: Preparation of the core 1. 50 mg of ingredient 2 and 10 mg of ingredient 3 were dissolved in a sufficient quantity of purified water and 40 mg esomeprazole magnesium was dispersed into it with stimng. The dispersion was spray dried.

2. The remaining 50 mg of ingi-edient 2, 4.5 mg of esomeprazole magnesium and 20 mg of ingredient 4 were taken in a fluid bed granulator to form a powder blend. Although a fluid bed granulator was used, a rapid mixer granulator may instead be used.

3. Ingi-edient 5 and 5 mg of ingi-edient 3 were dissolved in a sufficient quantity of water to form a granulating solution.

4. The granulating solution of step 3 was added onto the powder blend of step 2 so as to form granules. 5. The granules of step 4 were dried until the loss on drying of granules was about 1.5-2 % w/w.

6. The granules of step 5 were sifted through a suitable mesh and the retentions milled.

7. The granules of step 6 were blended with ingredients 6-9 and compressed into tablets / mini tablets / micro tablets of suitable diameter using a rotary tablet compression machine. Enteric coating:

Procedure as described in example 11 was followed. Example 15

Plasdone S-630 is copolymer of N-vιnyl-2-pyrrolιdone and vinyl acetate Procedure: Preparation of the core:

1. 50 mg of ingredient 2, 5 mg of ingredient 3, and ingi-edient 4 were taken in a Fluid Bed granulator to form a powder. Although a fluid bed granulator was used, a rapid mixer granulator may instead be used.

2. Ingredient 5 was dissolved in a sufficient quantity of purified water and esomeprazole magnesium 40 mg was added into it with stirring to foπn a dispersion.

3. 50 mg of ingi-edient 2 and 10 mg of ingi-edient 3 was dissolved in sufficient quantity of water to foπri a solution. 4. The solution of step 3 was added to the dispersion of step 2 and continued stimng was applied for about 15-30 minutes to foπn a dispersion.

5. The dispersion of step 4 was sprayed onto the powder of step 1 until granules of sufficient strength were fonned.

6. The granules of step 5 were dried until the LOD of granules was about 1.5 - 2 % w/w. 7. The granules of step 6 were sifted through a suitable mesh and the retentions milled.

8. The granules of step 7 were blended with ingredient 6-9 and compressed into micro tablets using a rotary tablet compression machine.

9. Ingredient 12 was dissolved in sufficient quantity of purified water.

10. Ingredients 11 and 13 were dispersed into the solution of step 9 and continued stimng was applied for about 15-30 minutes to form a dispersion.

11. The dispersion of step 10 was sprayed onto micro tablets placed in suitable coating equipment.

Enteric coating:

Procedure as described in Example 11 was followed. Example 16

*Plasdone S-630 is copolymer of N-vinyl-2-pyrrolidone and vinyl acetate Procedure:

Preparation of core: Procedure as described in Example 11 was followed.

Enteric coating: Procedure as described in Example 11 was followed.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the invention. Other nonessential ingredients optionally can be added to the blend or mixture for cosmetic, aesthetic and/or manufacturing puiposes. These include colorants, diluents, lubricants, and glidants. Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

We Claim: 1. A stable oral benzimidazole pharmaceutical composition, the composition comprising: a) a core comprising a benzimidazole compound and one or more pharmaceutically acceptable excipients; b) a separating layer surrounding the core comprising a water-insoluble and non- disintegrating polymer and, optionally, one or more water soluble excipients; and c) an enteric coating surrounding the separating layer.

2. The composition of claim 1, wherein the benzimidazole compound comprises one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole, and single enantiomers thereof.

3. The composition of claim 1, wherein the one or more phamiaceutically acceptable excipients comprise one or more diluents, disintegrants, binders and lubricants.

4. The composition of claim 1, wherein the water-soluble excipient comprises one or more of a water-soluble polymer and a water-soluble excipient.

5. The composition of claim 4, wherein the water-soluble polymer comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyiTolidone, sodium alginate, sodium carboxymethyl cellulose and copolymer of vinylpyiTolidone and vinyl acetate.

6. The composition of claim 4, wherein the water-soluble excipient comprises one or more of lactose, mannitol, sorbitol, sucrose and glucose.

7. The composition of claim 1, wherein the water insoluble and substantially non- disintegOrating polymer comprises one or more of cellulose acetate, ethylcellulose, hydroxyethylcellulose and zein.

8. A stable oral benzimidazole phaπnaceutical composition, the composition comprising: a) a core containing a benzimidazole compound and one or more pharmaceutically acceptable excipients; and b) an enteric coating surrounding and directly in contact with the core, said enteric coating having a pH less than 6.5, wherein the composition is devoid of a separating layer between the core and the enteric coating.

9. The composition of claim 8, wherein the benzimidazole compound comprises one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole and single enantiomer thereof.

10. The composition of claim 8, wherein the one or more pharmaceutically acceptable excipients of the core comprise one or more of diluents, disintegrants, binders and lubricants.

11. A process for the preparation of a stable oral benzimidazole pharmaceutical composition, the process comprising: a) dispersing a benzimidazole compound, and one or more pharmaceutically acceptable excipients in an aqueous medium to obtain a dispersion; b) spray drying the dispersion to form granules; c) compressing the granules to form a core; d) coating the core with a separating layer foπned by a water insoluble and non- disintegrating polymer and optional pharmaceutically acceptable excipients; and e) coating the core with an enteric coating.

12. The process of claim 11, wherein the benzimidazole compound comprises one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole and single enantiomers thereof.

13. The process of claim 11 , wherein the one or more phaπnaceutically acceptable excipients of the core comprise one or more of diluents, disintegrants, binders and lubricants.

14. A method inhibiting gastric acid secretion, the method comprising administering a pharmaceutical composition, wherein the composition comprises: a) a core comprising a benzimidazole compound and one or more pharmaceutically acceptable excipients; b) a separating layer surrounding the core and comprising a water-insoluble and non-disintegrating polymer and, optionally, one or more water soluble excipients; and c) an enteric coating surrounding the separating layer.

15. The method of claim 14, wherein the benzimidazole compound comprises one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole and single enantiomers thereof.

16. A method inhibiting gastric acid secretion, the method comprising administering a pharmaceutical composition, wherein the composition comprises: a) a core containing a benzimidazole compound and one or more phaπnaceutically acceptable excipients; and b) an enteric coating surrounding and directly in contact with the core, said enteric coating having pH less than 6.5, wherein the composition is devoid of a separating layer between the core and the enteric coating.

17. The method of claim 16, wherein the benzimidazole compound comprises one or more of omeprazole, lansoprazole, pantoprazole, rabeprazole, and single enantiomers thereof.