WO2009113090A2

WO2009113090A2 - Process for preparing an oral formulation of an acid-sensitive benzimidazole drug

Info

Publication number: WO2009113090A2
Application number: PCT/IN2009/000033
Authority: WO
Inventors: Dhananjay Sahoo; Babasaheb Aware; Mavuleti Krishna Prasad; V. Satyanarayana; Ashok Rampal
Original assignee: Alkem Laboratories Ltd.
Priority date: 2008-01-17
Filing date: 2009-01-12
Publication date: 2009-09-17
Also published as: WO2009113090A3

Abstract

The present invention relates to A process for preparing an oral formulation comprising an acid-sensitive benzimidazole drug comprising depositing a stabilizer layer, free of the said drug and comprising an alkaline material on a core made from one or more excipients; or depositing a drug layer, free of an alkaline material and comprising the said drug, on a core made from one or more excipients; depositing one or more of the said stabilizer layer(s) on the said drug layer(s); depositing one or more of the said drug layer(s) on the said stabilizer layer(s); depositing one or more sub-coating layer(s) on the core achieved and depositing an enteric coating layer on the sub-coating layer(s) achieved.

Description

PROCESS FOR PREPARING AN ORAL FORMULATION OF AN ACID-SENSITIVE BENZIMIDAZOLE DRUG

FIELD OF THE INVENTION

The present invention relates to a process for preparing an oral formulation comprising an acid-sensitive benzimidazole drug.

BACKGROUND OF THE INVENTION

Benzimidazolic compounds such as omeprazole, lansoprazole, pantoprazole, pariprazole, leminoprazole, and rabeprazole are potent proton pump inhibitors known for inhibition of gastric acid secretion. They are used in the therapy of diseases related to gastric acidity in mammals, especially in humans, including gastric and duodenal ulcers, reflux oesophagitis, gastritis, duodenitis and Zollinger-Ellison syndrome. Benzimidazoles such as omeprazole and lansoprazole are sensitive to light, heat and moisture. They exhibit fast decomposition below a pH of 7.8 and have a maximum stability at a pH of 11. Hence, the oral dosage containing benzimidazole needs to be protected from the acidic ingredient used to manufacture the dosage and from acidic gastric fluid so that it reaches the small intestine intact from where it is absorbed systemically. Benzimidazole also has very low aqueous solubility and its solubility is pH dependent. Therefore, there is a need in the field of the active ingredient manufacturing to overcome the above-mentioned problem.

A preferred acid-sensitive benziinidazole drug is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trmuoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Lansoprazole is indicated in the United States of America for the treatment of Short-Term Treatment of Active Duodenal Ulcer, H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence, Maintenance of Healed Duodenal Ulcers, Short-Term Treatment of Active Benign Gastric Ulcer, Healing of NSAI D- Associated Gastric Ulcer, Risk Reduction of NSAID-Associated Gastric Ulcer, Gastroesophageal Reflux Disease (GERD), Maintenance of Healing of Erosive Esophagitis and Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome. Lansoprazole is available in the United States of America as PREVACID Delayed- Release Capsules, PREVACID for Delayed-Release Oral Suspension and PREVACID SoluTab Delayed- Release Orally Disintegrating Tablets.

United States Patent No. 5,045,321 and 5,093,132 relate to a stabilized pharmaceutical composition for the inhibition of gastric acid secretion, comprising an effective amount of a 2-benzimidazole; a basic inorganic salt stabilizing agent which is present in an amount effective to stabilize the composition, the benzimidazole derivative being in contact with the basic inorganic salt evenly; and an enteric coating for the composition. The patents disclose the use of ladling technique to prepare cores coated with the 2- benzimidazole derivative and basic inorganic salt stabilizing agent. The patents disclose nonpareils being put on a centrifugal fluidized coating granulator and then coated with dusting powder comprising a 2-benzimidazole compound, magnesium carbonate, sucrose, corn starch and crystalline cellulose, while spraying hydroxypropylcellulose solution to give spherical granules.

United States Patent No. 6,346,269 relates to a method for preparing an oral formulation containing acid-sensitive drugs comprising: (a) spreading a solution or a suspension consisting essentially of stabilizers, an inorganic solvent and acid-sensitive drugs or its pharmaceutically acceptable salts on a core made from one or more excipients, and then drying the spread core to make a core coated with an active ingredient layer; (b) spreading a composition solution or suspension consisting essentially of adhesives, plasticizer, anti-tackiness and an inorganic solvent on the active ingredient layer containing the core achieved in (a) and then drying it to form a sub-coating layer over the active ingredient layer; and (c) spreading a suspension comprising enteric-soluble coating material and an inorganic solvent on the sub-coating layer achieved in (b) and then drying it to make an enteric coating layer over the sub- coating layer.

United States Application No. 2005/0191353A1 relates to a process for manufacture of a pharmaceutical composition, which comprises: depositing, on non- panel seeds, an alkaline material layer comprising a water insoluble alkaline material to obtain treated non-pariel seeds with increased resistance to breakage; depositing, on the treated non- pariel seeds, a drug layer comprising benzimidazole in an amount of up to about 40% w/w of the composition and being substantially free of propylene glycol, to obtain drug pellets; depositing, on the drug pellets, a sealant polymer layer which is substantially free of propylene glycol, to obtain sealed pellets; and depositing, on the sealed pellets, an enteric polymer layer containing surfactants to obtain a pharmaceutical composition comprising enteric coated pellets which are substantially free of surfactants, disintegrating agents, or fillers in contact with the benzimidazole.

In spite of the prior art disclosures, there exists a need for better processes for preparing stable oral formulation comprising an acid-sensitive benzimidazole drug.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing an oral formulation comprising an acid-sensitive benzimidazole drug comprising:

(a) (i) Depositing a stabilizer layer, free of the said drug and comprising an alkaline material on a core made from one or more excipients; or depositing a drug layer, free of an alkaline material and comprising the said drug, on a core made from one or more excipients;

(ii) Depositing one or more of the said stabilizer layer(s) on the said drug layer(s); (iii) Depositing one or more of the said drug layer(s) on the said stabilizer layer(s);

(b) Depositing one or more sub-coating layer(s) on the core achieved in (a); and (c) Depositing an enteric coating layer on the sub-coating layer(s) achieved in (b).

The present invention also provides an oral formulation comprising acid- sensitive benzimidazole drug comprising:

(a) A core made from one or more excipients;

(b) A stabilizer layer free of the said drug and comprising an alkaline material; or a drug layer free of an alkaline material and comprising the said drug, deposited on the said core;

(c) One or more of the said stabilizer layer(s) deposited on the drug layer(s) (d) One or more of the said drug layer(s) deposited on the stabilizer layer(s);

(e) One or more sub-coating layer(s) deposited on the core with the drug layer(s) and the stabilizer layer(s); and

(f) An enteric coating layer deposited on the sub-coating layer(s).

The present invention may be summarized as follows: A. A process for preparing an oral formulation comprising an acid-sensitive benzimidazole drug comprising:

(ii) Depositing one or more of the said stabilizer layer(s) on the said drug layer(s); (ϋi) Depositing one or more of the said drug layer(s) on the said stabilizer layer(s); (b) Depositing one or more sub-coating layer(s) on the core achieved in (a); and (c) Depositing an enteric coating layer on the sub-coating layer(s) achieved in (b).

B. The process as in A above, wherein the said acid-sensitive benzimidazole drug is selected from the group comprising omeprazole, lansoprazole, pantoprazole, pariprazole, leminoprazole, and rabeprazole and the like.

C. The process as in A above, wherein the alkaline material in step (a) is selected from the group comprising hydroxides of alkali-metals and alkaline earth metals, bases of phosphates and organic acid salts, organic amines and the like and mixtures thereof.

D. The process as in A above, wherein the stabilizer layer and drug layer in step (a) further comprises a polymer.

E. The process as in D above, wherein the polymer is selected from the group comprising polyvinyl pyrrolidone (PVP), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), vinyl acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalates (CAP), xanthan gum, alginic acid, salts of alginic acid, Eudragit®, copolymer of methyl acrylic acid/ methyl methacrylate with polyvinyl acetate phthalate (PVAP) and the like or mixtures thereof.

F. The process as in A above, wherein the drug layer in step (a) further comprises pharmaceutically acceptable excipients such as glidants, wetting agents, diluents and the like or mixtures thereof.

G. The process as in A above, wherein the subcoating layer in step (b) contains at least one sealant polymer selected from the group comprising hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose, and the like or mixtures thereof.

H. The process as in A above, wherein the said enteric layer in step (c) contains at least one polymer selected from the group comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose of acetate phthalate (CAP), polyvinyl phthalic acetate (PVPA), Eudragit and shellac and the like or mixtures thereof.

I. An oral formulation comprising acid- sensitive benzimidazole drug comprising:

(a) A core made from one or more excipients;

(c) One or more of the said stabilizer layer(s) deposited on the drug layer(s)

(d) One or more of the said drug layer(s) deposited on the stabilizer layer(s);

(e) One or more sub-coating layer(s) deposited on the core with the drug layer(s) and the stabilizer layer(s); and (f) An enteric coating layer deposited on the sub-coating layer(s).

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

By the term "stable" it is meant that the oral formulation of an acid sensitive benzimidazole drug when packed in high density poly ethylene (HDPE) bottle with a child resistant cap (CRC), induction sealed and subjected to accelerated studies for 3 months at 40⁰C (± 2°C) and 75% (± 5%) relative humidity, there is no change in dissolution profile in 0.1 N HCl and pH 6.8 buffer; and total impurities percentage do not exceed 2 % by weight of an acid sensitive benzimidazole drug.

(a) (i) Depositing a stabilizer layer, free of the said drug and comprising an alkaline material on a core made from one or more excipients; or depositing a drug layer, free of an alkaline material and comprising the said drug, on a core made from one or more excipients; (ϋ) Depositing one or more of the said stabilizer layer(s) on the said drug layer(s); (Ui) Depositing one or more of the said drug layer(s) on the said stabilizer layer(s);

(b) Depositing one or more sub-coating layer(s) on the core achieved in (a); and

(c) Depositing an enteric coating layer on the sub-coating layer(s) achieved in (b).

(a) A core made from one or more excipients;

(c) One or more of the said stabilizer layer(s) deposited on the drug layer(s)

(d) One or more of the said drug layer(s) deposited on the stabilizer layer(s);

(f) An enteric coating layer deposited on the sub-coating layer(s).

The acid-sensitive benzimidazole drug of the invention may be selected from a Benzimidazolic compounds such as omeprazole, lansoprazole, pantoprazole, pariprazole, leminoprazole, and rabeprazole and the like which are potent proton pump inhibitors known for inhibition of gastric acid secretion.

Stage I: Deposition of the stabilizer layers and drug layers on the core

The first stage in the manufacture of the oral formulation comprising acid-sensitive benzimidazole drug is in one embodiment, the deposition of a stabilizer layer free of the drug and comprising a alkaline material on the core or the deposition of a drug layer free of an alkaline material and comprising the said drug on the core. In a preferred embodiment the core is a non-pariel seed or sugar sphere. The stabilizer layer comprising alkaline material, along with a polymer is sprayed on to the core or on the stabilizer layer if it has been deposited first on the core. This process may be carried out in a fluid bed bottom processor wherein the cores are coated with a mixture of a polymer which is selected from the group including hydroxypropylmethylcellulose, and a water insoluble alkaline material, for example magnesium carbonate, and mixtures thereof.

The suitable stabilizers useful for the solution or suspension in step (a) of the method in accordance with the present invention is an alkaline material selected from the group consisting of hydroxides of alkali-metals and alkaline earth metals, bases of phosphates and organic acid salts, organic amines and the like and mixtures thereof. A preferred stabilizer is magnesium carbonate.

The polymer used may be selected from the group comprising polyvinyl pyrrolidone (PVP), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), vinyl acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalates (CAP), xanthan gum, alginic acid, salts of alginic acid, Eudragit®, copolymer of methyl acrylic acid/ methyl methacrylate with polyvinyl acetate phthalate (PVAP) and the like and mixtures thereof. A preferred polymer used is hydroxypropylmethylcellulose.

Alternatively the drug layer may be deposited on the core or may be deposited on the core coated with stabilizer layer. The process includes the deposition of a suspension/ solution of dissolved acid-sensitive benzimidazole drug on the core or on the core coated with stabilizer layer. The solution/ suspension of acid-sensitive benzimidazole drug can be prepared by adding excipients such as glidants, wetting agents and diluents such as sucrose to water, further adding a polymer to form a dispersion. The acid-sensitive benzimidazole drug is further added to the dispersion.

This solution is then sprayed on the on the core or on to the core with stabilizer layer.

Suitable glidants may be selected from the group comprising of talc, stearic acid, stearate, sodium stearyl fumarate, glyceryl behenate, kaolin, aerosol and the like and mixtures thereof. Wetting agents used may be selected from Polysorbate 80 and the like.

The polymer used may be selected from the group comprising polyvinyl pyrrolidone (PVP), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), vinyl acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalates (CAP), xanthan gum, alginic acid, salts of alginic acid, Eudragit®, copolymer of methyl acrylic acid/ methyl methacrylate with polyvinyl acetate phthalate (PVAP) and the like and mixtures thereof. A preferred polymer used is hydroxypropylmethylcellulose. One or more stabilizer layerjs) as described above, comprising an alkaline material may be deposited on the drug layer(s): and one or more drug layer(s) comprising acid- sensitive benzimidazole drug as described above may be deposited on the one or more stabilizer layer. In a preferred embodiment there are in all three stabilizer layers and three drug layers on the core, of which the first stabilizer layer is deposited on the core followed by a drug layer followed by another stabilizer layer followed by another drug layer followed by another stabilizer layer which is followed by a drug layer. In another preferred embodiment, there are in all three drug layers and three stabilizer layers on the core, of which the first drug layer is deposited on the core followed by a stabilizer layer followed by another drug layer followed by another stabilizer layer followed by another drug layer which is followed by a stabilizer layer.

Stage H: Depositing one or more sub-coating layerfs) on the core achieved in (a) The next stage is the deposition of sub-coating layer(s) on the core coated with the stabilizer layers and drug layers. A sub-coat/ seal coating suspension is prepared by dispersing and/ or dissolving a sealant polymer in water. A glidant is added to the above solution. The suspension is filtered through an appropriate mesh and is sprayed on the drug pellets in a fluid bed processor to form a seal coat, which prevents the contact of acidic enteric coating material with drug layer. The sealant polymer is selected from a group that includes hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyroUidone, sodium carboxymethylcellulose, _vmethylcellulose, and their mixtures, and is preferably hydroxypropylmethylcellulose. The glidant is selected from a group that includes talc, colloidal silicon dioxide, glyceryl monostearate, glyceryl behenate, and their mixtures, preferably, the glidant includes talc. Optionally, an alkaline agent such as light magnesium carbonate can also be added to the seal coating suspension to improve the barrier property of the membrane.

Stage III: Depositing an enteric coating layer on the sub-coating layer achieved in (b). The final stage in the process for manufacture of the oral formulation comprising acid- sensitive benzimidazole drug is the deposition of an enteric layer on the sub-coated cores. The enteric- soluble coating material suitable for the present invention is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate(HPMCP), cellulose of acetate phthalate(CAP), polyvinyl phthalic acetate (PVPA), Eudragit and shellac. Optionally, plasticizers and glidants can further be added to the enteric coating layer. In one of the embodiments of the invention, the process involving all the stages is carried out continuously in a single equipment fluid bed processor. In another embodiment of the invention, the process is a batch process, but all stages are preferably carried out in a single fluid bed processor, where representative samples are sampled at the end of each stage. Other equipment, such as a coating pan or a tangential spray coater can also be used for manufacturing oral formulation comprising an acid-sensitive benzimidazole drug using the above process.

The stable pharmaceutical composition of the invention may be filled into capsules of suitable size or provided as any suitable composition such as compressed tablet or sachet.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

EXAMPLE 1 The oral formulation comprising acid-sensitive benzimidazole drug may be prepared as given in table 1.

Table 1

Step 1; Drug Loading Preparation of Drug solution

1) In one portion of water polysorbate-80 and Talc were add.

2) Another portion of water was heated to 70 -80⁰C and HPMC added to it under stirring for 15 minutes and dispersion cooled to room temperature.

3) The dispersion of step 1 and step 2 were mixed.

4) Lansoprazole was added to the dispersion of step 3 and mixed properly.

5) The dispersion of step 4 was passed through Nylon cloth of mesh # 200.

6) The drug solution was divided in to three parts (a, b & c)

Preparation of stabilizer solution

1) Water was heated to 70 -80⁰C and HPMC added to it under stirring for 15 minutes and the dispersion cooled to room temperature.

2) Magnesium carbonate was added to the dispersion of step 1 and mixed.

3) The stabilizer solution was divided in to three parts.

4) One part of stabilizer coating was deposited over the sugar spheres followed by deposition of one part of drug solution coating. Then the second part of stabilizer coating was deposited followed by second part of drug coating. Finally in a similar way the third part of stabilizer coating was deposited followed by third part of drug coating. Step 2: SubCoating: 1) In one portion of water talc and syloid-244 FP were added and homogenized. 2) Another portion of water was heated to 70 -80⁰C and HPMC was added to it under stirring for 15 minutes.

3) The dispersion of step 2 was cooled to room temp

4) The dispersion of talc & Syloid -244FP of step 1 was added to the dispersion of step 3 under stirring and the dispersion passed through Nylon cloth of mesh # 200.

5) The drug loaded pellets were sub-coated using the dispersion of step 4 using a Fluidized bed coater.

Step 3: Enteric Coating;

1) One portion of water was added to Eudragit L30D-55 under stirring .

2) In another portion of water titanium dioxide is added and homogenized.

3) Dispersion of step 2 was added to step 1 under stirring.

4) Solution of PEG-6000 was prepared in water and added to the dispersion of step 3 under stirring.

5) The Enteric coating of sub coated pellets by the dispersion of step 4 was done using Fluidized bed coater.

Step 4; Capsule Filling;

1) The enteric coated pellets were filled in size 1 capsule Shell using an Automatic capsule filling machine.

EXAMPLE 2

The oral formulation comprising acid- sensitive benzimidazole drug may be prepared as given in table 2.

Table 2

Step 1; Drug Loading; Preparation of Drug solution

1) In one portion of water polysorbate-80 and Talc were add. 2) Another portion of water was heated to 70 -80⁰C and HPC added to it under stirring for 15 minutes and dispersion cooled to room temperature.

3) The dispersion of step 1 and step 2 were mixed.

4) Lansoprazole was added to the dispersion of step 3 and mixed properly.

5) The dispersion of step 4 was passed through Nylon cloth of mesh # 200. 6) The drug solution was divided in to three parts (a, b & c)

Preparation of stabilizer solution

1) Water was heated to 70-80°C and HPC added to it under stirring for 15 minutes and the dispersion cooled to room temperature.

2) Magnesium carbonate was added to the dispersion of step 1 and mixed. 3) The stabilizer solution was divided in to three parts.

4) One part of drug solution or suspension coating was deposited over the sugar spheres followed by deposition of one part of alkaliser suspension or solution coating. Then the second part of drug coating was deposited followed by second part of alkaliser coating. Finally in a similar way the third part of drug coating was deposited followed by third part of alkaliser coating. Step 2; SubCoating;

1) In one portion of water talc and syloid-244 FP were added and homogenized.

2) Another portion of water was heated to 70 -80⁰C and HPC was added to it under stirring for 15 minutes. 3) The dispersion of step 2 was cooled to room temp

4) The dispersion of talc & Syloid -244FP of step 1 was added to the dispersion of step 3 under stirring and th£ dispersion passed through Nylon cloth of mesh # 200.

5) The drug loaded pellets were sub-coated using the dispersion of step 4 using a Fluidized bed coater. Step 3; Enteric Coating;

1) One portion of water was added to Eudragit L30D-55 under stirring.

2) In another portion of water titanium dioxide is added and homogenized.

3) Dispersion of step 2 was added to step 1 under stirring.

Step 4; Capsule Filling;

EXAMPLE 3

The oral formulations comprising acid-sensitive benzimidazole drug may be prepared as given in table 3. Table 3

The oral formulation comprising acid-sensitive benzimidazole drug of example 3 was prepared by the process given in example 1.

EXAMPLE 4

Capsules having the formulation listed in example 3 were packed in high density poly ethylene (HDPE) bottle with a child resistant cap (CRC), induction sealed and subjected to accelerated studies for 3 months at 40°C (± 2⁰C) and 75% (± 5%) relative humidity and the results are shown in Table 4.

Table 4

Lansoprazole Storage Time

* USP type II dissolution apparatus, 75 rpm, 0.1 N HCl (500 ml) for first 1 hour followed by pH 6.8 buffer (900 ml) for 60 min. (as per USP method)

NMT: Not more than NLT: Not less than

ND: Not Detected

It can be seen that the compositions of the present invention were stable even at 3 months stability testing at 4O°C (± 2°C) and 75% (± 5%) relative humidity

Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above- described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Claims

Claims:

1. A process for preparing an oral formulation comprising an acid- sensitive benzimidazole drug comprising: (a) (i) Depositing a stabilizer layer, free of the said drug and comprising an alkaline material on a core made from one or more excipients; or depositing a drug layer, free of an alkaline material and comprising the said drug, on a core made from one or more excipients;

(ϋ) Depositing one or more of the said stabilizer layer(s) on the said drug layer(s); (iii) Depositing one or more of the said drug layer(s) on the said stabilizer layer(s);

2. The process as claimed in claim 1. wherein the said acid- sensitive benzimidazole drug is selected from the group comprising omeprazole, lansoprazole, pantoprazole, ^" pariprazole, leminoprazole, and rabeprazole and the like.

3. The process as claimed in claim 1, wherein the alkaline material in step (a) is selected from the group comprising hydroxides of alkali-metals and alkaline earth metals, bases of phosphates and organic acid salts, organic amines and the like and mixtures thereof.

4. The process as claimed in claim 1, wherein the stabilizer layer and drug layer in step (a) further comprises a polymer.

5. The process as claimed in claim 4, wherein the polymer is selected from the group comprising polyvinyl pyrrolidone (PVP), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), vinyl acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalates (CAP), xanthan gum, alginic acid, salts of alginic acid, Eudragit®, copolymer of methyl acrylic acid/methyl methacrylate with polyvinyl acetate phthalate (PVAP) and the like or mixtures thereof.

6. The process as claimed in claim 1, wherein the drug layer in step (a) further comprises pharmaceutically acceptable excipients such as glidants. wetting agents. diluents and the like or mixtures thereof.

8. The process as claimed in claim 1, wherein the subcoating layer in step (b) contains at least one sealant polymer selected from the group comprising hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose, and the like or mixtures thereof.

9. The process as claimed in claim 1, wherein the said enteric layer in step (c) contains at least one polymer selected from the group comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose of acetate phthalate (CAP), polyvinyl phthalic acetate (PVPA), Eudragit and shellac and the like or mixtures thereof.

10. An oral formulation comprising acid- sensitive benzimidazole drug comprising:

(a) A core made from one or more excipients;

(c) One or more of the said stabilizer layer(s) deposited on the drug layer(s)

(d) One or more of the said drug layer(s) deposited on the stabilizer layerfs);

(f) An enteric coating layer deposited on the sub-coating layer(s).