FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
"PROCESS FOR PREPARING AN ORAL FORMULATION OF AN ACID-SENSITIVE BENZIMIDAZOLE DRUG"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRD3ES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:

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 benzimidazole drug is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-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 NSAID-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. 2005/0191353 relates to a process for manufacture of a pharmaceutical composition, which comprises: depositing, on non-pariel 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 may be summarized as follows:
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; or (ii) a drug layer, free of an alkaline material and comprising the said drug, on a core
made from one or more excipients; (iii) Depositing one or more of the said stabilizer layer(s) on the drug layer(s); (iv) Depositing one or more of the said drug layer(s) on the 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).
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).
DESCRIPTION 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; or (ii) a drug layer, free of an alkaline material and comprising the said drug, on a
core made from one or more excipients; (iii) Depositing one or more of the said stabilizer layer(s) on the drug layer(s);
and (iv) Depositing one or more of the said drug layer(s) on the 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 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 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 nlaterial 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 consisting 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 layer(s) 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 II: Depositing one or more sub-coating layer(s) 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, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose, 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 glidantincludes 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 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

Name of Ingredients % w/w Mg/Cap Category
Drug Loading

Drug Solution
Sugar spheres NF 20/25 44.93 168.5 Inert core (Base)
Lansoprazole 8.0 30.0 Active
hydroxypropylmethylcellulose (HPMC) 4 15 Polymer
Talc 0.4 1.5 Glidant
Polysorbate-80 0.008 0.03 Wetting agent
Water q s Vehicle
Alkaliser Solution
Magnesium Carbonate (Heavy) 8.0 30.0 Alkalizer
HPMC 1.2 4.5 Polymer
Water q s Vehicle
Sub coating
HPMC 4.96 18.6 Polymer
Talc 1.75 6.58 Glidant
Sylloid-244 FP 1.75 6.58 Glidant
Water q s Vehicle
Enteric coating
Eudragit L 30D-55 20.99 78.73 Polymer
PEG-6000 2.97 11.15 Plastisizer
Titanium dioxide 1.04 3.91 Opacifier
Water q s Vehicle

Total 375mg
Capsule Filling
Empty Capsule Shell Size-1
Step 1: Drag 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 -80°C 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 -80°C 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; Sub-Coating:
1) In one portion of water talc and syloid-244 FP were added and homogenized.
2) Another portion of water was heated to 70 -80°C 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 lunder 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

Name of Ingredients % w/w Mg/Cap Category
Drug Loading

Drug Solution
Sugar spheres NF 20/25 44.93 168.5 Inert core (Base)
Lansoprazole 8.0 30.0 Active
hydroxypropylmethylcellulose (HPMC) 4 15 Polymer
Talc 0.4 1.5 Glidant
Polysorbate-80 0.008 0.03 Wetting agent
Water qs Vehicle
Alkaliser Solution
Magnesium Carbonate ( Heavy) 8.0 30.0 Alkalizer
HPMC 1.2 4.5 Polymer
Water qs Vehicle
Sub coating
HPMC 4.96 18.6 Polymer
Talc 1.75 6.58 Glidant
Sylloid-244 FP 1.75 6.58 Glidant
Water qs Vehicle
Enteric coating
Eudragit L 30D-55 20.99 78.73 Polymer
PEG-6000 2.97 11.15 Plastisizer

Titanium dioxide 1.04 3.91 Opacifier
Water qs Vehicle
Total 375mg
Capsule Filling
Empty Capsule Shell Size-1
Step 1: Drue 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 -80°C 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 -80°C 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 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: SubCoatine:
1) In one portion of water talc and syloid-244 FP were added and homogenized.
2) Another portion of water was heated to 70 -80°C 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 coaler.
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.
EXAMPLES 3 and 4
The oral formulations comprising acid-sensitive benzimidazole drug maybe prepared as given in table 3.
Table 2

Name of Ingredients % w/w Mg/Cap Category
Drug Loading

Drug Solution
Sugar spheres NF 20/25 44.93 168.5 Inert core (Base)
Lansoprazole 8.0 30.0 Active
hydroxypropylmethylcellulose (HPMC) 3.2 12 Polymer
Sucrose 0.8 3 Diluent
Talc 0.4 1.5 Glidant
Polysorbate-80 0.008 0.03 Wetting agent
Water qs Vehicle
Alkaliser Solution
Magnesium Carbonate (Heavy) 8.0 30.0 Alkalizer
HPMC \2 4.5 Polymer
Water qs Vehicle
Sub coating
HPMC 4.96 18.6 Polymer
Sucrose 3.5 13.16
Water qs Vehicle
Enteric coating


Eudragit L 30D-55 20.99 78.73 Polymer
PEG-6000 2.97 11.15 Plastisizer
Talc 2.97 11.15 Glidant
Titanium dioxide 1.04 3.91 Opacifier
Water qs Vehicle
Total 375mg
Capsule Filling
Empty Capsule Shell Sizse-1
The oral formulation comprising acid-sensitive benzimidazole drug of example 3 was prepared by the process given in example 1.
The oral formulation comprising acid-sensitive benzimidazole drug of example 4 was prepared by the process given in example 2.
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.
Dated this 17th day of January 2008

To:
The Controller of Patents, Patent Office, Mumbai 400 037