BENZIMIDAZOLE COMPOSITIONS
INTRODUCTION TO THE INVENTION
The present invention relates to pharmaceutical compositions comprising substituted benzimidazoles or their pharmaceutically acceptable salts, solvates, single isomers, enantiomers or mixtures thereof. More particularly, present invention relates to pharmaceutical composition in the form of a capsule comprising substituted benzimidazoles with sinking attributes, wherein the capsule does not float when placed in aqueous dissolution media.
The substituted benzimidazoles are a class of compounds, which find use in a variety of gastrointestinal disorders such as gastroesophageal reflux disease (GERD), gastric ulcers, erosive esophagitis and gastritis.
Molecules from the substituted benzimidazole class of compounds which have been commercialized internationally include omeprazole as PRILOSEC® (a capsule dosage form for oral administration that comprises delayed release pellets of 10, 20 and 40 mg of omeprazole), omeprazole magnesium as PRILOSEC OTC® (a tablet containing equivalent to 20 mg omeprazole base), esomeprazole magnesium as A/EX/L//W® (a capsule dosage form for oral administration ttiat comprises delayed release pellets of 20 and 40 mg oftfie magnesium salt of the (-)-enantiomer of omeprazole), lansoprazole as PREVACID® (a capsule dosage form for oral administration that comprises delayed release pellets of 15 and 30 mg of lansoprazole), pantoprazole as PROTONIX® (a delayed release tablet dosage form for oral administration of 20 and 40 mg of pantoprazole sodium) and rabeprazole as ACIPHEX® (a delayed release tablet dosage form for oral administration of 20 mg of rabeprazole sodium).
This class of compounds and certain commercially successful analogues are represented by the following general structural formula:


U.S. Patent Nos. 6,428,810 and U.S. Patent Application Publication No. 2006/0051421 describe omeprazole and esomeprazole formulations.
U.S. Patent No. 6,248,355 discloses stable omeprazole compositions, exempt of alkaline reacting compounds or mannitol.
U.S. Patent Nos. 6,147,103, 5,690,960, 4,853,230 and 4,786,505 disclose compositions comprising omeprazole and esomeprazole.

U.S. Patent Application Publication No. 2002/0128293 describes a pharmaceutical composition comprising a mixture of omeprazole and at least one water insoluble polymer.
U.S. Patent No. 6,749,864 and International Application Publication No. WO 2005/077342 discloses lansoprazole compositions.
It was surprisingly found that pharmaceutical composition of the present invention in the form of a capsule comprising substituted benzimidazole, wherein the capsule does not float when placed in an aqueous dissolution media, showed relatively higher bioavailability as compared to non-sinking capsules, when administered orally to human volunteers.
Thus, the present invention provides for a pharmaceutical composition in the form of a capsule with sinking attributes comprising substituted benzimidazole, which shows desired in vitro dissolution and in vivo absorption profiles.
This and other such needs are addressed by the present invention.
SUMMARY OF THE INVENTION
An aspect of present invention provides for pharmaceutical compositions in the form of a capsule comprising substituted benzimidazoles with sinking attributes, wherein the capsule does not float when placed in aqueous dissolution media.
Another aspect of present invention provides for pharmaceutical compositions in the form of a capsule with sinking attributes comprising omeprazole or its pharmaceutically acceptable salts, wherein the capsule does not float when placed In aqueous dissolution media at about 37 "C.
Still further aspect of present invention provides for pharmaceutical composition in the form of a capsule with sinking attributes comprising omeprazole or its pharmaceutically acceptable salts, wherein the capsule has a density more than 1 g/mL and said capsule does not float when placed in aqueous dissolution media at about 37 °C.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions in the form of capsules comprising substituted benzimidazoles with sinking attributes, wherein the capsule does not float when placed in an aqueous dissolution media.
In the context of the present invention, substituted benzimidazoles comprise omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole and the like, and their pharmaceutically acceptable salts, or mixtures thereof.
In one embodiment, the capsule composition of the present invention comprises inert cores coated with a layer comprising drug and a binder. These drug coated cores are further coated with an enteric coating, and may have an optional sub-coating between the drug coating and an enteric coating.
In another embodiment of the present invention, the inert core and the drug coat are optionally separated by an intermediate seal coating comprising one or more pharmaceutically acceptable polymers.
In accordance with the invention, the inert cores comprise pharmaceutically acceptable excipients, pellets, beads, spheres, particles or seeds that can be water-soluble, water swellable, or water-insoluble; and can be organic or inorganic, or mixtures thereof. The size of cores ranges from about 50 to 5000 fjm, or from about 100 to 500 pm, or from about 150 to 300 pm.
In the context of the present invention, the pharmaceutically acceptable excipients serving as inert cores comprise: insoluble inert materials, such as glass particles/beads or silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose, or cellulose derivatives; or soluble cores such as sugar spheres having sugars like dextrose, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol, starches, sorbitol, sucrose; insoluble inert plastic materials such as spherical or nearly spherical core beads of polyvinyl chloride, polystyrene or any other pharmaceutically acceptable insoluble synthetic polymeric material; and the like or mixtures thereof.

In one embodiment, the inert cores comprise commercially available ready-to-use pellets including sugar spheres and microcrystalline cellulose spheres such as the commercially available Celsphere®; or a powder blend comprising one or more pharmaceutically acceptable excipients. Alternatively, the inert cores can be prepared from pharmaceutically acceptable excipients by techniques known in the art such as extrusion-spheronization, granulation, and the like.
Typical non limiting examples of seal coating and sub-coating polymers include: celluloses such as carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC); ethyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), cellulose acetate, homopolymers or copolymers of N-vinylpyrrolidone; vinyl and acrylic polymers; polyacrylic acid, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate; polyalkyi methacrylates; polyalkyi acrylates; polyvinyl acetate (PVA); chitosan; stearic acid, gum arable, crosslinked vinylpyrrolidone polymers; hydrogenated castor oil; and the like. Other classes of release-controlling polymers or their mixtures in various ratios as required are also within the purview of this invention without limitation.
Various pharmaceutically acceptable excipients that may be used for acid insoluble layers or enteric coating include but are not limited to cellulosic polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropylcellulose phthalate, hydroxypropyl methylcellulose hexahydrophthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS) cellulose acetate phthalate, cellulose ester-ether phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, cellulose acetate hexahydrophthalate, acrylic acid polymers and copolymers such as methacrylic acid (EUDRAGIT®); vinyl polymers and copolymers such as polyvinylacetate phthalate; shellac and the like. Other classes of polymers, copolymers of these polymers or their mixtures in various ratios as required are within the scope of this invention without limitation.
In the context of present invention, sinking attributes of the capsule can be achieved by various means such as but not limited to: use of pharmaceutical excipients; pellets, beads, spheres, or particles thereof; tablets

and capsules comprising pharmaceutical excipients; and mixtures thereof. These means which impart sinking attributes to the capsule formulation of present invention may be uncoated or coated, and are filled in a capsule along with delayed release pellets comprising substituted benzimidazoles, such that the resultant capsule does not float when placed in an aqueous dissolution media. The sinking means Increase the capsule density to more than about 1 g/ml so that the capsule does not float when placed in aqueous dissolution media.
The excipients that impart density of at least 1g/ml or more may be solid, semi-solid, liquid or powder form or the excipients may be further formulated into placebo tablets or pellets or particles and they can be filled into the empty capsule shells for increasing the density. Such excipients include but are not restricted to sucrose, dextrose, lactose, fructose, microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, sorbitol, xylitol, isomalt, gelatin and starches. The fillers can be added either during granulation or extrusion-spheronization process or in the coating material or can be mixed externally with the other fill material. These placebo tablets or pellets or particles may be further coated to increase density. For coating any hydrophilic or hydrophobic polymers may be used. The polymers used for coating include but not limited to cellulose derivatives such as hydroxy propyl cellulose, hydroxy methyl cellulose, ethyl cellulose; hydrogenated castor oil. For coating the other adjuvants such as plasticizers, opacifier, antitacking agents etc may be used.
A tablet, optionally with coating, has been particularly found to be useful for imparting sinking attributes to the capsule compositions of present invention.
In an embodiment, pharmaceutical compositions of the present invention are prepared as follows:
a) Beads or cores or granules or particles are layered or sprayed over with or without seal coating, optionally with pharmaceutically acceptable excipients, by techniques such as powder coating, spray coating, dip coating, fluidized bed coating, and the like.

b) The cores of step (a) are layered with drug layer, followed by subcoating and enteric coating and dried by the techniques known to the one skilled in the art.
c) The dried cores are filled into capsules, optionally with pharmaceutlcally acceptable excipients, to obtain capsules with sinking attributes.
In the context of the present invention, during the preparation of the pharmaceutical compositions into finished dosage form, one or more pharmaceutlcally acceptable excipients may optionally be used which include but are not limited to: diluents such as microcrystalline cellulose (MCC), silicified MCC (e.g. Prosolv™), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; binders or adherents such as acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methylcellulose (e.g. METHOCEL®), carboxymethyl cellulose sodium, povidone (various grades of KOLLIDON®, PLASDONE®), starch and the like; disintegrants such as carboxymethyl cellulose sodium (e.g. Ac-Di-Sol®, Primellose®), crospovidone (e.g. Kollidon®, Polyplasdone®), povidone K-30, polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate (e.g. Explotab®), and the like; plasticizers such as acetyltributyl citrate, phosphate esters, phthalate esters, amides, mineral oils, fatty acids and esters, glycerin, triacetin or sugars, fatty alcohols, polyethylene glycol, ethers of polyethylene glycol, fatty alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol and the like; solvents that may be used in layering or coating or granulation or extrusion-spheronization include water, methanol, ethanol, isopropyl alcohol, acetone, methylene chloride, dichloromethane and the like or mixtures thereof.
Pharmaceutical compositions of the present invention may further include any one or more of pharmaceutically acceptable glidants, lubricants like sodium stearyl fumarate, opacifiers, colorants and other commonly used excipients.

In an embodiment, pharmaceutical compositions of the present invention comprising substituted benzimidazoles are used in the treatment of variety of gastrointestinal disorders such as gastroesophageal reflux disease (GERD), gastric ulcers, erosive esophagitis and gastritis.
The following examples illustrate certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.



Manufacturing process:
A. Seal coating
1. Hydroxy propyl methylcellulose was dissolved in water.
2. Sugar spheres were coated using the solution of step 1 to a weight
build-up of 5% w/w, in a fluidized bed processor with the following
parameters:
• Inlet air temperature 50 - 60° C
• Product temperature 40 - 45° C
• Spray rate 4 - 6 g/minute.
B. Drug coating
3. Hydroxypropyl methylcellulose was dissolved in a mixture of methanol
and dichloromethane followed by addition of magnesium oxide and
omeprazole magnesium.
4. Drug dispersion of step 3 was loaded on seal coated sugar spheres
(300 9) of step 2 to a weight gain of 75% w/w, using a fluidized bed
processor with bottom spray and following parameters:
• Inlet air temperature 30-40°C
• Product temperature 26 - 28° C
• Spray rate 12-16 g/minute.
C. Sub-coating
5. HPMC was dissolved in a mixture of methanol and dichloromethane
followed by addition of talc, silicon dioxide and magnesium stearate.

6. Drug loaded pellets (400 g) of step 4 were sub-coated with a dispersion
of step 5 to a weight gain of 34% w/w, using a fluidized bed processor with bottom spray with following parameters:
• Inlet air temperature 35-45°C
• Product temperature 30 - 32° C
• Spray rate 12-14 g/minute.
D. Enteric coating
7. Methacrylic acid copolymer type C was dispersed in water with stirring
followed by addition of triethyl citrate. A pigment dispersion was prepared by adding titanium dioxide and talc in water and homogenization for 10 minutes. The pigment dispersion was mixed with polymer dispersion.
8. The sub-coated pellets (300 g) of step 6 were enteric coated with the
dispersion of step 7 to a weight gain of 100% w/w, using a fluidized bed processor with bottom spray with the following parameters:
• Inlet air temperature 32 - 35° C
• Product temperature 28 - 32° C
• Spray rate 4 - 6 g/minute.
COMPARATIVE EXAMPLE 2: Non-sinking capsules containing delayed release pellets of omeprazole magnesium.
Enteric-coated pellets of omeprazole magnesium of Example 1 were filled into hard gelatin capsules of size '1' (each capsule containing 276.2 mg pellets equivalent to 20.6 mg omeprazole magnesium).
EXAMPLE 3: Sinking capsules containing delayed release pellets of omeprazole magnesium.



Manufacturing process:
1. Tribasic calcium phosphate was lubricated by blending with magnesium
stearate and compressed into 12 mmx5 mm capiat shaped tablets
weighing 450 mg.
2. Tablets of step 1 were coated with a dispersion of ethyl cellulose and
triethyl citrate in isopropyl alcohol to a weight gain of 2% w/w.
3. Enteric-coated pellets (276.2 mg pellets equivalent to 20.6 mg
omeprazole magnesium) of omeprazole magnesium of Example 1 along
with one coated tablet of step 2 were filled into each hard gelatin
capsule of size '0'


Manufacturing process:
1. Dibasic calcium phosphate and microcrystalline cellulose were blended together for 15 minutes, the blend was lubricated with magnesium stearate for 5 minutes and the lubricated blend was compressed into 12 mmx5 mm caplet shaped tablets weighing 450 mg.
2. Eudragit S100 was dissolved in a solvent mixture (isopropyl alcohol and water), followed by addition of triethyl citrate and talc and stirring for 1 hour.
3. Tablets of step 1 were coated with the coating dispersion of step 2 to a weight gain of 2% w/w.
4. Enteric-coated pellets (276.2 mg pellets equivalent to 20.6 mg omeprazole magnesium) of omeprazole magnesium of Example 1 along with one coated tablet of step 2 were filled into each hard gelatin capsule of size '0'.
EXAMPLE 5: Disintegration and sinking behavior of capsules
Capsules of Example 2 and Example 3 were placed in 300 ml of 0.1 N HCI in USP apparatus II (Paddle), described in Test 711 "Dissolution," United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2006, and stirred at 100 rpm for 2 hours at 37 °C.
Complete dissolution of the capsule shell occurred in 6 minutes for the Example 3 product, and in 16 minutes for the product of Example 2. This difference may be because capsules of Example 2 do not sink for an initial few minutes (about 6 to 12) and disintegrate slowly, while capsules of Example 3 do not float, under the above-mentioned conditions.
EXAMPLE 6: In vitro release profile of Example 2 and Example 3 in comparison with PRILOSEC OTC™ with the following parameters: Acid stage

• Media: 300 ml of 0.1 NHCI
• Apparatus: USP apparatus II (Paddle) from Test <711> Dissolution in
United States Pharmacopeia 29, United States PInarmacopeial
Convention, Inc., Rockville, Maryland (2006).
• Rpm: 100 rpm

the assay of the pellets (without acid exposure) and assay of the remaining pellets after acid exposure.
Buffer stage
• Media: 1000 ml of pH 6.8 phosphate buffer
• Apparatus: USP apparatus II (Paddle) from Test 711 "Dissolution" in
United States Pharmacopeia 29, United States Pharmacopeial
Convention, Inc., Rockville, Maryland (2006).


EXAMPLE 7: In vivo bioequivalence study
The compositions of Example 2 and Example 3 were compared with a reference product, PRILOSEC OTC™ 20 mg, in an open label, balanced, randomized three treatment, three-period, three sequence, analyst blind and three-way crossover bioequivalence study with 10 days washout period between each drug administration, under fasted conditions, using 18 healthy volunteers.

i

CLAIMS
1. A pharmaceutical dosage form comprising a capsule containing a
substituted benzimidazole drug compound, or a salt thereof, and having a
density greater than 1 g/mL.
2. The pharmaceutical dosage form of claim 1, wherein a substituted
benzimidazole drug compound comprises a salt of omeprazole.
3. The pharmaceutical dosage form of claims 1 or 2, wherein a density
greater than 1 g/mL is achieved by including at least one pharmaceutical
excipient having a density greater than 1 g/mL.
4. The pharmaceutical dosage form of claim 3, wherein a pharmaceutical
excipient having a density greater than 1 g/mL is placed inside the capsule.
5. The pharmaceutical dosage form of claims 3 or 4, wherein a
pharmaceutical excipient having a density greater than 1 g/mL is contained in
a tablet placed inside the capsule.
6. The pharmaceutical dosage form of claim 3, wherein a pharmaceutical
excipient having a density greater than 1 g/mL is incorporated into the capsule
shell.
7. A process of preparation of the pharmaceutical dosage form comprising
a capsule containing a substituted benzimidazole drug compound, or a salt
thereof, and having a density greater than 1 g/mL