FIELD OF INVENTION

The invention relates to stable pharmaceutical compositions comprising an acid labile benzimidazole compound.

More particularly, the invention relates to stable pharmaceutical compositions comprising dexlansoprazole or its pharmaceutically acceptable salts thereof.

The invention also relates to a process for preparation of stable pharmaceutical composition comprising dexlansoprazole or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Dexlansoprazole is a substituted benzimidazole compound and chemically known as (+)-2-((R)-{(3-methyl-4-(2, 2, 2-trifluoroethoxy) pyridin-2-yl) methyl} sulfinyl)-lH-benzimidazole which is also commonly known as (+) or (R)-isomer of lansoprazole.

Dexlansoprazole is marketed under the trade name DEXILANT® in the form of delayed release capsule in the U.S. for the treatment and maintenance of patients with erosive oesophagitis and non-erosive gastroesophageal reflux disease (GERD or GORD).

Dexlansoprazole, being a benzimidazole proton pump inhibitor is very much susceptible to degradation/ transformation in an acidic medium which adversely affect the various biological and pharmacological effect and may also lead to some adverse effect such as gastric mucosa irritation.

To overcome the above disadvantages, various compositions of dexlansoprazole were developed. Some of the patents/ patent applications, which disclose compositions of acid labile benzimidazole or dexlansoprazole, are cited below.

U.S. 5,045,321, U.S. 5,093,132, U.S. 5,433,959, U.S. 5,639,478, U.S. 5,879,708, U.S. 6,017,560, U.S. 6,123,962, U.S. 6,296,875, U.S. 6,380,234, U.S. 6,521,256 and U.S. 6,749,864 discloses compositions, wherein the compositions are made up into tablets or granules and then coated by an enteric coating agent, wherein the compositions comprise an effective amount of dexlansoprazole and at least one of the basic inorganic salts of magnesium and calcium, wherein the amount of the basic inorganic salt relative to the benzimidazole compound being about 0.3-20 parts by weight and the benzimidazole compound being in contact with the basic inorganic salt evenly and also the process for preparing the same. These patents further disclose granules prepared by coating nonpareils seed with a mixture of a benzimidazole compound, a basic inorganic salt stabilizing agent and an additive and finally enteric coated and filled into a hard gelatin capsule.

U.S. 6,576,258 and U.S. 2003/1075348 discloses a method for stabilizing benzimidazole compound including lansoprazole and an optically active isomer of lansoprazole, comprising anhydrous granulation with an organic solvent of the active substance and dried pharmaceutically acceptable auxiliary substances for the preparation of pellet cores or granules, which are then either coated with a gastro-resistant coating or compressed into tablets under addition of a dried pharmaceutically acceptable auxiliary substance and the tablets are further coated with a gastro-resistant coating.

U.S. 6,605,303 disclose an extended release dosage form consisting of proton pump inhibitor, embedded in a hydrophilic or hydrophobic matrix for extended release of the active ingredient and optionally by pharmaceutically acceptable excipients, a water soluble separating layer and an enteric coating layer. This patent further discloses the dosage form may be in the form of enteric coated tablet or pellets filled in the capsule.

U.S. 7,041,313 and U.S. 7,402,321 discloses an oral fixed combination administration form of pyridine-2-ylmethylsulfinyl-lH-benzimidazole or a pharmaceutically acceptable salt thereof, which comprises the active compound in a capsule in two different administration forms, which release the active compound at two different points of time, wherein one administration form comprises the active compound together with a tablet disintegrant and bears a sustained-release coating film comprising a water-insoluble and physiologically tolerable plastic membrane having low swelling power in water and wherein the other administration form comprises the active compound and bears an enteric coating film.

U.S. 7,285,668 and U.S. 2008/0306118 discloses capsule compositions comprising dexlansoprazole crystal mixed with other additive to form dusting powder which is coated to nonpareil seed along with binder solution to form spheroid granules. The granules further coated with enteric coating agent and mixed with other additive and finally encapsulated in a hard gelatin capsule.

U.S. 7,790,755 disclose a capsule composition (i) comprising a tablet, granule or fine granule in which a release of an active ingredient is controlled; said tablet, granule or fine granule comprising a core particle containing an imidazole compound as the active ingredient, and a pH-dependently soluble release-controlled coating-layer which comprises one kind of polymeric substance or a mixture of two or more kinds of polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac; said polymeric substance is soluble in the pH range of 6.0 to 7.5, and composition (ii) comprising a tablet, granule or fine granule comprising a core particle containing the active ingredient and enteric coat such that the active ingredient is released in the pH range of no less than 5.0 to no more than 6.0.

U.S. 2004/0265370 and U.S. 2007/0166370 disclose an oral composition comprising multiple populations of at least one of beads, pellets, tablets and granules provided in a capsule, comprising: (i) a population of a pharmaceutical active including lansoprazole or its optically active ingredients; (ii) a population of a basic substance; (iii) a population of enteric coated pharmaceutical active; and (iv) a population of enteric coated basic substance. These patent publications further discloses population of (i) to (iv) is formed about a core material, i.e. a sugar sphere or microcrystalline cellulose of about 0.1 mm to about 4 mm or alternatively, as a tablet and finally provided within a suitable capsule.

U.S. 2006/0057195 discloses a stabilized solid dosage form which comprises a layer containing an amorphous dexlansoprazole and at least one basic inorganic salt selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium bicarbonate and sodium hydroxide, an intermediate coating layer formed on said layer, and an enteric coating layer formed on said intermediate coating layer. This patent publication further discloses the solid dosage form is in the form of granules or fine granules which may be formulated as tablets, or capsules by filling in capsules.

U.S. 2006/0159760 discloses a granule, fine particle or tablet having a core particle and on said core particle, an active ingredient containing A layer formed by spraying a solution or suspension containing an active ingredient including proton pump inhibitor and a binder and an active ingredient-containing B layer surrounding the A layer formed by dispersing a dusting powder containing an active ingredient including proton pump inhibitor while spraying a solution containing a binder which further coated with enteric coating and finally encapsulated in a capsule.

U.S. 2006/0177509 discloses a controlled release composition comprising release of an active ingredient controlled in two or more steps at different release rates, which comprises 1) a release-controlled part A comprising a proton pump inhibitor and low substituted hydroxypropyl cellulose, which is capable of controlling release of the active ingredient to occur at a predetermined rate; and 2) a release-controlled part B comprising a proton pump inhibitor, which is capable of controlling release of the active ingredient to occur at a predetermined rate lower than the release rate of the release-controlled part A; wherein the release of the active ingredient from the release-controlled part B precedes the release of the active ingredient from the release-controlled part A.

U.S. 2007/0141137 disclose a capsule preparation comprising a water-soluble polysaccharide (e.g. a pullulan capsule) or a PEG-containing gelatin capsule containing a medicine unstable to moisture such as an imidazole type compound having a proton pump inhibitory activity including dexlansoprazole which may be in the form of powdered medicine, fine granules, granules and tablets.

U.S. 2007/065513 disclose a stable composition in the form of pellets for lansoprazole comprising: (a) a substrate comprising lansoprazole or a pharmaceutically suitable salt thereof excluding any alkaline agent; (b) a subcoating layer comprises an alkaline agent; and (c) an enteric coating material layered over said subcoating layer and finally compressed into tablets or filled into capsule. This patent publication further discloses "lansoprazole" preferably refers to lansoprazole base, but may also refer to one of its single enantiomers or an alkaline salt of lansoprazole.

U.S. 2008/0095853 disclose an oral solid dosage form comprising: (i) an acid sensitive proton pump inhibitor and (ii) a core material containing the proton pump inhibitor and in the form of pellets, wherein: (A) a first population of the pellets gives a delayed release pulse of the proton pump inhibitor, wherein pellets of this first population have the following sequence of layers on the core material: Al) a delay release modifying layer comprising a water soluble polymer(s), talc and a hydrophobizing agent; A2) a lag time controlling layer comprising a high viscosity water soluble polymer; A3) an optional subcoating layer; and A4) an outer enteric coating layer; and (B) a second population of the pellets gives an immediate release pulse of the proton pump inhibitor, wherein pellets of this second population have the following sequence of layer(s) on the core material: Bl) an optional subcoating layer; and B2) an outer enteric coating layer.

U.S. 2008/0138427 disclose a method for producing granules containing a active substance including dexlansoprazole comprises a process for producing the granules, by heating the granules to the temperature of about 50°C or higher and then maintaining the granules at the said temperature for about 1 minute or longer.

U.S. 2009/0098199 disclose a method of treating a gastrointestinal disorder comprising the steps of: administering to patient a composition comprising: (a) first solid particle, wherein said first solid particle comprises an active agent and a first enteric coating, wherein the first enteric coating releases the active agent from the solid particle at a pH of about 5.0 to about 5.5; and (b) a second solid particle, wherein said second solid particle comprises an active agent and a second enteric coating, wherein the second enteric coating releases the active agent from the solid particle at a pH of about 6.2 to about 6.8 and further the said pharmaceutical composition is capable of being administered to a patient independent of the intake of food.

U.S. 2009/0162449 disclose stable oral benzimidazole compositions comprising; a) a benzimidazole core in the form of bead comprising a pharmaceutically acceptable inert carrier coated with one or more amorphous benzimidazole compounds and one or more pharmaceutically acceptable additives; b) a separating layer surrounding the core; and c) an enteric coating surrounding the separating layer, wherein the composition contains less than about 30% by weight of crystalline benzimidazole.

U.S. 2009/0208575 disclose a composition for oral use comprising: a) a core comprising acid-labile active substance and an organic stabilizing agent b) an intermediate layer comprising of a water insoluble polymer and an organic stabilizer c) an outer enteric coating layer, which further filled into a capsule.

U.S. 2009/0263475 discloses a solid premix for use in pharmaceutical formulations comprising (a) dexlansoprazole or pharmaceutically acceptable salts thereof and (b) a water-soluble excipient. The patent publication further discloses the premixes can be used directly or used in combination with additional excipients, to prepare desired pharmaceutical dosage forms.

WO 2010/117756 a process for preparing a pharmaceutical formulation, comprising: a) applying a layer of a powder, suspension, dispersion, or solution comprising dexlansoprazole or a salt thereof, at least one stabilizer, and one or more pharmaceutically acceptable excipients, onto inert particles, and drying; b) optionally, applying an intermediate coating; c) applying an enteric coating over particles of a) or an intermediate coating of b); d) mixing coated particles of c) and one or more pharmaceutically acceptable excipients, and e) forming the mixture of d) into a dosage form.

The above prior art references disclose various enteric coated preparations which are mainly in the form of granules, tablets or as a capsule filled with enteric coated granules. However, in case of granules it is required that the granules should be in uniform shape and size to result a satisfactory enteric and acid-resistant characteristics. Moreover, to meet such requirement, better techniques and a large quantity of an enteric coating material and varied coating conditions are used depending on the type of drug, granules shape and size to be required.

So many efforts have been taken to provide stable pharmaceutical composition of dexlansoprazole, which can overcome the above disadvantages. Surprisingly, the present inventors found that inert core comprising a hard gelatin capsule filled with an inert filler, when coated with drug layer, which is further coated with enteric polymers and separated by means of sub coating layer in between the core and the drug layer produces a stable pharmaceutical composition which is acid resistant and also at the same time having comparable in-vitro drug release as compared to commercially available DEXILANT®.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to stable pharmaceutical compositions of dexlansoprazole or its pharmaceutically acceptable salts thereof.

In particular, the invention relates to a stable pharmaceutical composition comprising dexlansoprazole or its pharmaceutically acceptable salts and an inert capsule shell, wherein the inert capsule shell is alternatively over-coated with multiple layers of dexlansoprazole or its pharmaceutically acceptable salts and an enteric polymer(s).

In particular, the invention relates to stable pharmaceutical compositions of dexlansoprazole comprising an inert capsule shell coated with multiple layers of drug and an enteric polymer(s), in such a way that the drug is released in two different time duration and pH zone of the gastrointestinal tract.

More particularly, the invention relates to stable pharmaceutical compositions of dexlansoprazole or its pharmaceutically acceptable salts comprising:

a. An inert capsule shell,

b. A first coating layer coated over the capsule shell, comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and
one or more pharmaceutically acceptable excipients;

c. A first enteric coating layer coated over the above first coating layer,
comprising an enteric polymer and one or more pharmaceutically acceptable excipients;

d. A second coating layer coated over the above first enteric coating layer, comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; and

e. A second enteric coating layer coated over the above second coating layer, comprising an enteric polymer and one or more pharmaceutically acceptable excipients.

The invention also relates to a process for preparing a stable pharmaceutical composition of dexlansoprazole comprising an inert capsule shell coated with multiple layers of drug and enteric layer, which are coated on the inert capsule shell alternatively.

Yet another objective of the invention is to provide stable pharmaceutical compositions comprising dexlansoprazole or its pharmaceutically acceptable salts thereof in such a way that it will comply with the reference product DEXILANT® in terms of in vitro parameters such as dissolution.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to stable pharmaceutical compositions comprising dexlansoprazole or its pharmaceutically acceptable salts thereof.

In particular, the invention relates to a stable pharmaceutical composition of dexlansoprazole or its pharmaceutically acceptable salts thereof, comprising an inert capsule shell, which is alternatively coated with multiple layers of above drug and enteric polymers.

In particular, the invention relates to stable pharmaceutical compositions of dexlansoprazole comprising an inert capsule shell, coated with multiple layers of drug and enteric polymers, in a way that the drug is released in two different time duration and pH zone of gastrointestinal tract.

In context of the invention, terms such as "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for dexlansoprazole or its pharmaceutically acceptable salts thereof.

"Stable" according to the invention implies that dexlansoprazole or its pharmaceutically acceptable salts in the composition, retains its potency within the range of 90% to 110% during shelf life storage. Further, stable according to invention also relate to the ability of the drug within the composition, to resist changes against both physical and chemical instability.

"Pharmaceutical composition" as described herein, includes dosage forms such as tablets, mini-tablets, layered tablets, coated tablets, capsules, coated capsule and the like.

The "inert capsule core" according to the invention includes empty hard capsule shell which is filled with suitable inert filler. The capsule shell can be made up of gelatin, hydroxypropylmethyl cellulose, pullulan or any other suitable material or mixtures thereof.

"Inert filler" according to the invention is selected from a group comprising microcrystalline cellulose, starch, sucrose, mannitol, dicalcium phosphate and the like or combinations thereof. More preferably, the filler used according to the invention is dicalcium phosphate.

Dicalcium phosphate used according to the invention mainly reduces the floating tendency of the empty capsule shell and also enhances the strength of the capsule to adopt a multilayer coating on the capsule shell without any breakage.

In an embodiment of the invention, the first drug layer comprises dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients such as binders, stabilizers, glidants and lubricants.

Binders used according to the invention are selected from a group comprising povidone, starch, methyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like or combinations thereof.

Stabilizers used according to invention are selected from a group comprising basic inorganic salts such as salt of sodium, potassium, calcium, magnesium which may be in the form of carbonate, bicarbonate, oxide and hydroxide. More preferably, the stabilizer used according to the invention is potassium hydroxide.

In an embodiment of the invention, the above drug coated capsule of the invention is further coated with first enteric coating layer which comprises enteric polymer and an inorganic pigment, among other excipients.

Enteric polymers used according to the invention are selected from a group comprising copolymer of methacrylic acid-methyl acrylate (1:1), (Eudragit®), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and hydroxymethylcellulose acetate succinate and the like or combinations thereof.

Inorganic pigments used according to the invention are selected from a group comprising talc, titanium oxide and ferric oxide.

Yet in another embodiment, Eudragit® used may be in the form of various grades such as Eudragit® E 100, Eudragit® FS, Eudragit® RL, Eudragit® L, Eudragit® S , Eudragit® L 100-55 and the like or combinations thereof. More preferably, the enteric polymers used according to the invention are Eudragit® L, Eudragit® S or Eudragit® L 100-55.

The first enteric coating layer according to the invention further comprises one or more pharmaceutically acceptable excipients such as plasticizers, surfactants and anti-tacking agents.

Plasticizers used according to the invention are selected from a group comprising polyethylene glycol (e.g. Macrogol 4000, Macrogol 6000), triethyl citrate, diethyl phthalate, dibutyl phthalate, cetyl alcohol, triacetin and the like or combinations thereof.

Surfactants used according to the invention are selected from a group comprising sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, Tween® and the like or combinations thereof.

Anti-tacking agents used according to the invention are selected from a group comprising talc, magnesium stearate, glyceryl monostearate, titanium dioxide and the like or combinations thereof.

In particular, the first enteric coating layer comprising enteric polymer(s), which have the property of releasing the drug in those part of the gastrointestinal tract wherein the pH is equal to or greater than about 6.

Further, the second drug coating layer over the first enteric coating layer; comprises dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients such as binders, stabilizers, glidants and lubricants which can be similar to that of first drug coating layer.

The second drug coating layer is further coated with a second enteric coating layer comprising an enteric polymer(s) and other pharmaceutically acceptable excipients similar to that of first enteric coated layer but differ in the type of enteric polymer used.

In particular, the second enteric coating layer comprising enteric polymer(s) have the property of releasing the drug in those parts of the intestine wherein the pH is about 5 to 6.

Preferably, the first enteric coating layer comprises enteric polymer such as Eudragit® L, Eudragit® S and the like or mixtures thereof and second enteric coating layer comprises Eudragit® L 100-55.

In another embodiment, the drug coating and enteric coating layers over the inert capsule core according to the invention are arranged in such a way that the drug layer and enteric layer may optionally be separated from each other by means of a sub-coat layer in between them which ultimately help in reducing any interaction between the drug and the enteric coating layer.

Sub-coat layers used according to invention comprises film-forming polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose or carboxymethylcellulose and optionally one or more pharmaceutically acceptable excipients such as plasticizer selected from a group comprising polyethylene glycol, polyvinyl alcohol, triethyl citrate, diethyl phthalate, dibutyl phthalate, cetyl alcohol, triacetin and the like or combinations thereof.

The coating according to the invention is applied by preparing a solution/ dispersion/ emulsion of the polymer(s) and optionally other excipients in solvents such as methanol, ethanol, isopropyl alcohol, water, acetone, dichloro methane and the like or combinations thereof, and spraying over the inert capsule core or sub-coated layers using conventional techniques, known to a person skilled in the art.

Yet in another embodiment, the amount of drug present in the composition is in the range of about 0.1-15% w/w in the first drug layer and about 0.1-5% w/w in the second drug layer relative to the total weight of the coated capsule.

Yet in another embodiment, the amount of drug present in the first and second drug layers may be in the ratio of about 95:5 or 5:95 or vice-versa. Preferably the ratio of drug within the two drug coating layers may be in the ratio of about 90:10 or 10:90 or vice-versa. More preferably, the ratio of drug within the two drug coating layers may be in the ratio of about 80:20 or 20:80 or vice-versa. Still more preferably, the ratio of drug within the two drug coating layers may be in the ratio of about 75:25 or 25:75 or vice-versa.

Yet in another embodiment, amount of first enteric coating layer is in the range of about 1-15% w/w and second enteric coating layer is in the range of about 1-15% w/w based on the total weight of the composition.

Yet in another embodiment, the drug coating and enteric coating layers over the inert capsule core according to the invention are arranged in such a way that the drug is released in two different time and in two different pH of small intestine such as one drug layer is released in the proximal part of the intestine whereas the another drug layer is subsequently released in the distal part of the intestine to provide an unique dual delayed release capsule.

The invention also provides a process for preparing a stable pharmaceutical composition of dexlansoprazole comprising inert capsule core coated with multiple layers of drug and enteric layer, which are coated on the said core alternatively, comprises the steps of:

a. Encapsulating inert filler in hard capsule shell to form an inert capsule core,
which is followed by optionally coating with a sub-coat layer I;

b. Coating the inert capsule core of step (a) with first coating layer comprising
drug, which is followed by optionally coating with a sub-coat layer II;

c. Coating the drug-coated capsule of step (b) with a first enteric coating layer,
which is followed by optionally coating with a sub-coat layer III;

d. Coating the enteric-coated capsule of step (c) with a second drug coating
layer, which is followed by optionally coating with a sub-coat layer IV;

e. Coating the drug-coated capsule of step (d) with a second enteric coating layer; and

f. Finally coating the enteric-coated capsule of step (e) with a film coat
comprising Opadry®.

As compared to conventional capsule preparations which mainly comprise capsules filled with enteric coated granules or drug-filled capsules coated with an enteric coating externally in the conventional manner, the enteric coated capsules obtained in accordance with the invention are superior in enteric and acid-resistant characteristics by providing subsequent release of the drug in the simulated intestinal fluid. Further, the quantities of the coating agent used can be reduced and the products obtained are of improved quality and cost effective.

The following examples illustrate 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.

Example 1

Ingredients mg/unit
Core
Dicalcium phosphate 575.00
Hard gelatin capsule shell 95.00
Sub-Coating I
Hydroxypropyl methyl cellulose 13.50
Polyethylene glycol 1.50
Drug Coat I
Dexlansoprazole 22.50
Methanol q.s.
Potassium hydroxide 5.13
Povidone 45.00
Sub-Coating II
Hydroxy propyl methyl cellulose 13.50
Polyethylene glycol 1.50
Enteric coating I
Eudragit S 14.06
Eudragit L 14.06
Talc 14.06
Triethyl citrate 2.82
Sub-Coating III
Hydroxypropyl methyl cellulose 13.50
Polyethylene glycol 1.50
Drug Coat II
Dexlansoprazole 7.50
Methanol q.s.
Potassium hydroxide 1.71
Povidone 15.00
Sub-Coating IV
Hydroxypropyl methyl cellulose 13.50
Polyethylene glycol 1.50
Enteric Coating II
Eudragit L-100 55 29.00
Macrogol 2.86
Titanium dioxide 2.86
Talc 8.97
Polysorbate 80 1.30
Total [core + coated layers] 916.83
Film coating
Opadry' 15.0
Dichloromethane and methanol q.s.
Total wt. 931.83

Brief Manufacturing Process:

1. Hard gelatin capsule shell was filled with dicalcium phosphate.

2. The sub-coating solution I was prepared by dissolving hydroxypropyl methyl cellulose and polyethylene glycol in a mixture of dichloromethane and methanol.

3. The filled capsule of step 1 was coated with sub-coating solution prepared in step 2.

4. The drug coating layer I was prepared by dissolving dexlansoprazole, potassium hydroxide and povidone in a solution of methanol.

5. The drug coating layer I prepared in step 4 was coated over the sub-coated capsule of step 3.

6. The sub-coating solution II was prepared by dissolving hydroxypropyl methyl cellulose and polyethylene glycol in a mixture of dichloromethane.

7. The sub-coating solution of step II of step 6 was coated over the drug coated capsule of step 5.

8. The enteric coating I was prepared by dissolving a mixture of Eudragit® S and L along with talc and triethyl citrate in mixture of ethanol and water in 9:1 mixture.

9. The enteric coating I prepared in step 8 was coated over the sub-coated capsule of step 7.

10. The sub-coating solution III was prepared by dissolving hydroxypropyl methyl cellulose and polyethylene glycol in a mixture of dichloromethane.

11. The sub-coating solution of step III of step 10 was coated over the enteric coated capsule of step 9.

12. The drug coating layer II was prepared by dissolving dexlansoprazole, potassium hydroxide and povidone in a solution of methanol.

13. The drug coating layer II prepared in step 12 was coated over the sub-coated capsule of step 11.

14. The sub-coating solution IV was prepared by dissolving hydroxypropyl methyl cellulose and polyethylene glycol in a mixture of dichloromethane.

15. The sub-coating solution of step 14 was coated over the drug coated capsule of step 13.

16. The enteric coating II was prepared by dissolving a mixture of Eudragit® L-100 55 along with macrogol, talc, titanium dioxide polysorbate in a mixture of ethanol and water which is present in the ratio of 9:1 and

17. Finally the enteric coated capsule of step 16 was coated with film coating composition.

Example 2

Ingredients mg/unit
Core
Dicalcium phosphate 575.00
Hard gelatin capsule shell 95.00
Sub-Coating I
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Drug Coat I
Dexlansoprazole 22.50
Methanol q.s.
Potassium hydroxide 5.13
Povidone 45.00
Sub-Coating II
Hydroxy Propyl methyl cellulose 13.50
Polyethylene Glycol 1.50
Enteric coating I
Eudragit S 28.12
Talc 14.06
Triethyl citrate 2.82
Sub-Coating III
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Drug Coat II
Dexlansoprazole 7.50
Methanol q.s.
Potassium hydroxide 1.71
Povidone 15.00
Sub-Coating IV
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Enteric Coating II
ISudragit L-10055 29.00
Macrogol 2.86
Titanium dioxide 2.86
Talc 8.97
Polysorbate 80 1.30
Total [core + coated layers] 916.83
Film coating
Opadry 15
Dichloromethane and methanol q.s.
Total wt. 931.83

Example 3

Ingredients mg/unit
Core
Dicalcium phosphate 575.00
Hard gelatin capsule shell 95.00
Sub-Coating I
Hydroxypropyl Cellulose 8.0
Drug Coat I
Dexlansoprazole 22.50
Methanol q.s.
Potassium hydroxide 5.13
Povidone 45.00
Sub-Coating II
Hydroxy Propyl Cellulose 8.0
Enteric coating I
Eudragjt S 14.06
Eudragit L 14.06
Talc 14.06
Triethyl citrate 2.82
Sub-Coating III
Hydroxypropyl Cellulose 8
Drug Coat II
Dexlansoprazole 7.50
Methanol 0.00
Potassium hydroxide 1.71
Povidone 15.00
Sub-Coating IV
Hydroxypropyl Cellulose 13.50
Enteric Coating II
Eudragit L-lOOSS 29.00
Macrogol 2.86
Titanium dioxide 2.86
Talc 8.97
Polysorbate 80 1.30
Total [core + coated layers] 894.33
Film coating
Opadry 15
Dichloromethane and methanol q.s.
Total wt. I 909.33

Example 4

Ingredients mg/unit
Core
Dicalcium phosphate 575.00
Hard gelatin capsule shell 95.00
Sub-Coating I
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Drug Coat I
Dexlansoprazole 22.50
Methanol q.s.
Potassium hydroxide 5.13
Povidone 45.00
Sub-Coating II
Hydroxy Propyl methyl cellulose 13.50
Polyethylene Glycol 1.50
Enteric coating I
1udragit S 20.0
Itatragif L 20.0
Talc 20.0
Triethyl citrate 4.0
Sub-Coating III
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Drug Coat II
Dexlansoprazole 7.50
Methanol 0.00
Potassium hydroxide 1.71
Povidone 15.00
Sub-Coating IV
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Enteric Coating II
EudragitL-10055 29.00
Macrogol 2.86
Titanium dioxide 2.86
Talc 8.97
Polysorbate 80 1.30
Total [core + coated layers] 935.83
Film coating
Opadry 15
Dichloromethane and methanol q.s.
Total wt. 950.83

Example 5

Ingredients mg/unit
Core
Dicalcium phosphate 575.00
Hard gelatin capsule shell 95.00
Sub-Coating I
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Drug Coat I
Dexlansoprazole 22.50
Methanol q.s.
Potassium hydroxide 5.13
Povidone 45.00
Sub-Coating II
Hydroxy Propyl methyl cellulose 13.50
Polyethylene Glycol 1.50
Enteric Coating I
Eudragrr S 40.0
Talc 20.0
Triethyl citrate 4.0
Sub-Coating III
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Drug Coat II
Dexlansoprazole 7.50
Methanol 0.00
Potassium hydroxide 1.71
Povidone 15.00
Sub-Coating IV
Hydroxypropyl Methyl Cellulose 13.50
Polyethylene Glycol 1.50
Enteric Coating II
Eudragit L-100 55 29.00
Macrogol 2.86
Titanium dioxide 2.86
Talc 8.97
Polysorbate 80 1.30
Total [core + coated layers] 935.83
Film coating
Opadry 15
Dichloromethane and methanol q.s.
Total wt. 950.83

The compositions given in Examples 2 to 5 were prepared using similar procedure as described in Example 1.

STABILITY DATA:

The capsules prepared according to Example-1 of the present invention were subjected to accelerated conditions [40°C/75% RH] for 12 weeks and parameters such as assay [potency], drug release [dissolution] and related substance [impurities] were analyzed.

Samples were analyzed by both HPLC and UV methods and the results are summarized in Table 1,2, 3 and 4.

Table-1

Assay (%) Initial 12 weeks 24 weeks
DEXILANT™ 102.4 - 100.5
Example-1 100.3 98.2 |
Table-2
Dissolution 1 DEXILANT™ I Example!
Acid release (0.1N HC1) Initial 24 weeks Initial 12 weeks
l_hr L5 11 2 3.1
Buffer release Initial 24 weeks Initial 12 weeks
(pH 7.2 Phosphate Buffer)
l0min 7.6 7.1 102 6.4
20min 8.8 10.6 21 16.5
30min 17.5 16.2 31.2 26
45min 48.5 42.1 60.5 58
60min 62.0 56.0 76.9 71
90min 76.7 71.2 80.8 76
120 min 86.3 | 82.3 | 83.6 | 82.1 ~

Table-3
Related Substance I DEXILANT™ I Example-1
Initial 24 weeks Initial 12 weeks
Highest Unknown impurities 0.01 0.041 0.06 0.07
Total impurities | 0.24 | 0.695 0.94 1 1.07
Table-4
Acid Resistant Test I DEXILANT™ I Example-1
[0.1N HC1] Initial [Assay] Initial [Assay]
2_hrs 98.04 98.34
4_hrs 96.50 94.50
6 hrs | 88.97 | 92.32

WE CLAIM:

1. A stable pharmaceutical composition comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and an inert capsule shell, wherein said inert capsule shell is alternatively over-coated with multiple layers of said dexlansoprazole or its pharmaceutically acceptable salts and an enteric polymer(s).

2. A stable pharmaceutical composition of dexlansoprazole or its pharmaceutically acceptable salts thereof, comprising:

i. An inert capsule shell;

ii. A first coating layer over said capsule shell, comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients;

iii. A first enteric coating layer over said first coating layer, comprising an enteric polymer(s) and one or more pharmaceutically acceptable excipients;

iv. A second coating layer over said first enteric coating layer, comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; and

v. A second enteric coating layer over said second coating layer, comprising an enteric polymer(s) and one or more pharmaceutically acceptable excipients.

3. A process for preparing a stable pharmaceutical composition of dexlansoprazole or its pharmaceutically acceptable salts comprising:

i. An inert capsule shell;

ii. A first coating layer over said capsule shell, comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients;

iii. A first enteric coating layer over said first coating layer, comprising an enteric polymer(s) and one or more pharmaceutically acceptable excipients;

iv. A second coating layer over said first enteric coating layer, comprising dexlansoprazole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; and

v. A second enteric coating layer over said second coating layer, comprising an enteric polymer(s) and one or more pharmaceutically acceptable excipients.

wherein said process comprises the steps of:

a. Encapsulating inert filler in hard capsule shell to form an inert capsule core, which is followed by optionally coating with a sub-coat layer I;

b. Coating the inert capsule core of step (a) with first coating layer comprising drug, which is followed by optionally coating with a sub-coat layer II;

c. Coating the drug-coated capsule of step (b) with a first enteric coating layer, which is followed by optionally coating with a sub-coat layer III;

d. Coating the enteric-coated capsule of step (c) with a second drug coating layer, which is followed by optionally coating with a sub-coat layer IV;

e. Coating the drug-coated capsule of step (d) with a second enteric coating layer; and

f. Finally coating the enteric-coated capsule of step (e) with a film coat comprising Opadry®.

4. The composition according to any of the preceding claims, wherein said shell is filled with suitable inert filler.

5. The filler according to claim 4, is selected from a group comprising microcrystalline cellulose, starch, sucrose, mannitol, dicalcium phosphate or combinations thereof.

6. The composition according to any of the preceding claims, further comprises one or more excipients selected from a group of binders, stabilizers, glidants lubricants, plasticizers, surfactants and anti-tacking agents or combinations thereof.

7. The composition according to claim 2 or 3, wherein the enteric polymer in said first enteric coating layer is selected from a group comprising Eudragit® L, Eudragit® S or combinations thereof.

8. The composition according to claim 2 or 3, wherein the enteric polymer in said second enteric coating layer is Eudragit® L 100-55.

9. The composition according to claim 2 or 3, wherein the amount of dexlansoprazole present in the first and second drug layers is in the ratio of about 95:5 or 5:95 or vice-versa.

10. The composition according to claim 2 or 3, wherein the amount of both first and second enteric coating layer is in the range of about l-15%w/w respectively, based on the total weight of the composition.