FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(SECTION 10 and rule 13)
"DEXLANSOPRAZOLE COMPOSITIONS"
Glenmark Generics Limited
An Indian Company, registered under the Indian company's Act 1957
having office at
Glenmark House,
HDO - Corporate Bldg,
Wing -A, B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION
AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF INVENTION:
(00011 The present invention relates to a delayed-release pharmaceutical composition, comprising a core consisting of dexlansoprazole or pharmaceutically acceptable salt thereof, and an enteric coat which dissolves in the pH range of 5.0 to 5.5.
BACKGROUND OF INVENTION:
[0002] Lansoprazole, also known as 2-[[[3-memyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl] benzimidazole, is a Proton Pump Inhibitor, sold commercially under the brand name PREVACID®. Lansoprazole is a racemic compound, that contains a R-enantiomer and a S-enantiomer.
[0003] The R-enantiomer of lansoprazole i.e. Dexlansoprazole is chemically known as (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfm- yl]-lH-benzimidazole. The R-enantiomer of lansoprazole, was first described in WO 1992008716.
[0004] U.S. Pat. Nos. 6,462,058 and 6,664,276 discloses various crystalline forms of dexlansoprazole. U.S. Pat. No. 7,790,755 discloses amorphous dexlansoprazole.
[0005] In United states, Takeda Pharmaceuticals North America, Inc. sells Dexlansoprazole as 30 mg and 60 mg dual delayed release capsules (brand name Dexilant®) for the treatment of erosive esophagitis and heartburn associated with non-erosive gastroesophageal reflux disease. Several patents assigned to Takeda, describes controlled and/or delayed release compositions comprising Dexlansoprazole. Out of aforesaid compositions patents, US patent 7,790,755 describes controlled release capsules comprising (i) granules containing dexlansoprazole, wherein the release of dexlansoprazole is controlled by polymeric substance which is soluble in the pH range of 6.0 to 7.5, (ii) granules containing dexlansoprazole and enteric coat that releases dexlansoprazole in the pH range of no less than 5.0 to no more than 6.0.
[0006] Another U.S. patent application 20090098199 describes method of treating a gastrointestinal disorder by administering a pharmaceutical composition comprising dexlansoprazole, wherein the action of dexlansoprazole is independent of the intake of food.

The pharmaceutical composition described in Patent application 199, comprises at least two solid particles comprising dexlansoprazole, wherein first solid particles are coated with enteric coating that releases dexlansoprazole at pH of about 5.0 to about 5.5 and second group of solid particles are coated with enteric coating that releases dexlansoparzole at pH of about 6.2 to about 6.8.
[0007] The present invention provides a delayed release composition comprising dexlansoprazole or pharmaceutically acceptable salt thereof, and an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
SUMMARY OF THE INVENTION:
[0008] The present invention provides a delayed release capsule comprising dexlansoprazole or pharmaceutically acceptable salt thereof, and an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
[0009] In one of the embodiments, the present invention provides a delayed release capsule, comprising
a) a core comprising of dexlansoprazole, alkaline agent and at least one pharmaceutically acceptable carrier
b) a subcoat.
c) about 0 to 50 % of the subcoated core, coated with enteric coat that dissolves in the pH range of about 5.0 to about 5.5
d) about 50 to 100% of the subcoated core, coated with water insoluble and/ or water soluble polymer followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
[0010] However in a preferred embodiments, the present invention provides a delayed release capsule, comprising
a) a core comprising of dexlansoprazole, alkaline agent and at least one pharmaceutically acceptable carrier
b) a subcoat.

c) about 20-40 % of the subcoated core, coated with enteric coat that dissolves in the pH range of about 5.0 to about 5.5
d) about 60-80% of the subcoated core, coated with water insoluble and/ or water soluble polymer followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
DETAILED DESCRIPTION OF INVENTION:
[0011] A "delayed release composition" of present invention is a composition coated with enteric polymer that dissolves in the pH range of 5.0 to 5.5.
[0012] The active ingredient of present invention is R-enantiomer of lansoprazole i.e. Dexlansoprazole, chemically known as (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy) pyridrn-2-yl]methyl}sulfin- yl]-lH-benzimidazole or pharmaceutically acceptable salt thereof. However a Dexlansoprazole base is more preferred for the purpose of present invention. The dexlansoprazole of the present invention may be amorphous, crystalline or a solvate such as dexlansoprazole monohydrate isobutanol solvate, but amorphous form of dexlansoprazole is more preferred.
[0013] The "core" of the present invention is preferably a spherical granules or pellets comprising Dexlansoprazole or pharmaceutically acceptable salt thereof, alkaline agent and atleast one pharmaceutically acceptable carrier. In the preferred aspect, the core of present invention comprises Dexlansoprazole, pharmaceutically acceptable salt thereof, coated upon an inert solid support, such as sugar spheres or cellulose spheres and the like, using the technique such as powder layering, solution spraying, or suspension spraying. Alternatively, the core of present invention can also be produced by using an extruder and spheronizer, to obtain the small spherical pellets comprising Dexlansoprazole or pharmaceutically acceptable salt thereof, atleast one alkaline agent and a pharmaceutically acceptable carrier.
[0014] The core of the present invention is coated with a subcoat, comprising a water soluble film forming polymers.

[0015] In a preferred embodiment, present invention provides a delayed release capsule of comprising; a core containing dexlansoprazole or pharmaceutically acceptable salt thereof, alkaline agent and at least one pharmaceutically acceptable carrier, a subcoat of water soluble film forming polymers; wherein about 0 to 50 % of the subcoated core, is coated with an enteric coat that dissolves in the pH range of about 5.0 to about 5.5 and about 50 to 100% of the subcoated core, is coated with water insoluble polymer, water soluble film forming polymer and plasticizer; followed by the coating comprising an enteric polymer that dissolves in the pH range of 5.0 to 5.5.
[0016] In a still preferred embodiment, the present invention provides a delayed release capsule comprising a core containing dexlansoprazole or pharmaceutically acceptable salt thereof, alkaline agent and at least one pharmaceutically acceptable carrier, a subcoat of water soluble film forming polymers; wherein about 20 to 40 % of the subcoated core, is coated with an enteric coat that dissolves in the pH range of about 5.0 to about 5.5 and about 60 to 80% of the subcoated core, is coated with water insoluble polymer, water soluble film forming polymer, and plasticizer; followed by the coating comprising an enteric polymer that dissolves in the pH range of 5.0 to 5.5
[0017] The present invention also provides a process for the preparation of an delayed release capsule composition that comprises a) layering of dexlansoprazole, alkaline agent with the aid of binder on the inert solid support, b) applying sub coat and c) coating about 0 to 50 % of the subcoated core, with an enteric coat that dissolves in the pH range of about 5.0 to about 5.5 and coating about 50 to 100% of total subcoated core, with water insoluble polymer, water soluble film forming polymer, and plasticizer; followed by coating an additional coat comprising an enteric polymer that dissolves in the pH range of 5.0 to 5.5 f) mixing the enteric coated cores with lubricant and g) filling into the capsule of suitable capsule size such as 3,1,0 or 00.
[0018] Preferably the core of present invention is produced by coating, a mixture consisting of a dexlansoprazole, at least one alkaline agent, upon the inert sugar spheres, followed by the sub coat layer over the dexlansoprazole layer. Subsequently about 0 to 50 % of the sub coated core, is coated with an enteric coat that dissolves in the pH range of about 5.0 to about 5.5 and about 50 to 100% of the sub coated core, is coated with mixture comprising

water insoluble polymer, water soluble film forming polymer and plasticizer, followed by an additional enteric coat that dissolves in the pH range of about 5.0 to about 5.5, such that the quantity of dexlansoprazole is less than about 20% by weight, preferably less than 12 % by weight, based on total weight of enteric coated cores.
[0019] In one of the aspects of the present invention, the polymorphic form of dexloansoprazole thus used in preparation of delayed release capsules, doesn't convert to another polymorph during the course of normal shelf life.
[0020] The alkaline agent used in the present invention includes are basic inorganic salts
of magnesium, calcium, potassium and sodium. Such as basic inorganic salts of potassium are
potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like.
Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium
carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate,
magnesium silicate, magnesium aluminate, synthetic hydrotalcite
[Mg.sub.6Al.sub.2(OH).sub.l6.CO.sub.3.4H.sub.20], and aluminum hydroxide-magnesium oxide [2.5MgO.Al.sub.20.sub.3.xH.sub.20], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide and the like.
[0021] Inert solid support, thus mentioned in the current specification, includes the sugar spheres such as "Pharma-a- spheres" 25-30 mesh or 30-35 mesh ASTM, NONPAREIL (NONPAREIL-101 (particle diameter: 850-710, 710-500, and 500-355 micron), NONPAREIL-103 (particle diameter: 850-710, 710-500, and 500-355 microti), NONPAREIL-105 (particle diameter: 710-500, 500-355 and 300-180 micron); manufactured by Freund Industrial Co., Ltd.) and Celphere (CP-507 (particle diameter: 500-710 micron), and CP-305 (particle diameter: 300-500 micron); manufactured by Asahi Kasei Corporation are used in the present invention to load the Dexlansoprazole dispersed in the solvent system with the aid of solubilizer, binder and disintegrating agents.
[0022] In a preferred embodiment, the core containing dexlansoprazole is coated to provide a sub coating layer upon dexlansoprazole layer. Although it is not essential, but preferable from the viewpoint of improving the stability of dexlnasoprazole, to have a sub-

coating layer to intercept the direct contact of dexlaasoprazole containing core particles with the enteric coating-layer.
[0023] The coating materials for the sub coating layer include those obtained by appropriately compounding polymeric materials such as low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (for example, (Methocel™ E 3 LV, E 5 LV, E 6 LV, E 10 LV, E 15 LV available from Dow Chemical, Midland and the like), polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and hydroxyethyl methylcellulose with antistatic agents (titanium oxide, talc and the like). The coating can be carried out by conventional methods. For example, preferably, the components of the sub coating layer are diluted with purified water and sprayed to coat in liquid form.
[0024] About 0 to 50 % of the sub coated core, coated with enteric coat that dissolves in the pH range of about 5.0 to about 5.5 and about 50 to 100% of the sub coated core, coated with water insoluble polymer, water soluble film forming polymer and plasticizer; followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
[0025] For the purpose of present invention "enteric coat" is applied directly on dexlansoprazole layer or on the sub coated layer that encapsulates the dexlansoprazole layer. "Enteric polymers" as used in the present invention are the polymer which dissolves in the pH range of 5.0 to 5.5.
[0026] The enteric coating layer of present invention are obtained by using the enteric polymer selected from the class comprising of but not limited to, hydroxypropyl methylcellulose phthalate (HP-55, HP-50 manufactured by Shin-Etsu Chemical Co., Ltd.), methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55 (dried methacrylic acid copolymer LD), Eudragit L30D-55 (methacrylic acid copolymer LD); manufactured by Rohm Co.), polyvinyl acetate phthalate, cellulose acetate Phthalate, hydroxypropyl methylcellulose succinate. Preferred enteric coating polymer can be selected from either hydroxypropylmethylcellulose phthalate (HP55) or Eudragit(R) L30D-55. The enteric polymers of present invention are then mixed with plasticizers such as a polyethylene glycol, dibutyl sebacate, diethyl phthalate, triacetin and triethyl citrate, stabilizers and antistatic

agents/opacifier like titanium oxide, talc and the like. The coating can be carried out by conventional methods. For example, preferably, the components of the enteric coat layer are mixed in the purified water or alcohol or hydro- alcoholic solvent and the mixture thus obtained is sprayed on the core. Alternatively, few enteric polymers, such Eudragit L30D-55, is available as 30% dispersion in purified water along with emulsifying agents such as Sodium Lauryl Sulfate, Polysorbate 80 and the like, which can be added, if desired, with the suitable plasticizer and antistatic agent/ opacifier, and can be used as an enteric coat.
[0027] For the purpose of present invention the water insoluble sustained release polymer used are such as cellulose ether, such as ethylcellulose, cellulose esters, such as cellulose acetate, polyvinylalcohol, etc. The preferred film-forming polymer is ethylcellulose (available from Dow Chemical under the trade name Ethocel™ 4 cps, Ethocel™ 7 cps, Ethocel™ 10 cps, Ethocel™ 20 cps, Ethocel™ 45 cps, Ethocel™ 100 cps), ethyl cellulose pseudolatex (such as Surelease® as supplied by 10 Colorcon, West Point, Pa. or Aquacoat™. as supplied by FMC Corporation, Philadelphia, Pa. The water-soluble polymer is preferably hydroxypropyl methylcellulose (HPMC) (Methocel™ E 3 LV, E 5 LV, E 6 LV, E 10 LV, E 15 LV available from Dow Chemical, Midland) or polyvinylpyrrolidone. The plasticizer can be an ester such as a citrate ester such as Triethyl Citrate, oil such as castor oil, a polyalkyleneglycol such as polyethyleneglycol of various MWs. The preferred plasticizer is Triethyl Citrate. Some other excipients can be used in the coating such as stabilizers and antistatic agents (titanium oxide, talc and the like). The coating can be carried out by conventional methods. For example, preferably, the water insoluble polymer, plasticizer and water-soluble polymer film forming polymer are diluted with purified water or alcohol or hydro- alcoholic solvent or and sprayed to coat in liquid form. The sustained release coating layer comprises a mixture of at least one water-insoluble polymer and at least one water-soluble polymer in a weight ratio to each other of within the range of from about 1:4 to about 4:1.
[0028] Dexlansoprazole solution prepared for layering on the inert solid support contains excipients like, stabilizers, solubilizers, binder and disintegrating agents.
[0029] Apart from the alkaline agents mentioned earlier, the stabilizers useful in present invention are the Organic bases that may be used in the present invention are pharmaceutically

acceptable organic bases, including, without limitation thereto, meglumine, lysine, N,N'-dibenzylethylenediamine, chloroprocain, choline, diethanolamine, ethylenediamine, procaine. Buffers like citrate, phosphate or tris (hydroxymethyl) amino methane and mixtures of any two or more thereof.
[0030] The solubilizers useful in present invention include, for example, sodium lauryl sulphate, polysorbates, decussate sodium, benzalkonium chloride, benzethonium chloride, cetrimide, polyvinyl alcohol, saccharides such as sucrose (fine grade Sugars), fructose, lactose, mannitol and the like and mixtures thereof.
[0031] Suitable binders include, for example, polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose (Methocel™ E 3 LV, E 5 LV, E 6 LV, E 10 LV, E 15 LV), hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate.
[0032] Suitable disintegrating agents include Low substituted Hydroxypropyl cellulose (L-HPC LH 31), croscarmellose sodium (e.g. Ac Di Sol.TM., Primellose.TM.), crospovidone (e.g. KollidonTM, PolyplasdoneTM), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. ExplotabTM, PrimoljelTM.) and starch. Preferred disintegrant include Low substituted Hydroxypropyl cellulose (L-HPC LH 31).
[0033] The coating is applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and 1,1,1-trichloroethane.
[0034] As mentioned lubricants used in the present invention are selected from stearic acid, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, talc and colloidal silicon dioxide or mixtures thereof.

[0035] In an embodiment, present invention provides a delayed release capsule of comprising; a core containing dexlansoprazole less than about 20% by weight, preferably less than 12 % by weight, based on the total weight of the enteric coated cores before filling in the capsule, wherein an alkaline agent used to stabilize dexlansoprazole is from about 5 to 25 % by weight, and most preferably from about 8 to 20 % by weight based on the total weight of the core. The Said core is further coated with a subcoat of water soluble film forming polymer, wherein total weight build up of subcoat layer is from about 5 to 40 % by weight, preferably from about 10 to 30 % by weight and most preferably from about 15 to 25 % by weight, based on the total weight of the core.
[0036] About 0 to 50 % of the above subcoated core, is coated with an enteric coating that dissolves in the pH range of about 5.0 to about 5.5; wherein total weight build up of enteric coat layer is from about 10 to 60 % by weight, preferably from about 15 to 50 % by weight and most preferably from about 20 to 40 % by weight based on the total weight of the sub coated core.
[0037] About 50 to 100% of the above subcoated core, is coated with sustained release layer comprising water insoluble and water soluble polymers, wherein total weight build up of the sustained release layer is from about 1.0 to 50 % by weight, preferably from about 2.0 to 40 % by weight and most preferably from about 2.5 to 30 % by weight based on the total weight of the sub coated core. Said sustained release layer coated core is further coated with an enteric coating that dissolves in the pH range of about 5.0 to about 5.5, wherein total weight build up of enteric coat layer is from about 10 to 60 % by weight, preferably from about 15 to 50 % by weight and most preferably from about 20 to 40 % by weight based on the total weight of sustained release coated core.
[0038] In a preferred embodiment, present invention provides a delayed release capsule of comprising; a core containing dexlansoprazole is less than 12 % by weight based on the total weight of enteric coated cores before filing in the capsule, wherein an alkaline agent used to stabilize dexlansoprazole is from about 8 to 20 % by weight based on the total weight of the core. The said core is further coated with a subcoat of water soluble film forming polymer,

wherein total weight build of subcoat layer is from about 15 to 25 % by weight based on the total weight of the core.
[0039] About 0 to 50 % of the above sub coated core, is then coated with an enteric coating that dissolves in the pH range of about 5.0 to about 5.5; wherein total weight build up of enteric coat layer is from about 20 to 40 % by weight based on the total weight of the subcoated core and about 50 to 100% of the subcoated core, is then coated with sustained release layer comprising water insoluble and water soluble polymers, wherein total weight build of the sustained release layer is from about 1.5 to 30 % by weight based on the total weight of the sub coated core. Said sustained release layer coated core further coated with an enteric coating that dissolves in the pH range of about 5.0 to about 5.5, wherein total weight build up of enteric coat layer is from about 20 to 40 % by weight based on the total weight of the sustained release coated core.
[0040] As mentioned in this specification and wherever applicable the term "sustained release" or "sustained release layer" is used to describe the coating composition comprising water insoluble polymer, water soluble film forming polymer and plasticizer along with other excipients. In particular the coating applied on 50 to 100% of the subcoated core comprising water insoluble polymer, water soluble film forming polymer and plasticizer along with other excipients is termed as sustained release layer.
[0041] The term "enteric coated core" used herein, describe the final composition comprising, about 0 to 50 % of the subcoated core, coated with an enteric coating that dissolves in the pH range of about 5.0 to about 5.5 and about 50 to 100% of the subcoated core, first coated with sustained release coat followed by an enteric coating that dissolves in the pH range of about 5.0 to about 5.
[0042] In one of the aspects, the present invention relates to a method of treating a
gastrointestinal disorder in a patient in need of the treatment thereof. The method comprises
the
administering capsule composition of dexlansoprazole which comprises dexlansoprazole
containing cores of about 0 to 50 %, preferably about 20-40 %, coated with enteric coat that
dissolves in the pH range of about 5.0 to about 5.5 and about 50 to 100%, preferably about 60-

80% by weight of dexlansoprazole containing cores, coated with water insoluble and/ or water soluble polymer followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
[0043] Typically the dexlansoprazole or pharmaceutically acceptable salt thereof will be present in the capsule composition of present invention are in an amount within rang of from about 15 mg to about 120 mg. preferably from about 30 mg to about 90 mg.
J0044] The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined.
[0045] Example I: A) Core: comprising dexlansoprazole (14.5 % by weight based on the total weight of the enteric coated core before filling in the capsule) & Magnesium carbonate B) coated with a subcoat of Methocel™ E 3 LV. C) 50% of the core coated with enteric coat enteric coat of Eudragit® L30D55 D) 50% of the core coated with Ethyl cellulose (Ethocel™ 4 cps) and Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV) (SR coat), followed by E) an enteric coat of Eudragit® L30D55.

Table 1
S.No Ingredients Function 30 MG
(mg/cap) 60 MG
(mg/cap)
A Dexlansoprazole loading
1 Dexlansoprazole ( Amorphous) Active 30 60
2 Light Magnesium carbonate Stabilizer 20 40
3 Tris buffer [ tris (hydroxymethyl) amino methane) Stabilizer 5 ' 10
4 Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV) Binder 10 20
5 Sugar Solubiliser 7.5 15
6 Low substituted Hydroxypropyl cellulose (L-HPCLH 31) Disintegrant 10 20
7 Sugar Sphere (30-35 mesh) Base 50 100
8 Purified Water: Ethanol (55 : 45) Solvent Q.S. Q.S.
Core pellet weight (mg) - 132.5 265.0
B Subcoating :
Dexlansoprazole loaded pellets 132.5 265.0

9 Hydroxypronyl Methyl Cellulose (Methocel™E3 LV) Film former 20.39 40.77
10 Talc Anti adherent 3.06 6.12
11 Titanium Dioxide Pigment 3.06 6.12
12 Purified Water $ Solvent QS QS
Wt of subcoated pellet (mg) - 159.0 318.0
C Enteric Coating-I (EC-I) : on 50% Sub Coated Dellets
Wt. of Sub coated pellets 79.5 159
13 Methacrylic Acid Copolymer Dispersion (Eudragit® L30D 55) Enteric polymer 19.87 39.74
14 Triethyl Citrate Plasticizer 1.99 3.98
15 Talc Anti adherent 1.99 3.98
16 Purified Water$ Solvent Q.S. Q.S.
Wt of EC-I coated pellets (mg) 103.35 206.70
D Sustained Release Coating (SR Coat): on 50 % of Sub coated pellets
Sub coated pellets 79.5 159
17 Ethyl cellulose (Ethocel™ 4 cps) Release controlling agent 0.76 1.52
18 Hydroxypropyl Methyl Cellulose (Methocel™E3 LV) Film Former 1.77 3.54
19 Triethyl Citrate Plasticizer 0.25 0.5
20 IPA : MDC (50 : 50) $ Solvent Q.S. Q.S.
Wt of SR coated pellets 82.28 164.57
E Enteric Coating - II (EC-II) : on SR Coated pell ets
SR coated pellets 82.28 164.57
21 Methacrylic Acid Copolymer Dispersion (Eudragit® L30D55) Enteric polymer 20.56 4L14
22 Triethyl Citrate Plasticizer 2.06 4.11
23 Talc Anti adherent 2.06 4.11
24 Purified Water $ Solvent Q.S. Q.S.
Wt of EC-II coated pellets (mg) 106.96 213.94
F Lubrication of EC coated pellets
25 EC Coated pellets I 103.35 206.70
26 EC Coated pellets II 106.96 213.94
27 Talc Lubricant 0.21 0.42
28 Colloidal silicon dioxide Lubricant 0.21 0.42
Wt of lubricated EC-I coated pellets (mg) 210.73 421.48

[0046] Manufacturing Process
A) DEXLANSOPRAZOLE LOADING
1. Dexlansoprazole dispersion was prepared by dissolving Sugar, Tris buffer & Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV) and Dispersing L-HPC-LH 31 followed by Light Magnesium carbonate & Dexlansoprazole in Water: Ethanol mixture under stirring.
2. Sugar spheres (30-35 mesh) loaded in to Fluid Bed Processor such as a GPCG-1.1 (available from Glatt Air Techniques, Inc. of Ramsey, N.J.), bottom spray assembly.
3. Dexlansoprazole dispersion of step 1 Sprayed on to the Sugar spheres.
4. The Dexlansoprazole loaded pellets were dried for 50-60 min in Fluid Bed Processor at 40° C
B) Sub Coat
1. The sub coat solution prepared by dissolving Hydroxypropyl Methyl Cellulose (Methocel™ E3LV) in purified water followed by Dispersing Talc & Titanium Dioxide (Ti02) under stirring.
2. Sub coat dispersion of step 1 sprayed on to the Dexlansoprazole loaded pellets using Fluid Bed Processor such as a GPCG-1.1 bottom spry assembly.
3. The Sub coated pellets are then dried for 20-30 min in Fluid Bed Processor at 40° C
4. The sub coated pellets are then divided into 50% and 50% lots for further coating.
C) Enteric Coat on 50% of sub coated pellets (EC-I)
1. Enteric coat solution was prepared by dispersing Eudragit® L 30 D 55, Triethyl Citrate & Talc in purified water under stirring.
2. Enteric coat solution of stepl was sprayed on to the Sub coated pellets using Fluid Bed Processor such as a GPCG-1.1 bottom spry assembly.
3. The enteric coated pellets are then dried for 20-30 min in Fluid Bed Processor at 40° C
D) Sustained release (SR) Coat on 50% of sub coated pellets
1. Sustained release coating solution was prepared by dissolving Ethyl cellulose (Ethocel™ 4 cps), Hydroxypropyl Methyl Cellulose (MethocelT™ E 3 LV) and triethyl citrate in MDC (Dichloromethane) under continuous stirring followed by addition of isopropyl alcohol.

2. Sustained release coat solution prepared of step 1 Sprayed on sub coated pellet using Fluid Bed Processor such as a GPCG-1.1 bottom spry assembly.
3. Sustained release coated pellet are then dried for 20-30 min in Fluid Bed Processor at 40° C
E) Enteric Coat on SR Coated Pellets (EC-II)
1. Enteric coat solution was prepared by dispersing Eudragit® L30D55, Triethyl Citrate &
Talc in purified water under stirring.
2. Enteric coat solution of step 1 was sprayed on to the SR coated pellets using Fluid Bed
Processor such as a GPCG-1.1 bottom spry assembly.
3. The enteric coated pellets are then dried for 20-30 min in Fluid Bed Processor at 40° C
F Lubrication of enteric coated pellets
1. Enteric coated pellets of step C and E are mixed with Talc & Colloidal silicon dioxide, in double cone blender for 2-3 min at 12 rpm.
2. The lubricated pellets of step 1 are then filled into hard gelatin capsule.
[0047] Dexlansoprazole used in the example I is in a substantially amorphous form, wherein said form is substantially retained during the manufacturing of the composition and also during storage for at least 3 months period.
[0048] Example II: A) Core: comprising dexlansoprazole (10 % by weight based on the total weight of the enteric coated cores before filling in the capsule) & Magnesium carbonate B) coated with a subcoat of Methoce™ E3LV. C) 50% of the core coated with enteric coat enteric coat of Eudragit® L30D55 D) 50% of the core coated with Ethyl cellulose (Ethoce™ 4 cps) and Hydroxypropyl Methyl Cellulose (Methoce™ E 3 LV) (SR coat), followed by E) an enteric coat of Eudragit® L30D55

Table 2
S.No Ingredients Function 30 MG
(mg/cap) 60 MG
(mg/cap)
A Dexlansoprazole loading
1 Dexlansoprazole (Amorphous) Active 30 60
2 Light Magnesium carbonate Stabilizer 20 40
3 Meglumine Stabilizer 10.5 21
4 Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV) Binder 10 20

5 Polysorbate 80 Solubiliser 3.7 7.4
6 Low substituted Hydroxypropyl cellulose (L-HPCLH 31) Disintegrant 10 20
7 Sugar Sphere (25 -30 #) Base 100 200
8 Purified Water : Ethanol (10 : 90) $ Solvent Q.S. Q.S.
Core pellet weight (mg) - 184.2 368.40
B Sub Coating :
Dexlansoprazole loaded pellets 184.2 368.40
9 Hydroxypropyl Methyl Cellulose (MethoceltmESLV) Film former 27.57 55.14
10 Meglumine Stabilizer /Alkalizer 1.00 2.00
11 Talc Anti adherent 4.14 8.27
12 Titanium Dioxide Pigment 4.14 8.27
13 Purified Water $ Solvent QS QS
Wt of sub coated pellet (mg) - 221.04 442.08
C Enteric Coating -1 (EC-I) : on 50% Subcoated pell ets
Wt. of Sub coated pellets 110.52 221.04
14 Methacrylic Acid Copolymer Dispersion (Eudragit® L30D 55) Release controlling agent 27.63 55.26
15 Triethyl Citrate Plasticizer 2.76 5.53
16 Talc Anti adherent 2.76 5.53
17 Purified Water $ Solvent Q.S. Q.S.
Wt of EC-I coated pellets (mg) 143.68 287.35
D Sustained Release Coating (SR C oat) : on 50 % of Sub coated pel ets
Sub coated pellets 110.52 221.04
18 Ethyl cellulose (Ethocel™ 4 cps) Release controlling agent 6.03 12.06
19 Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV) Film Former 14.07 28.13
20 Triethyl Citrate Plasticizer 2.01 4.02
21 IPA : MDC (50 : 50) $ Solvent Q.S. Q.S.
Wt. of SR coated pellets 132.62 265.25
E Enteric Coating-II (EC-II) : on SR Coated pellets
SR coated pellets 132.62 265.25
22 Methacrylic Acid Copolymer Dispersion (Eudragit® L30D55) Release controlling agent 33.16 66.31
23 Triethyl Citrate Plasticizer 3.32 6.63
24 Talc Anti adherent 3.32 6.63
25 Purified Water $ Solvent Q.S. Q.S.
Wt. of EC-II coated pellets
(mg) 172.41 344.83

F Lubrication of EC coated pellets
26 EC Coated pellets I 143.68 287.35
27 EC Coated pellets II 172.41 344.83
28 Talc Lubricant 032 0.63
29 Colloidal silicon dioxide Lubricant 0.32 0.63
Wt. of lubricated EC-I coated pellets (mg) 316.73 633.44
[0049] Manufacturing Process
A) DEXLANSOPRAZOLE LOADING
5. Dexlansoprazole dispersion was prepared by dissolving Meglumine, Polysorbate 80 & Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV) and Dispersing L-HPC-LH 31 followed by Light Magnesium carbonate & Dexlansoprazole in Water: Ethanol mixture under stirring.
6. Sugar spheres (25-30 mesh) were loaded in to Fluid Bed Processor such as a GPCG-1.1 (available from Glatt Air Techniques, Inc. of Ramsey, N.J.), bottom spray assembly.
7. Dexlansoprazole dispersion of step 1 was sprayed on to the Sugar spheres.
8. The Dexlansoprazole loaded pellets were dried for 50-60 min in Fluid Bed Processor at 40° C
B) Subcoat
5. The sub coat solution prepared by dissolving Hydroxypropyl Methyl Cellulose (Methocel™ E 3 LV), Meglumine in purified water followed by Dispersing Talc & Titanium Dioxide (Ti02) under stirring.
6. Sub coat dispersion of step 1 was sprayed on to the Dexlansoprazole loaded pellets using Fluid Bed Processor such as a GPCG-1.1 bottom spry assembly.
7. The Sub coated pellets are then dried for 20-30 min in Fluid Bed Processor at 40° C
8. The sub coated pellets are divided in 50% and 50% lots for further coating.
C) Enteric Coat on 50% of subcoated pellets (EC-I)
4. Enteric coat solution was prepared by dispersing Eudragit® L30D55, Triethyl Citrate & Talc in purified water under stirring.
5. Enteric coat solution of stepl was sprayed on to the Subcoated pellets using Fluid Bed Processor such as a GPCG-1.1 bottom spry assembly.
6. the enteric coated pellets are then dried for 20-30 min in Fluid Bed Processor at 40° C

D) Sustained release Coat on 50% of subcoated pellets
4. Sustained release coat solution was prepared by dissolving Ethyl cellulose (Ethocel 4 cps), Hydroxypropyl Methyl Cellulose (Methocel™ E3LV) and triethyl citrate in MDC (Dichloromethane) under continuous stirring followed by addition of isopropyl alcohol.
5. Sustained release coat solution prepared of step 1 Sprayed on sub coated pellet using Fluid Bed Processor such as a GPCG-1.1 bottom spry assembly.
6. Sustained release coated pellet are then dried for 20-30 min in Fluid Bed Processor at 40° C
E) Enteric Coat on SR Coated Pellets (EC-II)
1. Enteric coat solution was prepared by dispersing Eudragit® L 30 D 55, Triethyl Citrate & Talc in purified water under stirring.
4. Enteric coat solution of step 1 was sprayed on to the SR coated pellets using Fluid Bed
Processor such as a GPCG-1.1 bottom spry assembly.
5. The enteric coated pellets are then dried for 20-30 min in Fluid Bed Processor at 40° C
F Lubrication of enteric coated pellets
3. Enteric coated pellets of step C and E are mixed with Talc & Colloidal silicon dioxide, in double cone blender for 2-3 min at 12 rpm.
4. The lubricated pellets of step 1 are then filled into hard gelatin capsule.

Clams,
1. A delayed release capsule, comprising
e) a core comprising of dexlansoprazole, alkaline agent and at least one pharmaceutically acceptable carrier
f) a subcoat.
g) about 0 to 50 % of the subcoated core, coated with enteric coat that dissolves in the pH range of about 5.0 to about 5.5
h) about 50 to 100% of the subcoated core, coated with water insoluble and/ or water soluble polymer followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
2. The subcoat of claim 1 comprises a polymer selected from low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and hydroxyethyl methylcellulose.
3. The water insoluble polymer of claim 1 is selected from ethylcellulose, cellulose acetate and polyvinylalcohol.
4. The enteric coat polymer of claim 1 is selected from hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, polyvinyl acetate phthalate, cellulose acetate Phthalate and hydroxypropyl methylcellulose
succinate.
5. A delayed release capsule, comprising
e) a core comprising of dexlansoprazole, alkaline agent and at least one
pharmaceutically acceptable carrier
f) a subcoat.
g) about 20-40 % of the subcoated core, coated with enteric coat that dissolves in the
pH range of about 5.0 to about 5.5

h) about 60-80% of the subcoated core, coated with water insoluble and/ or water soluble polymer followed by an enteric coat that dissolves in the pH range of about 5.0 to about 5.5.
6. The subcoat of claim 5 comprises a polymer selected from low substituted hydroxypropyl cellulose., hydroxypropyl cellulose, hydroxypropyl methylcellulose polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and hydroxyethyl methylcellulose.
7. The water insoluble polymer of claim 5 is selected from ethylcellulose, cellulose acetate and polyvinylalcohol.
8. The enteric coat polymer of claim 5 is selected from hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, polyvinyl acetate phthalate, cellulose acetate Phthalate and hydroxypropyl methylcellulose succinate.