FIELD OF INVENTION

The present invention relates to oral pharmaceutical compositions comprising proton pump inhibitors or its pharmaceutically acceptable salts, enantiomers, solvates/hydrates, and mixtures thereof.

More particularly, the present invention relates to pharmaceutical compositions comprising at least one proton pump inhibitor, that is designed such that a core containing proton pump inhibitor is coated with modified semi-permeable membrane, which loses its semi-permeable characteristics on exposure to aqueous environment irrespective to the change in pH and allows the drug passage across the coating by diffusion, though maintaining the physical integrity of coating.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Esophagitis is a term used to indicate any inflammation, swelling, or irritation of the esophagus. Refluxed stomach contents into the esophagus are the most common cause of esophagitis. The most common condition that causes reflux is gastro-esophageal reflux disease. Other causes of reflux include pregnancy, obesity, smoking, alcohol, and caffeinated beverages, fatty or spicy foods.

Proton pump inhibitors (PPIs) act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly gastric proton pump) of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.

Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of R- and S-enantiomers). Chemically it is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl] methyl) sulflnyl]-lH-benzimidazole, having the structure (I) as presented below; which is indicated for healing of all grades of erosive esophagitis for up to 8 weeks, maintenance of healed erosive esophagitis for up to 6 months and for the treatment of heartburn with non-erosive gastro-esophageal reflux disease for 4 weeks.

PPIs being acid-labile, a majority of the formulation approaches in the art to date have focused on designing a dosage form that protects the PPI from acid degradation. Hence, enteric-coated systems that protect the PPI from acid degradation and triggering the release of drug in alkaline pH have become an integral part of PPI dosage form. Further an intermediate layer also has therefore become necessary to avoid the acidic moieties of enteric coating polymer from coming in contact with PPI which is critical for shelf-life stability of enteric based formulation.

Treatment of erosive esophagitis, non-erosive gastro-esophageal reflux disease and the likes require multiple doses of immediate-re lease dosage form every day which is inconvenient and leads to reduced patient compliance. These conditions may be effectively treated by maintaining the plasma levels of the active moiety for sufficient time. This can be achieved by designing a dosage form comprising PPIs which sustains the drug releases over period of time.

PPIs though being effective in treating the above mentioned gastric problems, a majority of patients experience nocturnal acid breakthrough (NAB). NAB is defined as a condition in which gastric pH of less than 4 prevails for any 1 hour period between 10:00 PM and 8:00 AM, which is contrasted with daytime acid breakthrough (DAB) which is defined as a condition in which gastric pH of less than 4 prevails for any 1 hour period between 8:00 AM and 10:00 PM. NAB usually occurs at about 1:00 AM, and extends until about 5:00 AM.

Though the exact basis of this pattern is not known it is believed that it reflects a circadian rhythm in terms of synthesis and processing of the proton pump with the generation/appearance of new pumps at night.

Dosing PPIs at evening or night has resulted in limited success in reducing the incidence of NAB. The reason for this is believed to be systemic availability of the proton pump inhibitor after evening or night-time dosing is not aligned to the "circadian" pattern of acid secretion and will be metabolized and eliminated prior to the NAB peak.

Since most of the formulations available for PPIs employ pH-dependent polymers for modifying the release of drug, the desired sustained action is difficult to achieve with these types of dosage forms.

For the reasons mentioned above, there is a necessity to design a dosage form to achieve a release profile of PPIs that provide a full day therapy which is aligned with the NAB pattern. A number of approaches have been reported in the prior art to design a dosage form to address NAB.

U.S. 6,749,867 discloses a solid dosage form that provides a delayed and subsequently rapid release of omeprazole into an environment of use comprising a core containing omeprazole and at least one pharmaceutical percipients, wherein the core rapidly releases the omeprazole after the core is contacted with a fluid in an environment of use; and a time-release non-enteric water soluble or water erodible coating surrounding and in contact with the core, wherein the coating delays the contact of the core with a fluid in an environment of use for a sufficient period of time to delay the release of the omeprazole from the core, and the coating loses its physical integrity in an essentially pH independent manner after the delay thereby permitting the core to rapidly release the omeprazole into the environment of use. This patent further discloses the dosage form excludes an enteric release coating and the time-release coating is sufficiently thick to retain its chemical and physical integrity in the stomach when administered orally; and the time-release coating loses its physical integrity in the upper portion of the GI tract downstream from the stomach thereby releasing omeprazole.

U.S. 2006/0013868, is directed to a solid dosage unit for delayed release of a drug characterized in that a tablet, granule or fine granule wherein the release of an active ingredient is controlled by a pH-dependently soluble release-controlled coating layer which comprises one kind of polymeric substances or mixture of two or more kinds of polymeric substance having different release properties and the polymer substance is soluble in the pH range of 6.0 to 7.5 and 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. 2006/0177509, is directed to controlled release composition showing 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 PPI as an active ingredient, 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 as an active ingredient, 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.

The controlled release composition disclosed in this application, further comprises a release-controlled part C comprising an active ingredient the same as or different from the active ingredient contained in the release-controlled part A and/or the release-controlled part B, which part C is capable of controlling release of the active ingredient to occur at a predetermined rate faster than the release rate of the release-controlled part B; wherein the release of the active ingredient from the re lease-control led part C precedes the release of the active ingredient from the release-controlled part B.

U.S. 2007/0166370, is directed to an oral pharmaceutical composition comprising multiple populations of at least one of beads, pellets, tablets and granules provided in a capsule, the composition comprising: (i) a first population of a pharmaceutical active comprising a pharmaceutical active substance releasable at a first rate; (ii) a population of a basic substance; and (iii) a second population of a pharmaceutical active comprising a pharmaceutical active substance releasable at a second rate.

U.S. 2009/0098199 discloses plurality of particles comprising an active agent and enteric coating over the particles. The plurality of particles comprises first group of particles being coated with an enteric coating which releases the active agent from the solid particle at a pH of about 5.0 to about 5.5; and in another group of particles being coated with a second enteric coating, wherein it releases the active agent from the solid particle at a pH of about 6.2 to about 6,8. The division of the pellets is such that first group pellets comprises from about 15% to about 50% by weight of the pharmaceutical composition and the second group pellets comprises from about 50% to about 85% by weight of the pharmaceutical composition.

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 00/78293, is directed to a dosage form which is prepared without an enteric coating, and which comprises a core material containing an active ingredient selected from omeprazole, an alkaline salt thereof, S-omeprazole or an alkaline salt thereof, one or more alkaline additives which are alkalizing agents having a pH of not less than 8.5 when measured in a 2% w/w water solution/dispersion with a pH-measuring electrode, and one or more swelling agents. The core is coated with a semi-permeable membrane that is able to disrupt or may change its permeability after a predetermined time. This patent application does not appear to teach or suggest any specific desirable dissolution profile, but appears to indicate that after the pellet formulations have left the stomach, generally within 2-4 hours, the semi-permeable membrane covering the individual pellets disrupt and/or start to release the active ingredient in the small intestine. The sole dissolution profile disclosed in this application is in Example 4 wherein dissolution is measured for 2 hours using 0.1 M HCl and then at pH 6.8. The dissolution profile appears to exemplify a low initial release followed by a rapid release of active ingredient when exposed to the pH 6.8 environment. The problem with this dosage form is that it releases the drug with time irrespective of the pH of surrounding medium. In case of delayed gastric empting, it may release the drug in the conditions where significant amount of drug may get degraded due to the pH of the surrounding medium

WO 01/24777 is directed to compositions, which include pharmaceutical compositions for multiphase delivery of PPIs. It discusses that current immediate release dosing regimes often results in period during the day where the intra-gastric pH is maintained above 3.0, preferably above 4.0, preferably over a 24 hour period is not achieved, and this may become particularly acute during the night where "breakthrough pH" occurs. This application further discloses that there is not a constant requirement for the inhibitor because it is postulated that the initial dose inhibits the receptors and it is only when the receptors begin to regenerate that further inhibitor is required. So this application discloses that the use of sustained release formulations therefore involves the use of more inhibitor than necessary.

Therefore, it is disclosed that it is desirable to provide pulsed release formulations capable of releasing a second dose of inhibitor when the effects of the first dose begin to diminish. WOO 1/24777 broadly discloses delayed release of drugs in anticipation of symptoms. However, the only disclosure relative to release of PPI drugs appears to be a delayed release of the proton pump inhibitor in order to delay the release of the proton pump inhibitor for a lengthy period of time, such as 5 or 6 hours or longer (Examples 1 and 3) for apparently release of the active ingredient upon waking, or an immediate release of proton pump inhibitor in a two population formulation (Example 2). Also, WOOl/24777 discloses the use of disintegrates which result in swelling and disintegration of the dosage unit.

WO 2006/009602 is directed to a dosage form comprising a PPI wherein the PPI is released from the dosage form as a first and a second dose wherein each of the first and second doses comprises sufficient amount of the PPI to raise plasma levels of the PPI to a threshold concentration of at least l00ng/ml. The first and second doses are released from the dosage form as discreet pulses of the PPI while the second dose begins to be released between 2 and 20 hours after the first dose begin to release.

WO 2006/049565, is directed to an oral solid dosage form comprising as the active drug an acid sensitive PPI, the dosage form comprises two PPI releasing portions, tablets releasing the PPI with a delayed release pulse and pellets releasing the PPI with an immediate release pulse, characterized in that the PPI is formulated into a core material in the form of small tablets, and the tablets giving the delayed release pulse have the following layers on the core material in given order; a delay release modifying layer; - a lag time controlling layer comprising as essential component a high viscosity water soluble polymer; - an optional sub-coating layer; and - an outer enteric coating layer; and the pellets giving an immediate release pulse have the following layer(s) on a core material in the form of pellets; an optional sub-coating layer; and an outer enteric coating layer.

The prior art mentioned above generally either have formulations with pH dependent polymers which release the entire amount of drug when exposed to a particular pH or the dosage forms having pH independent polymers which release the drug in time dependent manner irrespective of the pH of surrounding medium. However, both these types of formulations suffer from some disadvantages, like either the inability to provide the sustained plasma levels of active moiety or likely chances of reduced bioavailability due to change in gastro-intestinal residence time of the product. Moreover, use of pellets has also some disadvantages as the process of preparing it is tedious and lengthy and further the mixing of different types of pellets if not properly carried out, it may result in a product lacking desirable therapeutic effect.

To overcome the above disadvantages, the inventors of the present invention designed a dosage form that can address the problem of NAB. They have designed the pharmaceutical formulation comprising PPIs, such that the core containing drug is coated with modified semi-permeable membrane, which loses its semi-permeable characteristics on exposure to aqueous environment irrespective to the change in pH and allows the drug passage across the coating by diffusion, though maintaining the physical integrity of coating.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to oral pharmaceutical compositions comprising PPIs or its pharmaceutically acceptable salts, enantiomers, solvates/hydrates, and mixtures thereof.

More particularly, the present invention relates to pharmaceutical compositions comprising at least one PPI, is designed, such that the core containing drug is coated with modified semi-permeable membrane, which loses its semi-permeable characteristics on exposure to aqueous environment irrespective to the change in pH and allows the drug passage across the coating by diffusion, though maintaining the physical integrity of coating.

In one embodiment, the present invention provides a pharmaceutical composition comprising at least one proton pump inhibitor, wherein the outer modified semi-permeable coating layer further comprise a pH dependent channeling agent, which acts as a pore former.

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one PPI, wherein the core containing the active ingredient is coated with a modified semi permeable membrane, followed by a drug coating layer and an another membrane coating comprising of biodegradable pharmaceutically acceptable excipients, surrounding the said drug layer.

Yet in another embodiment, the present invention provides a pharmaceutical compositions comprising at least one PPI, which is designed in a way such that the drug release from said composition is multi-phasic, preferably bi phasic in nature.

More particularly, the present invention relates to pharmaceutical compositions comprising at least one PPI, which is designed in a way so as avoid the food effect on oral administration.

In another embodiment, the present invention also provides the process for preparing a pharmaceutical composition comprising PPIs or its pharmaceutically acceptable salts, enantiomers, solvates/hydrates, and mixtures thereof

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a solid pharmaceutical dosage form for once a day administration of one or more PPIs. The dosage form may include but without limitation a compound (s), a derivative, a form such as an isomer, salt, stereoisomer, solvate and/or hydrate of pantoprazole, omeprazole, esomeprazole, lansoprazole, rabeprazole, dexlansoprazole and the likes.

The invention relates to pharmaceutical compositions comprising a core containing at least one PPI and a coating of modified semi-permeable membrane, which loses its semi-permeable characteristics on exposure to aqueous environment irrespective to the change in pH and allows the drug passage across the coating by diffusion, though maintaining the physical integrity of coating.

In an embodiment of the present invention, the modified semi permeable membrane may include either water soluble pH independent or water-insoluble water-permeable rate-controlling polymer or mixtures of both.

The present invention describes pharmaceutical composition comprising any or all of the following ingredients; an active ingredient, a water-insoluble pH-independent rate-controlling polymer, a water-insoluble water-permeable rate-controlling polymer alone or a mixture thereof, a plasticizer and/or a pH-dependent channeling agent, other suitable pharmaceutical excipients may be incorporated.

Yet in another embodiment, the present invention relates to pharmaceutical compositions comprising at least one proton pump inhibitor, which is designed in a way such that the drug release from said composition is multi-phasic or preferably biphasic in nature.

More particularly, the present invention relates to pharmaceutical compositions comprising at least one proton pump inhibitor, which is designed in a way so as avoid the food effect on oral administration.

Pharmaceutical composition according to the invention generally relates to a solid dosage form.

The term "solid dosage" defines a system in a solid state in the form of a tablet, mini-tablet, pellet, granule or a micro-granule comprising a core containing the active ingredient along with other suitable pharmaceutical excipients.

The first aspect of the invention is to prepare; a) a core comprising drug along with at least one disintegrant and binder b) a modified semi permeable membrane surrounding the core, which comprises of a water-insoluble water-permeable rate-controlling polymer alone, or a mixture thereof and/or a pH dependent channeling agent and optionally a water soluble pH independent rate-controlling polymer.

In other aspects of the invention is to prepare pharmaceutical composition comprising: a) a core comprising drug along with at least one disintegrant and binder b) a modified semi permeable membrane surrounding the core, which comprises of a water-insoluble water-permeable rate-controlling polymer alone, or a mixture thereof (c) a drug coating layer over the semi permeable membrane and (d) another membrane coating layer comprising of biodegradable pharmaceutically acceptable excipients, surrounding the drug layer.

Yet in another embodiment, the invention relates to pharmaceutical composition comprising: a) a core comprising drug along with at least one disintegrant and binder b) a modified semi permeable membrane surrounding the core, which comprises of a water-insoluble water-permeable rate-controlling polymer alone, or a mixture thereof (c) a drug coating layer over the semi permeable membrane and (d) another membrane coating layer comprising of enteric polymer and one or more pharmaceutically acceptable excipients, surrounding the drug layer.

The core may be formulated into a tablet, mini-tablet, pellet, granule or a micro-granule by a known approach in the prior art. The drug with or without disintegrant(s) and binder may be incorporated in the core by coating over non¬pareil seeds or granulating the mass followed by extrusion-spheronization. The drug, binder and disintegrant may be applied as a mixture over the core or may be incorporated in the core as separate layers. The core may optionally also contain an alkaline reacting agent and other suitable pharmaceutical excipients.

The core may also be produced by mixing drug along with disintegrant, dry binder, alkaline reacting agent, lubricant etc. and then compressing into mini-tablets of 1 mm to 3 mm diameter.

The release of drug from the core can be controlled by a water-in soluble water-permeable rate controlling polymer alone or a mixture thereof with or without a plasticizer and other pharmaceutically acceptable excipients.

The pH-independent water-soluble polymer is selected from the group of hydroxypropyl methyl cellulose, hydroxypropyl cellulose and the like.

The water-insoluble water-permeable rate-controlling polymer may be selected from the group comprising ethyl cellulose, cellulose acetate, ammonio methacrylate copolymers, polymethracrylic acid esters and the like or combinations thereof.

Suitable plasticizers may be selected from the group comprising of triethyl citrate, triacetin, acetyl triethyl citrate, dibutyl sebacate, dibutyl phthalate, soybean oil, olive oil, propylene glycol, glycerin, polyethylene glycol etc.

The biodegradable pharmaceutically acceptable excipients that form the coating membrane may be selected from a prolamine, such as gliadan, hordein or more preferably zein.

The coat may also contain channeling agents which are acidic in nature such as methacrylic acid and its copolymer, hydroxypropyl methylcellulose phthalate, PVAP, cellulose acetate phthalate, and other pharmaceutically acceptable ingredients having solubility above pH 5.

The dosage form of the present invention may be in the form of pellets, granules, tablet, tablets(s) / spheroids filled in capsule.
The invention also relates to a process for preparing pharmaceutical composition comprising a core containing at least one PPl and a coating of modified semi-permeable membrane, comprising the steps of:

a) Preparing a core composition comprising at least one PPI and one or more pharmaceutically acceptable excipients either in the form of pellet or granules or tablet.

b) Preparing and optionally coating the core by sub-coating solutions of hydroxypropyl methyl cellulose and polyethylene glycol in water.

c) Preparing a semi permeable coating by dissolving either water-soluble pH-independent rate-controlling polymer or a water-insoluble water-permeable rate-controlling polymer in water.

d) Coating the core or sub coated core of step (b) by semi permeable coating of step (c) to form coated composition and

e) Optionally coating the final composition by film coating composition to form tablets or further encapsulated in capsule.

Yet in another embodiment, the composition may also be prepared comprising the steps of:

a) Preparing a core composition comprising at least one PPI and one or more pharmaceutically acceptable excipients either in the form of pellet or granules or tablet.

b) Preparing a semi permeable coating by dissolving either water-soluble pH-independent rate-controlling polymer or a water-insoluble water-permeable rate-controlling polymer in water.

c) Coating the core of step (a) with the semi permeable coating of step (b) to produce coated core.

d) Preparing a drug coating layer by dissolving least one PPI and one or more pharmaceutically acceptable excipients in water.

e) Coating the drug layer prepared in step (d) over the semi permeable coated core of step (c) to form the drug-coated composition.

f) Preparing another membrane coating composition by dissolving biodegradable pharmaceutically acceptable excipients in organic solvent.

g) Finally coating the drug-coated core of step (e) with the coating composition of step (f) to form the required tablets or further encapsulated into capsule.

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.

Preparation of core containing PPI:

Example 1
Instant release drug cores in the form of pellets with the following composition were prepared by powder drug layering technique.

Core pellet formulation
Ingredients Qty % (w/w)
Sugar spheres 31.80
Lansoprazole 10.60
Magnesium carbonate, heavy 10.04
Sucrose 17.60
Cornstarch 12.86
Hydroxypropyl cellulose (Low-substituted) 15.55
Hydroxypropyl cellulose 1.55

Sugar spheres were loaded in a powder drug layering machine and the fluidized bed is simultaneously sprayed with binder solution and sprinkled with blend of lansoprazole, magnesium carbonate, sucrose, com starch and hydroxypropyl cellulose (low-substituted). Wet pellets were dried in a vacuum tray drier.

Example 2
Drug cores in the form of granules with the following composition were prepared by extrusion spheronization.

Core granules formulation
Ingredients Qty % (w/w)
Omeprazole 35.70
Magnesium carbonate, heavy 9.80
Microcrystalline cellulose 25.00
Lactose monohydrate 14.60
Crospovidone 12.40
Hydroxypropyl cellulose 2.50

Dry mix of omeprazole, magnesium carbonate, microcrystalline cellulose, lactose and crospovidone, was granulated with a binder solution of hydroxypropyl cellulose. The resulting wet mass was extruded and spheronized to form granules. The wet granules were dried for further use.

Example 3

Instant release drug cores in the form of tablets with the following composition were prepared by dry granulation and compression.

Core tablet formulation
Ingredients Qty % (w/w)
Dexlansoprazole 16.20
Magnesium carbonate, heavy 12.80
Microcrystalline cellulose 28.00
Lactose monohydrate 27.10
Cros-povidone 12.40
Hydroxypropyl cellulose 2.75
Magnesium stearate 0.75

Dry granulation of the above mentioned composition was prepared by mixing dexlansoprazole, magnesium carbonate, microcrystalline cellulose, lactose
monohydrate, cros-povidone, hydroxypropyl cellulose and magnesium stearate. The resulting dry mix was compressed into mini-tablets.

Example 4
Instant release drug cores in the form of pellets with the following composition were prepared by powder drug layering technique.

Core pellet formulation
Ingredients Qty % (w/w)
Non-pareil seeds 31.80
Dexlansoprazole 10.60
Magnesium carbonate, heavy 10.04
Sucrose 15.00
Starch 15.46
Hydroxypropyl cellulose (Low-substituted) 15.10
Hydroxypropyl cellulose 2.00

A blend of dexlansoprazole, magnesium carbonate, sucrose, starch, hyroxypropyl cellulose (low-substituted) was prepared by mixing in the bin blender for about 20 minutes. This powdered blend was then charged in the powder feeder of solid powder layering machine. Non-pareil seeds were loaded in a chamber of powder drug layering machine and were rotated such that bed of non-pareil seeds get fluidized. Binder solution of hydroxypropyl cellulose was then sprayed onto the non-peril seeds and powdered blend of dexlansoprazole, magnesium carbonate, sucrose, starch and hydroxypropyl cellulose (low-substituted) was sprinkled simultaneously. Wet pellets were then dried in a vacuum tray drier.

Example 5

The drug containing cores of dexlansoprazole are also prepared in the form of mini-tablets.

Core tablet formulation
Ingredients Qty % (w/w)
Dexlansoprazole 24.00
Magnesium carbonate, heavy 16.00
Mannitol 37.00
Crospovidone 10.00
Hydroxypropyl cellulose (Low-substituted) 12.00
Magnesium stearate 1.00

Dexlansoprazole, magnesium carbonate, mannitol, crospovidone and hyroxypropyl cellulose (low-substituted) were mixed and sifted through sieve of mesh# 30 (ASTM). The sifted material was then blended in a bin blender for 30 minutes and then lubricated with magnesium stearate. The lubricated blend was then compressed into mini-tablets of 1.5 mm on rotary compression machine.

Preparation of sub-coating composition

Example 6
The formulations mentioned in Examples 1, 2, and 3 can be optionally sub-coated with the aqueous solutions of hydroxypropyl methyl cellulose and polyethylene glycol such that a coating weight built-up on the core in the range of about 10 -15% w/w was achieved.

Sub-coating formulation
Ingredients Qty % (w/w)
Lansoprazole cores from Example I 88.00
Hydroxypropyi methyl cellulose 11.00
Polyethylene glycol 1.00

Preparation of coating composition

Example 7
The instant release dexlansoprazole multi-particulate cores of Example 3 were then coated to different extents with a number of release-controlling polymers in order to achieve a desired profile of drug release. The rate-controlling membrane may comprise one or more polymers that have different release-retardation properties as mentioned in the table below.

Modified semi-permeable membrane coating
(% w/w of coating_composition)

Ingredients Formula 7A Formula 7B Formula 7C Formula7D
Eudragit TM
RL 30 D 65.0 60.0 50.0 50.0
Eudragit’ RS 30D 5.0 9.0 19.0 13.0
Eudragit’TM
Ll00 D55 5.0 6.0 6.0 12.0
Talc 7.5 7.5 7.5 7.5
Triethyl citrate 15.0 15.0 15.0 15.0
Polysorbate80 2.5 2.5 2.5 2.5
Water q.s. q.s. q.s. q.s.

Example 8

The mini-tablets of Example 3 were also coated with following coating compositions:

Modified semi-permeable membrane coating
(% w/w of coating composition)

Ingredients Formula Formula Formula Formula Formula Formula
8A 8B 8C 8D 8E 8F
(%wAv) (%w/w) (%w/w) (%w/w) (%w/w) (%w/w)
Ethyl cellulose 77.0 70.0 81.0 - - -
Cellulose acetate - - - 70.0 65.0 600
Shellac 10.0 12.0 6.0 15.0 15.0 20.0
Polyethylene
glycol - 8.0 8.0 5.0 10.0 10.0
(400)
Triethyl citrate 8. 5.0 - 10.0 10.0 10.0
Talc 5.0 5.0 5.0 - - -
Isopropyl alcohol q.s q.s q.s q.s q.s q.s.
Water q.s q.s q.s q.s q.s q.s.

Example 9

Drug cores prepared in the Example 5 were further coated using following composition and process.

Coating composition
Ingredients Qty % (w/w)
Cellulose acetate 50.00
Polyethylene glycol 8000 40.00
Triethyl citrate 10.00

About 1200g of dexlansoprazole cores of Example 5 were loaded in Wurster coater and coated with the coating composition of cellulose acetate, polyethylene glycol 8000 and triethyl citrate in solvent system of acetone and water. The coating was done till a weight built-up of about 5-7% w/w was achieved.

Example 10

The coated cores of Example 9 were further coated with the drug and other excipients using solid drug powder layering technique. The detailed composition and process is as follows:

Drug coating composition
Ingredients Qty % (w/w)
Dexlansoprazole 24.00
Magnesium carbonate, heavy 16.00
L-HPC 18,00
Sucrose 10.00
Hydroxypropyl cellulose
Starch 17.00

A blend (about 1600 g) of dexlansoprazole, magnesium carbonate, sucrose, hyroxypropyl cellulose (low substituted) was prepared by mixing in the bin blender for about 20 minutes. This powdered blend was then charged in the powder feeder of solid powder layering machine. Coated cores of Example 9 (About 1100 g) were loaded in a chamber of powder drug layering machine and were rotated such that bed get fluidized. Binder solution of hydroxypropyl cellulose was then sprayed onto the coated cores of Example 9 and powdered blend of dexlansoprazole, magnesium carbonate, sucrose, starch and hydroxypropyl cellulose (low-substituted) was sprinkled simultaneously. Wet pellets were then dried in a vacuum tray drier.

Example 11

The formulation mentioned in Example 10 was finally coated with a coating comprising biodegradable excipient. This biodegradable excipient is broken down in the intestine by the intestinal enzymes into various amino-acids.

Ingredients Qty % (wiw)
Dexiansoprazole cores of Example 10 80.00
Gliadan 18.00
Polyethylene glycol 400 2.00

Coating composition

The drug loaded cores of Example 10 were further coated with the hydro-alcoholic solution of gliadan and polyethylene glycol 400 till desired weight built-up was observed.

Example 12

The formulation mentioned in Example 10 was also coated with the following composition.
Coating composition
Ingredients Qty % (w/w)
Dexlansoprazole cores of Example 10 80.00
Zein 18.00
Polyethylene glycol 400 2.00

The drug loaded cores of Example 10 were further coated with the hydro-alcoholic solution of zein and polyethylene glycol 400 till desired weight built-up was observed.

Example 13

Instant release drug cores in the form of tablets with the following composition were prepared by dry granulation and compression.
Core tablet formulation

Ingredients Qty % (w/w)
Dexlansoprazole 16.20
Magnesium carbonate, heavy 12.80
Microcrystalline cellulose 28.00
Lactose monohydrate 27.10
Crosspovidone 12.40
Hydroxypropyl cellulose 2.75
Magnesium stearate 0.75

Dry granulation of the above mentioned composition was prepared by mixing dexlansoprazole, magnesium carbonate, microcrystalline cellulose, lactose monohydrate, crospovidone, hydroxypropyl cellulose and magnesium stearate. The resulting dry mix was compressed into mini-tablets.

Example 14

The mini-tablets of Example 13 were coated with following coating compositions:

Modified semi-permeable membrane coating formulation
(% wlw of coating composition)

Ingredients Formula 14A. (%w/w) Formula 14B (%w/w)Formula 14(%wlw)
Cellulose acetate 40.00 50.00 60.00
Polyethylene glycol (400).30.00 25.00 20.00
Glyceryltriacetate 20.00 15.00 10.00
Talc 10.00 10.00 10.00

The minitablet cores of Example 13 were coated with the non-aqueous solution of cellulose acetate, polyethylene glycol 400, glyceryl triacetate and talc till desired weight built-up was observed.

Example 15

The minitablets of Example 14 were further coated with the following drug coating compositions to give an immediate release of drug.

Drug coating composition
(% w/w of coating composition)

Ingredients Formula HA (%w/w) Formula 15B (%w/w) Formula 15C (%w/w)
Dexlansoprazole 30.00 30.00 30.00
Sodium hydroxide 10.00 - -
Potassium hydroxide - 10.00 -
Meglumine - - 10.00
Povidone 60.00 60.00 60.00

Example 16

The minitablets of Example 15 were subcoated with the following coating composition.
Sub-coating formulation
(% w/w of coating composition)

Ingredients Formula 16A Formula 16B Formula 16C
(%w/w) (%w/w) (%w/w)
Minitablets of Example 15 95.00 91.00 87.00
1-lydroxypropyl methyl 4.50 8.00 12.00
cellulose (3cps)
Polyethylne glycol (6000) 0.50 1.00 1.00

Example 17

The minitablets of Example 16 were further coated with the following enteric coating compositions.

Enteric-coating formulation
(% wiw of coating composition)

Ingredients Formula 17A Formula 178B Formula 17C
Eudragit L-10055 60.00 65.00 70.00
Polyethylene
Glycol (6000) 12.00 6.00 7.00
Titanium dioxide 5.00 6,00 4.00
Talc 20.00 20.00 16.00
Polysorbate 80 3.00 3.00 3.00

Dissolution Study:
Drug dissolution profile of dexlansoprazole capsules prepared according to the present invention was carried out under following.dissolution conditions:

Acid Release:

Media: 0.lNHCl,
Volume: 900ml,
Apparatus: USP Dissolution Apparatus Type 11,
Rotational Speed: 75 rpm,
Time: 1 hr
Buffer Release:
Media: pH 7.2 phosphate buffer.
Volume: 900ml,
Apparatus: USP Dissolution Apparatus Type II,
Rotational Speed: 75 rpm,
Time: 2 hr

The samples of the media were periodically withdrawn and spectrophotometrically analyzed for dexlansoprazole content. The dissolution profile is given in Table 1.
(%) Dexlansoprazole Release

Table 1

stability Data

The capsule prepared according to Example-17 of the present invention was subjected to stability study for 1 month and parameters such as assay, drug dissolution and related substance were analyzed.

Samples were analyzed by HPLC method and the results are summarized in Table 2, 3 and 4.

Tbale-2, Tbale-3, Tbale-4

CLAIM:

1. A pharmaceutical composition comprising a core comprising at least one proton pump inhibitor and a modified semi-permeable membrane coated over said core.

2. The pharmaceutical composition according to claim 1, wherein said proton pump inhibitor consists of pantoprazole, omeprazole, esomeprazole, lansoprazole, rabeprazole or dexlansoprazole.

3. The pharmaceutical composition according to claim I, wherein said
modified semi-permeable membrane comprises either a pH-independent
water-soluble polymer or water-in soluble water-permeable rate-controlling
polymer or combinations thereof.

4. The pharmaceutical composition according to claim 1, wherein said modified semi-permeable membrane further comprises a plasticizer and an pH-dependent channeling agent.

5. The pharmaceutical composition according to claim 3, wherein said pH-independent water-soluble polymer is selected from either hydroxypropyl methyl cellulose or hydroxypropyl cellulose or combinations thereof

6. The pharmaceutical composition according to claim 3, wherein said water-insoluble water-permeable rate-controlling polymer is selected from the group comprising ethyl cellulose, cellulose acetate, ammoniomethacrylate copolymers, polymethracrylic acid esters, or combinations thereof.

7. The pharmaceutical composition according to claim 4, wherein said plasticizer is selected from triethyl citrate, triacetin, acetyl triethyl citrate, dibutyl sebacate, dibutyl phthalate, soybean oil, olive oil, propylene glycol, glycerin, polyethylene glycol or combinations thereof.

8. The pharmaceutical composition according to claim 4, wherein said pH-dependent channeling agent is selected from methacrylic acid and its copolymer, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate or combinations thereof.

9. A process for preparing a pharmaceutical composition comprising a core containing at least one proton pump inhibitor and a modified semi-permeable membrane coated over said core, involving the following steps:

a) Preparing a core composition comprising at least one proton pump inhibitor and one or more pharmaceutically acceptable excipients either in the form of pellet or granules or tablet;

b) Preparing and optionally coating the core by sub-coating solutions of hydroxypropyl methyl cellulose and polyethylene glycol in water;

c) Preparing a semi-permeable coating by dissolving either water-soluble pH-independent rate-controlling polymer or a water-insoluble water-permeable rate-controlling polymer in water;

d) Coating the core or sub coated core of step (b) by semi-permeable coating of step (c) to form coated composition and;

e) Optionally coating the final composition by film coating composition to form tablets or further encapsulated in capsule.

10. A pharmaceutical composition comprising:

a) a core comprising a proton pump inhibitor along with at least one disintegrant and a binder;

b) a modified semi-permeable membrane surrounding said core, which comprises of a water-insoluble water-permeable rate-controlling polymer alone, or a mixture thereof;

c) a drug coating layer over said semi-permeable membrane and
optionally;

d) an outer membrane coating layer comprising a pharmaceutically
acceptable biodegradable excipient, coated over said drug layer.