WO2015150943A1

WO2015150943A1 - Pharmaceutical composition of nsaid and ppi or salt thereof

Info

Publication number: WO2015150943A1
Application number: PCT/IB2015/051837
Authority: WO
Inventors: Amit SHEWALE; Vishal KANERIA; Sachin K SALAMPURE; Jitendrakumar CHORDIYA
Original assignee: Wockhardt Limited
Priority date: 2014-03-29
Filing date: 2015-03-13
Publication date: 2015-10-08

Abstract

The present invention relates to a pharmaceutical composition of NSAID and PPI or salt thereof. In particular, the invention relates to a composition of NSAID and PPI or salt thereof comprising a core and two or more layers coated on the core. The invention also includes a method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID -associated gastric ulcers.

Description

PHARMACEUTICAL COMPOSITION OF NSAID AND PPI OR SALT THEREOF

Field Of The Invention

The present invention relates to a pharmaceutical composition of NSAID and PPI or salt thereof. In particular, the invention relates to a composition of NSAID and PPI or salt thereof comprising a core and two or more layers coated on the core. The invention also includes a method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID -associated gastric ulcers. The invention also includes process of preparing such composition.

Background Of The Invention

Non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAID or NSAIDs) are widely accepted as effective agents for controlling pain; however their administration can lead to the development of gastro-duodenal lesions, e.g., ulcers and erosions, in susceptible individuals. It appears that a major factor contributing to the development of these lesions is the presence of acid in the stomach and upper small intestine of patients. Other major factors contributing to NSAID-associated gastropathy include a local toxic effect of NSAIDs and inhibition of protective prostaglandins, which may also make some patients more susceptible to the ulcerogenic effects of other noxious stimuli.

In general, more potent and longer lasting proton pump inhibitors (hereinafter referred to as PPI or PPIs), are thought to be more protective during chronic administration of NSAIDs than shorter acting agents, e.g., histamine H₂ receptor antagonists (H-2 blockers). The most likely explanation for this is that gastric pH fluctuates widely throughout the dosing interval with short acting acid inhibitors leaving the mucosa vulnerable for significant periods of time. In particular, the pH is at its lowest point, and hence the mucosa is most vulnerable, at the end of the dosing interval (least amount of acid inhibition) and for some time after the subsequent dose of PPI. In general, it appears that when a short acting acid inhibitors and an NSAID are administered simultaneously, NSAID-related mucosal damage occurs before the pH of the gastrointestinal tract can be raised and after the acid inhibiting effect of the short acting acid inhibitors dissipates.

Although longer lasting agents, such as proton pump inhibitors (PPIs), usually maintain a consistently higher gastroduodenal pH throughout the day, after several days dosing, their antisecretory effect may be delayed for several hours and may not take full effect for several days. Their effect may be diminished toward the end of the usual dosing interval. Intragastric pH rises particularly slowly with the first dose in a course of treatment since this class of drugs is enteric coated to avoid destruction by stomach acid. As a result, absorption is delayed for several hours. Even then, some patients fail to respond consistently to drugs of this type and suffer from "acid breakthrough" which again leaves them vulnerable to NSAID-associated gastroduodenal damage.

Despite a significant reduction in gastro-duodenal lesions with the concomitant administration of a proton pump inhibitor during six months of NSAID therapy, up to 16% of patients still develop ulcers, indicating that there remains substantial room for improvement. Thus, the addition of a pH sensitive enteric coating to an NSAID could provide additional protection against gastroduodenal damage not provided by the H₂ blocker or PPI alone.

Recognizing the potential benefits of PPIs for the prevention of NSAID-induced gastroduodenal damage, there are strategies disclosed in the art for combining the two types of active agents for therapeutic purposes, other than by concomitant administration.

U.S. Patent No. 6,365,184 discloses a means of delivery that would expose the gastrointestinal tract to complete dose of NSAIDs prior to onset of PPI activity. U.S. Patent No. 6,926,907 and 8,206,741 discloses pharmaceutical formulations that provide coordinated release of an acid inhibitor and an NSAID. Particularly, NSAID is released when the pH of the surrounding medium is 3.3 or higher.

U.S. Patent Application Publication No. 2010/0305163 discloses a fixed dose composition of a NSAID and a proton pump inhibitor.

However, the prior art is suggesting only overcoming NSAID induced gastric or duodenal erosions and ulcers, while it may not effectively control the pain. This issue has been addressed in our co-pending application 2223/MUM/2014, which discloses a combination composition of NSAID core coated with at least one layer of PPI and one or more outer layer of NSAID. Such pharmaceutical composition provides at least a portion of NSAID available for therapeutic effect and alongside releases the PPI that can avoid undesirable intra-gastric acid level prior to the release of remaining substantial amount of NSAID for continuous and effective pain management.

Aspirin and many other NSAIDs are carboxylic acid derivatives. As a result, they may remain in unionized form at acidic pH found in the gastric lumen. Such unionized form of aspirin or NSAID may get absorbed across the gastric mucosa and eventually result in NSAID induced gastric side effects.

Therefore, there still exists a need for an improved composition of a NSAID and a PPI that may reduce or eliminate such NSAID induced gastric side effects.

Summary Of The Invention

The inventors of the present invention have surprisingly found that the damage to the epithelial cells can be avoided by providing alkaline microenvironment to the outer layer of NSAID in the composition. The said objectives can be addressed by devising a formulation of NSAID and PPI in the form of a core comprising NSAID and two or more layers coated on the core comprising PPI and NSAID, such that at least a part of the NSAID is coated over the PPI layer, wherein the composition comprises one or more alkalizers along the vicinity of the outer NSAID layer.

In one general aspect, there is provided a pharmaceutical composition comprising:

(a) at least one core comprising NSAID or salt thereof coated with at least one enteric coating layer comprising one or more enteric polymers;

(b) at least one PPI layer comprising one or more PPI coated over the core;

(c) at least one NSAID layer comprising one or more NSAIDs or salt thereof coated over the PPI layer, and

(d) optionally, at least one outermost layer coated over the NSAID layer (c); wherein said NSAID layer (c) and/or said outermost layer (d) comprises one or more alkalizers.

In another general aspect, the release of the NSAID from the outer NSAID layer begins before the release of PPI from said PPI layer starts.

In another general aspect, there is provided a pharmaceutical composition comprising:

(a) at least one core comprising NSAID or salt thereof;

(b) at least one enteric coating layer coated over the core comprising one or more enteric polymers and one or more pharmaceutical excipients;

(c) at least one coating layer coated over the core comprising PPI or salt thereof and one or more pharmaceutical excipients;

(d) at least one coating layer coated over the core comprising NSAID or salt thereof and one or more pharmaceutical excipients; and

(e) at least one outermost layer coated over the NSAID layer (d); wherein said NSAID layer (d) and/or said outermost layer (e) comprises one or more alkalizers.

In another general aspect, there is provided a pharmaceutical composition sequentially comprising:

(a) at least one core comprising NSAID or salt thereof;

(b) optionally, at least one seal coating layer coated over the core comprising one or more pharmaceutical excipients;

(c) at least one enteric coating layer coated over the core comprising one or more enteric polymers and one or more pharmaceutical excipients;

(d) optionally, at least one seal coating layer coated over the core comprising one or more pharmaceutical excipients;

(e) at least one coating layer coated over the core comprising PPI or salt thereof and one or more pharmaceutical excipients;

(f) optionally, at least one seal coating layer coated over the core comprising one or more pharmaceutical excipients;

(g) at least one coating layer coated over the core comprising NSAID or salt thereof and one or more pharmaceutical excipients;

(h) optionally, at least one outer coating layer coated over the core comprising one or more pharmaceutical excipients, and

wherein said NSAID layer (g) and/or said outermost layer (h) comprises one or more alkalizers.

In another general aspect, the alkalizer in pharmaceutical composition is present in an amount ranging from about 1 to about 5% w/w by total weight of the composition.

In another general aspect, ratio of the amount of NSAID in the outer layer to the total amount of alkalizer in the composition ranges from 1 :0.1 to 1 :2. In another general aspect, NSAID in the core of the pharmaceutical composition is not released until the pH of the surrounding medium is higher than 3.5.

In another general aspect, PPI and NSAID in the layers of the pharmaceutical composition are released in the medium having pH 3.5 or less.

In another general aspect, the ratio of the amount of NSAID in the core to the amount of NSAID in the layer ranges from about 1 :0.4 to 1 :0.01 .

In another general aspect, there is provided a tablet which sequentially comprises of:

(a) a core comprising NSAID or salt thereof;

(b) a seal coating layer coated over the core comprising one or more pharmaceutical excipients;

(c) an enteric coating layer coated over the core comprising one or more enteric polymers and one or more pharmaceutical excipients;

(d) a seal coating layer coated over the core comprising one or more pharmaceutical excipients;

(e) a coating layer coated over the core comprising PPI or salt thereof and one or more pharmaceutical excipients;

(f) a seal coating layer coated over the core comprising one or more pharmaceutical excipients;

(g) a coating layer coated over the core comprising NSAID or salt thereof and one or more pharmaceutical excipients;

(h) an outer coating layer coated over the core comprising one or more pharmaceutical excipients, and

In another general aspect, the outer layer of the composition comprises colorants and one or more polymers to differentiate compositions of various strengths. In another general aspect, there is provided a process for preparation of a pharmaceutical composition comprising NSAID, PPI or salt thereof, which process sequentially comprises steps of:

(a) providing at least one core comprising NSAID or salt thereof coated with at least one enteric coating layer comprising one or more enteric polymers;

(b) coating at least one PPI coating layer comprising one or more PPI over the core;

(c) coating at least one NSAID coating layer comprising one or more NSAIDs or salt thereof over the core; and

(d) optionally, coating at least one outermost layer over the core;

wherein said NSAID layer (c) and/or said outermost layer (d) comprises one or more alkalizers.

In another general aspect, there is provided a process for preparation of a pharmaceutical composition comprising NSAID, PPI or salt thereof, which process sequentially comprises steps of:

(a) providing at least one core comprising NSAID or salt thereof;

(b) optionally, coating at least one seal coating layer over the core comprising one or more pharmaceutical excipients;

(c) coating at least one enteric coating layer over the core comprising one or more enteric polymers and one or more pharmaceutical excipients;

(d) optionally, coating at least one seal coating layer over the core comprising one or more pharmaceutical excipients;

(e) coating at least one layer over the core comprising PPI or salt thereof and one or more pharmaceutical excipients;

(f) optionally, coating at least one seal coating layer over the core comprising one or more pharmaceutical excipients;

(g) coating at least one layer coated over the core comprising NSAID or salt thereof and one or more pharmaceutical excipients; (h) optionally, coating at least one outer layer over the core comprising one or more pharmaceutical excipients; and

wherein said NSAID layer (g) and/or said outer layer (h) comprises one or more alkalizers.

In another general aspect, the coating layers on the core are applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.

In another general aspect, in the process for preparation of pharmaceutical composition comprising NSAID, PPI or salt thereof, the coating layers are applied as a suspension of the polymer in a coating solvent.

In another general aspect, the pharmaceutical composition of NSAID, PPI or salt thereof retains at least 90% w/w of total potency of NSAID and PPI after storage at 40°C and 75% relative humidity for at least 3 months.

In another general aspect, there is provided a method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID-associated gastric ulcers in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

Detailed Description Of The Invention

The inventors of the present invention have surprisingly found that by using alkalizer along the vicinity of the outer NSAID layer in the pharmaceutical composition of NSAID and PPI, the resulting composition may effectively control the pain as well as reduce the risk of gastrointestinal side effects of NSAID. The composition thus may improve the patient compliance. The pharmaceutical composition of the present invention may exhibit excellent storage stability over the storage period.

In an embodiment, the pharmaceutical composition of the present invention comprises:

(b) at least one PPI coating layer comprising one or more PPI coated over the core;

(c) at least one NSAID coating layer comprising one or more NSAIDs or salt thereof coated over the core, and

(d) optionally, at least one outermost layer coated over the NSAID layer (c), wherein the release of the NSAID from said NSAID layer (c) begins before the release of PPI from said PPI layer (b) starts and characterized in that said NSAID layer (c) and/or said outermost layer (d) comprises one or more alkalizers.

In a further embodiment, release of NSAID from said NSAID layer completes before the release of PPI from said PPI layer.

In another embodiment, the pharmaceutical composition of NSAID, PPI or salt thereof retains at least 90% w/w of the total potency of both NSAID and PPI after storage at 30°C and 60% relative humidity, at 40°C and 75% relative humidity, or at 25°C and 60% relative humidity for at least 3 months.

The term "NSAID" and "PPI" or "proton pump inhibitor" used throughout the specification refers to not only NSAID and PPI per se, but also various pharmaceutically acceptable salt, solvates, derivatives and hydrates thereof.

The term "alkalizer" used throughout the specification refers to the excipients those are capable of raising the pH of the micro-environment in the composition. Suitable alkalizer include, but are not limited to, organic and inorganic basic compounds of a wide range of aqueous solubilities and molecular weights and the like and mixtures thereof. Representative examples of inorganic basic salt include ammonium hydroxide, aluminum hydroxide, alkali metal salt, alkaline earth metal salt such as magnesium oxide, magnesium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate and the like and mixtures thereof.

The term "core" used throughout the specification encompasses inert beads (e.g. sugar or microcrystalline cellulose beads), core of a tablet, a placebo core tablet, or one or more NSAID layers coated thereon.

NSAID suitable for use in the composition of the present invention may be selected from, but not limited to, aspirin, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, lornoxicam, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, nabumetone and cycloxogenase-2 inhibitor.

PPI suitable for use in the composition of the present invention may be selected from, but not limited to, omeprazole, esomeprazole, lansoprazole, rabeprazole and Pantoprazole.

The core employed in the composition of the invention may include conventional pharmaceutical excipients to enable formation of a pharmaceutically acceptable solid core. The core may be in the form of a tablet, bead, or pill.

In an embodiment, the core comprises NSAID or salt thereof in an amount ranging from about 5 to about 80% w/w of the composition.

In another embodiment, the ratio of the amount of NSAID in the core to the amount of NSAID in the layer ranges from about 1 :0.4 to 1 :0.01 . In another embodiment, the alkalizer in the composition is present in an amount ranging from about 1 to about 5% of the total weight of the composition.

In another embodiment, the ratio of amount of NSAID in the outer layer to the amount of alkalizer in the composition ranges from 1 :0.1 to 1 :2.

The core may be formed of one or more pharmaceutical excipients selected from, but not limited to one or more of bulking agents or fillers, binders, disintegrants, and lubricants.

The bulking agents or fillers may be present in the core in an amount within the range from about 1 to about 95% w/w and preferably from about 10 to about 85% w/w of the composition. Examples of bulking agents or fillers suitable for use herein include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salt such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, compressible sugars, and other known bulking agents or fillers, and/or mixtures thereof, preferably microcrystalline cellulose.

The binder may be present in the core in an amount within the range from about 0 to about 20% w/w, preferably from about 1 to about 10% w/w of the composition. Examples of binders suitable for use herein include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP) (molecular weight ranging from about 5,000 to about 1 ,000,000, preferably about 40,000), hydroxypropyl methylcellulose (HPMC), lactose, gum acacia, ethyl cellulose, cellulose acetate, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose. The disintegrant may be present in the core in an amount within the range from about 0 to about 20% w/w, preferably from about 0.25 to about 10% w/w of the composition. Examples of disintegrants suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose or other known disintegrant, preferably croscarmellose sodium.

The lubricant may be present in the core in an amount within the range from about 0.1 to about 5% w/w, preferably from about 0.2 to about 2% w/w of the composition. Examples of tabletting lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate or hydrogenated vegetable oils and fats, or mixtures thereof, preferably magnesium stearate.

In another embodiment, the bulking agents are microcrystalline cellulose, the disintegrant is pregelatinized starch, and the lubricant/glidant is colloidal silica.

In an embodiment, the core preferably contain at least one bulking agent or filler; optionally at least one binder; optionally at least one disintegrant; and preferably but optionally at least one lubricant. The bulking agent or filler may present in an amount within the range from about 1 to about 95% w/w, preferably from about 10 to about 85% w/w of the composition. The binder may present in an amount within the range from about 0 to about 20% w/w, preferably from about 1 to about 10% w/w of the composition. The disintegrant may present in an amount within the range from about 0 to about 20% w/w, and preferably from about 0.25 to about 10% w/w of the composition. The lubricant may present in an amount within the range from about 0 to about 5% w/w, preferably from about 0.2 to about 2% w/w of the composition. In an embodiment, NSAID in the core of the pharmaceutical composition is not released until the pH of the surrounding medium is higher than 3.5.

The cores present in the composition of the invention can be prepared by a variety of processes and order of addition of excipients. The utility of these formulations is not limited to a specific dosage form or manufacturing process. The cores may be manufactured by wet granulation, dry granulation, direct blending or any other pharmaceutically acceptable process.

In an embodiment, the process of preparing the cores includes the steps of blending the one or more excipients such as bulking agent, optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate core formation.

In another embodiment, the process of preparing the cores includes the steps of coating the dispersion comprising NSAID and one or more pharmaceutical excipients over inert beads of sugar or microcrystalline cellulose.

The seal coating layers including the outer coating layer over the NSAID layer in the pharmaceutical composition of the present invention comprises one or more pharmaceutical excipients. Preferably, the seal coating layers comprises one or more polymers.

The coating formulation for seal coating layers contains at least one polymer and a coating solvent, which preferably is water, which is used for processing and removed by drying. Suitable polymer for first coating layer may be selected from, but not limited water-soluble polymer, water-insoluble polymer, or mixtures thereof. Particularly, water-soluble polymers are preferred. Examples of polymers suitable for seal coating layers include, but not limited to cellulose base polymers such as hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose; methacrylic polymers. The coating layer may also optionally include a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; and an anti-adherent or glidant such as talc, fumed silica or magnesium stearate, opacifying agent such as titanium dioxide. The coating layer may also include iron oxide based colorants.

Examples of suitable coating solvents include, but not limited to water, ethanol, methanol, dichloro methane and isopropyl alcohol, with water being preferred.

The enteric coatings work by presenting a surface that is not soluble in acidic aqueous medium while soluble in neutral or basic aqueous medium. Enteric coating agent is an excipient that allows releasing the active substance from the composition only under certain environmental condition and or by a certain release rate.

Enteric polymers are applied onto the cores as solutions or dispersion in organic or aqueous solvents. The solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof. The choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution.

Acid resistant or enteric polymers suitable for enteric coating layer may be selected from, but not limited to acrylic acid polymers, phthalate polymers, copolymers or mixtures thereof. An acrylic polymer such as polyacrylates or polymethacrylates is the preferred polymer for enteric coating layer applied over the cores. Polyacrylates, the polymethacrylates and the copolymers of acrylic and methacrylic acid are commercially available under the name Eudragit® and are particularly suitable. Examples of Eudragit® products include Eudragit L30D, Eudragit® L30 and Eudragit® D-55 etc. Other suitable enteric polymers include, for example, cellulose derivates such as, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, etc.

Furthermore enteric coating polymers may be combined together in order to induce both time dependent and pH dependent control of the release of tamsulosin. The amount of enteric coating calculated on the uncoated core basis is more than 15%, preferably more than 18%, more preferably more than 20%.

In an embodiment, the enteric coating layer of the composition comprises one or more pharmaceutical excipients, pharmaceutically acceptable acid resistant acrylic polymers and optionally one or more polymers.

The amount of acid resistant enteric polymer in the coating layer is more than 50% by weight of the coating. In an embodiment, said amount is more than 70% by weight of coating. In a further embodiment more than 80% by weight relative to the total weight of the coating layer.

The amount of acid resistant polymer is preferably within the range of 20-85 mass %, more preferably 30 to 75%, and typically 50 to 75%, calculated on a dry basis of the coating layer.

The coating formulation for enteric coating contains at least one polymer and a coating solvent, which preferably is water, which is used for processing and removed by drying. Suitable polymer for first coating layer may be selected from, but not limited to pharmaceutically acceptable acid resistant acrylic polymers, water-soluble polymer, water-insoluble polymer, or mixtures thereof. Particularly, water-soluble polymers are preferred. The coating layer of the composition of the invention comprising PPI, or salt thereof, further comprises of one or more pharmaceutical excipients and optionally, one or more polymers. Suitable coating solvent is employed to facilitate the coating, which preferably is water, which is used for processing and removed by drying.

The amount of PPI, or salt thereof in the respective coating layer is in the range from about 20 to about 80%, preferably from about 40 to about 80% w/w, based on the weight of the coating layer.

The amount of polymer in the PPI coating layer may range from about 1 to about 50%, preferably from about 5 to about 30% w/w of the coating layer.

The PPI coating layer may be present in an amount within the range from about 10 to about 40%, preferably from about 15 to about 25% w/w of the composition.

In an embodiment, PPI in the layers of the pharmaceutical composition is released in the medium having pH 3.5 or less.

In an embodiment, the PPI layer will preferably be formed by coating the composition comprising PPI or salt thereof, polymer in an amount within the range from about 5 to about 60%, preferably from about 10 to about 30% w/w of the coating layer, one or more surfactants in an amount within the range from about 0.1 to about 20%, optionally plasticizer in an amount within the range from about 1 to about 20%, preferably from about 5 to about 10% w/w of the first coating layer, and anti-adherent or glidant in an amount within the range for about 15 to about 30%, preferably from about 10 to about 15% w/w of the first coating layer. The composition of the present invention comprises at least a part of the NSAID coated over the over the PPI containing layer. Said coating layer further may comprise one or more pharmaceutical excipients.

The amount of NSAID, or salt thereof in the respective coating layer is in the range from about 50 to about 99%, preferably from about 70 to about 90% w/w, based on the weight of the coating layer.

In an embodiment, NSAID is present in the layer in amount insufficient to cause gastric ulcerogenic effect.

The amount of polymer in the NSAID coating layer may range from about 1 to about 30%, preferably from about 10 to about 20% w/w of the coating layer.

The NSAID coating layer may be present in an amount within the range from about 1 to about 25%, preferably from about 5 to about 15% w/w of the composition.

In an embodiment, NSAID in the layers of the pharmaceutical composition is released in the medium having pH 3.5 or less.

The composition of the invention further may include one or more outer layers where the coating suspension is prepared as in the case of the other coating compositions but without active ingredient and acid resistant polymer. The coating suspension is then can be coated onto the previously coated composition to form a protective coating layer thereon. Preferably, the composition of the outer layer is same that of the seal coating layers.

The composition of the present invention further may comprise a second outermost protective layer comprising one or more polymers and one or more pharmaceutical excipients. Pharmaceutical excipients suitable for employing in the coating layers of the composition may include, nut not limited to, bulking agents or diluents, binders, plasticizers, surfactants, lubricants, colorants, pH adjusting agents, or mixtures thereof.

The composition of the present invention may be prepared by various processes known to the person skilled in the art, particularly process adopted for coating.

In an embodiment, the pharmaceutical composition comprising NSAID, PPI or salt thereof is prepared by the process which comprises steps of:

(c) coating at least one NSAID coating layer comprising one or more NSAIDs or salt thereof over the core, and

(d) optionally, coating at least one outermost layer over the core;

In another embodiment, the pharmaceutical composition comprising NSAID, PPI or salt thereof is prepared by the process which sequentially comprises steps of:

(a) providing at least one core comprising NSAID or salt thereof;

(d) optionally, coating at least one seal coating layer over the core comprising one or more pharmaceutical excipients; (e) coating at least one layer over the core comprising PPI or salt thereof and one or more pharmaceutical excipients;

(g) coating at least one layer over the core comprising NSAID or salt thereof and one or more pharmaceutical excipients;

(h) optionally, coating at least one outer layer over the core comprising one or more pharmaceutical excipients; and

In a further embodiment, the coating layers on the core are applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.

In a further embodiment, all coating layers are subjected to sufficient drying after application over the core, or before application of the subsequent coating layer.

In a further embodiment, in the process for preparation of pharmaceutical composition comprising NSAID, PPI or salt thereof, the coating layers are applied as a suspension of the polymer in a coating solvent.

The composition of the present invention may be formulated in suitable a dosage form including, but not limited to, a tablet, caplet, mini-tablet, pellets, granules, capsule filled with tablets, pellets, granules or mini-tablets or combinations thereof.

The present invention further provides a method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID -associated gastric ulcers in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 : Aspirin and Omeprazole Tablet (325mg/40mg)

Table 1

Dichloromethane q. s.

Seal coated tablet weight 45-90

Omeprazole Coating

Omeprazole 3-10

Polyvinyl pyrrolidone 0.1 -1 .5

Sodium lauryl sulfate 0.005-0.5

Disodium hydrogen phosphate 0.5-3

Lactose monohydrate 0.5-3

Crosslinked polyvinyl pyrrolidone 0.25-1 .5

Purified water

Coated tablet weight 48-95

Seal Coating III

Hydroxypropyl methylcellulose 2-6

Hydroxypropyl cellulose 0.2-0.6

Sodium lauryl sulfate 0.01 -0.2

Talc 0.5-2

Isopropyl alcohol q. s.

Dichloromethane q. s.

Seal coated tablet weight 50-95

Aspirin Coating

Aspirin 5-10

Hydroxypropyl methylcellulose 0.1 -1 .5

Crosslinked polyvinyl pyrrolidone 0.2-0.6

Isopropyl alcohol q. s.

Dichloromethane q. s.

Coated tablet weight 55-98

Seal Coating IV

Hydroxypropyl methylcellulose 1 .5-4

Hydroxypropyl cellulose 0.15-0.4

Sodium lauryl sulfate 0.01 -0.2 41 Talc 0.1 -2

42 Isopropyl alcohol q. s.

43 Dichloromethane q. s.

Seal coated tablet weight 60-99

Film Coating

44 Opadry coating 1 -4

45 Magnesium oxide 1 -4

46 Purified Water q. s.

Final tablet weight 100

Process: Aspirin, pregelatinized starch, microcrystalline cellulose, colloidal anhydrous silica and stearic acid were mixed together to form uniform blend and compressed together by direct compression to form aspirin tablet. The aspirin tablet was then seal coated (Seal Coat I) using hydroxypropyl methylcellulose, hydroxypropyl cellulose and talc as coating excipients and isopropyl alcohol and dichloromethane as solvents. Enteric coat of methacrylic acid copolymer dispersion was then coated over the seal coated aspirin tablet. The enteric coated tablet was then applied with a seal coat (seal coat II).

An omeprazole layer containing omeprazole, polyvinyl pyrrolidone, sodium lauryl sulfate, disodium hydrogen phosphate, lactose monohydrate and crosslinked polyvinyl pyrrolidone was coated over the seal coat II. The omeprazole layer coated tablet was then seal coated (seal coat III).

An aspirin layer containing aspirin, crosslinked polyvinyl pyrrolidone, hydroxypropyl methylcellulose as coating excipient and isopropyl alcohol and dichloromethane as solvents was coated over the seal coat III. A seal coat (seal coat IV) is then applied over the aspirin layer and finally, an outermost coating containing magnesium oxide was applied over the seal coated tablet.

Coatings of various layers were subjected to sufficient drying before application of each subsequent coating.

Claims

Claim:

1 . A pharmaceutical composition comprising:

(a) at least one core comprising Non-steroidal anti-inflammatory drugs (NSAID) or salt thereof coated with at least one enteric coating layer comprising one or more enteric polymers; (b) at least one proton pump inhibitor (PPI) layer comprising one or more PPI coated over the core;

(d) optionally, at least one outermost layer coated over the NSAID layer, wherein said NSAID layer (c) and/or said outermost layer (d) comprises a alkalizers.

2. A pharmaceutical composition sequentially comprising:

(a) at least one core comprising NSAID or salt thereof;

(b) optionally, at least one seal coating layer coated over the core comprising a pharmaceutical excipients;

(c) at least one enteric coating layer coated over the core comprising one or more enteric polymers and a pharmaceutical excipients;

(d) optionally, at least one seal coating layer coated over the core comprising a pharmaceutical excipients;

(e) at least one coating layer coated over the core comprising PPI or salt thereof and a pharmaceutical excipients;

(f) optionally, at least one seal coating layer coated over the core comprising a pharmaceutical excipients;

(g) at least one coating layer coated over the core comprising NSAID or salt thereof and a pharmaceutical excipients, and

(h) optionally, at least one outer coating layer coated over the core comprising a pharmaceutical excipients;

wherein said NSAID layer (g) and/or said outermost layer (h) comprises a alkalizers or combination thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein the release of the NSAID from the outer NSAID layer (c) or (g) begins before the release of PPI from said PPI layer (b) or (e) starts.

4. The pharmaceutical composition of claim 1 or 2, wherein the alkalizer in the composition is present in an amount ranging from about 1 to about 5% w/w by total weight of the composition.

5. The pharmaceutical composition of claim 1 or 2, wherein the ratio of the amount of NSAID in the outer layer (c) or (g) to the total amount of alkalizer in the composition ranges from 1 :0.1 to 1 :2.

6. The pharmaceutical composition of claim 1 or 2, wherein the NSAID in the core of the composition does not release until the pH of the surrounding medium is higher than 3.5.

7. The pharmaceutical composition of claim 1 or 2, wherein the ratio of the amount of NSAID in the core to the amount of NSAID in the layer (c) or (g) ranges from about 1 :0.4 to 1 :0.01 .

8. The pharmaceutical composition of claim 1 or 2, wherein the PPI and NSAID in the layers of the composition release in the medium having pH 3.5 or less.

9. A tablet which sequentially comprises of:

(a) a core comprising NSAID or salt thereof;

(b) a seal coating layer coated over the core comprising a pharmaceutical excipients;

(c) an enteric coating layer coated over the core comprising a enteric polymers and a pharmaceutical excipients; (d) a seal coating layer coated over the core comprising a pharmaceutical excipients;

(e) a coating layer coated over the core comprising PPI or salt thereof and a pharmaceutical excipients;

(f) a seal coating layer coated over the core comprising a pharmaceutical excipients;

(g) a coating layer coated over the core comprising NSAID or salt thereof and a pharmaceutical excipients;

(h) an outer coating layer coated over the core comprising a pharmaceutical excipients, and

10. A process for preparing a pharmaceutical composition comprising NSAID, PPI or salt thereof, which process sequentially comprises steps of:

(a) providing at least one core comprising NSAID or salt thereof coated with at least one enteric coating layer comprising a enteric polymers;

(b) coating at least one PPI coating layer comprising a PPI over the core;

(d) optionally, coating at least one outermost layer over the core;

wherein said NSAID layer (c) and/or said outermost layer (d) comprises a alkalizers.

1 1 . The process of claim 10, wherein the release of the NSAID from the outer NSAID layer (c) begins before the release of PPI from said PPI layer (b) starts.

12. The process of claim 10, wherein the PPI and NSAID in the layers of the composition release in the medium having pH 3.5 or less.

13. A process for preparing a pharmaceutical composition comprising NSAID, PPI or salt thereof, which process sequentially comprises steps of:

(a) providing at least one core comprising NSAID or salt thereof;

(b) optionally, coating at least one seal coating layer over the core comprising a pharmaceutical excipients;

(c) coating at least one enteric coating layer over the core comprising a enteric polymers and a pharmaceutical excipients;

(d) optionally, coating at least one seal coating layer over the core comprising a pharmaceutical excipients;

(e) coating at least one layer over the core comprising PPI or salt thereof and a pharmaceutical excipients;

(f) optionally, coating at least one seal coating layer over the core comprising a pharmaceutical excipients;

(g) coating at least one layer coated over the core comprising NSAID or salt thereof and a pharmaceutical excipients;

(h) optionally, coating at least one outer layer over the core comprising a pharmaceutical excipients; and

wherein said NSAID layer (g) and/or said outer layer (h) comprises a alkalizers.