DESC:FIELD OF THE INVENTION
The present invention relates in part to a multiparticulate dosage form comprising Aspirin, a nonsteroidal anti-inflammatory drug and Pantoprazole or a pharmaceutically acceptable salt thereof, a proton pump inhibitor. The present invention, more particularly, relates to capsule formulation comprising an enteric coated aspirin and an enteric-coated pantoprazole or a pharmaceutically acceptable salt thereof, methods of preparation thereof, and their use in medical therapy.

BACKGROUND OF THE INVENTION
The efficacy of aspirin in preventing thrombotic events was convincingly demonstrated during the 1980s. Today, aspirin is a first-line antiplatelet drug in the setting of secondary cardio- and cerebrovascular prevention owing to a 25% reduction of serious vascular events compared to placebo. Importantly, cardiovascular protection by aspirin is obtained at the expense of more upper gastrointestinal bleeding events making aspirin the most prominent contributor to gastrointestinal bleeding-related mortality. Aspirin is imperative for most patients suffering a cardiovascular event, yet many of these patients require antiulcerant co-treatment to tolerate aspirin. Gastrointestinal bleeding is life-threatening, especially in patients presenting with acute coronary syndromes, and currently the use of proton pump inhibitors (PPI) is the recommended strategy for the prevention of gastrointestinal bleeding during antiplatelet therapy. Even in patients who continue taking aspirin after suffering a gastrointestinal bleeding event, aspirin seems to confer a net clinical benefit, as the increased bleeding risk is outbalanced by a better cardiovascular outcome.
Recently, increasing interest has focused on a potential drug interaction between PPIs and aspirin. PPIs exert an antacid effect by inhibiting the enzyme responsible for gastric acid secretion: the H+/K+-exchanging ATPase. Inhibiting this enzyme in gastric parietal cells raises intragastric pH, which has proven an effective pharmacological approach to prevent ulcer and bleeding. However, changing the intragastric milieu, such as raising pH, potentially affects the bioavailability of drugs, in particular those being absorbed across the gastric mucosal membrane. Aspirin is one such drug, and it has been hypothesized that caution should be taken when co-prescribing aspirin and PPIs. Under physiological conditions, aspirin is absorbed in its non-ionized lipid state across the gastric mucosal barrier. Proton pump inhibitors exert their antacid effect by inhibiting the H+/K+-exchanging ATPase of the gastric parietal cells. Intragastric pH rises above the pKa (3.5) of aspirin causing a pronounced reduction in the lipophilicity of aspirin thereby reducing its gastric absorption. Morten Würtz (Research Fellow) & Erik Lerkevang Grove (2012) Combining aspirin and proton pump inhibitors: for whom the warning bell tolls?, Expert Opinion on Drug Metabolism & Toxicology, 8:9, 1051-1055.
Aspirin is a nonsteroidal anti-inflammatory drug. The antiplatelet agent aspirin (acetylsalicylic acid) is chemically known as benzoic acid, 2- (acetyloxy)-, and has the following structural formula:

Compound A: Aspirin
Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction. USV Ltd, the original developer, is marketing a tablet form (ECOSPRIN® – strength 150) containing aspirin as an active ingredient. ECOSPRIN® 150 Tablet is an antiplatelet medicine used to treat and prevent heart attacks, strokes, and heart-related chest pain (angina). It helps to prevent the formation of blood clots in your blood vessels. It is a very widely used medicine for heart protection.
Pantoprazole is a proton pump inhibitors (PPI) drug. a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion, and has the following structural formula:

Compound B: Pantoprazole
Pantoprazole is a PPI that suppresses the final step in gastric acid production by covalently binding to the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the (H+,K+)- ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg). Wyeth Pharmaceuticals Llc, the original developer is marketing a delayed release tablet form, (PANTODAC® Strength – EQ 20MG BASE & EQ 40MG BASE) pantoprazole as an active ingredient. PANTODAC® is a proton pump inhibitor (PPI) indicated for the short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including zollinger-ellison (ZE) syndrome.
Presently there are numerous antiplatelet drugs which are widely available, however, most antiplatelet drugs are associated with side effects. For example, the administration of antiplatelet agents, such as aspirin and clopidogrel, have been associated with gastrointestinal disorders such as ulcers and gastrointestinal bleeding. In addition, the administration of antiplatelet agents, such as clopidogrel, may make some patients more susceptible to the ulcerogenic effects of ulcerogenic stimuli. It appears that a major factor contributing to the development of these gastrointestinal disorders is the presence of acid in the stomach and upper small intestine. While the mechanisms associated with ulcers and gastrointestinal bleeding are not entirely known, there are many causes of ulcers, including stress, alcohol irritation, Helicobacter pylori infection, and the side effects of non-steroid anti-inflammatory drugs such as aspirin, for example. Patients in need of long-term antiplatelet drug therapy often may interrupt or not receive such therapy due to gastrointestinal disorders, and as a result, patients are deprived of beneficial antiplatelet drug therapy. There is a need for oral pharmaceutical combination formulations to reduce or eliminate the gastrointestinal disorders associated with use of antiplatelet drugs.
WO2007115305 discloses oral dosage forms comprising an antiplatelet agent and an acid inhibitor, as well as methods of treating subjects with an antiplatelet agent and an acid inhibitor.
WO 9725064 describes an oral pharmaceutical dosage forms comprising an acid susceptible proton pump inhibitor and one or more NSAIDs in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer. The fixed formulation is in the form of an enteric coating layered tablet, a capsule or a multiple unit tableted dosage form. The multiple unit dosage forms are most preferred.
US 20020155153 Al discloses a fixed unit dosage form which can as one alternative be a capsule filled with more than one pharmaceutically active compound. The active compounds are preferably an acid susceptible proton pump inhibitor in combination with one or more NSAIDs and wherein at least the proton pump inhibitor is protected by an enteric coating layer.
WO2007115305 discloses methods of protecting the gastrointestinal tract from side effects associated with antiplatelet therapy using the oral dosage forms. The invention also relates to methods of protecting the gastrointestinal tract from side effects associated with antiplatelet therapy by co-administering an antiplatelet agent and an acid inhibitor. The oral dosage form comprises clopidogrel or prasugrel, in combination with aspirin and a proton pump inhibitor which is a member selected from omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole.
US20100009005 discloses oral pharmaceutical formulation which contains the dose of acetylsalicylic acid in the microcapsules of between about 50 and 325 mg, the dose of gastric acid suppressing agent is between about 5 and 120 mg, and the formulation is in a twice-a-day administration form. Preferably the gastric acid suppressing agent is a proton pump inhibitor. The NSAID of the oral pharmaceutical formulation may be in an immediate and/or controlled form. Further, the gastric acid suppressing agent of the oral pharmaceutical formulation may be in an immediate and/or controlled form.
Patients in need of long term antiplatelet drug therapy often may interrupt or not receive such therapy due to gastrointestinal disorders, and as a result, patients are deprived of beneficial antiplatelet drug therapy and despite of the above-mentioned prior art(s) disclosing pharmaceutical compositions of aspirin and proton pump inhibitors, there still exists a need for a stable oral pharmaceutical composition of enteric coated aspirin and enteric coated proton pump inhibitor such as pantoprazole or a pharmaceutically acceptable salt thereof which ensures the desired therapeutic effect, when correctly administered. also, there is a need for oral pharmaceutical combination formulations to reduce or eliminate the gastrointestinal disorders associated with use of antiplatelet drugs.
Hence, there is an unmet need in the art to develop a simple, robust process for pharmaceutical composition of aspirin and pantoprazole or a pharmaceutically acceptable salt thereof, which also offers desired pharmaceutical technical attributes such as dissolution, stability, bioequivalence, and manufactured by fluidized granulation process at industrial scale.
Within the scope of the present invention, it has now surprisingly been found that a stable pharmaceutical composition of enteric coated aspirin pellets and enteric coated pantoprazole sodium pellets prepared using optimised concentration of cetyl alcohol to create a thin hydrophobic layer which not only improves the texture of pellets and increases consistency but also, act as moisture barrier. This moisture barrier prevents the catalyzed hydrolysis of aspirin and improves stability of the pharmaceutical composition.

OBJECT OF THE INVENTION
It is an object of the present invention to provide a stable capsule dosage form comprising an enteric coated aspirin multiparticulates and an enteric-coated pantoprazole sodium multiparticulates.
It is another object of the present invention to provide a stable pharmaceutical composition comprising an enteric coated aspirin multiparticulates and an enteric coated pantoprazole or a pharmaceutically acceptable salt thereof multiparticulates, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage condition of 30 ± 2°C / 75 ± 5 % RH for a period of 18 months.
It is another object of the present invention to provide a multiparticulate dosage form comprising a plurality of pellets filled in to capsule comprising:
(A) aspirin multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising Aspirin,
b. about 10% to about 15% weight percent of an enteric coating layer surrounding the drug layered core based on the total weight of the dosage form, wherein the enteric coating comprises a hydroxy propyl methyl cellulose phthalate as an enteric polymer; and
(B) pantoprazole sodium multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising pantoprazole Sodium,
b. about 20% to about 26% weight percent of an enteric coating surrounding the drug layered subunit, based on the total weight of the dosage form, wherein the enteric coating comprises methacrylic acid copolymer as an enteric polymer; and
wherein the multiparticulate dosage form contains not more than 2% of total impurities for each of Aspirin and Pantoprazole Sodium respectively after storage at under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity for the period of at least 18 months.

It is another object of the present invention to provide a multiparticulate dosage form comprising a plurality of pellets filled in to a capsule comprising:
(A) aspirin multiparticulates:
c. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising aspirin,
d. about 10% to about 15% weight percent of an enteric coating layer surrounding the drug layered core based on the total weight of the dosage form, wherein the enteric coating comprises a hydroxy propyl methyl cellulose phthalate as an enteric polymer and cetyl alcohol as a plasticizer in amount of 0.10%w/w to about 0.50%w/w; and
(B) pantoprazole sodium multiparticulates:
c. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising pantoprazole Sodium,
d. about 20% to about 26% weight percent of an enteric coating surrounding the drug layered subunit, based on the total weight of the dosage form, wherein the enteric coating comprises methacrylic acid copolymer as an enteric polymer and cetyl alcohol as a plasticizer in amount of 0.10%w/w to about 0.50%w/w; and
wherein the multiparticulate dosage form contains not more than 2% of total impurities for each of aspirin and pantoprazole Sodium respectively after storage at under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity for the period of at least 18 months.

It is another object of the present invention to provide a stable capsule composition suitable for oral administration comprising:
a. 25%w/w of enteric coated aspirin in a multiparticulate form;
b. 60%w/w of enteric coated pantoprazole sodium in a multiparticulate form.

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) aspirin;
b) pantoprazole sodium;
c) one or more enteric coating polymers selected from the group comprising hydroxy propyl methyl cellulose phthalate (HPMCP) and methacrylic acid copolymer (L-30D) or combinations thereof;
d) one or more stabilizer selected from the group consisting of cetyl alcohol and diethyl sebacate or combinations thereof;
e) one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION
The present invention provides the following aspects, subject-matters and preferred embodiments, which respectively taken alone or in combination, further contribute to solving the object of the present invention.
In one aspect of the present invention, there is provided a stable capsule formulation comprising an enteric coated aspirin multiparticulates and an enteric-coated pantoprazole sodium multiparticulates.
In another aspect of the present invention, there is provided a stable pharmaceutical composition comprising an enteric coated aspirin multiparticulates and an enteric coated pantoprazole or a pharmaceutically acceptable salt thereof multiparticulates, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage condition of 30 ± 2°C / 75 ± 5 % RH and for a period of 18 months.
In further aspect of the present invention, there is provided a capsule dosage form comprising a plurality of pellets filled in a capsule comprising:
(A) aspirin multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising aspirin,
b. about 10% to about 15% weight percent of an enteric coating layer surrounding the drug layered core based on the total weight of the dosage form, wherein the enteric coating comprises a hydroxy propyl methyl cellulose phthalate as an enteric polymer; and
(B) pantoprazole sodium multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising pantoprazole sodium,
b. about 20% to about 26% weight percent of an enteric coating surrounding the drug layered subunit, based on the total weight of the dosage form, wherein the enteric coating comprises methacrylic acid copolymer as an enteric polymer; and
wherein the capsule dosage form contains not more than 2% of total impurities for each of aspirin and pantoprazole sodium respectively after storage at under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity for the period of at least 18 months.

In further aspect of the present invention, there is provided a Capsule dosage form comprising a plurality of pellets in a capsule comprising:
(A) aspirin multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising aspirin,
b. about 10% to about 15% weight percent of an enteric coating layer surrounding the drug layered core based on the total weight of the dosage form, wherein the enteric coating comprises a hydroxy propyl methyl cellulose phthalate as an enteric polymer and cetyl alcohol as a plasticizer in amount of 0.10%w/w to about 0.50%w/w; and
(B) pantoprazole sodium multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising pantoprazole sodium,
b. about 20% to about 26% weight percent of an enteric coating surrounding the drug layered subunit, based on the total weight of the dosage form, wherein the enteric coating comprises methacrylic acid copolymer as an enteric polymer and cetyl alcohol as a plasticizer in amount of 0.10%w/w to about 0.50%w/w; and
wherein the Capsule dosage form contains not more than 2% of total impurities for each of aspirin and pantoprazole sodium respectively after storage at under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity for the period of at least 18 months.

In further aspect of the present invention, there is provided a stable Capsule composition suitable for oral administration comprising:
a. 25%w/w of enteric coated aspirin in a multiparticulate form;
b. 60%w/w of enteric coated pantoprazole sodium in a multiparticulate form.

In another aspect of the present invention, there is provided a stable pharmaceutical composition, for oral administration comprising:
a) aspirin;
b) pantoprazole sodium;
c) one or more enteric coating polymers selected from the group comprising hydroxy propyl methyl cellulose phthalate (HPMCP) and methacrylic acid copolymer (L-30D) or combinations thereof
d) one or more stabilizers selected from the group consisting of cetyl alcohol and diethyl sebacate or combinations thereof;
e) one or more pharmaceutically acceptable excipients.
The invention also relates to methods of protecting the gastrointestinal tract from side effects associated with antiplatelet therapy using the oral dosage forms described herein. The invention also relates to methods of protecting the gastrointestinal tract from side effects associated with antiplatelet therapy by administering combination of an antiplatelet agent and an acid inhibitor.

DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas, or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is to describe particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
In an embodiment, the stable pharmaceutical composition for oral administration comprises:
a) aspirin;
b) pantoprazole sodium;
c) one or more enteric coating polymers;
d) one or more stabilizers;
e) one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a stable pharmaceutical composition in the form of multiparticulates filled in a capsule dosage form.
In another embodiment, the present invention provides a stable pharmaceutical composition in a capsule dosage form comprising 20 mg to 500 mg of aspirin and 20 mg to 100 mg of pantoprazole or a pharmaceutically acceptable salt thereof, wherein each of aspirin and pantoprazole are in an enteric coated and multiparticulate form.
In another preferred embodiment, the present invention provides a stable pharmaceutical composition in a capsule dosage form comprising 81 mg to 150 mg of enteric coated aspirin multiparticulates and 20 mg to 100 mg of enteric coated pantoprazole or a pharmaceutically acceptable salt thereof, multiparticulates.
In another embodiment, the present invention provides a stable capsule dosage form comprising a plurality of pellets in a capsule comprising:
(I) Aspirin portion comprising about 20-70%w/w aspirin, about 15- 30%w/w sugar spheres, about 0.5-20%w/w starch and polyvinylpyrrolidone, about 0.5-7%w/w sodium starch glycolate, about 1-10%w/w of citric acid, about 5-25%w/w of enteric coating dispersion, wherein the enteric coating dispersion comprises hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, cetyl alcohol and suitable excipients;
(II) Pantoprazole portion comprising about 15- 30% w/w pantoprazole sodium, about 20-40% w/w sugar spheres, about 2-15% w/w hypromellose, about 0.5-5%w/w sodium carbonate and disodium orthophosphate, about 0.5-7% w/w sodium starch glycolate, about 0.5-7% w/w of sodium lauryl sulphate, about 1-10% w/w of talc, about 1-10 % w/w of enteric coating dispersion, wherein the enteric coating dispersion comprises methacrylic acid copolymer (L-30D), hydroxypropyl methylcellulose phthalate, cetyl alcohol and suitable excipients.
In another embodiment, the present invention provides a stable pharmaceutical composition in a capsule dosage form wherein the composition comprises:
about 20 mg to about 200 mg aspirin, about 15mg to about 80mg pantoprazole sodium, about 80 mg sugar spheres, about 5 mg starch, polyvinylpyrrolidone and hypromellose, about 4 mg sodium starch glycolate, about 8 mg of citric acid, sodium carbonate and disodium orthophosphate, about 5 to 12.115 mg of enteric coating dispersion, wherein the enteric coating dispersion comprises polymers selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, methacrylic acid copolymer (L-30D) and hydroxypropyl methylcellulose phthalate and cetyl alcohol and suitable excipients.
In another embodiment, the present invention provides a stable capsule dosage form comprising a plurality of pellets in a capsule comprising: (I) aspirin portion comprising about 60 % w/w aspirin, about 22 % w/w sugar spheres, about 2 % w/w starch and polyvinylpyrrolidone, about 1.2 % w/w sodium starch glycolate, about 2.4 % w/w of citric acid, about 12 % w/w of enteric coating dispersion, wherein the enteric coating dispersion comprises hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, cetyl alcohol and suitable excipients;
(II) Pantoprazole portion comprising about 28 % w/w pantoprazole sodium, about 30 % w/w sugar spheres, about 11 % w/w hypromellose, about 2.4 % w/w sodium carbonate and disodium orthophosphate, about 1.2 % w/w sodium starch glycolate, about 1.2 % w/w of sodium lauryl sulphate, about 2.2 % w/w of talc, about 24 % w/w of enteric coating dispersion, wherein the enteric coating dispersion comprises methacrylic acid copolymer (L-30D), hydroxypropyl methylcellulose phthalate, cetyl alcohol and suitable excipients.
In another embodiment, the present invention provides a stable capsule dosage form comprising a plurality of pellets in a capsule comprising:
(I) Aspirin portion comprising:
a) about 150 mg aspirin, b) about 55.86 mg sugar spheres, c) about 5 mg starch and polyvinylpyrrolidone, d) about 3 mg sodium starch glycolate, e) about 6 mg of citric acid, f) about 30 mg of enteric coating dispersion, wherein the enteric coating dispersion comprises hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, cetyl alcohol and suitable excipients.
(II) Pantoprazole portion comprsing:
a) about 22.5 mg pantoprazole sodium, b) about 24 mg sugar spheres, c) about 8.5 mg hypromellose, d) about 2 mg sodium carbonate and disodium orthophosphate, e) about 1 mg sodium starch glycolate, f) about 1 mg of sodium lauryl sulphate, g) about 1.8 mg of talc, h) about 19.5 mg of enteric coating dispersion, wherein the enteric coating dispersion comprises methacrylic acid copolymer (L-30D), hydroxypropyl methylcellulose phthalate, cetyl alcohol and suitable excipients.

In another embodiment, the oral dosage form comprises a plurality of pellets filled in a capsule comprising:
(A) aspirin multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising aspirin,
b. about 10% to about 15% weight percent of an enteric coating layer surrounding the drug layered core based on the total weight of the dosage form, wherein the enteric coating comprises a hydroxy propyl methyl cellulose phthalate as an enteric polymer; and
(B) pantoprazole sodium multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising pantoprazole Sodium,
b. about 20% to about 26% weight percent of an enteric coating surrounding the drug layered subunit, based on the total weight of the dosage form, wherein the enteric coating comprises methacrylic acid copolymer as an enteric polymer; and
wherein the capsule dosage form contains not more than 2% of total impurities for each of aspirin and pantoprazole sodium respectively after storage at under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity for the period of at least 18 months.

In another embodiment, the capsule dosage form comprises a plurality of pellets in a capsule comprising:
(A) aspirin multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising aspirin,
b. about 10% to about 15% weight percent of an enteric coating layer surrounding the drug layered core based on the total weight of the dosage form, wherein the enteric coating comprises a hydroxy propyl methyl cellulose phthalate as an enteric polymer and cetyl alcohol as a plasticizer in amount of 0.10%w/w to about 0.50%w/w; and
(B) pantoprazole sodium multiparticulates:
a. a drug layered pellets comprising a sugar sphere core, and a drug layer surrounding the sugar sphere comprising pantoprazole Sodium,
b. about 20% to about 26% weight percent of an enteric coating surrounding the drug layered subunit, based on the total weight of the dosage form, wherein the enteric coating comprises methacrylic acid copolymer as an enteric polymer and cetyl alcohol as a plasticizer in amount of 0.10%w/w to about 0.50%w/w; and
wherein the capsule dosage form contains not more than 2% of total impurities for each of aspirin and pantoprazole Sodium respectively after storage at under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity for the period of at least 18 months.
The term "composition" or "formulation" or "dosage form" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles, granules and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The compositions in accordance with the present invention can be prepared by dry granulation, wet granulation, direct compression, roller compaction process, hot melt extrusion or fluidized bed granulation techniques.
The compositions in accordance with the present invention prepared by fluidized bed granulation technique.
The term “multiparticulate” as used herein refers to plurality of physically discrete units, wherein each discrete unit is coated with an enteric polymer. The discrete unit comprises a drug core in the form of pellets, beads, particles, granules, or minitablets. In the present specification, the term “multiparticulates”, “discrete units”, “pellets”, “beads”, are used interchangeably.
The multiparticulate dosage form may be present in the form of easy to open capsules, conventional hard capsules (e.g. a capsule of gelatin, HPMC or a starch derivative), or a sachet.
The term “about”, as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "pharmaceutically acceptable salt" is suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of a reasonable medical evaluation, and has a reasonable benefit. A preferable salt suitable for pantoprazole is the sodium, potassium, magnesium, zinc, Lithium and the like. The most preferred salt is pantoprazole sodium.
The term "excipient" as used herein refers to a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, stabilizer, disintegrant, lubricant, glidant, surfactant, colorant, coating agent or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic, and acceptable for human use.
The term "stable" as used herein, refers to the chemical stability of Aspirin and Pantoprazole Sodium in which not more than 2% total impurities are formed for each of Aspirin and Pantoprazole Sodium respectively when the capsule dosage form is stored under conditions of stability at 30 ± 2°C / 75 ± 5 % relative humidity and 25 ± 2°C / 60 ± 5 % relative humidity for the period of at least 18 months.
The terms “solubility enhancer” or “solubilizing agent” are used interchangeably to refer to any chemical and/or biological agent able to improve the solubility of an active agent in a solvent. Exemplary solubility enhancers include povidone, cholesterol, cyclodextrins, polyethylene glycols, polysorbates and sodium lauryl sulphate.
The term “impurity” or “impurities” refers to undesired contents present or produced in a pharmaceutical composition.
The term “fluidized bed granulation” as used herein, refers to the formation of granules using a granulation liquid (water, organic solvent, or a solution) using a fluid bed processor.
In a further embodiment, the fillers or diluents used in the composition of the present invention are selected from, but are not limited to, sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches, carbohydrate derivatives, polysaccharides (including dextrose and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In certain preferred embodiments, the filler or diluent is lactose, microcrystalline cellulose, or a combination thereof. Several types of microcrystalline cellulose are suitable for use in the formulations described herein, for example, microcrystalline cellulose selected from the group consisting of Avicel® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. Several types of lactose are suitable for use in the formulations described herein, for example, lactose is selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flow, directly compressible anhydrous lactose, and modified lactose monohydrate. Preferably, the filler or diluent, if present, is a one or combination of microcrystalline cellulose and lactose monohydrate.
In a further embodiment, the binders used in the composition of the present invention are selected from, but are not limited to, cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, ethylcellulose, and sodium carboxymethyl cellulose), sugar (including sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), glycol, corn syrup, polysaccharides (including acacia, tragacanth, guar, alginates, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like. Preferably, the binding agent, if present, is hydroxypropyl methyl cellulose. Binder may be used in the range of 1 - 15 % w/w of the total weight of the stable oral pharmaceutical composition.
In a further embodiment, the disintegrants used in the composition of the present invention are selected from, but are not limited to, starches, clays, celluloses, alginates, and gums, and crosslinked starches, celluloses, and polymers, combinations thereof, and the like. Representative disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar, and related gums, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.
In a further embodiment, the glidants used in the composition of the present invention are selected from, but are not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, or mixtures thereof. Preferably, the glidant, if present, is a colloidal silicon dioxide. Glidant may be used in the range of 0.5 - 5 % w/w of the total weight of the stable oral pharmaceutical composition.
In a further embodiment, the lubricants used in the composition of the present invention are selected from, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and the like and mixtures thereof. Preferably, the lubricant, if present, is a calcium stearate. Lubricant may be used in the range of 0.5 - 5 % w/w of the total weight of the stable oral pharmaceutical composition.

“Colorants” may be selected from, but are not limited to, iron oxide yellow, iron oxide red, titanium dioxide, sunset yellow lake, Indigo carmine lake, Indigo carmine Supra or mixtures thereof. Colorants may be used in the range of 2 - 10 % w/w of the total weight of the stable oral pharmaceutical composition.
The stable pharmaceutical compositions of the present invention may be further coated with a functional or non-functional coating. The coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers. The total weight gain after coating may be about 1% w/w to 15% w/w of the uncoated pharmaceutical composition.
“Coating agents” which are useful in the coating process, may be selected from, but not limited to, water-soluble polymers such as, but not limited to, polyvinylpyrrolidone or water-soluble cellulose such as, but not limited to, hydroxypropyl methylcellulose or hydroxypropyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, com, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, intracoat aqua, polyvinyl alcohol, copolymers of vinylpyrrolidone, vinyl acetate, methacrylic acid copolymer or combinations thereof. These may be applied from aqueous or non-aqueous systems or combinations of the aqueous and non-aqueous systems as appropriate.
Examples of binders for coating include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, crospovidone, starch, pregelatinized starch, or mixtures thereof. Examples of plasticizers for coating include, but are not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof. Examples of opacifiers/stabilizers for coating include, but are not limited to, titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.
Anti-tacking agents such as, but are not limited to, talc, stearic acid, magnesium stearate, colloidal silicon dioxide, or the like. Examples of coloring agents for coating include but are not limited to, FDA-approved colorants such as iron oxide, the lake of tartrazine, allura red, the lake of quinoline yellow, the lake of erythrosine, titanium dioxide, or mixtures thereof. Suitable solvents for the coating include but are not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.
Another aspect of the present invention provides a capsule formulation comprising combination of aspirin and pantoprazole or a pharmaceutically acceptable salt thereof, used for the prevention of gastroduodenal mucosal damage inpatients taking aspirin for secondary prevention of cardiovascular disease cerebrovascular disease.
Yet another aspect of the present invention is to provide a process of preparation of capsule formulation comprising aspirin and pantoprazole or a pharmaceutically acceptable salt thereof.
A stability study carried out for the aspirin and pantoprazole sodium capsule which provided satisfactory data for all the physical and chemical parameters, wherein initial, 6 months, 12 months and 18 months stability studies were performed at 30 ± 2°C / 75 ± 5 % RH and 25 ± 2°C / 60 ± 5 % RH.
According to another embodiment of the invention, the capsules dosage form containing enteric coated aspirin 150 mg and enteric coated pantoprazole sodium 20 mg is bioequivalent to the existing pantodac 20mg tablets and ecospirin 150 mg tablets administered together.
It should be appreciated that the invention can be embodied / aspects in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Example 1:
Table 1
S.N. Ingredients
Mg / Capsule %w/w
I. Aspirin Enteric Coated (EC) Pellets 60 % w/w
A. Drug Loading
1. Sugar Spheres 55.860 22.344
2. Aspirin 150.000 60
3. Starch 2.970 1.188
4. Sodium Starch Glycolate 2.970 1.188
5. Citric Acid Anhydrous 5.938 2.375
6. Polyvinyl pyrrolidone (PVP K30) 1.980 0.792
7. Isopropyl Alcohol q.s. q.s.
8. Methylene Dichloride q.s. q.s.
B. Enteric Coating
9. Hydroxy propyl methyl cellulose Phthalate (HPMCP) 15.042 6.017
10. Hydroxy propyl methyl cellulose 12.667 5.067
11. Cetyl Alcohol 0.990 0.396
12. Sunset yellow lake 1.583 0.633
13. Acetone q.s. q.s.
14. Isopropyl Alcohol q.s. q.s.
II. Pantoprazole Enteric Coated (EC) Pellets 25 % w/w
A. Drug Loading
1. Sugar Spheres 24 30
2. Pantoprazole Sodium 22.5496 28.187
3. Hypromellose (HPMC E5) 8.5304 10.663
4. Sodium carbonate 0.9648 1.206
5. Disodium orthophosphate 0.9648 1.206
6. Sodium Starch Glycolate 0.9648 1.206
7. Sodium lauryl Sulphate 0.9648 1.206
8. Talc 1.7624 2.203
9. Isopropyl Alcohol q.s. q.s.
10. Purified Water q.s. q.s.
B Enteric Coating
11. Methacrylic Acid Copolymer (L-30D) 15.4664 19.333
12. Hydroxy propyl methyl cellulose Phthalate (HPMCP) 1.1248 1.406
13. Diethyl Phthalate 1.8744 2.343
14. Polysorbate 80 0.1016 0.127
15. Cetyl Alcohol 0.176 0.220
16. Titanium Dioxide 0.4224 0.528
17. Indigo carmine Lake 0.076 0.095
18. Indigo Carmine Supra 0.0568 0.071
19. Acetone q.s. q.ss
20. Isopropyl Alcohol q.s. q.s.
21. Purified Water q.s. q.s.
Manufacturing process:
I) Aspirin EC Pellets 60 % w/w
1. Drug Loading:
1.1 Aspirin, citric acid and sodium starch glycolate were accurately weighed and dissolved in isopropyl alcohol under stirring.
1.2 Starch and polyvinyl pyrrolidone were added into the step 1.1 solution under stirring, to this solution methylene chloride were added under stirring.
1.3 The solution obtained in step 1.2 was sprayed on the sugar spheres in a fluidized bed processor and dried under low fluidization to obtain drug-loaded pellets.
2. Enteric Coating:
2.1 Hydroxy propyl methyl cellulose phthalate was dissolved in a mixture of isopropyl alcohol and acetone in an S.S. container under stirring.
2.2 Hydroxy propyl methyl cellulose, cetyl alcohol and sunset yellow lake were added into the step 2.1 solution under stirring.
2.3 Drug-loaded pellets obtained in step 1.3 were coated with the solution obtained in step 2.2 and dried under low fluidization.
II. Pantoprazole EC Pellets 25 % w/w
3. Drug Loading:
3.1 Disodium orthophosphate, sodium carbonate and sodium starch glycolate were accurately weighed and dissolved in a mixture of isopropyl alcohol and purified water under stirring.
3.2 To the above solution pantoprazole sodium and sodium lauryl sulphate were added under constant stirring.
3.3 Hypromellose (HPMC E5) and talc was added into the step 3.2 solution under constant stirring.
3.4 The solution obtained in step 3.2 was sprayed on the sugar spheres in a fluidized bed processor and dried under low fluidization to obtain drug-loaded pellets.
4. Enteric Coating:
4.1 Methacrylic acid copolymer (L-30D) and polysorbate 80 were dissolved in purified water under stirring.
4.2 Hydroxy propyl methyl cellulose Phthalate, diethyl phthalate, cetyl alcohol, titanium dioxide, indigo carmine lake and indigo carmine supra were added to the solution of isopropyl alcohol and acetone under stirring.
4.3 Solution obtained in step 4.1 was added to the solution obtained in step 4.2 under stirring.
4.4 Drug-loaded pellets obtained in step 3.4 was coated with the solution obtained in step 4.3 and dried under low fluidization.
III. Aspirin EC and Pantoprazole EC Capsules
5. Capsule Filling
5.1 Empty hard gelatin size 1 clear transparent capsule shells were loaded in the hopper of the automatic capsules filling machine.
5.2 Pantoprazole Sodium enteric coated pellets 25% w/w obtained in step 4.4 and Aspirin enteric coated pellets 60% w/w obtained in step 2.3 into two separate hoppers of the capsules filling machine and adjust the average filled weight of capsules.
Example 2:
Table 2
S. N. Ingredients (% Range w/w)
I. Aspirin EC Pellets 20-70 % w/w
A. Drug Loading
1. Sugar Spheres 15-30
2. Aspirin 20-70
3. Starch 0.5-20
4. Sodium Starch Glycolate 0.5-0.7
5. Citric Acid Anhydrous 1-10
6. Polyvinyl pyrrolidone (PVP K30) 0.5-0.7
7. Isopropyl Alcohol q.s.
8. Methylene Dichloride q.s.
B. Enteric Coating
9. Hydroxy propyl methyl cellulose Phthalate (HPMCP) 1-6
10. Hydroxy propyl methyl cellulose 1-5
11. Cetyl Alcohol 0.1-0.5
12. Sunset yellow lake 0.1-0.7
13. Acetone q.s.
14. Isopropyl Alcohol q.s.
II. Pantoprazole EC Pellets 20-40 % w/w
A. Drug Loading
1. Sugar Spheres 20-40
2. Pantoprazole Sodium 15-30
3. Hypromellose (HPMC E5) 2-15
4. Sodium carbonate 0.5-5
5. Disodium orthophosphate 0.5-5
6. Sodium Starch Glycolate 0.5-7
7. Sodium lauryl Sulphate 0.5-7
8. Talc 1-10
9. Isopropyl Alcohol q.s.
10. Purified Water q.s.
B Enteric Coating
11. Methacrylic Acid Copolymer (L-30D) 10-20
12. Hydroxy propyl methyl cellulose Phthalate (HPMCP) 0.1-5
13. Diethyl Phthalate 0.1-5
14. Polysorbate 80 0.1-5
15. Cetyl Alcohol 0.5-7
16. Titanium Dioxide 0.5-5
17. Indigo carmine Lake 0.05-5
18. Indigo Carmine Supra 0.05-5
19. Acetone q.s.
20. Isopropyl Alcohol q.s.
21. Purified Water q.s.
Manufacturing Process: same as in Example 1

A. Stability study of Example 1: For 6 Months and 12 months at 250C /60% RH condition.
Table 3:

Sr. No. Test Initial 6 months 12 months 18 months
1. Dissolution
A. Pantoprazole: 0.0 % 0.32 % 2.1 % 3.1%
103.0 % 100.4 % 102.0 % 101.8%
B. Aspirin 0.6 % 1.2 % 4.0 % 4.2%
103.0 % 99.9 % 98.6 % 98.6%
2. Assay (% Label claim)

A.Pantoprazole content Claim: 20 mg / Capsule

105.3 %

104.3 %

104.1 %

103.8%
B. Aspirin content Claim: 150 mg / Capsule 103.5 % 106.0 % 108.7 % 108.3%
3. Related substances (% w/w By HPLC):

Pantoprazole:
Impurity A
Impurity B
Impurity D & F
Single highest unknown impurity
Total impurities (other than known impurities)

0.36 %
0.08 %
0.18 %
0.09 %
0.38 %

0.41 %
0.23 %
0.17 %
0.21 %
0.55 %

0.37 %
0.12 %
0.27 %
0.13 %
0.79 %

0.45%
0.25%
0.35%
0.25%
0.82%
Aspirin:
Salicylic acid
0.15 %
0.62 %
0.89 %
0.96%

All the physical and chemical parameters were found satisfactory and the initial, 6 Month, 12 month and 18 months stability data at 25 ± 2°C / 60 ± 5 % RH were found to be satisfactory and within acceptable limits.
B. Stability study: Stability Study of Example 1 for 6 Months and 12 months at 30 ± 2°C / 75 ± 5 % RH condition.
Table 4:
Sr. No. Test Initial 6 Month 12 Month 18 month
4. Dissolution
A. Pantoprazole: 0.0 % 1.98 % 4.3 % 1.98%
103.0 % 99.2 % 100.0 % 99.9%
B. Aspirin 0.6 % 2.4 % 4.2 % 4.8%
103.4 % 100.0 % 97.8 % 98%
5. Assay (% Label claim)

A.Pantoprazole content Claim: 20 mg / Capsule

105.3 %

102.5 %

102.0 %

102.2%
B. Aspirin content Claim: 150 mg / Capsule 103.5 % 104.8 % 102.7 % 102.5%
6. Related substances (% w/w By HPLC):

Pantoprazole:
Impurity A
Impurity B
Impurity D & F
Single highest unknown impurity
Total impurities (other than known impurities)

0.36 %
0.08 %
0.18 %
0.09 %

0.38 %

0.56 %
0.28 %
0.37 %
0.26 %

0.69 %

0.39 %
0.13 %
0.43 %
0.16 %

0.99 %

0.42%
0.14%
0.48%
0.28%

1.01%
Aspirin:

Salicylic acid

0.20 %

0.62 %

0.89 %

0.95%

All the physical and chemical parameters were found satisfactory and the initial, 6 months, 12 months and 18 months stability data at 30 ± 2°C / 75 ± 5 % RH were found to be satisfactory and within acceptable limits.

Example 3: The Bioequivalence Study
A. Scientific Title of Study:
A randomized, open-label, balanced, two treatment, two period, two sequence, crossover, single oral dose, bioequivalence study comparing pantoprazole sodium enteric coated and Aspirin Enteric coated Capsules (20 mg + 150 mg) obtained in Example 1 of Alkem Laboratories Ltd. India with Pantodac 20 Tablets (Pantoprazole Gastro- resistant Tablets IP 20 mg) manufactured by Zydus Healthcare Ltd. and Ecosprin-150 (Aspirin Gastro-Resistant Tablets IP 150 mg) manufactured by USV Private Limited in healthy adult male human subjects under fasting conditions.
B. Reference product:
Pantodac 20 Tablets (Pantoprazole Gastro- resistant Tablets IP 20 mg) manufactured by Zydus Healthcare Ltd. Ecosprin-150 (aspirin gastro-resistant tablets IP 150 mg) manufactured by USV Private Limited.
C. Test Product: Pantoprazole sodium enteric coated and aspirin enteric-coated capsules (20 mg + 150 mg) obtained in Example 1
D. Bioequivalence Results:
I. Geometric Means and 90% confidence interval for all the subject's data of pantoprazole (N=40)
Table No. 5
Parameters *Geometric mean % Ratio 90 % CI for Log transformed
Test (T) Reference (R) T/R Lower Limit Upper Limit
Cmax (ng/mL) 2213.305 2257.302 98.05 91.93 104.57
AUC(0-t)
(ng/mL x hr) 8467.668 8238.010 102.79 94.45 111.87
AUC(0-?)
(ng/mL x hr) 8897.165 8711.027 102.14 93.51 111.56
II. Geometric Means and 90% Confidence Interval for all the subject's data of acetylsalicylic acid (N=40)
Table No. 6
Parameters *Geometric mean % Ratio 90 % CI for Log transformed
Test (T) Reference (R) T/R Lower Limit Upper Limit
Cmax (ng/mL) 767.877 783.422 98.02 92.15 104.25
AUC(0-t)
(ng/mL x hr) 1956.418 1958.204 99.91 90.68 110.08
AUC(0-?)
(ng/mL x hr) 2012.805 2022.472 99.52 90.73 109.16

CONCLUSION:
Based on the statistical analysis of pantoprazole sodium and acetylsalicylic acid, it is concluded that the Test Product (T): pantoprazole sodium enteric coated and aspirin enteric-coated capsules (20 mg + 150 mg) of alkem laboratories ltd., India is bioequivalent to the reference product (R): pantodac 20 tablets (pantoprazole gastro-resistant tablets IP 20 mg) manufactured by Zydus Healthcare Ltd. And ecosprin-150 (aspirin gastro-resistant tablets IP 150 mg) manufactured by USV Private Limited in terms of rate and extent of absorption under fasting conditions.

,CLAIMS:We claim:
1. A stable pharmaceutical composition comprising: a) aspirin or a pharmaceutically acceptable salt thereof; b) pantoprazole or a pharmaceutically acceptable salt thereof; c) one or more enteric coating polymer and d) one or more pharmaceutically acceptable excipients.
2. The stable composition as claimed in claim 1, wherein the enteric coating polymer is selected from the group consisting of hydroxy propyl methyl cellulose phthalate and methacrylic acid copolymer.
3. The stable composition as claimed in claim 1, wherein the composition comprises aspirin or a pharmaceutically acceptable salt thereof in an amount of about 20 % w/w to about 70 % w/w.
4. The stable composition as claimed in claim 1, wherein the composition comprises pantoprazole or a pharmaceutically acceptable salt thereof in an amount of about 15 % w/w to about 30 % w/w.
5. The stable composition as claimed in claim 1, wherein the composition further comprises one of more excipients selected from the group consisting of talc, titanium dioxide and red iron oxide.
6. The stable pharmaceutical composition comprising: (I) aspirin portion comprising a) about 60 % w/w aspirin, b) about 22 % w/w sugar spheres, c) about 2 % w/w starch and polyvinylpyrrolidone, d) about 1.2 % w/w sodium starch glycolate, e) about 2.4 % w/w of citric acid, f) about 12 % w/w of enteric coating dispersion, wherein the enteric coating dispersion comprises hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, cetyl alcohol and suitable excipients (II) pantoprazole portion comprising a) about 28 % w/w pantoprazole sodium, b) about 30 % w/w sugar spheres, c) about 11 % w/w hypromellose, d) about 2.4 % w/w sodium carbonate and disodium orthophosphate, e) about 1.2 % w/w sodium starch glycolate, f) about 1.2 % w/w of sodium lauryl sulphate, g) about 2.2 % w/w of talc, h) about 24 % w/w of enteric coating dispersion, wherein the enteric coating dispersion comprises methacrylic acid copolymer (L-30D), hydroxypropyl methylcellulose phthalate, cetyl alcohol and suitable excipients.
7. A stable pharmaceutical composition, for oral administration comprising: aspirin; pantoprazole sodium; one or more enteric coating polymers selected from the group comprising hydroxy propyl methyl cellulose phthalate and methacrylic acid copolymer or combinations thereof; one or more stabilizer selected from the group consisting of cetyl alcohol and diethyl sebacate or combinations thereof, and; one or more pharmaceutically acceptable excipients.
8. The stable composition as claimed in claim 1, wherein the composition comprises cetyl alcohol or diethyl sebacate in amount of about 0.10%w/w to about 0.50%w/w of the composition.
9. The stable composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 30 ± 2°C / 75 ± 5 % relative humidity.
10. The stable pharmaceutical composition as claimed any of the preceding claims, wherein the composition is prepared using prepared by fluidized bed granulation technique.