WO2013054352A1

WO2013054352A1 - Pharmaceutical compositions of ibuprofen and famotidine

Info

Publication number: WO2013054352A1
Application number: PCT/IN2012/000552
Authority: WO
Inventors: Sunilendu Bhushan Roy; Sushrut Krishnaji Kulkarni; Pavak Mehta; Manish BHADANI
Original assignee: Cadila Healthcare Limited
Priority date: 2011-08-17
Filing date: 2012-08-17
Publication date: 2013-04-18

Abstract

The present invention discloses a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof, an optional barrier layer and a surrounding portion comprising famotidine or salt thereof.

Description

PHARMACEUTICAL COMPOSITIONS OF IBUPROFEN AND FAMOTIDINE

Field of the Invention

The present invention relates to pharmaceutical compositions of ibuprofen and famotidine or salts thereof. In particular, the present invention relates to a single unit dosage form comprising ibuprofen and famotidine or salts thereof. The pharmaceutical compositions are particularly suitable for reducing ibuprofen-mediated gastric or duodenal ulceration and simultaneously improving patient compliance to the dosage regimen. The invention also provides process of manufacturing the said pharmaceutical compositions.

Background of the Invention

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), has been used in humans for nearly forty years. While generally regarded as safe, ibuprofen and other NSAIDs can cause gastritis, dyspepsia, and gastric and duodenal ulceration. Gastric and duodenal ulceration is a consequence of impaired mucosal integrity resulting from ibuprofen-mediated inhibition of prostaglandin synthesis. This side-effect is a particular problem for individuals who take ibuprofen for extended periods of time, such as patients suffering from rheumatoid arthritis and osteoarthritis.

The risk of developing gastric or duodenal ulceration can be reduced by. co- therapy with the drug famotidine. Famotidine blocks the action of the histamine type 2 (H2) receptor, leading to a reduction of acid secretion in the stomach. Reducing stomach acid with famotidine during treatment with certain nonsteroidal antiinflammatory drugs is reported to decrease incidence of gastrointestinal ulcers (Taha et al., 1996, "Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal anti- inflammatory drugs" N Engl J Med, 334:1435-9, and Rostom et al., 2002, "Prevention of NSAID-induced gastrointestinal ulcers", Cochrane Database Syst Rev, 4:CD002296).

Famotidine is used for treatment of heartburn, ulcers, and esophagitis at daily doses from 10 mg to 80 mg. Approved schedules of famotidine administration include 10 or 20 mg QD or BID (for treatment of heartburn), 20 mg or 40 mg QD (for healing ulcers, such as 40 mg HS for 4-8 weeks for healing duodenal ulcers), 20 mg HS (maintenance dose following healing of ulcer), 20 mg BID for 6 weeks (for treatment of gastroesophageal reflux disease), and 20 or 40 mg BID (for treatment of esophageal erosion). For treatment of Zollinger-Ellison Syndrome, a disease characterized by hypersecretion of gastric acid, doses of up to 800 mg/day have been used.

Although, NSAID plus famotidine co-therapy reduces risk of developing gastric or duodenal ulceration, such therapies are not widely used. One explanation for this observation is that patient compliance is more problematic with a regimen that requires administration of two separate dosage forms. Various efforts to develop a single unit dosage form comprising both NSAID and acid reducing agents have been made in the art.

International (PCT) Patent publication No. WO 2008/027963 discloses a pharmaceutical unit dosage form, comprising- (a) a sustained release component comprising an amount of a histamine receptor antagonist effective to raise gastric pH above about 3.5; and (b) a immediate release component comprising a therapeutically effective amount of an NSAID.

U.S. Patent publication No. US 2009/0142393 discloses a pharmaceutical composition comprising: a core comprising a therapeutically effective amount of famotidine; and a surrounding portion comprising a therapeutically effective amount of ibuprofen in direct physical contact with the core. The surface are of physical contact between the two actives does not exceed an area calculated from the formula: (25mm²) + (3.75mm². X), where X is quantity (mg) of famotidine in the core.

International (PCT) Patent publication No. WO 2007/012022 discloses an oral dosage form for administration of ibuprofen to a subject in need of ibuprofen treatment is provided, in which an oral dosage form comprising a therapeutically effective amount of ibuprofen and a therapeutically effective amount of famotidine, in admixture with one or more excipients.

International (PCT) Patent publication No. WO 2008/01 1426 discloses an oral unit dose form containing from 775 mg to 825 mg ibuprofen and from 25 mg to 28 mg famotidine, where the ibuprofen and famotidine are present in a weight ratio in the range 29: 1 to 31 :1, and where the ibuprofen and the famotidine are formulated for immediate release; administering a second dose of the oral dosage form; and administering a third dose of the oral dosage form, where the first dose, the . second dose, and the third dose are administered within a 24 hour dosing cycle. The ibuprofen and the famotidine are in separate compartments in the oral dosage form.

International (PCT) Patent publication No. WO 2008/091957 discloses a pharmaceutical composition comprising: a) ibuprofen-containing particles, wherein at least 80% of the ibuprofen particles are retained by 60 mesh screen and not more than 5% of the ibuprofen particles are retained by 20 mesh screen, and b) famotidine- containing particles, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine-containing particles are retained by 20 mesh screen wherein the ratio of ibuprofen to famotidine • (w/w) is at least 20.

U.S. Patent No. 6,926,907 discloses a single, coordinated, unit-dose product that combines: a) an agent that actively raises intragastric pH to levels associated with less risk of NSAID-induced ulcers; and b) an NSAID that is specially formulated to be released in a coordinated way that minimizes the adverse effects of the NSAID on the gastroduodenal mucosa. The NSAID part of the unit-dose product is surrounded by a coating which prevents the release of NSAID unless the pH of the surrounding medium is 3.5 or higher.

U.S. Patent publication No. US 2005/0020671 discloses a pharmaceutical formulation which comprises a core comprising a first active ingredient, a coating comprising a second active ingredient which is incompatible with the first active ingredient and a barrier between the core and the coating which prevents physical contact between the core and the coating, characterized in that the barrier is formed on the core by film-coating and the coating is formed on the barrier by press-coating.

To devise a stable and therapeutically effective formulation of ibuprofen and famotidine, however, is more challenging due to chemical incompatibility between the two actives.

Recognizing the potential benefits of famotidine for the prevention of ibuprofen-induced gastro-duodenal damage, others have disclosed strategies for combining the two active agents for therapeutic purposes. However, these suggestions do not provide for coordinated drug release or for reducing intra-gastric acid levels to a non-toxic level prior to the release of ibuprofen. With the earlier suggested means of delivery, there is likelihood of ibuprofen getting exposed to gastrointestinal tract prior to onset of famotidine activity.

Overall, it may be concluded that the risk of inducing gastrointestinal ulcers is a recognized problem associated with the administration of ibuprofen and that, despite considerable effort, there still exist a need of an ideal formulation, which is more simplified, enabling the simple production of the composition and exhibiting exceptional stability. Summary of the Invention

In one general aspect, there is provided a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof; and a surrounding portion comprising famotidine or salt thereof.

In another general aspect, there is provided a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof; and a surrounding portion comprising famotidine or salt thereof in direct physical contact with the core.

In another general aspect, there is provided a stable pharmaceutical composition in a single unit dosage form comprising:

(a) a core comprising ibuprofen or salt thereof;

(b) a barrier layer coated over the core; and

(c) at least one layer comprising famotidine or salt thereof coated over the barrier layer coated core.

(a) a core comprising ibuprofen or salt thereof;

(b) a barrier layer coated over the core;

(c) at least one layer comprising famotidine or salt thereof coated over the barrier layer coated core; and

(d) a protective layer coated over the famotidine coated core.

In another general aspect, there is provided a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising from 775 mg to 825 mg of ibuprofen or salt thereof; and a surrounding portion comprising from 24 mg to 28 mg of famotidine or salt thereof.

In another general aspect, there is provided a stable multilayer tablet comprising: at least one layer comprising ibuprofen or salt thereof; and at least one layer comprising famotidine or salt thereof.

In another general aspect, there is provided a stable pharmaceutical composition in a single unit, dosage form comprising: plurality of multiple unit particles (MUPS) comprising ibuprofen or salt thereof; and plurality of multiple unit particles (MUPS) comprising famotidine or salt thereof in direct physical contact with ibuprofen MUPS.

In another general aspect, there is provided a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof; and a surrounding portion comprising famotidine or salt thereof, wherein the composition retains at least 80% of the potency of ibuprofen and famotidine or salts thereof in the composition after storage for three months at 40° C and 75% relative humidity.

Embodiments of the stable pharmaceutical composition may include one or more of the following features. For example, the stable pharmaceutical composition may include one or more pharmaceutically acceptable excipients selected from binders, fillers, lubricants, disintegrants, glidants, antioxidants, solvents, flavors, sweeteners and the like.

In another general aspect, there is provided a process for the preparation of a stable pharmaceutical composition in a single unit dosage form comprising:

(a) preparing a core comprising ibuprofen or salt thereof;

(b) optionally, coating the core by a barrier layer;

(c) coating at least one layer comprising famotidine or salt thereof over the core or barrier layer coated core; and

(d) optionally, coating a protective layer over the core prepared in step (c).

In another general aspect, there is provided a method of treating chronic pain, an inflammatory condition, or a condition associated with chronic pain or an inflammatory condition, comprising administering a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof; and a surrounding portion comprising famotidine or salt thereof.

Detailed description of the Invention

The inventors of the present invention have developed a novel formulation of ibuprofen and famotidine that involves simple manufacturing steps enabling ease of production of unit dosage form containing ibuprofen and famotidine. The formulation reduces the risk of gastrointestinal side effects associated with ibuprofen therapy. The formulation comprises a core comprising ibuprofen that is specially formulated to be release in a coordinated way, i.e. release of famotidine followed by release of ibuprofen; that minimizes adverse effects of ibuprofen on the gastrointestinal mucosa, and a surrounding portion of famotidine that minimizes the adverse effects of ibuprofen on the gastro-duodenal mucosa.

Further, the formulation in accordance with the present invention can exhibit

o

excellent stability when stored for at least three months at 40 C and 75% relative humidity.

Thus, the embodiments of the present invention relates to a pharmaceutical composition, preferably in the form of a single unit dosage form, comprising a core comprising ibuprofen or salt thereof and a surrounding portion comprising famotidine or salt thereof.

The terms 'ibuprofen' and 'famotidine' used throughout the specification refers to ibuprofen and famotidine per se respectively, and also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs, and various crystalline or amorphous forms or mixtures thereof.

The term "core" as used herein, refers to a single interior compartment of the composition.

In an embodiment, the portion of famotidine in the pharmaceutical composition is in direct physical contact with the ibuprofen containing core.

The term "direct physical contact" refers to the absence of a barrier layer . between components or adjacent compartments of the composition.

In a further embodiment, the core of ibuprofen and surrounding portion of famotidine in the pharmaceutical composition are physically separated by a barrier layer.

In a further embodiment, the portion surrounding the ibuprofen core comprising famotidine in the pharmaceutical composition is further coated by at least one protective layer.

In a further embodiment, the composition of the barrier layer and protective layer of the pharmaceutical composition is substantially same.

The material suitable for use in the barrier and/or protective layer may comprise a water-soluble, pH dependent or independent film that promotes immediate disintegration for rapid release of the ibuprofen core. Materials that can be used for readily soluble films are well known in the art and include cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and ethyl cellulose; methacrylic polymers, amino-alkylmethacrylate copolymers (e.g. Eudragit®), polyvinyl acetate phthalate and polyvinyl alcohol (PVA). A plasticizer (e.g., triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol) may also be included.

The barrier and/or protective layer may include an anti-adherent or glidant (e.g., talc, fumed silica or magnesium stearate) and colorants such as titanium dioxide, iron oxide based colorants or others.

^■ i In a further embodiment the barrier layer comprises a non-toxic edible polymer, edible pigment particles, an edible polymer plasticizer, and a surfactant. Materials include, for example and not limitation, materials described in U.S. Patent No.

4,543,370, incorporated herein by reference.

Exemplary barrier and/or protective layers include OPADRY®; OPADRY II® which comprises HPMC, titanium dioxide, plasticizer and other components (e.g.

OPADRY® Blue, OPADRY® Clear 03F59016, OPADRY® Green 03B510016); and polyvinyl alcohol-polyethylene glycol copolymer marketed as Kollicoat® IR. Suitable barrier layers, for illustration and not limitation, include Kollicoat® IR (a polyvinyl alcohol-polyethylene glycol graft copolymer) and Kollicoat IR White®.

The thickness of the barrier and/or protective layer can vary over a wide range, but is generally in the range 20 to 3,000 microns, such as on the order of about 25 to 250 microns. Preferably the barrier layer retards the release of famotidine by less than 5 minutes, preferably less than 4 minutes and more preferably by less than 3 minutes.

The barrier and/or protective layer in the pharmaceutical composition may be prepared by suitable material such that it substantially inhibits the release of the active from their respective compartments in the gastric environment of pH below 4.5.

In a further embodiment, therapeutically effective amounts of famotidine and ibuprofen are released from the composition rapidly (e.g., under in vitro assay conditions). In one embodiment, the famotidine and ibuprofen are substantially released under low pH conditions.

The pharmaceutical composition described herein was found to retain at least 80% of potency of ibuprofen or salts thereof and famotidine or salts thereof when stored at 40°C/75% R.H for 3 months. The amount of Impurity A (USP) and impurity

C in the composition was found to be less than 1% by weight of famotidine or salt thereof, when determined after subjecting to storage in accelerated stability conditions.

Impurity A (USP) is 3-[2-(diaminomethyleneamino)-l,3-thiazol-4-yl methyl sulfinyl]- Nsulfamoyl-propanamidine. Impurity C is 3-[[[2-[(diaminomethylene) amino] thiazol- 4yl] methyl] sulphanyl]-N-sulphamoylpropanamide.

In a further embodiment, the pharmaceutical composition may comprises plurality of multiple unit particles (MUPS) comprising ibuprofen or salt thereof; and plurality of multiple unit particles (MUPS) comprising famotidine or salt thereof, which are in direct physical contact with each other.

The pharmaceutical composition can be prepared by various formulation techniques known to the person skilled in the art, such as, but not limited to direct compression, wet or dry granulation, slugging, hot melt granulation, extrusion- spheronization, hot melt extrusion, fluidized bed granulation, extrusion, spray drying spray coating, and solvent evaporation and the like.

In an embodiment, the process of preparing the stable pharmaceutical composition comprises steps of preparing a core comprising ibuprofen or salt thereof, coating the core at least partially by famotidine or salt thereof.

In a further embodiment, the process of preparing a stable pharmaceutical composition comprising:

(a) preparing a core comprising ibuprofen or salt thereof;

(b) optionally, coating the core by a barrier layer;

(d) optionally, coating a protective layer over the core prepared in step (c).

The pharmaceutical composition may developed in the form of a unit dosage form, such as tablet, minitablet, bilayer tablet, caplet, granules/pellets, and in the form of capsule or sachet filled with tablets, minitablets, granules/pellets.

The pharmaceutical composition may comprise single or plurality of multiple- compression tablets which are formed by two or more compression cycles. Each compression cycle uses, alternatively, separate portions of each of ibuprofen and famotidine. This results in a multiple-compression tablet which has at least two discrete layers defined by the presence of the said parts in the layer. A multiple-compression tablet can exist as, for example, a layered tablet, as a compression-coated tablet, or as an inlay tablet.

A layered tablet is a tablet which is made up of two or more distinct cores of granulation compressed together with the individual layers lying one on top of another. Layered tablets have the appearance of a sandwich because the edges of each layer or : core are exposed. Such conventional layered tablets are generally prepared by compressing a granulation onto a previously compressed granulation. The operation may be repeated to produce multilayered tablets of more than two layers.

A compression-coated tablet is a tablet which is made up of an inner core and one or more outer core or coats wherein the inner core is completely surrounded by the outer coat or coats. These tablets have at least three discrete zones of components compressed together, i.e., an inner core, middle core, and an outermost coat. Such tablets also referred to as press-coat or dry-coated tablets are prepared by feeding a previously compressed inner core into a special tableting machine and compressing one or more other granulation coats around the preformed inner core.

A variation of the compression-coated tablet is the inlay tablet, also referred to as a dot, or bull's-eye tablet. Instead of an inner core being completely surrounded by an outer coat, one surface of the inner core is exposed. These tablets have at least two cores of components compressed together, i.e., an inlay core and a base core. The preparation of inlay tablets is similar to the preparation of compression-coated tablets except that a surface of coating is eliminated. It will be within the pursuit of the skilled artisan to select any component or mixture thereof for preparing inlay core and base core.

The pharmaceutical composition in the form of a unit dosage form in accordance with the present invention may deliver Ibuprofen and famotidine at total daily doses of about 2400 mg and about 80 mg respectively. In some embodiments, the dosage form contains ibuprofen and famotidine in a ratio in the range of 29: 1 to 32: 1, such as the range of 30: 1 to 31 : 1. In one embodiment, the dosage form contains 750 mg to 850 mg (e.g. about 800 mg) ibuprofen and 24 mg to 28 mg (e.g., about 26.6 mg famotidine). In another embodiment, the dosage form contains 375 mg to 425 mg (e.g., about 400 mg) ibuprofen and 12 mg to 14 mg (e.g., about 13 mg) famotidine.

Ibuprofen, in the form of the pharmaceutical composition of the invention, may be administered to a subject is in need of ibuprofen treatment. In various embodiments, the subject is in need of ibuprofen treatment for a chronic condition (such as rheumatoid arthritis, osteoarthritis or chronic pain) or a condition such as acute or moderate pain, dysmenorrhea or acute inflammation.

In one embodiment, the pharmaceutical composition of the present invention comprises a core comprising ibuprofen or salt thereof; and a surrounding portion comprising famotidine or salt thereof, in a pharmacokinetically effective ratio such that said ibuprofen and said famotidine are released from the composition in a bioequivalent manner.

In. a further embodiment, famotidine and ibuprofen are released from the composition sequentially, simultaneously or concomitantly at a rate and in a ratio providing each in a therapeutically effective and non-toxic amount.

A variety of excipients may be combined with famotidine and/or ibuprofen ½ their respective compartments of the pharmaceutical compositions of the present invention. As mentioned above, the provision of various excipients may be useful to impart particular qualities to either the famotidine component or the ibuprofen component of the pharmaceutical composition, or to provide a beneficial characteristic that may be desirable for processing to prepare the composition.

Pharmaceutically acceptable excipients useful in compositions of the present invention can include binders, lubricants, diluents, disintegrants, and glidants, or the like.

Suitable diluents or bulking agents, which includes, but are not limited to, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol lactitol, and other bulking agents such as powdered cellulose, microcrystalline cellulose, sugar and derivatives thereof. The formulation may incorporate one or more of the above bulking agents, preferably, lactose & microcrystalline cellulose forms the bulking agent. The amount of the diluents or bulking agent is preferably in the range of 15% to 70% by weight of the composition.

Suitable binders may be selected from, but not limited to one or more of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, gum arabic, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carrageenan, polyethylene oxide, waxes, pullulan, agar, tragacanth, veegum, pregelatinized starch, sodium alginate, gums, sugars such as sucrose, maltose, dextrose, lactose, amylase, synthetic resins and the like. The amount of binder for use in the modified release composition is more than 3%, preferably more that 5% by weight of the composition.

Suitable disintegrants, which includes, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch and modified starches, calcium silicates, low substituted hydroxy- propylcellulose. The amount of disintegrating agent is preferably in the range of 5% to 35% by weight of the composition.

Suitable lubricants and/or glidants, which may include, but are not limited to, stearic acid and its derivatives or esters like sodium stearate, magnesium stearate and calcium stearate and the corresponding esters such as sodium stearyl fumarate; talc and colloidal silicon dioxide respectively. The amount of lubricant and/or glidant is preferably in the range of 0.25% to 5% by weight of the composition.

In the context of the present invention, "Bioequivalency" is determined by a 90% Confidence Interval (CI) of between 0.80 and 1.25 for both C_max and AUC under USFDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for C_max of between 0.70 to 1.43 under the European regulatory guidelines (EMEA).

The term "confidence interval, (CI)" as used herein refers to the plain meaning known to one of ordinary skill in the art. The confidence interval refers to a statistical range with a specified probability that a given parameter lies within the range.

The term "covariance, (CV)" as used herein refers to the plain meaning known to one of ordinary skill in the art. It is a statistical measure of the variance of two random variables that are observed or measured in the same mean time period. This measure is equal to the product of the deviations of corresponding values of the two variables from their respective means.

The bioequivalence studies were carried out between Duexis^® (reference) and compositions of the invention (test) in fasted and fed state. The study was monitored in terms of C_max, AUC, T_max achieved with the test products and the reference product (Duexis^®).

At 90% confidence interval; area under the concentration time curve (AUC_0-t and /or AUC₀.j_nf) and maximum plasma concentration (C_max) values of composition of the invention lies between 0.70 and 1.70 as compared to that obtained by ibuprofen and famotidine formulation marketed under the trade name Duexis^®.

The results of relative bioavailability study of ibuprofen and famotidine composition of the invention and ibuprofen and famotidine formulation marketed under the trade name Duexis® with varying dose and frequency of administration as demonstrated in Table 4 concludes that the formulation explored in the present invention provides equivalent extent of absorption compared to ibuprofen and famotidine formulations marketed under the trade name Duexis^®.

While the present invention has been described in terms of its specific embodiments, 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:

Table 1

Sr. Quantity (%

Ingredients

No. w/w )

Ibuprofen Tablet part

1 Ibuprofen 71.43

2 MCC PH 105 7.26

3 Croscarmellose sodium 1.79

4 Colloidal silicon dioxide 0.46

5 Sodium lauryl sulphate 1.19

6 Polyvinylpyrrolidone 25 ^* 0.95

7 Polyvinylpyrrolidone K90 0.48

8 Purified water Q. S.

Extra-granular

9 MCC PH 102 3.95

10 Croscarmellose sodium 1.79

1 1 Colloidal silicon dioxide 1.43

12 Magnesium stearate 0.95

Famotidine dispersion part

13 Famotidine 2.38

14 HPMC 3cps 2.38

15 Lactose monohydrate 1.19

16 Polysorbate 80 0.08

17 PEG 400 0.24

18 Talc 1.19

19 Titanium dioxide 0.86

20 Color Blue 0.01

21 Purified water Q. S.

Process: Mixture of ibuprofen, MCC, croscarmellose sodium, colloidal silicon . dioxide and sodium lauryl sulphate was granulated using aqueous dispersion of polyvinylpyrrolidone K25 and polyvinylpyrrolidone 90. Granules were then blended with MCC PH 102, croscarmellose sodium, colloidal silicon dioxide, lubricated with magnesium stearate and the resulting blend was then compressed to form ibuprofen part.

Separately, an aqueous dispersion of famotidine containing polysorbate 80, PEG 400, HPMC, lactose monohydrate, talc, titanium dioxide and color blue was prepared. The aqueous dispersion of famotidie was then finally coated over the ibuprofen part.

Example 2:

Table 2

14 MCC 8.12

15 Croscarmellose sodium 1.22

16 Colloidal silicon dioxide 0.41

17 Povidone K30 0.81

18 Lactose monohydrate 4.06

19 Magnesium stearate 0.41

20 Purified water OR IPA/Ethanol Q. S.

Coating

21 Opadry blue 2.84

22 Purified water Q. S.

Total 100.00

Process: Mixture of ibuprofen, MCC, croscarmellose sodium, colloidal silicon dioxide and sodium lauryl sulphate was granulated using aqueous dispersion of polyvinylpyrrolidone K25 and polyvinylpyrrolidone K90. Granules were then blended with MCC PH 102, croscarmellose sodium, colloidal silicon dioxide and lubricated with magnesium stearate to form ibuprofen part.

Separately, a mixture of MCC, croscarmellose sodium, colloidal silicon dioxide and lactose monohydrate was granulated using aqueous dispersion of Povidone 30. The granules were then lubricated with magnesium stearate to form famotidine part.

The ibuprofen and famotidine parts were then compressed together using specific tooling to form a bilayer tablet.

Example 3:

Table 3

6 Polyvinylpyrrolidone K25 0.96

7 Polyvinylpyrrolidone K90 0.48

8 Purified water Q. S.

Extra-granular

9 MCC PH 102 3.13

10 Croscarmellose sodium 1.34 ;

1 1 Colloidal silicon dioxide 0.90 ;

12 Magnesium stearate 0.96

Famotidine granules/pellets

13 Famotidine 2.38

14 MCC 1.79

15 Croscarmellose sodium 0.90

16 Colloidal silicon dioxide 0.45

17 Povidone 30 0.90

18 Lactose monohydrate 1.34

19 Magnesium stearate 0.45

20 Purified water OR IPA/Ethanol Q. S.

Famotidine granules/Pellets coating

21 HPMC 3/5 cps/ Eudragit EPO 5.82

22 PEG 400 0.45

23 Purified water/Ethanol 0.04

Coating

24 Opadry blue 3.13

25 Purified water Q. S.

Total 100.00

Process: Mixture of ibuprofen, MCC, croscarmellose sodium, colloidal silicon dioxide and sodium lauryl sulphate was granulated using aqueous dispersion of polyvinylpyrrolidone K25 and polyvinylpyrrolidone 90. Granules were then blended with MCC PH 102, croscarmellose sodium, colloidal silicon dioxide and lubricated with magnesium stearate to form ibuprofen part. Separately, a mixture of famotidine MCC, croscarmellose sodium, colloidal silicon dioxide and lactose monohydrate was granulated using aqueous or hydro-alcoholic dispersion of HPMC/Eudragit EPO and PEG 400 to form famotidine part.

The ibuprofen and famotidine parts were then compressed together to form a tablet The tablets were finally coated with aqueous dispersion of Opadry blue.

Example 4:

Table 4

Protective coat

21 Opadry 1.05

22 Purified water/Ethanol Q. S.

Total 100.00

Process: Mixture of ibuprofen, MCC, croscarmellose sodium, colloidal silicon dioxide and sodium lauryl sulphate was granulated using aqueous dispersion of pdlyvinyipyrrolidone K25 and polyvinylpyrrolidone K90. Granules were then blended with MCC PH 102, croscarmellose sodium, colloidal silicon dioxide, lubricated with magnesium stearate and then compressed to form ibuprofen tablet.

Aqueous dispersion of Opadry was then coated over ibuprofen tablets.

An aqueous dispersion of famotidine containing Opadry, lactose monohydrate, polysorbate 80 and PEG 400 was then coated over Opadry coated ibuprofen tablets. Finally, an aqueous dispersion of Opadry was coated over the famotidine coated ibuprofen tablets.

Claims

We claim:

1) A stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof, an optional barrier layer and a surrounding portion comprising famotidine or salt thereof.

2) The composition as claimed in claim 1, wherein the core is in direct contact with the surrounding portion.

3) The composition as claimed in claim 1, wherein the potion of famotidine is coated with a protective layer.

4) The composition as claimed in claim 1, wherein the composition comprises ibuprofen or salt thereof in an amount from 775 mg to 825 mg; and famotidine or salt thereof in an amount from 24 mg to 28 mg.

5) The composition as claimed in claim 1, wherein the composition is in the form of a multilayer tablet.

6) A stable pharmaceutical composition in a single unit dosage form comprising: plurality of multiple unit particles (MUPS) comprising ibuprofen or salt thereof; and plurality of multiple unit particles (MUPS) comprising famotidine or salt thereof in direct physical contact with ibuprofen MUPS.

7) The composition as claimed in claim6, wherein the multiple unit particles are coated with a barrier layer.

8) The composition as claimed in claim 1 or 7, wherein the barrier layer comprises a polymer selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and ethyl cellulose; methacrylic polymers, amino-alkylmethacrylate copolymers, polyvinyl acetate phthalate or polyvinyl alcohol.

9) The composition as claimed in claim 1 or 7, wherein the barrier layer has a thickness ranging from 20 to 3,000 microns. 10) The composition as claimed in claim 1 or 7, wherein the barrier layer has a thickness ranging from 25 to 250 microns.

1 1) The composition as claimed in claiml or 6, wherein the composition rapidly releases the ibuprofen and the famotidine.

12) The composition as claimed in claiml or 6, wherein the composition retains at least

80% of the potency of ibuprofen and famotidine or salts thereof in the composition o ^'

after storage for three months at 40 C and 75% relative humidity.

13) The stable composition as claimed in claiml or 6, wherein said composition contains less than 1.0% w/w of impurity A (USP) relative to total weight of famotidine or salt thereof after storage for three months at 40°C and 75% relative humidity. 14) The stable composition as claimed in claiml or 6, wherein said composition contains less than 1.0% w/w of impurity C relative to total weight of famotidine or salt thereof after storage for three months at 40°C and 75% relative humidity.

15) The composition as claimed in claiml or 6, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from binders, fillers, lubricants, disintegrants, glidants, antioxidants, solvents, flavors, sweeteners and the like.

16) A process for the preparation of a stable pharmaceutical composition in a single unit dosage form comprising:

(a) preparing a core comprising ibuprofen or salt thereof;

(b) optionally, coating the core by a barrier layer;

(c) coating at least one layer comprising famotidine or salt thereof over the core of step (a) or barrier layer coated core of step (b); and

(d) optionally, coating a protective layer over the product prepared in step (c).

17) A stable pharmaceutical composition comprising a composition prepared process as claimed in claim 16. 18) The stable pharmaceutical composition as claimed in claim 1, wherein said composition exhibits no significant difference in rate and/or extent of absorption of ibuprofen and famotidine as compared to commercially marketed formulation of ibuprofen and famotidine marketed under the trade name Duexis^®.

19) A method of treating chronic pain, an inflammatory condition, or a condition associated with chronic pain or an inflammatory condition, comprising administering a stable pharmaceutical composition in a single unit dosage form comprising: a core comprising ibuprofen or salt thereof, an optional barrier layer and a surrounding portion comprising famotidine or salt thereof.