DESC:FIELD OF THE INVETION
This invention relates to a stable pharmaceutical composition comprising Ibuprofen or a pharmaceutically acceptable salt and Famotidine or a pharmaceutically acceptable salt thereof and process of preparing the same.

BACKGROUND OF THE INVENTION
Ibuprofen is nonsteroidal anti-inflammatory drug. Chemically Ibuprofen is (±)-2-(p-isobutylphenyl) propionic acid.

The chemical formula of Ibuprofen is C13H18O2 and the molecular weight is 206.28. Ibuprofen is a white powder that is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. The log P value is 3.84 and the pKa value is 4.85. The ibuprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of the ibuprofen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Ibuprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to an increase of prostaglandins in peripheral tissues.

Famotidine is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. Its chemical formula is C8H15N7O2S3 and molecular weight is 337.45. The log p value is -2 and pKa values are 9.29 (strongest acidic), 8.38 (strongest basic). Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.

Famotidine is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output.

Systemic effects of famotidine in the CNS, cardiovascular, respiratory, or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine.

Non- steroidal anti-inflammatory drugs have been used in human for many years. NSAID has been utilized in the treatment of pain or inflammation and a number of other symptoms including stiffness that are associated with painful conditions affecting muscle, bones and joints. Treatment of osteoarthritis and rheumatoid arthritis requires use of Ibuprofen for extended period of time which comes with potential side effects and risk associated with its long term use. NSAID’s in general can cause gastritis, dyspepsia, and gastric and duodenal ulceration. MOA of Ibuprofen involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Inhibition of Prostaglandin synthesis leads to impaired muscle integrity which in turn leads to gastric and duodenal ulceration.

This Drawbacks associated with Ibuprofen can be overcome by co-therapy with H2 antagonists. H2 antagonists are commonly prescribed to treat and prevent ulcers in the walls of the stomach, duodenum, or esophagus. Famotidine (N'-(aminosulfonyl)-3-[[[2-[(diamino­methylene)amino]-4-thiazolyl]methyl]thio] propanimidamide),a H2 antagonist is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity of Famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine. Reducing stomach acid with Famotidine during treatment with certain nonsteroidal anti-inflammatory drugs is reported to decrease incidence of gastrointestinal ulcers.

Co-therapy regimen requires administration of two separate dosage form which is not patient friendly. In past, many attempts has been made to develop one single unit dosage form comprising both Ibuprofen and Famotidine. WO 94/07541 discloses a particular pharmaceutical composition which includes “(S)-ibuprofen-(S)-lysine combined with an H2 antagonist such as famotidine. The pharmaceutical compositions described in WO ‘541 may be orally “administered in the form of tablets, caplets, gel caps, capsules,” etc., and the active ingredients may be admixed with pharmaceutically acceptable excipients. The disclosed formulations also include a “layered formulations” which provide for distinct release ratio and thus may be more effective in allowing for short and long term relief.

The pharmaceutical composition comprising Ibuprofen and Famotidine is available in the United States of America in the form of oral tablet dosage form under the brand name DUEXIS® and indicated for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. It is available in strength of 800 mg/26.6 mg for oral administration.

While preparing single unit dosage form comprising Ibuprofen and Famotidine; the major challenges faced was incompatibility between famotidine and Ibuprofen. Due to chemical incompatibility between Ibuprofen and Famotidine it is challenging to develop stable single unit dosage form. The disclosure of WO ‘541 does not seem to overcome the incompatibility challenges between Famotidine and Ibuprofen.

WO ‘815 teaches “[c]hemically incompatible components can be incorporated into a multi-layer tablet by integrating them into separate layers.” (WO ‘815 at 17:23-25). The multilayer tablet is preferably prepared by first producing the NSAID containing core (in the form of a layer structure), followed by at least partially coating it with an erodible layer comprising a first portion of the H2- receptor antagonist, providing for a sustained release layer of the antagonist. An immediate release layer comprising a second portion of the H2-receptor antagonist is then applied.

Another prior art reference WO2004060355 discloses ‘multilayer pharmaceutical tablets in which an NSAID and a second active ingredient are present in separate and distinct layers’ and that the ‘layers are in side-by-side configuration, which allows the dissolution of the second active and NSAID to occur independently and immediately’ Further WO’355 discloses that ‘substantially all of the triptan and substantially all of the NSAID in the dosage forms should be in separate layers’ and that ‘the layers should be arranged such that the individual therapeutic agents dissolve independently of one another’. In addition, WO’355 discloses that the ‘layers may come into direct contact with one another or, alternatively, they may be separated by one or more additional layers e.g., a barrier layer or coating which prevents the therapeutic agents from interacting with one another’.

However none of the above mentioned prior art references specifically teaches a stable pharmaceutical composition comprising Ibuprofen or a salt thereof and Famotidine or salt thereof configured in a way to exhibit the unexpected stability of the composition.

The US’033 discloses the pharmaceutical composition comprising Famotidine and Ibuprofen wherein surface area of direct physical contact between Famotidine core and Ibuprofen shell does not exceed 130 mm2. The US’033 discloses the tablet-in tablet composition wherein the process requires preparation of first Famotidine core and then for the core is centered in tablet-in-tablet composition by compressing the Ibuprofen DC 85TM around the Ibuprofen core using tablet press and 0.4100”×0.7500” Oval tooling. However; the process of preparation of the pharmaceutical composition comprising Ibuprofen or salt thereof and Famotidine or salt thereof disclosed in US’033 seems expensive and requires special tableting equipment.

There is a need in art to develop a pharmaceutical composition comprising Ibuprofen or salt thereof and Famotidine or salt thereof which exhibit improved stability and to develop a simple, less time consuming and cost effective process for preparation of the same.

OBJECTIVE OF THE INVENTION:
1. The present invention relates to stable pharmaceutical composition comprising Ibuprofen and Famotidine and process of preparation of the same.

2. It is another object of the present invention to provide a stable pharmaceutical composition comprising:
a) a core portion comprising Ibuprofen or salt thereof;
b) a shell portion comprising Famotidine or salt thereof
c) and a barrier layer interposed between two portions
wherein, substantially there is no chemical interaction between portion comprising Ibuprofen or salt thereof and portion comprising famotidine or salt thereof.

3. It is also an object of the present invention to provide a stable pharmaceutical composition comprising
a. a core portion comprising from about 775 mg to about 825 mg of Ibuprofen or salt thereof;
b. a surrounding portion comprising from about 24 mg to about 28 g of Famotidine or salt thereof
c. and an barrier layer interposed between two portions
wherein, substantially there is no chemical interaction between portion comprising Ibuprofen or salt thereof and portion comprising Famotidine or salt thereof.

4. It is yet another object of the present invention to provide an oral solid stable pharmaceutical composition of Ibuprofen and Famotidine and processes for preparing thereof, which uses a new and different beneficial formulation but is still bioequivalent to the commercially available compositions in the United States of America i.e. DUEXIS®.

SUMMARY OF THE INVENTION
The present invention relates to stable pharmaceutical composition comprising Ibuprofen and Famotidine and process of preparation thereof.
More particularly it relates to:

A. A stable pharmaceutical composition comprising Ibuprofen and Famotidine and process of preparation thereof.

B. A stable pharmaceutical composition comprising a core portion comprising Ibuprofen or salt thereof and a shell portion comprising Famotidine or salt thereof and process of preparation thereof.

C. A stable pharmaceutical composition comprising:
a. a core portion comprising Ibuprofen or salt thereof;
b. a shell portion comprising Famotidine or salt thereof
c. and a barrier layer interposed between two portions
wherein, substantially there is no chemical interaction between portion comprising Ibuprofen or salt thereof and portion comprising famotidine or salt thereof.

D. In an embodiment of the invention there is provided a stable pharmaceutical composition comprising:
a. a core portion comprising from about 775 mg to about 825 mg of Ibuprofen or salt thereof;
b. a surrounding portion comprising from about 24 mg to about 28 g of Famotidine or salt thereof
c. and an barrier layer interposed between two portions
wherein, substantially there is no chemical interaction between portion comprising Ibuprofen or salt thereof and portion comprising Famotidine or salt thereof.

E. A stable pharmaceutical composition comprising Ibuprofen and Famotidine is prepared by process comprising:
a. providing the mixture of Ibuprofen and pharmaceutically acceptable excipients; compressing the mixture to form the core comprising Ibuprofen or salt thereof.
b. coating the obtained Ibuprofen core with barrier coating
c. the barrier coated Ibuprofen core is then proceed for coating with Famotidine or salt thereof.
d. optionally, the obtained tablet of step c proceed for coating with film coating excipients.

F. The pharmaceutical formulation according to present invention exhibit bioequivalent to the reference listed drug DUEXIS®.

DESCRIPTION OF THE INVENTION:

Ibuprofen" refers to 2-(p-isobutylphenyl) propionic acid (C13H1802), including various crystal forms and pharmaceutically acceptable salts. Two enantiomers of ibuprofen exist. As used herein in the context of solid formulations of the invention, "ibuprofen" refers to a racemic mixture or both enantiomers as well as racemic mixtures that contain more of one enantiomer than another (including, for example, mix­tures enriched in the S-enantiomer), and enantiomerically pure preparations (including, for example, compositions sub­stantially free of the R-enantiomer). Ibuprofen is available commercially, typically as a racemic mixture, and, for example, ibuprofen preparations with mean particle sizes of 25, 38, 50, or 90 microns can be obtained from BASF Aktiengesellschaft (Ludwigshafen, Germany). One useful ibuprofen product is a directly compressible fomrnlation described in WO 2007 /042445 (incorporated herein by refer­ence), a version of which is available from BASF under the trade name Ibuprofen DC 85™. Ibuprofen's properties have been described in the medical literature (see, e.g., Davies, 1998, "Clinical pharmacokinetics of ibuprofen. The first 30 years" Clin Pharmacokinet 34: 101-54 ).

"Famotidine" refers to 3-[2-(diaminomethyleneamino) thiazol-4-y lmethy lthio ]-N-sulfamoylpropionamidine, including the polymorphic forms designated Form A and Fom1B (see, e.g. U.S. Pat. Nos. 5,128,477 m1d5,120,850) and their mixtures, as well as pharmaceutically acceptable salts thereof. Famotidine can be prepared using art-known meth-ods, such as the method described in U.S. Pat. No. 4,283,408. Famotidine's properties have been described in the medical literature (see, e.g., Echizen et al., 1991, Clin Pharmacokinet. 21: 178-94).

A "component" in the context of a unit dosage form is a physical region of a tablet or other dosage form. Two components of a unit dosage form are distinct compartments if there exists a recognizable demarcation between the two components, even though they may be in direct physical contact with one another.

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

In one aspect the present invention relates to the improvements in the formulation of pharmaceutical compositions where two or more active ingredients are present in the composition and wherein two of the active ingredients are incompatible. The Famotidine and Ibuprofen are chemically incompatible and therefore it is challenging to develop the single unit dosage form comprising Ibuprofen and Famotidine. To overcome the drawbacks of incompatibility between Ibuprofen and Famotidine the composition of present invention is formulated to exhibit improved stability.

In one aspect of the invention there is provided a stable pharmaceutical composition comprising a core portion comprising from about 775 mg to about 825 mg of Ibuprofen or salt thereof; a surrounding portion comprising from about 24 mg to about 28 g of Famotidine or salt thereof and a barrier layer interposed between two portions.

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. It 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.

In a further embodiment the barrier layer comprises a non-toxic edible polymer, edible pigment particles, an edible polymer plasticizer, and a surfactant.

Exemplary barrier and/or protective layers include OPADRY®; OPADRY-II; 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 configuration of dosage form is critical to obtain the stable pharmaceutical composition. The configuration of the dosage form of the present invention unexpectedly results in more stable composition. The present invention provides a stable pharmaceutical composition comprising core comprising Ibuprofen or salt thereof; shell coated over the Ibuprofen core comprising Famotidine or salt thereof and barrier layer interposed between two portions.

In one aspect of the invention, the volume of Ibuprofen in a core along with other excipients is from about 80% to about 95% of dosage form and that of Famotidine is from about 1% to about 5%. So, the volume occupied by the Ibuprofen component along with excipients is more which lead to increase the area of contact between Ibuprofen component and Famotidine component.

In one aspect of the invention there is provided a pharmaceutical composition comprising a stable pharmaceutical composition comprising a core comprising Ibuprofen core or salt thereof and a shell comprising famotidine or salt thereof wherein there is barrier layer separating Ibuprofen core and Famotidine shell. The configuration of the pharmaceutical composition of the present invention wherein the Ibuprofen core along with excipients forms a volume of an about 80% to about 95% of the dosage form.

In an aspect of the present invention there is provided a stable pharmaceutical composition comprising a core portion comprising from about 775 mg to about 825 mg of Ibuprofen or salt thereof; a surrounding portion comprising from about 24 mg to about 28 g of Famotidine or salt thereof and an barrier layer interposed between two portions wherein substantially there is a no chemical interaction between both portions. The insubstantial chemical interaction between Ibuprofen portion and Famotidine portion exhibited a marked improved stability of pharmaceutical composition of the present invention.

Following examples are offered to illustrate but not to limit the scope of the invention.

Example 1
The compressed coated tablet of the present invention can be prepared by preparing first Ibuprofen core which is then surrounded by barrier layer and Further which is surrounded by Famotidine shell.

The Ibuprofen core is prepared by: i) mixing and co-sifting of Ibuprofen and colloidal silicon dioxide, through suitable S.S. sieve ii) sifting the Microcrystalline Cellulose (GR 101) and Croscarmellose Sodium through suitable sieve iii) Loading of the sifted materials of step i and ii into the blender and blend it for 50-60 minutes iv) compressed the mixture v) simultaneously passing the material through multimill fitted with suitable S.S. screen vi) passing the milled material through #14 S.S. sieve vii) Sifting the 14# passed material of step (vi) through 60# S.S sieve viii) Mixing of 60# retained (granules) and 60# passed material (fines) of in blender and blend for 5 minutes at 9 RPM ix) Co-sifting Colloidal Silicon Dioxide USP/NF/Ph.Eur and Material of (viii) (part quantity) and passing through specified 14# S.S and loading it alongwith remaining material of step viii in blender; mixing for 30 minutes at 9 RPM x) compressing the blend into tablet core (Ibuprofen core). The compressed Ibuprofen core is coated with the barrier coating. Barrier coating on the tablet core (Ibuprofen care) can be performed by placing the tablet core (Ibuprofen core) in an Autocoater. Preheating the tablet till the bed temperature reaches to 40°C ±5°C. Then coating the dispersion comprising Opadry Clear in water onto the tablet core (Ibuprofen core) to a weight gain of 5.0%.

The barrier coated Ibuprofen core is then proceed for coating with Famotidine. The famotidine coating can be performed by i) adding the famotidine in water placed in S.S.vessel and stirring for 10 minutes; ii) then slowly adding the Opadry Clear and stirring for 45 minutes to get uniform dispersion; iii) loading the tablet core (Ibuprofen core or barrier coated Ibuprofen core) in Autocoater; preheating the tablet till the bed temperature reaches to 40°C ± 5°C and coating the opadry dispersion of step (ii) on the tablet core (Ibuprofen core or barrier coated Ibuprofen core).

The summary of materials used composition described in example 1 are provided in table 1 below.

Formulation A
A. Ibuprofen tablet core

Sr. No. Ingredients Std. Qty in mg/Tab
Intragranular
1 Ibuprofen USP
800
2 Microcrystalline Cellulose 50- 700
3 Croscarmellose Sodium 20-30
4 Colloidal Silicon Dioxide 30-40
Lubrication
5 Colloidal Silicon Dioxide 10-20

B. Barrier Coating
Sr. No. Ingredients Std. Qty in mg/Tab
6 Opadry II Clear 40-50
7 Purified Water Q.S.

C. Famotidine drug layering
Sr. No. Ingredients Std. Qty in mg/Tab
Ibuprofen tablet core part A
Ibuprofen tablet barrier coated part B
Famotidine drug layering
1 Famotidine USP 26.6
2 Opadry Clear 100-110
3 Purified Water Q.S.
Film coating
4 Opadry II Blue 30-40
5 Purified Water Q.S.

Example 2
In another embodiment the pharmaceutical composition for comparative studies is prepared by step by step process as follows: i) weighing Ibuprofen, famotidine, MCC PH-101 and croscarmellose sodium and sifting through sieve no. 20#; ii) loading the blend of step (i) in RMG and dry mixing it for 10 minutes; iii) dissolving PVP K-90 in water and under continuous stirring; iv) adding the binder solution of step (iii) to the blend material of step no. (ii) then kneading the material for 8 minutes; v) adding the above blend to rapid dryer and drying for 20 minutes at inlet air temperature of 55?C; vi) passing the dried blend through 20# sieve manually; vii) mixing the blend of step (vi) with the MCC PH 102, croscarmellose sodium and syloid for 20 minutes; viii) then adding the kouiwax HCO passed through 60# in step no. vii and mixing in blender for 10 minutes; ix) adding magnesium stearate in step no. viii and mixing in blender for 5 minutes; x) finally compressing the blend to form a tablet. The qualitative and quantitative composition is as described in table 2 below:

Formulation B

Sr No Ingredients Qty/Batch (gm)
1. Ibuprofen USP 400-800
2. Famotidine USP 20-30
3. MCC PH-101 30-40
4. Crosscarmellose sodium 20-300
5. Polyvinylpyrrolidone 5-15
6. Purified water Q.S
7. MCC PH-102 35-45
8. Crosscarmellose sodium 15-25
9. Syloid AL-1FP 15-25
10. Kolliwax HCO 1-5
11. Magnesium stearate 5-15
Film coating
Opadry Blue 25-35
Purified water Q.S

The distinct formulations of the invention exemplified in example 1 and 2 were evaluated for stability under accelerated conditions 40?C and 75% RH for 1 month.

The result as provided in table below:

Table 3:
Stability at storage condition 40?C and 75% RH
Formulation Famotidine degradation Impurity C (%)
Initial 3 month 6 month
Formulation A 0.05 0.35 0.70
Formulation B 0.181 6.654 19.52

The degradation Impurity C of famotidine is an impurity generated due to incompatibility between Ibuprofen and Famotidine. Surprisingly, it has been observed that percentage of degradation Impurity C at storage conditions 40?C and 75% RH for 3 month is not more than 1% in the Formulation A whereas the percentage of Impurity C generated in Formulation B when placed at storage conditions at 40?C and 75% RH for 3 month is more than 6%. Therefore it has been concluded that, the Formulation A in accordance with the present invention provides unexpected marked improved in stability. The unexpected results of the composition of present invention is due to the configuration of dosage form wherein substantially there is no chemical interaction between both Ibuprofen and Famotidine compartment.
,CLAIMS:1. A stable pharmaceutical composition comprising a core portion comprising Ibuprofen or salt thereof and a shell portion comprising Famotidine or salt thereof and process of preparation thereof.

2. A stable pharmaceutical composition comprising:
a. a core portion comprising Ibuprofen or salt thereof;
b. a shell portion comprising Famotidine or salt thereof
c. and a barrier layer interposed between two portions
Wherein, substantially there is no chemical interaction between a portion comprising Ibuprofen or salt thereof and a portion comprising famotidine or salt thereof.

3. The pharmaceutical composition as in claim 2, wherein the barrier layer interposed between two portions include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and ethyl cellulose.

4. The pharmaceutical composition as in claim 2, wherein the barrier layer interposed between two portions as in claim include methacrylic polymers, amino-alkyl methacrylate copolymers, polyvinyl acetate phthalate and polyvinyl alcohol.

5. The stable pharmaceutical composition as in claim 2, wherein a stable pharmaceutical composition comprising:
a. a core portion comprising from about 775 mg to about 825 mg of Ibuprofen or salt thereof;
b. a surrounding portion comprising from about 24 mg to about 28 g of Famotidine or salt thereof
c. and a barrier layer interposed between two portions
wherein, substantially there is no chemical interaction between a portion comprising Ibuprofen or salt thereof and a portion comprising Famotidine or salt thereof.

6. A stable pharmaceutical composition as on claim 1, comprising Ibuprofen and Famotidine is prepared by a process comprising:
a. providing the mixture of Ibuprofen and pharmaceutically acceptable excipients; compressing the mixture to form the core comprising Ibuprofen or salt thereof.
b. coating the obtained Ibuprofen core with a barrier coating
c. the barrier coated Ibuprofen core then proceeds for coating with Famotidine or salt thereof.
d. optionally, the obtained tablet of step c proceed for coating with film coating excipients.

7. The pharmaceutical composition as in claim 6 wherein film coating excipients are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethene glycols, polyvinylpyrrolidone, polyvinyl alcohol and waxy materials.