DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITION COMPRISING IBUPROFEN AND FAMOTIDINE

AUROBINDO PHARMA LTD HAVING REGISTERED OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in
which it is to be performed.

FIELD OF THE INVENTION

This invention relates to a pharmaceutical composition comprising combination of Non-steroidal anti-inflammatory drug (NSAID) and histamine H2-receptor antagonist as an active agent, process of preparation thereof and method of using the same.

This invention relates to a solid oral layered tablet pharmaceutical composition which comprises combination of Ibuprofen and Famotidine, a process for preparing such tablet. The invention also relates to the use of said formulation for the relief of signs and symptoms of rheumatoid arthritis, osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers.

BACKGROUND OF THE INVENTION

Arthritis is a common health problem worldwide, affecting more than 46 million people and resulting in disability for nearly 19 million people. In fact, among chronic diseases, arthritis causes more disability than any other condition, including heart disease, diabetes, and back or spine problems. Rheumatoid Arthritis (RA) is a common chronic disease that affects about 1% of the world population. RA is the third most common type of arthritis behind osteoarthritis (prevalence 26.9 million) and gout (prevalence 6.1 million). RA affects approximately 1.3 million people worldwide. Osteoarthritis (OA) which sometimes called degenerative joint disease or degenerative arthritis is the most common chronic condition of the joints, affecting more than 30 million people.

Administration of NSAIDs generally causes damage to gastroduodenal mucosa via several mechanisms including topical irritant effect, suppression of gastric prostaglandin synthesis etc. To avoid these side effects usually acid secretion inhibitors used in combination with NSAIDs. H2 receptor antagonists are capable of blocking the action of histamine on parietal cells in the stomach and decreasing the production of acid by these cells.

Combination of Ibuprofen (NSAID) and Famotidine (H2 receptor antagonist) is currently available in the market as a tablet with dose 800 mg and 26.6 mg respectively under the brand name DUEXIS® for treatment of the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers.

The chemical name of Ibuprofen is (±)-2-(p-isobutylphenyl) propionic acid having chemical formula C13H18O2 and molecular weight of 206.28, its structural formula is:

(Ibuprofen)
The chemical name of Famotidine is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene) amino]-4-thiazolyl] methyl] thio] propanimidamide having chemical formula C8H15N7O2S3 and molecular weight of 337.45, its structural formula is:

(Famotidine)
U.S. Patent No. 8,067,033 discloses pharmaceutical compositions comprising Ibuprofen and Famotidine are placed in first and second portion respectively.

U.S. Patent No. 8,067,451 discloses pharmaceutical compositions comprising Ibuprofen and Famotidine as first and second portion respectively separated by a barrier layer.

U.S. Patent No. 8,309,127 and 8,318,202 disclose immediate release pharmaceutical compositions containing Ibuprofen and Famotidine as first and second layer in direct contact.

U.S. Patent No. 8,449,910 discloses pharmaceutical compositions of Ibuprofen and Famotidine in a bilayer tablet.

U.S. Patent Application No. 20140322313 and 2013078287 disclose bilayered or trilayered or liquid pharmaceutical compositions of a H2 receptor antagonist in which a core and a shell are separated by a barrier layer. U.S. Patent Application No. 2003035839 discloses pharmaceutical composition for both intraoral and oral administration containing a first portion and a second portion.

U.S. Patent Application No. 2008021078 and 2007043097 discloses methods for administration of Ibuprofen and Famotidine.

PCT publication WO 2013/054352 discloses pharmaceutical compositions containing Ibuprofen as a core, an optional barrier layer and Famotidine as a surrounding portion.

It is well known in the prior art that Ibuprofen and Famotidine in admixture are pharmaceutically incompatible and poses incompatibility and stability issues. In order to overcome this problem we have developed compositions comprising Ibuprofen and Famotidine in the form of layered dosage form in which both drugs are not in direct contact with each other and are stable.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising ibuprofen;
b) Second portion comprising famotidine;
c) Barrier layer comprising excipients selected from lactose, hydroxypropyl cellulose (HPC), corn starch, polyvinyl pyrrolidone (PVP or povidone), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyoxyethylene sorbitan monooleate (polysorbate 80), talc, glycerol triacetate (triacetin), microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer comprising 1-250 mg of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.
In another general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer comprising 1-20% w/w of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer comprising 15-60 mg of excipients selected from hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, talc, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer comprising 15-60 mg of excipients, wherein barrier layer preferably comprises combination of hydroxypropyl cellulose and microcrystalline cellulose in a ratio of 1:1.5 to 1:3 or combination of polyvinyl alcohol and talc in a ratio of 1: 0.4 to 1:1.
In another general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer comprising 2-8% w/w of excipients selected from hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, talc, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general aspect, an invention provides a formulation in triple layer tablet in which the first layer comprises of one active ingredient, second layer comprises of placebo and third layer comprises of another active ingredient.

In another general aspect, an invention provides the process for the preparation of stable pharmaceutical composition in which process involves:
a) Preparing a core comprising ibuprofen and suitable pharmaceutically acceptable excipients.
b) Applying seal coat over ibuprofen core.
c) Applying famotidine coating layer over coated core obtained in step (b).
d) Optionally, applying film coat over coated core obtained in step (c).

In another aspect of the invention provides the process of preparation of stable pharmaceutical composition in which process involves:
a) Preparing first portion comprising ibuprofen and suitable pharmaceutical acceptable excipients.
b) Applying barrier layer portion comprising lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof over first portion.
c) Applying second portion comprising famotidine and suitable pharmaceutical acceptable excipients.
d) Optionally film coating over second portion.

In another general aspect, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer disposed between the first and second portions comprises 1-20% w/w of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, said pharmaceutical composition contains not more than 2% of degradation products of combination of both the active ingredients when stored at 30°C/65% RH for one month in an open petri dish and two month in HDPE container.

DETAILED DESCRIPTION OF THE INVENTION

The term “layered or layer” are composed of two or more layers of different materials compressed together. It may be bilayered, tri-layered or multi-layered. The “multilayered tablets’’ consist of two or more active pharmaceutical ingredients in one unit” which includes both bilayer and trilayer inventions. The layered tablets can be in the form of tablet within a tablet (compression core tablet). The triple layer tablet can be of three layers that is formed by pressing one layer of the tablet first, and then pressing the second layer of the tablet and finally third layer of tablet onto it.

The term ‘‘stable’’ refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response when administered to the patient.

The term “core” as used herein, refers to an interior compartment of a unit dosage form.

The term ‘‘w/w’’ or ‘‘% w/w’’ refers to total weight of active pharmaceutical ingredients or excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.

The term ‘‘barrier layer’’ refers to a layer in the dosage form that is interposed between the ibuprofen containing compartment and the famotidine containing compartment. This layer does not contain active pharmaceutical ingredient. Barrier layer may be applied either by coating or by compression using suitable excipients.

The term ‘‘portion’’ refers to a part of any whole, either separated from or integrated with it.

The term “excipient” means a pharmacologically inactive component such as a solvent, diluent, disintegrant, carrier, or the like.
The term “composition” or “pharmaceutical composition” or “dosage form” as used herein synonymously include dosage forms such as tablets, capsule, spheroids, pellets, granules, pills and the like.

The term “Ibuprofen” and ‘‘Famotidine’’ includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms.

The term ‘‘Placebo’’ means a substance or material with no active therapeutic effect. In case of trilayer tablet invention, a placebo containing one or more excipients can be placed as an intermediate layer between two actives.

“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient Ibuprofen and Famotidine inorder to facilitate manufacture, enhance stability, product characteristics, patient acceptability etc. Pharmaceutically acceptable excipient(s) includes, but not limited to diluent, binder, disintegrant, glidant, lubricant, surfactant, plasticizer, solvent/vehicle, flavors or colors and any other excipient known to the art for making pharmaceutical composition of tablet.

‘‘Diluents’’ provide bulk, for example, in order to make the tablet a practical size for processing. Examples of diluents include but not limited to lactose, mannitol, microcrystalline cellulose (MCC), pregelatinized starch, powdered celluloses and the like and combinations thereof and the most preferably used diluent is lactose monohydrate and microcrystalline cellulose.

‘‘Disintegrant’’ are employed to facilitate breakup or disintegration of the formulation after administration. Examples of disintegrant include but not limited to starches, celluloses, and effervescent agents, such as corn starch, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, and the most preferably used disintegrant is croscarmellose sodium.

‘‘Binder’’ refers to a material that can be added to impart cohesive qualities to components of a pharmaceutical composition. Examples of binder include but not limited to polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized starch, carbomers and the like, and combinations thereof. Among the above examples of binder the most preferably used is polyvinyl pyrrolidone.

‘‘Glidant’’ refer to a substance that is added to a powder to improve its flowability. Examples of glidants include but not limited to colloidal silicon dioxide, magnesium silicate, talc etc. and combinations thereof. Among the above examples of glidant the most preferably used is colloidal silicon dioxide.

‘‘Lubricant’’ refers to an excipient that reduces sticking by a solid formulation to the equipment used for production of a unit dose form. Examples of lubricants include but not limited to magnesium stearate, stearic acid, sodium stearyl fumarate, and combinations thereof. Among the above examples of lubricant the most preferably used is magnesium stearate and stearic acid.

‘‘Surfactant’’ refers to one or more excipients that may be added to the pharmaceutical composition to facilitate dissolution of poorly soluble excipients and/or to increase dissolution rate of pharmaceutical composition or components thereof. Examples of surfactants include but not limited to sodium lauryl sulphate, glycerol monostearate, sorbitan monolaurate, polyoxyethylene sorbitan monooleate etc. The most preferably used is polyoxyethylene sorbitan monooleate.

‘‘Plasticizer’’ refers to an excipient that can impart flexibility and/or stretchability to a coat or membrane. Examples of plasticizers include but not limited to glycolates, glycerolates, benzoates, poly (alkylene glycols), polyesters of alkylene glycols, alkyl citrate, glycerol triacetate and citrates esters etc. Among the above examples the most preferably used is polyethylene glycol and glycerol triacetate.

A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute resulting in a solution. Examples include but not limited to water, ethyl acetate, isopropyl alcohol (IPA), ethanol, dichloro methane. The most preferably used solvent is isopropyl alcohol, purified water and dichloro methane.

‘‘Colorants’’ is a substance that is added or applied in order to change the colour of a material or surface. Pharmaceutically acceptable colors include but not limited to indigotine, amaranth lake, opadry systems, titanium dioxide, iron oxide yellow. The most preferably used is iron oxide yellow and indigotine (FD&C blue indigo carmine).

‘‘Tablet coating’’ refers to the phenomenon of application of coating to the tablet which involves plasticizer, polymers, color and solvent. Film coating refers to the process of polymeric solution to bring a uniform film. Examples of excipients selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose (HPC), povidone, polyvinyl alcohol. Opadry film coating is a one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate which result in attractive, elegant coatings on a variety of tablet cores. Seal coating prevents moisture penetration into the tablet core. Examples of excipients selected from polyethylene glycol (PEG 4000), polyvinyl alcohol, methylene chloride, glycerol triacetate, microcrystalline cellulose, hydroxypropyl cellulose.

Barrier layer may be applied either by coating or by compression using suitable excipients. Examples of the suitable excipients used in barrier layer as per present invention includes lactose, hydroxypropyl cellulose, polyethylene glycol, talc, corn starch, polyvinyl pyrrolidone (PVP or povidone), glycerol triacetate (triacetin), microcrystalline cellulose, polyvinyl alcohol, polyoxyethylene sorbitan monooleate (polysorbate 80) etc. Preferably hydroxypropylcellulose or polyethylene glycol or polyvinyl alcohol or talc or glycerol triacetate or microcrystalline cellulose or polyoxyethylene sorbitan monooleate or combinations thereof.

In one embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising ibuprofen;
b) Second portion comprising famotidine;
c) Barrier layer comprising excipients selected from lactose, hydroxypropyl cellulose (HPC), corn starch, polyvinyl pyrrolidone (PVP or povidone), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyoxyethylene sorbitan monooleate (polysorbate 80), talc, glycerol triacetate (triacetin), microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer comprising 1-250 mg of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer comprising 1-20% w/w of excipients selected from lactose, hydroxypropyl cellulose, corn starch, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer comprising 15-60 mg of excipients selected from hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, talc, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer comprising 15-60 mg of excipients, wherein barrier layer preferably comprises combination of hydroxypropyl cellulose and microcrystalline cellulose in a ratio of 1:1.5 to 1:3 or combination of polyvinyl alcohol and talc in a ratio of 1: 0.4 to 1:1.

In another general embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer comprising 2-8% w/w of excipients selected from hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, talc, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, barrier layer is disposed between the first and second portions.

In another general embodiment, an invention provides a formulation for triple layer tablet in which the first layer comprising of one active ingredient, second layer comprising of placebo and third layer comprising of another active ingredient.

In another general embodiment, an invention provides the process for the preparation of stable pharmaceutical composition in which process involves:
a) Preparing a core comprising ibuprofen and suitable pharmaceutically acceptable excipients.
b) Applying seal coat over ibuprofen core.
c) Applying famotidine coating layer over coated core obtained in step (b).
d) Optionally, applying film coat over coated core obtained in step (c).

In another embodiment of the invention provides the process of preparation of stable pharmaceutical composition in which process involves:
a) Preparing first portion comprising ibuprofen and suitable pharmaceutical acceptable excipients.
b) Applying barrier layer portion comprising lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof over first portion.
c) Applying second portion comprising famotidine and suitable pharmaceutical acceptable excipients.
d) Optionally film coating over second portion.

The barrier improves stability of the composition by reducing or eliminating reactive contact between the incompatible ingredients in the formulation. By improving the overall stability of the composition, the barrier prolongs the shelf life of the formulation.

By preventing reducing reactivity between the first and second ingredients in the formulation, the barrier minimizes degradation of one or both of the ingredients thereby improving the stability, prolonging the shelf life of the formulation, maintaining potency, less impurities level, lower toxicity, or a combinations thereof.

In another general embodiment, there is provided a stable pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer disposed between the first and second portions comprises 1-20% w/w of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof; wherein, said pharmaceutical composition contains not more than 2% of degradation products of combination of both the active ingredients when stored at 30°C/65% RH for one month in an open petri dish and two month in HDPE container .

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example – 1:
No. Ingredient name mg/tablet % w/w
First layer
1 Ibuprofen USP 800.00 62.99
2 Microcrystalline cellulose 75.00 5.91
3 Lactose monohydrate 75.00 5.91
4 Povidone 25.00 1.96
5 Water Qs -
Placebo (Between two actives) second layer
6 Lactose anhydrous 200.00 15.75
Third layer
7 Famotidine USP 26.60 2.09
8 Croscarmellose sodium 30.00 2.36
9 Colloidal silicon dioxide 7.00 0.55
Lubrication
10 Magnesium stearate 11.40 0.90
Film Coating (Opadry yellow 85F42129)
11 Polyvinyl alcohol 8.0 0.63
12 Titanium dioxide 4.76 0.38
13 Polyethylene glycol 4.04 0.32
14 Talc 2.96 0.23
15 Yellow iron oxide 0.24 0.02
16 Purified water Qs -
17 IPA Qs -
Total weight 1270.00 100%

Manufacturing process:
1. First layer: Sift ibuprofen USP, microcrystalline cellulose and lactose monohydrate through 30 mesh.
2. Granulation: Dissolve PVP in water to get binder solution, and then granulate.
3. Drying and Milling: Dry the granulated material obtained in step 2 until LOD reaches < 2%, and then mill the granules through screen and pass it through 30 mesh.
4. Second layer: Sift lactose through 30 mesh and further used in compression as middle layer.
5. Third layer: Sift famotidine USP, croscarmellose sodium, colloidal silicon dioxide through 30 mesh then add magnesium stearate to it and mix in blender for 5 minutes.
6. Compression: (Triple layer): Compress the first layer of ibuprofen, second layer of Placebo (lactose anhydrous) third layer of famotidine at the target weight using suitable punch dimension.
7. Film coating: Dissolve coating material in PVA and water and then coat core tablet until target weight is achieved.

Example - 2:
No. Name of Ingredients 2A 2B
mg/tablet % w/w mg/tablet % w/w
1 Ibuprofen USP 800.00 73.39 800.00 73.39
2 Microcrystalline cellulose 75.00 6.87 75.00 6.87
3 Lactose monohydrate 75.00 6.88 55.00 5.05
4 Polyvinyl pyrrolidone 25.00 2.29 25.00 2.29
5 Water Qs - Qs -
Prelubrication
6 Croscarmellose sodium 30.00 2.75 30.00 2.75
7 Colloidal silicon dioxide 5.00 0.46 5.00 0.46
Lubrication
8 Magnesium stearate 10.00 0.92 10.00 0.92
Seal Coating
9 Lactose/corn starch - - 25.00 2.29
10 Hydroxypropyl cellulose/Polyvinyl pyrrolidone 15.00 1.38 10.00 0.92
11 Polyethylene glycol/Glycerol triacetate 0.40 0.04 0.40 0.04
12 Isopropyl alcohol Qs - Qs -
13 Water Qs - Qs -
Drug layering
14 Famotidine USP 26.60 2.44 26.60 2.44
15 Polyvinyl pyrrolidone 4.0 0.37 4.0 0.37
16 Polyethylene glycol 4.0 0.37 4.0 0.37
17 Isopropyl alcohol Qs - Qs -
Film coating (Opadry white 12B580001)
18 Hydroxypropyl methyl cellulose (HPMC 2910) 11.97 1.10 11.97 1.10
19 Titanium dioxide 6.306 0.58 6.306 0.58
20 Polyethylene glycol 1.468 0.14 1.468 0.14
21 Polyoxyethylene sorbitan monooleate 0.256 0.02 0.256 0.02
22 Water Qs - Qs -
Total weight 1090.00 100% 1090.00 100%

Manufacturing process:
1. Sift ibuprofen USP, microcrystalline cellulose and lactose monohydrate through 30 mesh.
2. Granulation: Dissove PVP in water to get binder solution then granulate.
3. Drying and Milling: Dry the granulated material obtained in step 2 until LOD reaches < 2%, and then mill the granules through screen and pass it through 30 mesh.
4. Prelubrication: Sift croscarmellose sodium, colloidal silicon dioxide through 30 mesh, then add to step 3 and mix in blender for 10 mins.
5. Lubrication: Sift and add magnesium stearate to the previous obtained step 4 and finally mix in blender for 5 mins.
6. Compression: Compress the lubricated material at the target weight using suitable punch dimension.
7. Seal coating: Prepare coating solution with HPC or PVP, lactose or corn starch and PEG or glycerol triacetate in water and coat the ibuprofen core tablet until target weight is achieved.
8. Drug layer coating: Prepare solution of famotidine, PVP, PEG with IPA and coat on previous obtained step until target weight is achieved.
9. Film coating: Dissolve coating material in water and then coat core tablet until target weight is achieved.

Example-3:
No.
Name of Ingredients 3A 3B
mg/tablet % w/w mg/tablet % w/w
1 Ibuprofen USP 800.000 67.29 800.000 67.96
2 Microcrystalline cellulose 53.325 4.49 49.00 4.16
3 Croscarmellose sodium 15.000 1.26 14.00 1.19
4 Lactose monohydrate 20.000 1.68 22.00 1.87
5 Povidone K 30 17.500 1.47 19.00 1.61
6 Water Qs - Qs -
Prelubrication
7 Croscarmellose sodium 37.500 3.15 35.00 2.97
8 Colloidal silicon dioxide 7.275 0.61 6.00 0.51
Lubrication
9 Stearic acid 19.400 1.63 15.00 1.27
Seal Coating
10 Hydroxypropyl cellulose 72.750 6.12 65.00 5.52
11 Polyethylene glycol 7.275 0.61 3.00 0.26
12 Lactose monohydrate 65.475 5.51 75.00 6.37
13 Water Qs - Qs -
Drug layering
14 Famotidine USP 26.600 2.24 26.600 2.26
15 Povidone K30 10.000 0.84 11.00 0.93
16 Polyethylene glycol 2.120 0.18 2.00 0.17
17 Ethanol Qs - Qs -
Film coating (Opadry II 85F42129 Yellow)
18 Polyvinyl alcohol 13.8504 1.17 13.8504 1.18
19 Titanium dioxide 8.2401 0.69 8.2401 0.70
20 Polyethylene glycol 6.9945 0.59 6.9945 0.59
21 Talc 5.125 0.43 5.125 0.44
22 Iron oxide yellow 0.416 0.04 0.416 0.04
23 Water Qs - Qs -
Total weight 1188.847 100% 1177.226 100%

Manufacturing process: Same as per Example 2

Example -4:
No. Name of Ingredients 4A 4B
mg/tablet % w/w mg/tablet % w/w
1 Ibuprofen USP 800 81.63 800 81.63
2 Microcrystalline cellulose 38.38 3.92 36.39 3.71
3 Colloidal silicon dioxide 4.4 0.45 5.62 0.57
4 Polyvinyl pyrrolidone 8.9 0.91 8.9 0.91
5 Water Qs - Qs -
Prelubrication
6 Croscarmellose sodium 13.2 1.35 13.2 1.35
7 Colloidal silicon dioxide 8.8 0.90 8.8 0.90
Lubrication
8 Stearic acid 6.60 0.67 6.6 0.67
Seal Coating
10 Hydroxypropyl cellulose 13.2 1.35 12.54 1.28
11 Glycerol Triacetate 2.2 0.22 2.2 0.22
12 Microcrystalline cellulose 28.6 2.92 30.03 3.06
13 Water Qs - Qs -
Drug layering
14 Famotidine USP 26.6 2.71 26.6 2.71
15 Hydroxypropyl cellulose 5 0.51 5 0.51
16 Mannitol 5 0.51 5 0.51
17 Isopropyl alcohol Qs - Qs -
18 Dichloro methane Qs - Qs -
Film coating (Opadry AMB Coating system 80W505020 Blue)
19 Polyvinyl alcohol-part hydrolyzed 8.7 0.89 8.7 0.89
20 Titanium dioxide 5.962 0.61 5.962 0.61
21 Talc 3.825 0.39 3.825 0.39
22 Lecithin (soya) 0.383 0.039 0.383 0.04
23 Fd&c blue #2/indigo carmine Al. lake 0.122 0.012 0.122 0.01
24 Xanthan gum 0.092 0.009 0.092 0.01
25 Fd&c blue #2/indigo carmine Al. 3% - 5% 0.03 0.003 0.03 0.003
26 Fd&c blue #2 indigo carmine Al. lake 0.006 0.001 0.006 0.001
27 Water Qs - Qs -
Total weight 980.00 100% 980.00 100%
Manufacturing process: Same as per Example 2
Example -5:
No. Name of Ingredients 5A 5B
mg/tablet % w/w mg/tablet % w/w
1 Ibuprofen USP 800 82.05 800 82.05
2 Microcrystalline cellulose 37.87 3.88 32.78 3.36
3 Colloidal silicon dioxide 4.4 0.45 4.4 0.45
4 Polyvinyl pyrrolidone (Povidone K30) 8.71 0.89 9.15 0.94
5 Water Qs - Qs -
Prelubrication
6 Croscarmellose sodium 13.2 1.35 13.1 1.34
7 Colloidal silicon dioxide 8.8 0.90 8.8 0.90
8 Stearic acid (Lubrication) 6.6 0.68 6.6 0.68
Seal coating (Opadry II Coating system 85F19250 Clear)
9 Polyvinyl alcohol- part hydrolysed 18.395 1.89 16.56 1.70
10 Talc 10.56 1.08 11.62 1.19
11 Polyethylene glycol 5.189 0.53 5.189 0.53
12 Polyoxyethylene sorbitan monooleate 1.056 0.11 1.056 0.11
13 Isopropyl alcohol Qs - Qs -
14 Water Qs - Qs -
Drug layering
15 Famotidine USP 26.6 2.73 26.6 2.73
16 Hydroxypropyl cellulose 6.5 0.67 6.5 0.67
17 Talc 8 0.82 8 0.82
18 Isopropyl alcohol Qs - Qs -
19 Dichloro methane Qs - Qs -
Film coating (Opadry AMB Coating system 80W505020 Blue)
20 Polyvinyl alcohol-part hydrolyzed 8.7 0.89 9.104 0.93
21 Titanium dioxide 5.962 0.61 6.234 0.64
22 Talc 3.825 0.39 4 0.41
23 Lecithin (soya) 0.383 0.04 0.4 0.04
24 Fd&c blue #2/indigo carmine Al.lake 0.122 0.01 0.126 0.01
25 Xanthan gum 0.092 0.01 0.094 0.01
26 Fd&c blue #2/indigo carmine Al.3% - 5% 0.03 0.003 0.032 0.003
27 Fd&c blue #2 indigo carmine Al.lake 0.006 0.001 0.01 0.001
28 Water Qs - Qs -
Total weight 975.00 100% 975.00 100%
Manufacturing process: Same as per Example 2.
Table-1: Stability study data of Ibuprofen and Famotidine composition (Ex. 3):
A] Ibuprofen (Pack: Open exposure) B] Famotidine (Pack: Open exposure)
Related substances (Ibuprofen)
Condition Related substances (Famotidine)
Condition
Initial 40°C/75% RH
(15 Days-Open) Initial 40°C/75%RH
(15 Days-Open)
Ibuprofen Imp-J NMT 0.2% 0.11 0.12 Famotidine sulphoxide NMT 1.0% 0.16 0.07
Ibuprofen Imp-C NMT 0.25% 0.00 0.01 FRC-A NMT 0.5% 0.00 0.05
Ibuprofen Imp-K NMT 0.15% 0.01 0.03 FRC-D NMT 0.5% 0.01 0.08
Any unspecified degradation product NMT 0.2% 0.01 0.05 FRC-C NMT 0.5% 0.00 0.16
- - - FRC-G NMT 0.5% 0.00 0.06
- - - FRC-F NMT 0.5% 0.00 0.00
- - - FRC-E NMT 0.5% 0.02 0.00
- - - FRC-B NMT 0.5% 0.00 0.00
- - - Highest unknown NMT 0.2% 0.03 0.04
Total degradation products NMT 1.5% 0.13 0.21 Total degradation products NMT 1.5% 0.22 0.46

Table-2: Stability data of Ibuprofen and Famotidine composition (Ex. 4 and Ex. 5):
Tests Condition Example. 4 Example. 5

Initial 30°C/65% 30°C/65% Initial 30°C/65% 30°C/65%
Limits 1M OPD 2M HDPE 1M OPD 2M HDPE
Assay %
Lab. Amt. I 90–110% 100.0
104.70 99.90
104.40 99.20
96.20 101.30
106.0 105.6
100.20 104.80
99.90
F
Related substances
(% w/w, by HPLC)

I
IRC Imp J- NMT 0.2% 0.12 0.12 0.12 0.12 0.11 0.13
IRC Imp C- NMT 0.25% 0.00 0.00 0.00 0.00 0.00 0.00
Any unspecified degra. product –NMT 0.10% 0.06 0.06 0.06 0.06 0.05 0.05
F Famotidine sulfoxide- NMT1.0% 0.11 0.14 0.33 0.32 0.53 0.28
FRC Imp D-NMT 0.5% 0.01 0.01 0.04 0.04 0.05 0.02
FRC Imp C-NMT 0.5% 0.04 0.14 0.36 0.07 0.14 0.36
FRC Imp F-NMT 0.5% 0.00 0.00 0.01 0.01 0.01 0.01
Any unspecified degra. product- NMT 0.20% 0.01 0.01 0.03 0.02 0.07 0.04
Total impurities (I+F)-NMT 2.0% 0.41 0.53 1.16 0.84 1.23 1.09
Water content by KF NMT-3.0% 0.57 0.58 0.89 0.54 0.68 0.80
*IRC – Ibuprofen related compound; FRC – Famotidine related compound

As per the above given stability data of ibuprofen and famotidine at mentioned conditions and duration we can conclude that said composition is stable after having stored at above mentioned conditions. ,CLAIMS:WE CLAIM:
1. A pharmaceutical composition comprising:
a) First portion comprising 800 mg of ibuprofen;
b) Second portion comprising 26.6 mg of famotidine;
c) Barrier layer disposed between first and second portion comprising 1-250 mg of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, talc, glycerol triacetate, microcrystalline cellulose or combinations thereof.

2. A pharmaceutical composition as claimed in claim 1, wherein barrier layer preferably comprises 15-60 mg of excipients selected from hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, talc, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof.

3. A pharmaceutical composition comprising:
a) First portion comprising 60-90% w/w of ibuprofen;
b) Second portion comprising 1.5-4% w/w of famotidine;
c) Barrier layer disposed between first and second portion comprising 1-20% w/w of excipients selected from lactose, hydroxypropyl cellulose, corn starch, povidone, polyethylene glycol, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof.

4. A pharmaceutical composition as claimed in claim 3, wherein barrier layer preferably comprises 2-8% w/w of excipients selected from hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, talc, polyoxyethylene sorbitan monooleate, glycerol triacetate, microcrystalline cellulose or combinations thereof.

5. A pharmaceutical composition as claimed in claim 1 and claim 3, wherein barrier layer preferably comprises combination of hydroxypropyl cellulose and microcrystalline cellulose in a ratio of 1:1.5 to 1:3 or combination of polyvinyl alcohol and talc in a ratio of 1: 0.4 to 1:1.

6. A pharmaceutical composition as claimed in claim 1 and claim 3, wherein the barrier layer minimizes degradation of one or both of the ingredients which improves the stability of said pharmaceutical composition.

7. A pharmaceutical composition as claimed in claim 1 and claim 3, wherein said pharmaceutical composition is stable and contains not more than 2% of degradation products of combination of both the active ingredients when stored at 30°C/65% RH for two months in HDPE container.

8. A pharmaceutical composition as claimed in claim 1 and claim 3, wherein water content by KF is not more than 3%.

9. A pharmaceutical composition as claimed in claim 1 and claim 3, wherein said dosage form exhibit immediate release of ibuprofen and famotidine.

10. A pharmaceutical composition as claimed in claim 1 and claim 3, optionally contains film coating and it is in the form of tablet dosage form.