WO2020013781A2

WO2020013781A2 - Synergistic effect of flurbiprofen and a gastro protective agent for the treatment of pain and inflammation

Info

Publication number: WO2020013781A2
Application number: PCT/TR2019/050200
Authority: WO
Inventors: Mehmet Nevzat PISAK
Original assignee: Pisak Mehmet Nevzat
Priority date: 2018-03-27
Filing date: 2019-03-27
Publication date: 2020-01-16
Also published as: WO2020013781A3

Abstract

The present invention relates to an oral immediate release pharmaceutical composition in a single unit dosage form comprising flurbiprofen or a pharmaceutically acceptable salt thereof and a H2 receptor antagonist as a gastro protective agent, wherein H2 receptor antagonist is present in an amount of from 5 to 80% by weight of flurbiprofen. The present invention is also about an oral immediate release pharmaceutical composition in a single unit dosage form comprising flurbiprofen or a pharmaceutically acceptable salt thereof, an H2 receptor antagonist, or a pharmaceutically acceptable salt thereof, and a carbonate wherein the H2 receptor antagonist is present in an amount between 10 and 80% by weight based on the weight of flurbiprofen.

Description

SYNERGISTIC EFFECT OF FLURBIPROFEN AND A GASTRO PROTECTIVE AGENT FOR THE

TREATMENT OF PAIN AND INFLAMMATION

TECHNICAL FIELD

The present invention relates to pharmaceutical combinations comprising flurbiprofen and an H2 receptor antagonist as gastro-protective agent, preferably famotidine, to oral dosage forms comprising such combinations and to processes for the preparation thereof.

BACKGROUND ART

Flurbiprofen (2-(3-fluoro-4-phenylphenyl]propanoic acid] is a is a well known anti-inflammatory agent that possess analgesic and antipyretic activities. Flurbiprofen is a nonsteroidal antiinflammatory drug (NSAID] used in treatment of mild-to-moderate pain and symptoms of chronic arthritis.

However, the relatively poor solubility of flurbiprofen and its salts, in effect, limits their utility in therapy. It is often required that a higher dose be given or alternative routes of administration sought Although higher doses are required for an efficient therapy, they almost always associated with undesirable side effects, which are mostly gastro intestinal in the case of flurbiprofen and its salts. These gastrointestinal (GI] side effects can be sorted such as gastric and duodenal ulcers, bleeding and perforation, oesophageal inflammation and strictures, and small bowel and colonic ulcers and strictures.

Since its introduction, a number of different flurbiprofen drug products have been developed with the goal of improving efficacy, tolerability and patient convenience. Delayed and extended release forms of flurbiprofen were also developed with the goal of improving their safely profile and providing convenient, once-daily dosing for the treatment of patients with chronic pain.

There have been various attempts to enhance the permeability and bioavailability of poorly absorbed drugs including flurbiprofen. PCT/US1993/012040 makes use of caffeine together with flurbiprofen to hasten the onset of and enhance the analgesic effect.

Patent application PCT/PT2009/000009 mentions a solid dispersion technique to increase the bioavailability of some drugs including flurbiprofen.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs] are a diverse group of compounds that are mainly used to reduce fever, pain and inflammation. Laine L. (Semin. Arthritis Rheumatism 2002;32:25-32] reports that NSAIDs exert their pharmacological action by inhibiting the synthesis of prostaglandins (PGs] by non-selectively blocking cyclooxygenases 1 and 2 (COX-1 and COX-2] or by selectively blocking COX-2. Inhibition of COX-1 is also responsible, in part, for gastrointestinal side effects, which are the most frequent side effects of NSAIDs.

Gwaltney-Brant S.M. reports that non-selective(equipotent] COX inhibitors have other contributors to their gastrointestinal side effects, which are the carboxylic acid group in compounds such as aspirin, ibuprofen, flurbiprofen and diclofenac, and the acidic enolic group in oxicams, such as piroxicam (Charlene A.M., editor. Comprehensive Toxicology. 2nd ed. Elsevier; Oxford, UK: 2010. pp. 159-161] These acidic groups cause local irritation upon oral administration, which can lead to the clinically observed gastrointestinal side effects either independently or in tandem with inhibition of the COX-1 enzyme.

In a report, Lanas et al. (2011] have concluded that more than 90% of the treated patients with osteoarthritis are at increased GI risk, with 60% of them at high risk (Lanas A., Garcia-Tell G., Armada B., Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med. 2011;9:38]

Due to the fact that NSAIDs can cause GI ulceration, bleeding and perforation, especially in case of high and/or frequent dose usage, long-term treatments, history of a gastrointestinal disease or sensitivity to develop disease, additional use of gastro protective agent drugs for reducing GI side effects is needed.

There have been binary combinations of NSAIDs and gastro protective agents in single unit dosage forms disclosed in the state of the art, in order to prevent or treat gastrointestinal side effects. Many studies include the combination of NSAID molecules with acid inhibitors which are proton pump inhibitors, H2 receptor antagonists and prostaglandin analogues.

US patent application US 2014186439 relates to a new stable pharmaceutical composition comprising the combination of ibuprofen and famotidine with at least one pharmaceutically acceptable excipient

US patent application US 20070237820 Al relates to a solid oral dosage form comprising a first portion comprising an NSAID (preferably diclofenac]; and a coating comprising an anti-ulcerative compound (preferably misoprostol]; said coating at least partially surrounding said first NSAID portion. The pharmaceutical dosage described therein creates manufacturing difficulties. None of the prior art documents have disclosed a dual synergistic effect on permeation and absorption while providing a fast treatment for pain, inflammation and pyretic conditions and protecting against its side effects at the same time.

PCT/TR2013/000208 discloses a capsule formulation of flurbiprofen and famotidine which is formulated to provide sustained release. The document discloses that the oral capsule formulation comprises flurbiprofen and famotidine molecules in the same dosage form, yet separately due to the potential incompatibility of flurbiprofen and famotidine.

PCT/TR2013/000209 discloses a multilayer tablet comprising flurbiprofen and famotidine. Due to the intermolecular incompatibility between flurbiprofen and famotidin combinations the formulation is in the form of an oral solid multilayer tablet which creates obvious manufacturing difficulties.

Moreover both of the documents mentioned above fail to disclose any synergies between the two compounds as far as pharmacokinetic parameters or permeability and absorption is concerned.

WO 98/02182 discloses the use of terpenoids, preferably higher than a concentration of at least 0.5%, in combination with NSAIDs for the treatment of painful conditions and inflammatory conditions. The oral pharmaceutical compositions of this document are described to have valuable pharmacological properties with the added COX-2 inhibitory effects of terpenoids. The beneficial effects of the combinations are especially pronounced, when the terpenoid compound(s] is (are] administered in surprisingly high doses; using as high as 250 mg of menthyl lactate in a single dose with only 50 mg of diclofenac (NSAID. It is believed that the terpenoid compounds act as powerful and specifically COX2-inhibiting NSAIDs on their own and thus complement the activity of a NSAID. But the high dosage use of terpenoid compounds may create further risks due to an added COX-2 inhibitor such as major cardiovascular side effects.

W02010/020772 discloses pharmaceutical compositions comprising flurbiprofen, bicarbonate and organic acids such as carboxylic acids for the treatment of sore throats wherein bicarbonate is used as an effervescent.

Therefore a particular need exists in the art for a composition giving fast onset of action and long duration of treatment with decreased GI side effects.

BRIEF DESCRIPTION OF THE INVENTION

Aim of the present invention is to provide a composition which is simple to manufacture without the use of solid dispersion, bilayer tablet technology or any other technology that complicates and make the manufacturing process more expensive while providing a plethora of advantages. In one aspect the present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising flurbiprofen or a pharmaceutically acceptable salt thereof and a H2 receptor antagonist as a gastro protective agent, wherein H2 receptor antagonist is present in an amount of from 5 to 80% by weight of flurbiprofen.

In one aspect the present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising: a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] an H2 receptor antagonist, or a pharmaceutically acceptable salt thereof, and c] a carbonate wherein the H2 receptor antagonist is present in an amount between 10 and 80% by weight based on the weight of flurbiprofen.

In one aspect the present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising: a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] an H2 receptor antagonist, or a pharmaceutically acceptable salt thereof, c] a carbonate and d] a terpenoid compound wherein the H2 receptor antagonist is present in an amount between 5 and 80% by weight based on the weight of flurbiprofen.

In another aspect, the present invention provides a method for preparing the pharmaceutical compositioncomprising flurbiprofen or a pharmaceutically acceptable salt thereof and a H2 receptor antagonist as a gastro protective agent, wherein H2 receptor antagonist is present in an amount of from 5 to 80% by weight of flurbiprofen, comprising the step of wet granulating the mixture of flurbiprofen and famotidine with a a binder in a high shear granulator.

In another aspect, the present invention provides a method for preparing the pharmaceutical composition comprising a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] an H2 receptor antagonist, or a pharmaceutically acceptable salt thereof, and c] a carbonate wherein the H2 receptor antagonist is present in an amount between 10 and 80% by weight based on the weight of flurbiprofen, comprising the step of wet granulating the mixture of flurbiprofen and H2 receptor antagonist with a binder and/or disintegrant in a high shear granulator.

In another aspect, the present invention provides a method for preparing the pharmaceutical composition comprising a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] an H2 receptor antagonist, or a pharmaceutically acceptable salt thereof, c] a carbonate and d] a terpenoid compoundthe H2 receptor antagonist is present in an amount between 5 and 80% by weight based on the weight of flurbiprofen, comprising the step of wet granulating the mixture of flurbiprofen and H2 receptor antagonist with a binder and/or disintegrant in a high shear granulator. In another aspect, the present invention provides use of the pharmaceutical compositions according to the present invention for the treatment of inflammation or pain.

In another aspect, the present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising flurbiprofen or a pharmaceutically acceptable salt thereof and a H2 receptor antagonist as a gastro protective agent, wherein H2 receptor antagonist is present in an amount of from 5 to 80% by weight of flurbiprofen, wherein flurbiprofen is a permeability or absorption enhancer for H2 receptor antagonist and H2 receptor antagonist is a permeability or absorption enhancer for flurbiprofen, wherein H2 receptor antagonist is famotidine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an oral immediate release pharmaceutical composition in a single unit dosage form comprising flurbiprofen or a pharmaceutically acceptable salt thereof, and a H2 receptor antagonist as a gastro protective agent wherein H2 receptor antagonist is present in an amount of from 5 to 80% by weight of flurbiprofen.Thus, flurbiprofen and H2 receptor antagonist increase the absorption and permeability of each other, while gastrointestinal side effects are reduced or treated. This effect can be called as "dual synergistic effect".

As used herein the terms "pharmacokinetic profile” or "pharmacokinetic parameters” or "PK profile” mean one, two or three parameters of Cmax, AUC and Tmax.

As used herein "improving the PK profile” means either an increase in Cmax, or an increase in AUC within a certain period of time, or shortening of the Tmax of an active ingredient or an improvement in a single one or an improvement in the combination of the three parameters.

As used herein Tmax means the amount of time that a drug takes to reach the maximum peak concentration in serum; Cmax is the maximum peak serum concentration of a drug; and AUC (the area under the curve] represents the area under the plasma concentration curve, also called the plasma concentration-time profile, a measure of total systemic exposure to the drug within a period of time, also described as the maximum area under the curve at 0-12 hours (AUC-12]h.ng/mL.

As used herein, "active ingredients” or "active compounds” means flurbiprofen, H2 receptor antagonists.

As used herein, the term "permeability and absorption enhancer" is a material capable of decreasing the penetration barrier of the GI mucosa and enhancing permeation of an active ingredient through the GI mucosa. As used herein, "bioavailability" refers to a rate and extent to which the active ingredient or therapeutic moiety is absorbed from a drug product(composition] and becomes available for therapeutic action. Bioavailability is directly related with the absorption and the consequent blood concentration (serum or plasma levels of a drug] that can be achieved after oral administration.

As used herein,“dual synergistic effect” also means that famotidine or another H2 receptor antagonist, increases the Cmax, and/or AUC of flurbiprofen and/or also decreasing it’s Tmax or maintaining the same Tmax with higher plasma concentration at same Tmax and having the same effect on the pharmacokinetic parameters of the H2 receptor antagonist.

As used herein, "subject" means animals or humans.

It has been surprisingly found that flurbiprofen in combination with H2 receptor antagonist provides a dual synergistic effect with an increased level of absorption which results from increased levels of intestinal permeability perpetuated by both flurbiprofen and H2 receptor antagonist which will create a new treatment modality when a stronger, faster action is needed without the undesired GI side effects.

Now it has been surprisingly found that flurbiprofen in combination with famotidine, provides an improved pharmacokinetic profile (PK profile] compared to their singular use, e.g. a high level of permeability, absorption, Cmax and AUC is achieved for both active compounds, as evidenced by the studies detailed below.

With the surprising dual synergistic effect added benefit of increased levels of flurbiprofen blood concentration, the combination of flurbiprofen and famotidine demonstrates a superior treatment modality with a more solid therapeutic activity compared with the state of the art Thus in one preferred embodiment of the present invention the single unit pharmaceutical dosage form of the present invention has an immediate release of the active ingredients to provide a faster onset of action.

The present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] an H2 receptor antagonist or a pharmaceutically acceptable salt thereof as a gastro protective agent, c] a carbonate.

The addition of a carbonate to the combination of H2 receptor antagonist and flurbiprofen has added further synergistic effect, whereby higher plasma levels of flurbiprofen and famotidine is obtained in a shorter period of time compared to the combination of H2 receptor antagonist and flurbiprofen. Furthermore, the Cmax and AUC of flurbiprofen and H2 receptor antagonist have increased compared to the combination of two active ingredients, namely famotidine (an H2 receptor antagonist] and flurbiprofen. Thus the preferred pharmaceutical composition for the treatment of pain and inflammation comprises a carbonate in addition to a H2 receptor antagonist and flurbiprofen.

Now it has been surprisingly found that flurbiprofen in combination with H2 receptor antagonist, preferably famotidine and carbonate provides an improved pharmacokinetic profile compared to flurbiprofen and H2 receptor antagonist combination as an even higher level of absorption, Cmax and AUC is achieved for flurbiprofen and H2 receptor antagonist as evidenced by the studies detailed below. With the surprising synergistic effect added benefit of increased levels of flurbiprofen blood concentration, the combination of flurbiprofen, H2 receptor antagonist and a carbonate or bicarbonate demonstrates a superior treatment modality with a more solid therapeutic activity compared with the state of the art Thus in one embodiment of the present invention the single unit pharmaceutical dosage form of the present invention has an immediate release of the active ingredients to provide a faster onset of action. The reason why this combination can be stated as an efficient flurbiprofen treatment is that the results obtained in the current study demonstrate a superior, surprising effect that the permeability and absorption of flurbiprofen and famotidine are significantly increased and the Cmax and AUC of flurbiprofen and famotidine are also increased by at least 10% in a 12 hour period compared to their singular administration. These results clearly demonstrate the synergistic effect created by the carbonate, H2 receptor antagonists and flurbiprofen.

Thus the present invention provides a gastro protective, antiarthritic/analgesic pharmaceutical composition with fast and extended period of time pain relief and reduced risk of developing gastrointestinal damage such as ulcers, erosions and hemorrhages. In other words, the present invention is able to provide a longer period of therapeutic effect due to the slow elimination of flurbiprofen as evidenced by it’s high AUC value despite its instant release and fast onset of action.

The pharmaceutical composition of the present invention is synergistically effective for the treatment of inflammation and pain whilst reducing gastrointestinal side effects, therefore having a prophylactic effect on the primary side effect of flurbiprofen administration while increasing Cmax and AUC of flurbiprofen and famotidine at the same Tmax.

The pharmaceutical composition of the present invention would also allow for relatively safe administration of high doses of flurbiprofen and long administration duration, which would be especially important for patients who have acute pain attacks in a period shorter than 6 months but also for patients who have pain and inflammation related problems over a long period of time. The present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] an H2 receptor antagonist or a pharmaceutically acceptable salt thereof as a gastro protective agent, c] a carbonate, and a terpenoid compound.

Furthermore, the addition of a terpenoid compound to the combination of H2 receptor antagonist, flurbiprofen and carbonate added further synergistic effect, whereby higher plasma levels of flurbiprofen and H2 receptor antagonist is obtained in a shorter period of time compared to the combination of H2 receptor antagonist, flurbiprofen and carbonate. Moreover the Cmax and AUC of flurbiprofen and H2 receptor antagonist have increased compared to the combination of two active ingredients. Thus the preferred pharmaceutical composition for the treatment of pain and inflammation comprises a terpenoid compound in addition to a H2 receptor antagonist, flurbiprofen and a carbonate.

Now it has been surprisingly found that flurbiprofen in combination with H2 receptor antagonist, preferably famotidine, carbonate and a terpenoid compound, preferably menthol or levomenthol (1- menthol] provides an improved pharmacokinetic profile compared to flurbiprofen, H2 receptor antagonist and carbonate combination as an even higher level of absorption, Cmax and AUC is achieved for flurbiprofen and H2 receptor antagonist as evidenced by the studies detailed below. The reason why this combination can be stated as an efficient flurbiprofen treatment is that the results obtained in the current study demonstrate a superior, surprising effect that: the permeability and absorption of flurbiprofen are significantly increased;

the Cmax of flurbiprofen is also increased by at least 20%, the AUC of flurbiprofen is also increased by at least 15%, in a 12 hour period compared to their singular administration; and

the Tmax of flurbiprofen is lowered below 35 minutes.

Furthermore, another reason why this combination can be stated as the most efficient famotidine treatment is that the results obtained in the current study demonstrate a superior, surprising effect that: the permeability and absorption of famotidine are significantly increased;

the Cmax of famotidine is also increased by at least 35%, the AUC of famotidine is also increased to by 20%in a 12 hour period;

the Tmax of famotidine is lowered below 60 minutes.

These results clearly demonstrate the synergistic effect created by the terpenoid compound, the carbonate, the H2 receptor antagonists and flurbiprofen. Thus the present invention provides a gastroprotective, antiarthritic/analgesic pharmaceutical composition with fast and extended period of time pain relief and reduced risk of developing gastrointestinal damage such as ulcers, erosions and hemorrhages. In other words, the present invention is able to provide a longer period of therapeutic effect due to the slow elimination of flurbiprofen and H2 receptor antagonist as evidenced by their high AUC value despite their instant release and fast onset of actions.Thus the present invention allows for the possibility of administration of increased frequency uses of flurbiprofen and/or increased administration duration to provide desired inflammation and pain treatment with diminished side effects, which is also facilitated by providing a single unit pharmaceutical dosage form to increase patient compliance.

The pharmaceutical composition of the present invention would also allow for relatively safe administration of high doses of flurbiprofen and long administration duration, which would be especially important for patients who have acute pain attacks in a period shorter than 6 months but also for patients who have pain and inflammation related problems over a long period of time.

With the surprising synergistic effect added benefit of increased levels of flurbiprofen and famotidine blood concentrations, the combination of flurbiprofen, H2 receptor antagonist, a carbonate and a terpenoid compound demonstrates a superior treatment modality with a more solid therapeutic activity compared with the state of the art Thus in one embodiment of the present invention the single unit pharmaceutical dosage form of the present invention has an immediate release of the active ingredients to provide a faster onset of action.

In one embodiment of the present invention the pharmaceutical composition comprises flurbiprofen in its free acid form or flurbiprofen sodium salt, more preferably flurbiprofen in its free acid form.

In one embodiment of the present invention H2 receptor antagonist is selected from the group consisting of famotidine, ranitidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine, oxmetidine or pharmaceutically acceptable salt thereof; said H2 receptor antagonist is preferably famotidine or a pharmaceutically acceptable salt thereof. Famotidine protects the gastric mucosa against irritation, thus it is used in the treatment of gastrointestinal diseases. In one embodiment of the present invention carbonate is selected from the group consisting of potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, arginine bicarbonate and lysine carbonate, preferably an alkali metal carbonate, more preferably potassium bicarbonate or sodium bicarbonate. Potassium bicarbonate (also known as potassium hydrogen carbonate or potassium acid carbonate] is a colorless, odorless, slightly basic, salty substance used to neutralize acid in the stomach.

A terpenoid compound is, for example, a monoterpenoid compound, a diterpenoid compound, a triterpenoid compound or a sesquiterpenoid compound.

In another embodiment of the present invention the pharmaceutical composition comprises a terpenoid compound in free form or esterified by a carboxylic acid.

A monoterpenoid compound is e.g. camphor, 3-carene, carvacrol, carvone, chrysanthemic acid; cineol, e.g. 1,8-cineol; gefarnate, geraniol, linalool, limonene, menthol, levomenthol (1-menthol], pulegone or thymol.

A diterpenoid compound is e.g. aphidicolin, forskolin, phytanic acid or phytol.

A triterpenoid compound is, for example, glycyrrhetinic acid or diosgenin.

A sesquiterpenoid compound is e.g. farnesol or santonin.

The term "terpenoid compound” is intended also to cover any derivative and any pharmaceutically acceptable salt of a terpenoid compound. Preferred derivatives of a terpenoid compound having one or more hydroxy groups are those wherein one or more of the hydroxy groups are esterified by a carboxylic acid (= terpenoid compound esters].

In one embodiment of the present invention terpenoid compound is selected from the group consisting of camphor, 3-carene, carvacrol, carvone, chrysanthemic acid, cineol, gefarnate, geraniol, linalool, limonene, menthol, levomenthol (1-menthol], pulegone, thymol, aphidicolin, forskolin, phytanic acid, phytol, glycyrrhetinic acid, diosgenin, farnesol and santonin, or pharmaceutically acceptable salt thereof; said terpenoid compound is preferably menthol or 1-menthol.

The pharmaceutical composition of the present invention can be administered in various dosage forms and strength in pharmaceutically effective amount. A unit dosage form containing the combination of present invention may be in the form of a tablet, capsule, pellet, granule, effervescent tablet, tablet in tablet, tablet in capsule or powder, preferably tablet, capsule or powder form. The pharmaceutical compositions of the present invention may aso be in the form of drop, pellet, granule, solution, suspension, syrup, powder, suspension, sachet powder and solution.

The pharmaceutical compositions of the present invention may comprise active components in the form of a racemic mixture, or in the form of substantially pure enantiomers or salts thereof.

According to the present invention, the pharmaceutical composition comprises flurbiprofen or a pharmaceutically acceptable salt thereof and a H2 receptor antagonist as a gastro protective agent wherein H2 receptor antagonist is present in an amount of from 5 to 80%, preferably 10 to 60%and more preferably 20 to 40% by weight of flurbiprofen.

In one embodiment of the present invention, the pharmaceutical composition comprises H2 receptor antagonist in an amount selected from 10 to 70 mg, 10 to 65 mg, 10 to 60mg, 10 to 40 mg, 20 to 40 mg, and 20 to 30 mg, more preferably 15 and 30 mg of H2 receptor antagonist or pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the pharmaceutical composition comprises between 50 and 300 mg or between 20 and 200 mg, preferably between 75 and 200 mg or between 75 and 150 mg more preferably 50, 75, 100 or 200 mg of flurbiprofen or pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the pharmaceutical composition comprises H2 receptor antagonist in an amount of 10, 20, 30 or 40 mg.

In one embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen or a pharmaceutically acceptable salt thereof and famotidine wherein famotidine is present in an amount of from 10 to 65 mg.

In one embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen in an amount selected from 50 to 200 mg, 75 to 150, 75 to 110 mg.

In another embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen in an amount of 50, 75, 100, 150 or 200 mg.

Bioavailability is a major issue with NSAIDs, including flurbiprofen although flurbiprofen is a BCS class II drug and has low solubility and high permeability. Famotidine is a BCS class IV drug and has low permeability and low solubility, and this causes it to have low bioavailability The surprising discovery of the present invention detailed in the study below demonstrated that flurbiprofen and famotidine improve each others' PK profile, and increase permeability and absorption. Due to the increase in permeability and absorption of famotidine, rather than administering 80 mg a day, which is the normal usage of famotidine, the present invention can provide a surprisingly higher level of famotidine to allow for a total daily dose of maximum 65 mg when administered in a single unit dosage form with flurbiprofen with or without pharmaceutically acceptable excipients. The twice or more than twice administration also increases patient compliance due to the increase in permeability of famotidine, which provides a higher level of gastro-intestinal protection, even at high frequency dosing.

According to the present invention, the pharmaceutical composition comprises flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof, wherein famotidine is present in an amount of from 5 to 80% by weight based on the weight of flurbiprofen.

In one embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen and H2 receptor antagonist or a pharmaceutically acceptable salt thereof, wherein H2 receptor antagonist is present in an amount of from 10 to 60% by weight of flurbiprofen, wherein the total dose of flurbiprofen administered within a 24 hour period is between 100 and 300 mg and the total dose of H2 receptor antagonist administered within a 24 hour period is between 20 and 65 mg.

In another embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen and H2 receptor antagonist or a pharmaceutically acceptable salt thereof, wherein H2 receptor antagonist is present in an amount of from 20 to 40% by weight of flurbiprofen, wherein the total dose of flurbiprofen administered within a 24 hour period is between 200 and 300 mg and the total dose of H2 receptor antagonist administered within a 24 hour period is between 20 and 65 mg.

In one embodiment of the present invention, the pharmaceutical composition comprises between 10 and 120 mg, preferably between 20 and 80 mg, more preferably between 20 and 70 mg of a carbonate.

Further described is a pharmaceutical unit dosage form, preferably a tablet or capsule, wherein the active ingredients consist of: a] between 50 and 300 mg, preferably 75 and 200 mg of flurbiprofen or pharmaceutically acceptable salt thereof,

b] between 10 and 70 mg, preferably 10 and 60 mg of famotidine or pharmaceutically acceptable salt thereof,

c] between 10 and 120 mg, preferably 20 and 80 mg of potassium bicarbonate. Further described is a pharmaceutical unit dosage form, preferably a tablet or capsule, wherein the active ingredients consist of: d] 100 mg of flurbiprofen or pharmaceutically acceptable salt thereof,

e] 20 mg of famotidine or pharmaceutically acceptable salt thereof,

a] 36 mg of potassium bicarbonate.

In one embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen, H2 receptor antagonist or a pharmaceutically acceptable salt thereof, and a carbonate wherein the total dose of flurbiprofen administered within a 24 hour period is between 200 mg and 300 mg , and the total dose of H2 receptor antagonist administered within a 24 hour period is 20 to 70 mg with a carbonate.

In another embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen, H2 receptor antagonist or a pharmaceutically acceptable salt thereof, and a carbonate wherein the total dose of flurbiprofen administered within a 24 hour period is between 200 and 300 mg and the total dose of H2 receptor antagonist administered within a 24 hour period is between 40 and 70 mg.

Due to the increase in permeability/absorption and improvement of the PK profile of famotidine, rather than administering 80 mg a day, which is the normal usage of famotidine, the present invention can provide a surprisingly higher level of famotidine to allow for a total daily dose of maximum 70 mg when administered in a single unit dosage form with flurbiprofen, a carbonate and a terpenoid compound with or without pharmaceutically acceptable excipients. The normal usage of flurbiprofen is about 3 times with 100 mg tablets meaning 3 tablets a day (a maximum daily usage of 300 mg] and this normally causes a high level of GI side effects, especially upper GI system side effects, even for usage that is as long as a week. The normal use of famotidine is either 2 times 10, 20 or a single 40 mg dose but it can go up to 2 times 40 mg a day in certain indications (a maximum daily dosage of 80 mg].The dosage forms of the present invention allow twice or more than twice administration with diminished GI side effects is also made possible and increases patient compliance due to the higher level of gastro-intestinal protection, even at high frequency dosing.

According to the present invention, the pharmaceutical composition comprises flurbiprofen, H2 receptor antagonist or a pharmaceutically acceptable salt thereof, a carbonate, and a terpenoid compound, wherein the H2 receptor antagonist is present in an amount 5 to 80% by weight based on the weight of flurbiprofen, the carbonate is present in an amount 5 to 200% by weight based on the weight of flurbiprofen, and the terpenoid compound is present in an amount between 0.01 to 0.5% based on the weight of the whole composition. This combination synergistically improves the absorption and PK profile of flurbiprofen and H2 receptor antagonist

In one embodiment of the present invention, the pharmaceutical composition comprises 0.5to 30 mg, preferably 1 to 15, more preferably 1 to 10 mg of a terpenoid compound.

Further described is a pharmaceutical unit dosage form, preferably a tablet, solution, powder or capsule, wherein the active ingredients consist of: a] 50 to 200 mg, preferably 75to 110 mg of flurbiprofen or pharmaceutically acceptable salt thereof;

b] 5 to 80 mg, preferably 10 to 60 mg, more preferably 15 to 30 mg of famotidine or pharmaceutically acceptable salt thereof;

c] 10 to 200 mg, preferably 20 to 80 mg, more preferably 30 to 70 mg of potassium bicarbonate; and

d] 0.5 to 30 mg of a terpenoid compound.

Further described is a pharmaceutical unit dosage form, preferably a tablet, powder or capsule, wherein the active ingredients consist of: a] 50 or 100 mg of flurbiprofen or pharmaceutically acceptable salt thereof;

b] 20 to 30 mg of famotidine or pharmaceutically acceptable salt thereof;

c] 20 to 80 mg of potassium or sodium bicarbonate; and

d] 0.5 to 30 mg of menthol or levomenthol (1-menthol]

These weight ratios of active ingredients provide some difficulties and problems to obtain a homogeneous composition with content uniformity and having the correct weight ratio of both active ingredients with a direct compression technique and their content assays was not continuously reproducible and did not have a practical industrial applicability.

In one embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen, H2 receptor antagonist or a pharmaceutically acceptable salt thereof, a carbonate and a terpenoid compound wherein the total dose of flurbiprofen administered within a 24 hour period is 200 mg to 300 mg of flurbiprofen, and the total dose of H2 receptor antagonist administered within a 24 hour period is 20 to 70 mg.

In another embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen, H2 receptor antagonist or a pharmaceutically acceptable salt thereof, a carbonate and a terpenoid compound wherein the total dose of flurbiprofen administered within a 24 hour period is between 200 and 300 mg and the total dose of H2 receptor antagonist administered within a 24 hour period is between 40 and 70 mg.

In one preferred embodiment, the pharmaceutical composition is not in a modified release formulation such as delayed or sustained release formulation.

In another preferred embodiment, the pharmaceutical composition is not in the form of an multilayered tablet formulation.

In another embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient such as a carrier.

Oral dosage forms of the present invention may comprise suitable diluents, binders, lubricants, disintegrating agents, surfactants, sweetening agents, coloring agents and coating agents as pharmaceutically acceptable excipients.

Pharmaceutically acceptable diluents of the present invention may be selected from magnesium stearate, lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulphate, calcium carbonate, sodium starch glycolate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like or mixtures thereof; preferably lactose and/or microcrystalline cellulose are used.

Pharmaceutically acceptable binders of the invention may be selected from starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, polyvinylpyrrolidone, polyethylene glycol, waxes, sodium alginate, alcohols, water and the like or mixtures thereof; preferably polyvinylpyrrolidone is used.

Pharmaceutically acceptable lubricants of the present invention may be selected from metallic stearates, metallic lauryl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, polyvinylpyrrolidone, sodium benzoate, sodium acetate, sodium chloride, talk and the like or mixtures thereof; preferably metallic stearates are used and more preferably magnesium stearate is used.

Pharmaceutically acceptable disintegrating agents of the present invention may be selected from starches, cellulose derivatives, polyvinylpyrrolidone, crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like or mixtures thereof; preferably crospovidone is used.

Pharmaceutically acceptable surfactants of the present invention may be selected from sulfates, sulfonates, phosphates, carboxylates, primary-secondary-tertiary amines, quaternary ammonium compounds, fatty alcohols, sugar esters of fatly acids, glycerides of fatly acids, polyoxy ethylene glycol alkyl ethers, polysorbates, sorbitan alkyl esters, poloxamers and the like or mixtures thereof.

Pharmaceutically acceptable glidants of the present invention may be selected from silicon dioxide, magnesium trisilicate, starch, talc, colloidal silicon dioxide, silicon hydrogel and the like or mixtures thereof; preferably colloidal silicon dioxide is used.

The composition of the present invention makes use of multi-functional excipients, in order not to increase the total weight of the oral dosage form which can cause swallowing difficulties for the patients e.g.crospovidone which can act as a binder, but which also acts as a disintegration agent within the composition, and magnesium stearate which acts both as lubricant and glidant In one embodiment of the present invention, the pharmaceutical composition comprises at least one lubricant and at least one disintegrating agent or binder, wherein the weight ratio of lubricant to disintegrating agent is between 1:4 and 1:40, preferably 1:3 and 1:20, and more preferably between 1:2 and 1:20.

In one embodiment of the present invention, the pharmaceutical composition comprises magnesium stearate as lubricant and crospovidone as disintegrating agent.

In one embodiment of the present invention, the pharmaceutical composition comprises a] flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof as active ingredients, optionally potassium or sodium bicarbonate and menthol or 1-menthol, and b] at least one lubricant and disintegrating agent or binder, wherein the weight ratio of lubricant to disintegrating agent or binder is between 1:4 and 1:40, preferably 1:3 and 1:20 and more preferably 1:2 and 1:20.

In another embodiment of the present invention, the pharmaceutical composition comprises a] flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof as active ingredients, optionally potassium or sodium bicarbonate and menthol or 1-menthol and b] magnesium stearate as a lubricant or glidant and crospovidone as a disintegrating agent or binder.

In one embodiment of the present invention, the pharmaceutical composition comprises a] flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof as active ingredients, optionally potassium or sodium bicarbonate and menthol or 1-menthol and b] magnesium stearate as a lubricant and crospovidone as a disintegrating agent, wherein the weight ratio of magnesium stearate to crospovidone is between 1:4 and 1:40, preferably 1:3 and 1:20 and more preferably 1:2 and 1:20.

In one embodiment of the present invention, the pharmaceutical composition comprises: a] flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof, and potassium or sodium bicarbonate as active ingredients, and

b] magnesium stearate as a lubricant and crospovidone as a disintegrating agent, wherein the weight ratio of magnesium stearate to crospovidone is between 1:4 and 1:40, preferably 1:3 and 1:20 and more preferably 1:2 and 1:20.

In one embodiment of the present invention, the pharmaceutical composition comprises: a] flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof, potassium or sodium bicarbonate, and menthol or 1-menthol as active ingredients, and

In another embodiment of the present invention, the pharmaceutical composition comprises a lubricant and disintegrating agent as pharmaceutically acceptable excipients wherein the weight ratio of lubricant to disintegrating agent is between 1:4 and 1:40, preferably 1:3 and 1:20 and more preferably 1:2 and 1:20. Thus, content uniformity problem of low dose famotidine and high dose flurbiprofen is decreased and flow and process ability of the dosage form are increased moreover the fast disintegration of the active ingredients is also made possible.

In one embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen and famotidine or a pharmaceutically acceptable salt thereof, and potassium or sodium bicarbonate as active ingredients wherein the dosage form is prepared by wet granulation method. A granulation or preferably a wet granulation technique was employed wherein the active ingredients were granulated with a solution prepared with at least distilled water in a high shear granulator. Due to the large dose difference among active ingredients, it is difficult to obtain a homogeneous composition with content uniformity therefore a method of wet granulation was employed to obtain a homogeneous mixture of the active ingredients.

In one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulating the mixture of flurbiprofen and famotidine or pharmaceutically acceptable salt thereof with a granulation solution of distilled water and a binder in a high shear granulator. In one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulating the mixture of flurbiprofen and famotidine or pharmaceutically acceptable salt thereof with a granulation solution of distilled water and crospovidone in a high shear granulator.

In one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulation the mixture of flurbiprofen and famotidine or pharmaceutically acceptable salt thereof with a granulation solution of distilled water and a binder in a high shear granulator, wherein famotidine is present in an amount of5to 80mg, preferably 10 to60mg, and more preferably between 20 and30 mg.

In one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulation the mixture of flurbiprofen and famotidine or pharmaceutically acceptable salt thereof with a granulation solution of distilled water and crospovidone in a high shear granulator, wherein famotidine is present in an amount of 5 to 80 mg, preferably 10 to 60 mg, and more preferably between 20 and 30 mg.

According to the present invention, the mixture used in wet granulation step further comprisesat least one lubricant or glidant and at least one disintegrating agent or binder, preferably magnesium stearate and crospovidone providing a content uniformity between the range of 85% to 115% for both flurbiprofen and famotidine or pharmaceutically acceptable salt thereof in the pharmaceutical composition. The weight ratio of lubricant to disintegrating agent can be between 1:4 and 1:40.

In one embodiment, the present invention is related to a method for preparing said pharmaceutical composition which comprises the following steps:

1. Sieve Flurbiprofen, Famotidine, microcrystalline cellulose and hydroxypropylcellulose together

2. Granulated the mixture of items with granulation solution prepared by distilated water and Crospovidone (2mg] in high shear granulator

3. Dry mixture items in fluid-bed granulator and pass through a 0.8-mm sieve,

4. Add microcrystalline cellulose type 102, crospovidone (23mg], menthol and potassium bicarbonate and mix 15 minutes.

5. Add magnessium stearate to the mixture and mix 3 minutes.

6. Compress tablets,

7. Coat tablets with coating solution (Preffered HSP orange] Wet granulating famotidine and flurbiprofen with crospovidone provides better content uniformity, and magnesium stearate also helps with the flow and processability of final mixture and unit dosage.

In one preferred embodiment of the present invention the pharmaceutical composition is provided for use in a method for the treatment of inflammation or pain with reduced GI side effects.

In one preferred embodiment, the pharmaceutical composition of the present invention is useful for the treatment of inflammation or pain caused by muscular or skeletal system disease.

In another preferred embodiment, the pharmaceutical composition of the present invention is useful for the treatment of inflammation or pain is caused by chronic polyarthritis, ankylosing spondilytis, osteoarthritis, gout attacks, extra- articular rheumatism, post-traumatic and postoperative pain, dysmenorrhea, rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, colitis ulcerosa; acute musculoskeletal pain; chronic musculoskeletal pain muscle strain; toothache, muscular pain (myalgia, strain], back pain, knee pain, shoulder pain, bursitis, tendinitis or epicondylitis.

In another preferred embodiment, the pharmaceutical composition of the present invention is useful as an antipyretic medicament

In one embodiment of the present invention, pharmaceutical composition comprises flurbiprofen and H2 receptor antagonist, wherein H2 receptor antagonist increases the Cmax of flurbiprofen by at least 7%.

In another embodiment of the present invention, pharmaceutical composition comprises flurbiprofen and H2 receptor antagonist, wherein H2 receptor antagonist increases the Cmax of flurbiprofen by at leastl0%.

In another embodiment of the present invention, pharmaceutical composition comprises flurbiprofen and H2 receptor antagonist, wherein flurbiprofen increases the Cmax of famotidine by at least 7%.

In another embodiment of the present invention, pharmaceutical composition comprises flurbiprofen and H2 receptor antagonist, wherein flurbiprofen increases the Cmax of famotidine by at least 14%.

In one embodiment of the present invention, the pharmaceutical composition is provided for use in a method for the treatment of inflammation or pain wherein the pharmaceutical composition comprising a] flurbiprofen and famotidine as active ingredients, wherein famotidine is present in an amount of from 5 to 80%, preferably 10 to 60%, more preferably 20 to 40% by weight of flurbiprofen, b] at least one lubricant and at least one disintegrating agent as pharmaceutically acceptable excipients, and wherein the pharmaceutical composition is administered 2 times within a 24 hour period and wherein the total daily dose of flurbiprofen administered is between 100 and 300mg and wherein the total daily dose of famotidine administered is between 20 and 65 mg.

In one embodiment of the present invention, the pharmaceutical composition is provided for use in a method for the treatment of inflammation or pain wherein the pharmaceutical composition comprising a] flurbiprofen and famotidine as active ingredients, wherein famotidine is present in an amount of from 5 to 80%, preferably 10 to 60%, more preferably 20 to 40% by weight of flurbiprofen, b] at least one lubricant and at least one disintegrating agent as pharmaceutically acceptable excipients, and wherein the pharmaceutical composition is administered 2 times within a 24 hour period and wherein the total daily dose of flurbiprofen administered is between 200 and 300 mg and wherein the total daily dose of famotidine administered is between 20 and 65 mg.

In another embodiment of the present invention, the pharmaceutical composition is provided for use in a method for the treatment of inflammation or pain wherein the pharmaceutical composition comprising a] flurbiprofen and famotidine as active ingredients, wherein famotidine is present in an amount of from 5 to 80%, preferably 10 to 60%, more preferably 20 to 40% by weight of flurbiprofen, b] at least one lubricant and at least one disintegrating agent as pharmaceutically acceptable excipients, and wherein the pharmaceutical composition is administered 2 times within a 24 hour period and wherein the total daily dose of flurbiprofen administered is between 200 and 300 mg and wherein the total daily dose of famotidine administered is between 40 and 65 mg.

In one embodiment of the present invention, the immediate release pharmaceutical composition comprises flurbiprofen and famotidine wherein Tmax of flurbiprofen and famotidine is 15 minutes. Due to the fact that both flurbiprofen and famotidine have the same Tmax value when administered together famotidine can effectively diminish the gastro intestinal side effects of flurbiprofen.

In one embodiment of the present invention, the immediate release pharmaceutical composition comprises flurbiprofen and famotidine, wherein famotidine increases the Cmax of flurbiprofen by at least 7%, preferably by at least 10%, more preferably 14%.

Another embodiment of the present invention is related to a method for obtaining a Tmax of flurbiprofen in a human patient about 15 to60 minutes after administrating flurbiprofen to said patient, comprising orally administering flurbiprofen to said patient, wherein flurbiprofen composition comprises an H2 receptor antagonist, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 5 to 80% by weight based on the weight of flurbiprofen.

In one embodiment of the present invention, the immediate release pharmaceutical composition comprises flurbiprofen and famotidine, wherein flurbiprofen increases the Cmax of famotidine by at least 28%, preferably by at least 45%,.

In another embodiment of the present invention, the immediate release pharmaceutical composition comprises flurbiprofen and famotidine, wherein flurbiprofen increases the AUC of famotidine by at least 21% within a 12 hour period after administration.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine and a carbonate wherein the Tmax of flurbiprofen is less than 60 minutes, preferably less than 45 minutes, and more preferably between 15 and 45 minutes.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine and a carbonate wherein the Tmax of famotidine is less than 60 minutes, preferably less than 45 minutes, and more preferably between 15 and 45 minutes.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine and a carbonate wherein the AUC of flurbiprofen within 12 hours after administration is 10%, preferably 10 to 40% higher compared to the singular administration of flurbiprofen.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine and a carbonate, wherein the AUC of famotidine within 12 hours of after administration is 10%, preferably 10 to 40% higher compared to the singular administration of famotidine. In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine and a carbonate, wherein famotidine and the carbonate increase the Cmax of flurbiprofen by at least 10%, preferably 10 to 40%, more preferably 20%.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine and carbonate, wherein flurbiprofen and the carbonate increase the Cmax of famotidine by at least 10%, preferably 10 to 40%, more preferably 15%.

Another embodiment of the present invention is related to a method for obtaining a Tmax of flurbiprofen in a human patient about 15 to 60 minutes, preferably 15 to 40 minutes after administrating flurbiprofen to said patient, comprising orally administering flurbiprofen to said patient, wherein flurbiprofen composition comprises an H2 receptor antagonist and a carbonate, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 10 to 80% by weight based on the weight of flurbiprofen.

In another embodiment of the present invention, a method for obtaining a Tmax of flurbiprofen in a human patient about 15 to 60 minutes, preferably 15 to 40 minutes after administrating flurbiprofen to said patient, comprising orally administering flurbiprofen to said patient, wherein flurbiprofen composition comprises an H2 receptor antagonist and a carbonate, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 10 to 80% by weight based on the weight of flurbiprofen and wherein both flurbiprofen and famotidine have a Cmax of 10 to 40% higher than their singular administration and an AUC within 12 hours after administration, between 10 to 40% higher than their singular administration.

In one embodiment of the present invention, pharmaceutical composition comprises flurbiprofen, famotidine and carbonate, wherein flurbiprofen and the carbonate increase the absorbed fraction and P_app of famotidine by at least 5% in a Caco-2 cell model under in-vitro assay conditions.

In one embodiment of the present invention, pharmaceutical composition comprises flurbiprofen, famotidine and carbonate, wherein famotidine and carbonate increase the flurbiprofen transported across the Caco-2 Cell membrane by at least 25% under in-vitro assay conditions.

In another embodiment, pharmaceutical composition comprises flurbiprofen, famotidine and carbonate, wherein famotidine and carbonate increase the flurbiprofen transported across the Caco-2 Cell membrane by at least 50% at 30 minutes under in-vitro assay conditions.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine, a carbonateand a terponoid compound wherein the Tmax of flurbiprofen is less than 60 minutes, preferably less than 45 minutes, and more preferably between 15 and 35 minutes.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine, a carbonateand a terpenoid compound wherein the Tmax of famotidine is less than 60 minutes, preferably less than 45 minutes, and more preferably between 15 and 35 minutes.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine, a carbonate and a terpenoid compound wherein the AUC of flurbiprofen within 12 hours after administration is at least 10%, preferably at least 15%, more preferably 15 to 40% higher compared to the singular administration of flurbiprofen.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine, a carbonate and a terpenoid compound wherein the AUC of famotidine within 12 hours after administration is at least 10%, preferably at least 15%, more preferably 20 to 40% higher compared to the singular administration of flurbiprofen.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine, a carbonate and a terpenoid compound wherein the Cmax of flurbiprofen is at least 10%, preferably at least 20%, more preferably 20 to 40% higher compared to the singular administration of flurbiprofen.

In another embodiment of the present invention, an instant release pharmaceutical composition comprises flurbiprofen, famotidine, a carbonate and a terponoid compound wherein the Cmax of famotidine is at least 20%, preferably at least 28%, more preferably at least 35% higher compared to the singular administration of famotidine.

Another embodiment of the present invention is related to a method for obtaining a Tmax of flurbiprofen in a human patient about 15 to60 minutes, preferably 15 to 45 minutes, more preferably 15 to 35 minutes after administrating flurbiprofen to said patient, comprising orally administering flurbiprofen to said patient, wherein flurbiprofen composition comprises an H2 receptor antagonist, a carbonate and a terpenoid compound, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 5 to 80% by weight based on the weight of flurbiprofen.

In another embodiment of the present invention, a method for obtaining a Tmax of flurbiprofen in a human patient about 15 to 60 minutes, preferably 15 to 45 minutes, more preferably 15 to 35 minutes after administrating flurbiprofen to said patient, comprising orally administering flurbiprofen to said patient, wherein flurbiprofen composition comprises an H2 receptor antagonist, a carbonate and a terpenoid compound, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 5 to 80% by weight based on the weight of flurbiprofen and wherein both flurbiprofen and famotidine have a Cmax of 20 to 40% higher than their singular administration and an AUC within 12 hours after administration, between 20 to 40% higher than their singular administration.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

EXAMPLES

The present invention will be explained more in detail by an illustrating example and study. Example 1

Table 1 below provides the contents of an embodiment of the present invention. The composition is in the form of a film coated tablet of flurbiprofen in combination with famotidine.

Table 1

Manufacturing Directions (Wet Granulation)

1. Sieve Flurbiprofen, Famotidine, microcrystalline cellulose type 101 and

hydroxypropylcellulose together

2. Granulate the mixture of items with granulation solution prepared by distilled

water and crospovidone in high shear granulator

3. Dry mixture items in fluid-bed granulator and pass through a 0.8-mm sieve,

4.Add microcrystalline cellulose type 102, crospovidone (25 mg) and mix 15 minutes.

5. Add magnessium stearate to the mixture and mix 3 minutes.

6. Compress tablets,

7. Coat tablets with coating solution Content Uniformity Test:

The content uniformity of 10 dosage units randomly chosen, were assessed according to the USP requirements for content uniformity. The amount of the active ingredient in each of the 10 tested tablets containing 100 mg flurbiprofen and 20 mg famotidine were assayed by using HPLC, the method for the HPLC assay was based on Hanif et al. http://www.bioline.org.br/pdf7prl6081. The formulation was prepared by wet granulation with the same excipients and method used in the manufacturing example, all of the HPLC results were well within the range of 85% toll5% for the dosage forms of the present invention and the relative standard deviation(RSD) was less than 6%.

Study on permeability o f the active ingredients flurbiprofen(Flur) and Famotidine ( Earn) separately and in combination using Caco-2 intestinal permeability and absorption method wherein pharmaceutical compositions prepared according to the same ratio of active ingredients as the Example 1.

The Caco-2 cell system, a well characterized intestinal in vitro model, makes it possible to evaluate the ability of chemicals to cross the intestinal barrier, as well as to study their transport mechanisms. Permeability values estimated with this model correlate well with human in vivo absorption data for many drugs and chemicals. As a consequence, the use of the Caco-2 cellular model as a permeability assay to predict oral absorption in humans is growing, and its importance is increasing as a screening tool in drug-discovery strategies for the prediction of intestinal drug permeability (https://www.ncbi.nlm.nih.gov/pubmed/21400683]

Preparation of cells

Caco-2 cells were seeded at a density of 10.000 cells/well in the transwell plates for the preparation of permeability experiments. The cells were incubated at 37 °C in a humidified atmosphere of 5 % C02 in air. Medium was replaced on the next day following seeding and every other day thereafter for 21 days before permeability assay. Integrity, cell viability and permeability assays were carried out. Cell viability was determined by MTT, and integrity was determined by using lucifer yellow methods. Preparation of Stock and Test solutions wherein the ratio of the active ingredients flurbiprofen and famotidine were prepared according to the same ratio of active ingredients as the Example 1.

Flurbiprofen MW: 244.261 g/mol

Famotidin MW: 337.435 g/mol

Stock solution of Flurbiprofen was prepared in DMSO at 100 mg/ml Stock solution of Famotidine was prepared in DMSO at 20 mg/ml

All final concentrations were prepared by added 5 mΐ stock solution in 5 ml HBSS FaSSIF (Fasted State Simulated Intestinal Fluid] buffer.

Permeability and absorption experiment was performed for 2 hours.

Caco-2 Permeability Assay Culture medium on cells were withdrawn 21 days after the Caco-2 cells seeded in transwell plate. Caco-2 monolayers were washed twice with transport buffer Hank's Balanced Salt Solution (HBSS] suplemented with 10 mM HEPES (4-(2-hydroxyethyl]-l-piperazineethanesulfonic acid] and pH adjusted to 6.5 and 7.4 with HC1 or NaOH ] to remove the trace of culture medium.

At the established times (0, 30, 60, 90, and 120 min] the samples were collected from plates and analyzed by HPLC.

HPLC ANALYSIS

Samples were analyzed on a Shimadzu LC-2040 3D Nexera-i, and Methanol: Water (70:30 v/v] mixture was used as diluent for the samples. Chromatographic System:

Equipment: High Pressure Liquid chromatography (HPLC]; Shimadzu LC-2040 3D Nexera-i Column: Inertsil C8 250x4,6 mm; 5 pm Flow Rate: 1,0 ml/min Column Temperature: 35 °C Autosampler Temperature: 5 °C Wavelength: 254 nm Injection Volume: 50 pi Run Time: 12 min Diluent: Methanol: Water (70:30 v/v]

Mobile Phase: Methanol: Buffer (pH: 2.5] (70:30 v/v]

Buffer pH:2.5 : 0.01 M H₃PO₄ + 0.01 M NaH₂P0₄.H₂0 if necessary adjust to pH: 2.5 ± 0.2 RESULTS

Figure 1 shows intestinal permeability and absorption % of Flurbiprofen separately and in combination with famotidine.

Figure 2 shows intestinal permeability percentages of Famotidine separately and in combination with Flurbiprofen.

Table 2. Permeability percentages of flurbiprofen separately and in combination with Famotidine.

Table 3 Permeability percentages of famotidine separately and in combination with Flurbiprofen.

Table 4

Absorbed concentration of flurbiprofen alone and in the presence of famotidine.Also it demonstrates the amount of flurbiprofen transported across the Caco-2 cell membrane under in- vitro assay conditions.

Table 5

Absorbed concentration of Famotidine separately and in combination withflurbiprofen. It also demonstrates the amount of flurbiprofen transported across the Caco-2 cell membraneunder in- vitro assay conditions.

EVALUATION OF THE RESULTS

Flurbiprofen is a BCS Class II medicinal product BCS Class II medicinal products are characterized by low solubility and high permeability. Flurbiprofen alone showed 12.504% permeability at 30 minutes(min) and 42.387% permeability at 30 min in combination with famotidine.Flurbiprofen showed 70.906% permeability alone and 74.118% in combination with famotidine at 120 min. Based on the data obtained, famotidine increases intestinal permeability of flurbiprofen by about 240% at 30 min. Famotidine also increases the permeability and absorption of flurbiprofen by about 5% at 120min which also shows that the fast onset of action has not eliminated the effect of flurbiprofenin the subsequent periods, still providing a long lasting effect Thereby both active compounds increase each others permeability and/or absorption, even more surprisingly considering that Flurbiprofen is a BCS class II drug and already has high permeability, so to further increase of this parameter was astonishing.

Accordingly, permeability and absorption rate of Flurbiprofen will increase in the presence of Famotidine under in-vivo conditions. It would be known by anyone with ordinary skill in the art, that the increase in the permeability and absorption of flurbiprofen and famotidine will also definitely increase the blood concentration of flurbiprofen and famotidine in-vivo and this increase is created by the combination of famotidine with flurbiprofen as also evidenced by the PK study of the present invention.

As flurbiprofen has a high incidence of gastro intestinal side effects, it was ideal to have further increases in famotidine permeability and absorption, surprisingly it was found as such.The surprising discovery attained by the results of the study clearlydemonstrate that the co administration of flurbiprofen and famotidine increase the amount of flurbiprofen and famotidine transported across the Caco-2 cell membrane meaning that flurbiprofen acts as a permeability and absorption enhancer for famotidine and famotidine acts as a permeability and absorption enhancer for flurbiprofen, which was never reported before in the prior art or any other study

The surprising results of the study also demonstrate that a higher level of effectively both in a short and long period with the combinations of the present invention are achievable providing a fast onset of action for flurbiprofen without compromising the longer term effect of Flurbiprofen and famotidine.

DETAILS OF THE STUDY DEMONSTRATING THE SYNERGISTIC PHARMACOKINETIC EFFECT BETWEEN FLURBIPROFEN AND FAMOTIDINE

Example 2

Experimental procedure to compare the pharmacokinetic properties of flurbiprofen alone and flurbiprofen in combination with famotidinewherein the pharmaceutical compositionwas prepared according to the manufacturing method in Example 1.

The primary objective of this experimental study was to compare the pharmacokinetics of flurbiprofen when used as a single active compound as flurbiprofen in it’s free acid form in combination with famotidine. In this experimental study, the aim was to observe how the combination of flurbiprofen and famotidine would change their pharmacokinetic parameters, both study drugs were prepared with pharmaceutically acceptable excipients.

Animals

Male Wistar rats (240-260 g] were used in the study. The rats were maintained in an air- conditionedanimals quarter at a temperature of 22 ± 2 °C and a relative humidity of 50 ± 10 %. Food and water were allowed ad libitum. The animals were acclimatized to the facilities for five days, and then fasted with free access to water for 12 h prior to the experiment All the animals were housed under similar conditions. (Xie etal, 2011] Drug Administration

Bioavailability and pharmacokinetics of Flurbiprofen and famotidine were studied in all the normal state of rats; six male and/or female rats per group (Mojaverian et al., 1985] were gavaged with 10 mg/kg Flurbiporfen and a combinationwith 2 mg/kg famotidine (Mojaverian et. al., 1985] Blood (0.2 ml] was taken from the tail vein prior to administration of test substances (0 h] and after

0.083, 0.25, 0.5, 1, 2, 4, 8 and 12h.

Extraction of Blood Samples

Blood samples were collected (Parasuman et. al., 2010] in corning tubes and kept on ice until 50 ul dichloromethane (Pargal et al., 1988] was added and they were centrifuged at 7000 x g for 5 min at 4°C and supernatants were collected for HPLC analysis.

Results

Table 6 Concentrations of Flurbiprofen in blood

Figure 3 shows the effects of famotidine on blood concentrations of flurbiprofen. Table 7 Pharmacokinetic Parameters of Flurbiprofen in blood

Table 8 Concentrations of Famotidine in blood

Figure 4 shows the effects of flurbiprofen on blood concentrations of famotidine

Table 9 Pharmacokinetic Parameters of Famotidine in blood

Evaluation of the Results

Table 6 shows the plasma(blood) concentration values of flurbiprofen through a 12 hour period, with the same proportional dose of the formulation presented in the manufacturing example and the tablets were prepared accordingly with the same methods and pharmaceutically acceptable excipients. As it can be seen from Table 7, there is an evident increase in the Cmax values of both flurbiprofen and famotidine when it is used in combination with each other. The Cmax of flurbiprofen when used as a single active ingredient formulation is 2.79 pg/ml, whereas it is 3.23 pg/ml when administered in combination with famotidine showing an increase of about 15.7%. Similarly, Tmax values in Table 7 also show that combinations of the present invention provide a fast pain relief compared to the flurbiprofen alone due to the fact that the combination of the present invention provides a higher blood concentration at the same Tmax. Table 7also provides 12 hour AUC values of flurbiprofen. The combination of flurbiprofen and famotidine has about 2.5 %increase in AUC value, meaning this combination provides as long a duration of pain and inflammation relief as the singular administration of flurbiprofen but has a stronger effect in a shorter period of time due to the fact that the combination of the present invention has a higher Cmax and the same Tmax.

Table 8 shows the plasma(blood] concentration values of famotidine through a 12 hour period, with the same proportional dose of the formulation presented in the manufacturing example and the tablets were prepared accordingly with the same methods and pharmaceutically acceptable excipients. As it can be seen in Table 9 there is an evident increase in the Cmax values of famotidine when it is used in combination with flurbiprofen. The Cmax of famotidine when used as a single active ingredient formulation is about 0.99 pg/ml, whereas it is about 1.46 pg/ml when administered in combination with flurbiprofen showing an increase of about 46%. Similarly, Tmax values in Table 9 also show that combinations of the present invention provide a faster therapeutic level of gastro intestinal protection to famotidine administered alone due to the fact that the combination of the present invention provides a higher blood concentration of famotidine at the same Tmax.

It is also of notable value that flurbiprofen and famotidine had the same Tmax when administered together, so famotidine can effectively diminish the gastro intestinal side effects of flurbiprofen, by reaching their respective peak plasma concentrations at about the same time.

Table 9 also provides the 12 hour AUC values of famotidine. The combination of flurbiprofen and famotidine has about 21% increase in AUC value(4.85 to 5.88pg], meaning this combination provides a strong gastro intestinal protection during a longer period of time compared to the singular administration of famotidine, which is extremely beneficial to a subject in need of flurbiprofen administration.

Thus the combination of the present invention demonstrates a surprising dual synergistic effect increasing each others Cmax significantly while maintaining the same Tmax and also maintaining a similar AUC for flurbiprofen and significantly increasing the AUC of famotidine within a 12 hour period. Providing a superior treatment modality for pain, inflammation and pyretic conditions to receive a stronger effect from flurbiprofen with diminished side effects.

Example 3

An instant release oral formulation of flurbiprofen, famotidine and potassium bicarbonate combination. Flurbiprofen / Famotidine 100 mg / 20 mg Film Tablet

Unit Formula

Bill of Materials mg/tb.

Flurbiprofen 100,00

Famotidine 20,00

Potassium Bicarbonate 36,00

Hydroxypropylcellulose 7.50

Microcrystalline cellulose type 101 165,00

Crospovidone 40,00

Microcrystalline cellulose type 102 25,00

Colloidal silicone Dioxide 2,50

Magnessium Stearate 5,00

Weight of Core Tablet 401,00

AquariusTM Preferred HSP Orange 15

Weight of Coated T ablet 416, 00

Manufacturing Directions (Wet Granulation)

1. Sieve Flurbiprofen, Famotidine, microcrystalline cellulose type 101 and hydroxypropylcellulose together,

2. Granulate the mixture of items with granulation solution prepared by distilated water, and Crospovidone (15 mg) in high shear granulator,

3. Dry mixture items in fluid-bed granulator and pass through a 0.8-mm sieve,

4. Add microcrystalline cellulose type 102, crospovidone and potassium bicarbonate and mix 15 minutes

5. Add magnessium stearate to the mixture and mix 3 minutes 6. Compress tablets

7. Coat tablets with coating solution (Preffered HSP orange]

Content Uniformity Test:

The content uniformity of 10 dosage units randomly chosen, were assessed according to the USP requirements for content uniformity. The amount of the active ingredient in each of the 10 tested tablets containing 100 mg flurbiprofen and 20 mg famotidine were assayed by using HPLC. The formulation was prepared by wet granulation with the same excipients and method used in the manufacturing example, all of the HPLC results were well within the range of 85% toll5% for the dosage forms of the present invention and the relative standard deviation(RSD] was less than 6%. Details of the study proving the synergistic effect between flurbiprofen, famotidine and potassium bicarbonate.

Studying the effects of famotidine and potassium bicarbonate on the pharmacokinetics of flurbiprofen and famotidine in rats.

The primary objective of the test was to compare the pharmacokinetics of flurbiprofen when used as a single active compound as flurbiprofen in it’s free acid form and in combination with famotidine and/or potassium bicarbonate. In this experimental study, the aim was to observe how the addition of a carbonate to flurbiprofen and famotidine and their combination would change the pharmacokinetic properties of flurbiprofen and/or famotidine.

MATERIALS AND METHODS

Active ingredients

Flurbiprofen, famotidine,

Essential excipient Potassium bicarbonate

Animals Male Wistar rats (240-260 g] were used in the study. The rats were maintained in an air- conditionedanimals quarter at a temperature of 22 ± 2 °C and a relative humidity of 50 ± 10 %. Food and water were allowed ad libitum. The animals were acclimatized to the facilities for five days, and then fasted with free access to water for 12 h prior to the experiment All the animals were housed under similar conditions. (Xie etal, 2011]

Drug Administration

Bioavailability and pharmacokinetics of Flurbiprofen and Famotidine were studied in all the normal state of rats following an oral gavage of 10 mg/kg Flurbiprofen (Knihinicki et al., 1990; Muraoka et. al., 2004], 2 mg/kg famotidine (Mojaverian et al., 1985] and 3,6 mg/kg potassium bicarbonate. Each rat was administered Flurbiporfen and/ or combination with famotidine and potassium bicarbonate.

Six male and/or female rats per group (Mojaverian et. al., 1985] were gavaged with singular flurbiprofen or famotidine or their combinations with the doses described above. Blood (0.2 ml] was taken from the tail vein prior to administration of test substances (0 h] and after 0.083, 0.25, 0.5, 1, 2, 4, 8 and 12h.

Extraction of Blood Samples

HPLC ANALYSIS

Samples were analyzed on a Shimadzu LC-2040 3D Nexera-i, and Methanol: Water (70:30 v/v] mixture was used as diluent for the samples. Chromatographic System :

Equipment: High Pressure Liquid chromatography (HPLC]; Shimadzu LC-2040 3D Nexera-i Column: Inertsil C8 250x4,6 mm; 5 pm Llow Rate: 1.0 ml/min Column Temperature: 35 °C Autosampler Temperature: 5 °C Wavelength: 254 nm

Injection Volume: 50 pi Run Time: 12 min

Diluent: Methanol: Water (70:30 v/v]

Mobile Phase: Methanol: Buffer (pH: 2.5] (70:30 v/v]

Buffer pH:2,5: 0.01 M H3P04 + 0.01 M NaH2P04.H20 if necessary adjust to pH: 2.5 ± 0.2

Results

Table 10 Concentrations of Flurbiprofen in blood

Figure 5 shows the effects of famotidine and potassium bicarbonate on blood concentrations of flurbiprofen. Table 11 Pharmacokinetic Parameters of Flurbiprofen in blood

Table 12 Concentrations of Famotidine in blood

Figure 6 shows the effects of flurbiprofen and potassium bicarbonate on blood concentrations of famotidine Table 13 Pharmacokinetic Parameters of Famotidine in blood

Evaluation of the Results

Table 10 shows the plasma (blood] concentration values of flurbiprofen through a 12 hour period, with the same proportional dose of the formulation presented in the manufacturing example and the tablets were prepared accordingly with the same methods and pharmaceutically acceptable excipients. As it can be seen from Table 11, there is an evident increase in the Cmax value of flurbiprofen when it is used in combination with a carbonate, namely potassium bicarbonate (PB] The Cmax of flurbiprofen when used as a single active ingredient formulation is about 2.79 pg/ml, whereas it is about 3.39 pg/ml when administered in combination with famotidine and potassium bicarbonate showing an increase of about 21%. Table 11 also show that combinations of the present invention provide a fast pain relief compared to flurbiprofen alone due to the fact that the combination of the present invention provides a higher blood concentration at the same Tmax. Table 11 also provides 0 to 12 hour AUC values of flurbiprofen. The combination of flurbiprofen and famotidine has about a 14% increase in AUC value, meaning this combination provides as long duration of pain and inflammation compared to the singular administration of flurbiprofen but has a stronger effect in a shorter period of time due to the fact that the combination of the present invention has a higher Cmax and the same Tmax.

Table 12 shows the plasma (blood] concentration values of famotidine through a 12 hour period, with the same proportional dose of the formulation presented in the manufacturing example and the tablets were prepared accordingly with the same methods and pharmaceutically acceptable excipients. As it can be seen in Table 13 there is an evident increase in the Cmax value of famotidine when it is used in combination with flurbiprofen and PB. The Cmax of famotidine when used as a single active ingredient formulation is about 0.99 pg/ml, whereas it is about 1.26 pg/ml when administered in combination with flurbiprofen and PB showing an increase of about 26% . Although there is a decrease compared to the combination of flurbiprofen and famotidine, it is still far superior to famotidine administered alone. Similarly, Tmax values in Table 13 also show that combinations of the present invention provide a faster and higher level of gastro intestinal protection to famotidine administered alone due to the fact that the combination of the present invention provides a higher blood concentration of famotidine at the same Tmax.

Table 13 also provides the 12 hour AUC values of famotidine. The combination of flurbiprofen, famotidine and PB has about a 39% increase in AUC value (from 4.85 h. pg/ml to 6.79 h. pg/ml], meaning this combination provides a strong gastro intestinal protection during a longer period of time compared to the singular administration of famotidine, which is extremely beneficial to a subject in need of flurbiprofen administration.

Thus the combination of the present invention demonstrates a surprising dual synergistic effect increasing the Cmax and AUC of both flurbiprofen and famotidine significantly while maintaining the same Tmax. Providing a superior treatment modality for pain, inflammation and pyretic conditions to receive a stronger effect from flurbiprofen with diminished gastro intestinal side effects. Example 4

Study on permeability of the active ingredients flurbiprofen(Flur) and Famotidine (Fam 1 separately and in combination with potassium bicarbonate (PB Ί using an in-vitro Caco-2 permeability and absorption method Preparation of cells

Caco-2 cells were seeded at a density of 10.000 cells/well in the transwell plates for the preparation of permeability experiments. The cells were incubated at 37 °C in a humidified atmosphere of 5 % C02 in air. Medium was replaced on the next day following seeding and every other day thereafter for 21 days before permeability and absorption assay. Integrity, cell viability and permeability assays were carried out after the 21^st day Cell viability was determined by MTT, and integrity was determined by using lucifer yellow methods.

Preparation of Stock and Test solutions

Flurbiprofen MW: 244.261g/mol Famotidin MW: 337.435 g/mol Potassium bicarbonate MW: 100.115 g/mol

Stock solution of flurbiprofen was prepared in DMSO at 100 mg/ml

Stock solution of Famotidine was prepared in DMSO at 20 mg/ml

Stock solution of Potassium Bicarbonate was preapared in DDW at 36 mg/ml

All final concentrations were prepared by added 5 ul stock solution in 5 ml HBSS FaSSIF (Fasted State Simulated Intestinal Fluid] buffer.

Permeability and absorption experiment was performed for a 2 hour period.

Caco-2 Permeability Assay

Culture medium on cells were withdrawn 21 days after the Caco-2 cells seeded in transwell plate. Caco-2 monolayers were washed twice with transport buffer Hank's Balanced Salt Solution (HBSS] suplemented with 10 mM HEPES (4-(2-hydroxyethyl]-l-piperazineethanesulfonic acid] and pH adjusted to 6.5 and 7.4 with HC1 or NaOH to remove the trace of culture medium. At the established times (0, 30, 60, 90, and 120 min] the samples were collected from plates and analyzed by HPLC.

HPLC ANALYSIS

Samples were analyzed on a Shimadzu LC-2040 3D Nexera-i, and Methanol: Water (70:30 v/v] mixture was used as diluent for the samples.

Chromatographic System :

Equipment: High Pressure Liquid chromatography (HPLC]; Shimadzu LC-2040 3D Nexera-i Column: Inertsil C8 250x4,6 mm ; 5 pm Flow Rate: 1.0 ml/min Column Temperature: 35 °C

Autosampler Temperature: 5 °C Wavelength: 254 nm Injection Volume: 50 pi Run Time: 12 min Diluent: Methanol: Water (70:30 v/v]

Mobile Phase: Methanol: Buffer (pH: 2,5] (70:30 v/v]

Buffer pH:2,5 : 0.01 M H₃PO₄ + 0.01 M NaH₂P0₄.H₂0 if necessary adjust to pH: 2,5 ± 0.2 RESULTS

Figure 7 shows intestinal permeability and absorption % of flurbiprofen separately and in combination with famotidine and potassium bicarbonate.

Table 14 Permeability and absorption percentages of flurbiprofen separately and in combination with famotidine, potassium bicarbonate and famotidine

Figure 8 shows the absorbed fraction% of famotidine separately and in combination with flurbiprofen, and potassium bicarbonate (also demonstrating the % of the amount of famotidine transported across the Caco-2 cell membrane, between the singular use and with the composition of the present invention comprising flurbiprofen, famotidine and postassium bicarbonate]

Table 15 shows the absorbed fraction % and apparent permeability of famotidine separately and in combination with flurbiprofen, and potassium bicarbonate.

Figure 9 shows the apparent permeability (Papp] of famotidine separately and in combination with flurbiprofen, and potassium bicarbonate.

Table 16 Absorbed Concentration (pg/ml] of flurbiprofen separately and in combination with famotidine, potassium bicarbonate and menthol. (also demonstrating the amount of flurbiprofen transported across the Caco-2 cell membrane]

EVALUATION OF THE RESULTS

Flurbiprofen alone showed about 12.5 % permeability (5.002 pg/ml absorbed concentration] at 30 minutes (min] and about 42.3% (16.955 pg/ml absorbed concentration] permeability at 30 min in combination with famotidine. Flurbiprofen showed about 55% permeability (22.045 pg/ml absorbed concentration] in combination with famotidine and potassium bicarbonate at 30 min compared to the singular use of flurbiprofen alone. Based on the data obtained, famotidine, and potassium bicarbonate increased the intestinal permeability and absorption of flurbiprofen by at least 100% at 30 min also meaning that the amount of flurbiprofen transported across the Caco-2 cell membrane has increased by at least 100%, which would equate to a faster onset of action as it would be known by one with ordinary skill in the art. Flurbiprofen and potassium bicarbonate also increased the absorbed fraction and apparent permeability Papp of famotidine by at least 10 % which creates the dual synergistic effect of the present invention whereby both active compounds and a carbonate increases each other’s permeability and absorption, and a carbonate further increases the absorbed fraction and apparent permeability (Papp] of famotidine, the most surprising result of the present invention is that flurbiprofen is a BCS class II drug and already has high permeability and absorption, so to further increase this parameter by up to 3 times at 30 minutes and maintaining at least a 3% increase at 120 minutes, compared to flurbiprofen’s singular use was astonishing. Famotidine is a BCS class IV drug and has low permeability and as such the surprising results of the study is most beneficial to famotidine as it’s absorbed fraction is increased by at least 10% also meaning that the amount of famotidine transported across the Caco-2 cell membrane has increased by at least 10%, compared to famotidine’s singular use. Accordingly, permeability and absorption of flurbiprofen and famotidine will increase with the composition of the present invention under in-vivo conditions in a similar manner, as evidenced by the PK study detailed in the present invention.

The surprising results of the study demonstrate that a higher level of effectivity in a short period of time with the combinations of the present invention are achievable providing a fast onset of action without compromising the longer term effect of both active ingredients. The examples of pharmaceutical formulations and preparation methods of the invention given above are only given to illustrate the invention. The extent of the invention should not be limited by the examples.

Example 4

An instant release oral formulation of flurbiprofen, famotidine, potassium bicarbonate and 1- menthol combination.

Manufacturing Directions (Wet Granulation)

2. Granulated the mixture of items with granulation solution prepared by distilated water and Crospovidone (2 mg) in high shear granulator

3. Dry mixture items in fluid-bed granulator and pass through a 0.8-mm sieve,

4. Add microcrystalline cellulose type 102, crospovidone (23 mg), menthol and potassium bicarbonate and mix 15 minutes.

5. Add magnessium stearate to the mixture and mix 3 minutes.

6. Compress tablets,

7. Coat tablets with coating solution (Preffered HSP orange)

Content Uniformity Test:

The content uniformity of 10 dosage units randomly chosen, were assessed according to the USP requirements for content uniformity. The amount of the active ingredient in each of the 10 tested tablets containing 100 mg flurbiprofen and 20 mg famotidine were assayed by using HPLC. The formulation was prepared by wet granulation with the same excipients and method used in the manufacturing example, all of the HPLC results were well within the range of 85% toll5% for the dosage forms of the present invention and the relative standard deviation(RSD) was less than 6%. Studying the effects of potassium bicarbonate and l-menthol on the pharmacokinetics of flurbiprofen and famotidine in rats.

The primary objective of the test was to compare the pharmacokinetics of flurbiprofen when used as a single active compound as flurbiprofen in it’s free acid formand in combination with famotidine and/or potassium bicarbonate and/or a terpenoid compound. In this experimental study, the aim was to observe how the addition of a carbonateand/or a terpenoid compound to flurbiprofen and famotidine combination would change the pharmacokinetic properties of flurbiprofen and/or famotidine.

MATERIALS AND METHODS Active ingredients

Flurbiprofen, famotidine,

Essential excipients

Potassium bicarbonate and 1-menthol

Animals Male Wistar rats (240-260 g] were used in the study. The rats were maintained in an air- conditionedanimals quarter at a temperature of 22 ± 2 °C and a relative humidity of 50 ± 10%. Food and water were allowed ad libitum. The animals were acclimatized to the facilities for five days, and then fasted with free access to water for 12 h prior to the experiment. All the animals were housed under similar conditions. (Xie etal, 2011] Drug Administration

Bioavailability and pharmacokinetics of Flurbiprofen and Famotidine were studied in all the normal state of rats following an oral gavage of 10 mg/kg Flurbiprofen (Knihinicki et al., 1990; Muraoka et. al., 2004], 2 mg/kg famotidine (Mojaverian et al., 1985] and 3,6 mg/kg potassium bicarbonate. Each rat was administered Flurbiporfen and/ or combination with famotidine, potassium bicarbonate and 1-menthol.

Six male and/or female rats per group (Mojaverian et. al., 1985] were gavaged with different combinations as stated above.

Blood (0.2 ml] was taken from the tail vein prior to administration of test substances (0 h] and after 0.083, 0.25, 0.5, 1, 2, 4, 8 and 12h. Extraction of Blood Samples

Blood samples were collected (Parasuman et. al., 2010] in corning tubes and kept on ice until 50 mΐ dichloromethane (Pargal et al., 1988] was added and they were centrifuged at 7000 x g for 5 min at 4°C and supernatants were collected for HPLC analysis. HPLC ANALYSIS

Chromatographic System:

Equipment: High Pressure Liquid chromatography (HPLC]; Shimadzu LC-2040 3D Nexera-i Column: Inertsil C8 250x4.6 mm; 5 pm Flow Rate: 1.0 ml/min Column Temperature: 35 °C Autosampler Temperature: 5 °C Wavelength: 254 nm Injection Volume: 50 pi Run Time: 12 min

Diluent: Methanol: Water (70:30 v/v]

Mobile Phase: Methanol: Buffer (pH: 2.5] (70:30 v/v]

Buffer pH:2.5: 0.01 M H3P04 + 0.01 M NaH2P04.H20 if necessary adjust to pH: 2.5 ± 0.2 Results

Table 17 Concentrations of Flurbiprofen in blood

Figure 10 shows the effects of famotidine, potassium bicarbonate and 1-menthol on blood concentrations of flurbiprofen.

Table 18 Pharmacokinetic Parameters of Flurbiprofen in blood

Table 19 Concentrations of Famotidine in blood

Figure 11 shows the effects of flurbiprofen and potassium bicarbonate and 1-menthol on blood concentrations of famotidine Table 20 Pharmacokinetic Parameters of Famotidine in blood

Evaluation of the Results

Table 17 shows the plasma(blood] concentration values of flurbiprofen through a 12 hour period, with the same proportional dose of the formulation presented in the manufacturing example and the tablets were prepared accordingly with the same methods and pharmaceutically acceptable excipients. As it can be seen from Table 18, there is an evident increase in the Cmax value of flurbiprofen when it is used in combination with a carbonate, namely potassium bicarbonate (PB] and a terpenoid compound, namely 1-menthol. The Cmax of flurbiprofen when used as a single active ingredient formulation is about 2.79 pg/ml, whereas it is about 3.71 pg/ml when administered in combination with famotidine, potassium bicarbonateand 1-menthol showing an increase of about 32%. Tmax values in Table 18 also show that combinations of the present invention provide a fast pain relief compared to flurbiprofen alone due to the fact that the combination of the present invention provides a higher blood concentration at the same Tmax. Table 17 shows that the blood concentration levels of 2.55 pg/mL at 5 minutes after administration obtained with combination with famotidine, potassium bicarbonate and 1-menthol is the same with the Cmax of flurbiprofen when it is administered alone.

Table 18 also provides 0 to 12 hour AUC values of flurbiprofen. The combination of the present invention has about a 33% increase in AUC value, meaning this combination provides as long duration of pain and inflammation compared to the singular administration of flurbiprofen but has a stronger effect in a shorter period of time due to the fact that the combination of the present invention has a higher Cmax and the same Tmax.

Table 19 shows the plasma(blood] concentration values of famotidine through a 12 hour period, with the same proportional dose of the formulation presented in the manufacturing example and the tablets were prepared accordingly with the same methods and pharmaceutically acceptable excipients. As it can be seen in Table 20 there is an evident increase in the Cmax value of famotidine when it is used in combination with flurbiprofen, potassium bicarbonate and 1-menthol. The Cmax of famotidine when used as a single active ingredient formulation is about 0.99 pg/ml, whereas it is about 1.56 pg/ml when administered in combination with flurbiprofen, potassium bicarbonate and 1-menthol showing an increase of about 26% which surprisingly superior to famotidine administered alone and also superior to other combinations of famotidine as well. Although there is a decrease compared to the combination of flurbiprofen and famotidine, it is still far superior to famotidine administered alone. Tmax values in Table 4 also show that combinations of the present invention provide a faster and higher level of gastro intestinal protection to famotidine administered alone due to the fact that the combination of the present invention provides a higher blood concentration of famotidine at the same Tmax.

Table 20 also provides the 12 hour AUC values of famotidine. The combination of flurbiprofen, famotidine and PB has about a 39% increase in AUC value(from 4.85 h. pg/ml to 6.79h. pg/ml], meaning this combination provides a strong gastro intestinal protection during a longer period of time compared to the singular administration of famotidine, which is extremely beneficial to a subject in need of flurbiprofen administration. Table 19 shows that about 36% increase compared to famotidine’s Cmax at 15 minutes is obtained at only after 5 minutes after the administration of the combination of the present invention.

Table 20 also provides the 12 hour AUC values of famotidine. The combination of flurbiprofen, famotidine, potassium bicarbonate and 1-menthol has about a 66% increase in AUC value (from 4.85 to 8.07 h. pg/ml], meaning this combination provides a strong gastro intestinal protection during a longer period of time compared to the singular administration of famotidine, which is extremely beneficial to a subject in need of flurbiprofen administration with the advantage of diminished side effects.

Thus the combination of the present invention demonstrates a surprising dual synergistic effect increasing the Cmax and AUC of both flurbiprofen and famotidine significantly while maintaining the same Tmax. Providing a superior treatment modality for pain, inflammation and pyretic conditions to receive a stronger effect from flurbiprofen with diminished gastro intestinal side effects.

Claims

1. An oral immediate release pharmaceutical composition in a single unit dosage form comprising flurbiprofen or a pharmaceutically acceptable salt thereof and a H2 receptor antagonist as a gastro protective agent, wherein H2 receptor antagonist is present in an amount of from 5 to 80% by weight of flurbiprofen.

2. The pharmaceutical composition according to claim 1, wherein H2 receptor antagonist is present in an amount of from 10 to 60% by weight of flurbiprofen.

3. The pharmaceutical composition according to claim 2, wherein H2 receptor antagonist is present in an amount of from 20 to 40% by weight of flurbiprofen.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein flurbiprofen or a pharmaceutically acceptable salt thereof is in an amount of 50 to 200 mg.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein flurbiprofen or a pharmaceutically acceptable salt thereof is in an amount of 75 to 150 mg.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein flurbiprofen or a pharmaceutically acceptable salt thereof is in an amount of 75 to 110 mg.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein flurbiprofen is in its free acid form.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein H2 receptor antagonist is famotidine or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein famotidine or a pharmaceutically acceptable salt thereof is in an amount of from 10 to 65 mg.

10. The pharmaceutical composition according to claim 9, wherein famotidine or a pharmaceutically acceptable salt thereof is in an amount of from 10 to 40 mg.

11. The pharmaceutical composition according to any one of claim 10, wherein famotidine or a pharmaceutically acceptable salt thereof is in an amount of from 20 to 40 mg.

12. The pharmaceutical composition according to any one of claim 11, wherein famotidine or a pharmaceutically acceptable salt thereof is in an amount of from 20 to 30 mg.

13. The pharmaceutical composition according to any one of the preceding claims, further comprising a carbonate wherein the H2 receptor antagonist is present in an amount between 10 and 80% by weight based on the weight of flurbiprofen.

14. The pharmaceutical composition according to claim 13, wherein the carbonate is selected from the group consisting of potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, arginine bicarbonate and lysine carbonate.

15. The pharmaceutical composition according to claim 14, wherein the carbonate is potassium bicarbonate or sodium bicarbonate.

16. The pharmaceutical composition according to any one of claims 1 to 15 comprising a] between 50 and 300 mg of flurbiprofen or a pharmaceutically acceptable salt thereof, b] between 10 and 70 mg famotidine or a pharmaceutically acceptable salt thereof, and c] between 10 and 120 mg of potassium or sodium bicarbonate.

17. The pharmaceutical composition according to any one of claims 1 to 16 comprising a] 100 mg of flurbiprofen or a pharmaceutically acceptable salt thereof, b] 20 mg of famotidine or a pharmaceutically acceptable salt thereof, and c] 36 mg of potassium bicarbonate.

18. An oral pharmaceutical composition in a single unit dosage form comprising:

a] flurbiprofen or a pharmaceutically acceptable salt thereof;

b] an H2 receptor antagonist, or a pharmaceutically acceptable salt thereof;

c] a carbonate; and

d] a terpenoid compound

wherein the H2 receptor antagonist is present in anamount of 5 to 80% by weight based on the weight of flurbiprofen.

19. The pharmaceutical composition according to claim 18, wherein flurbiprofen is in its free acid form or sodium salt form.

20. The pharmaceutical composition according to claim 18 or 19, wherein the compound (b] is selected from the group consisting of famotidine, ranitidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine, or pharmaceutically acceptable salts thereof.

21. The pharmaceutical composition according to any one of claims 18 to 20, wherein the H2 receptor antagonist is famotidine or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the carbonate is selected from the group consisting of potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, arginine bicarbonate and lysine carbonate.

23. The pharmaceutical composition according to claim 22, wherein the carbonate is potassium bicarbonate or sodium bicarbonate.

24. The pharmaceutical composition according to any one of claims 18 to 23, wherein the terpenoid compound is selected from the groupconsisting of camphor, 3-carene, carvacrol, carvone, chrysanthemic acid, cineol, gefarnate, geraniol, linalool, limonene, menthol, pulegone, thymol, aphidicolin, forskolin, phytanic acid, phytol, glycyrrhetinic acid, diosgenin, farnesol and santonin, or pharmaceutically acceptable salt thereof; said terpenoid compound is preferably menthol or 1- menthol.

25. The pharmaceutical composition according to claim 24, wherein the terpenoid compound is menthol or 1-menthol.

26. The pharmaceutical composition according to any one of claims 18 to 25, wherein the carbonate is present in an amount of 5 to 200% by weight based on the weight of flurbiprofen.

27. The pharmaceutical composition according to any one of claims 18 to 26, wherein the terpenoid compound is present in an amount of 0.01 to 0.5% by weight of the whole composition.

28. The pharmaceutical composition according to claim 25, wherein menthol or 1-menthol is present in an amount of 0.5 to 30 mg.

29. The pharmaceutical composition according to claim 28, wherein menthol or 1-menthol is present in an amount of 0.5 to 15 mg.

30. The pharmaceutical composition according to claim 29, wherein menthol or 1-menthol is present in an amount of 0.5 to 10 mg.

31. The pharmaceutical composition according to any one of claims 18 to 30 comprising a] flurbiprofen or a pharmaceutically acceptable salt thereof, b] famotidine or a pharmaceutically acceptable salt thereof, c] potassium or sodium bicarbonate, and d] menthol or 1-menthol.

32. The pharmaceutical composition according to any one of claims 18 to 31 comprising a] between 50 and 200 mg of flurbiprofen or a pharmaceutically acceptable salt thereof, b] between 5and 80 mg of famotidine or a pharmaceutically acceptable salt thereof, c] between 10 and 200 mg of potassium or sodium bicarbonate, and d] 0.5 to 30 mg of menthol or 1-menthol.

33. The pharmaceutical composition according to any one of claims 18 to 32 comprising a] 100 mg of flurbiprofen or a pharmaceutically acceptable salt thereof, b] 20 mg of famotidine or a pharmaceutically acceptable salt thereof, c] 36 mg of potassium bicarbonate, and d] 1.5 mg of menthol or 1-menthol.

34. The pharmaceutical composition according to any one of claims 1 to 33, further comprising at least one pharmaceutically acceptable excipient which is selected from diluents, binders, lubricants, disintegrating agents, surfactants, glidants, sweetening agents, coloring agents and coating agents.

35. The pharmaceutical composition according to claim 34, wherein the weight ratio of lubricant to disintegrating agent is between 1:2 and 1:20.

36. The pharmaceutical composition according to claim 34 or 35, wherein the lubricant is magnesium stearate and the disintegrating agent is crospovidone.

37. The pharmaceutical composition according to any one of the preceding claims, wherein Tmax of flurbiprofen and famotidine is between 15 and 60 minutes.

38. The pharmaceutical composition according to claim 37, wherein Tmax of flurbiprofen and famotidine is between 15 and 45 minutes.

39. A method for preparing the pharmaceutical composition according to any one of claims 1 to 38, comprising the step of wet granulating the mixture of flurbiprofen and H2 receptor antagonist with a binder and/or disintegrant in a high shear granulator.

40. The method according to claim 39, comprising the step of wet granulating the mixture of flurbiprofen and famotidine with a granulation solution prepared with distilled water and a a disintegrating agent a high shear granulator.

41. The method according to claim 39 or 40, wherein the mixture further comprises at least one lubricant and at least one disintegrating agent as pharmaceutically acceptable excipients providing a content uniformity between the range of 85% to 115% for both flurbiprofen and famotidine in the pharmaceutical composition.

42. The method according to claim 39 or 40, wherein the weight ratio of lubricant to disintegrating agent is between 1:3 and 1:30.

43. The pharmaceutical composition according to anyone of claims 1 to 38 for use in the treatment of inflammation or pain.

44. The pharmaceutical composition for use according to claim 43, wherein the inflammation or pain caused by chronic polyarthritis, ankylosing spondilytis, osteoarthritis, gout attacks, extra- articular rheumatism, post-traumatic and postoperative pain, dysmenorrhea, rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, colitis ulcerosa; acute musculoskeletal pain; chronic musculoskeletal pain muscle strain; toothache, muscular pain (myalgia, strain], back pain, knee pain, shoulder pain, bursitis, tendinitis or epicondylitis.