WO2020013776A2

WO2020013776A2 - Synergistic effect of naproxen and a gastro protective agent for the treatment of pain and inflammation

Info

Publication number: WO2020013776A2
Application number: PCT/TR2019/050184
Authority: WO
Inventors: Mehmet Nevzat PISAK
Original assignee: Pisak Mehmet Nevzat
Priority date: 2018-03-21
Filing date: 2019-03-21
Publication date: 2020-01-16
Also published as: WO2020013776A3

Abstract

The present invention relates to pharmaceutical combinations comprising naproxen 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. The present invention relates also to an oral immediate release pharmaceutical composition comprising naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and at least one carbonate.

Description

SYNERGISTIC EFFECT OF NAPROXEN AND A GASTRO PROTECTIVE AGENT FOR THE

TREATMENT OF PAIN AND INFLAMMATION

TECHN1CAL F1ELD

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

Naproxen ((2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid) is a non-steroidal anti inflammatory drug (NSA1D) used to reduce pain, swelling and joint stiffness caused by conditions such as arthritis, osteoarthritis, ankylosing spondylitis, bursitis, and gout attacks. Pain associated with migraine headaches and menstrual periods is also alleviated by naproxen.

However, the relatively poor solubility of naproxen and its salts, in effect, limits their utility in therapy lt 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 naproxen and its salts. These gastrointestinal (Gl) 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 naproxen or naproxen sodium drug products have been developed with the goal of improving efficacy, tolerability and patient convenience.

Different naproxen formulations including instant release (plain tablets), enteric coated tablets or capsules have been clinically tested by Aabaken et al in their study:” Comparison of the gastrointestinal side effects of naproxen formulated as plain tablets, enteric-coated tablets, or enteric-coated granules in capsules” and it has been shown that naproxen has serious gastro intestinal side effects independent of the formulation and release profile of naproxen.

Naproxen sodium has a higher bioavailability than the free acid form of naproxen, and creates a higher blood concentration in a shorter period of time. Therefore, it is more advantageous to use naproxen sodium instead of its free acid form. On the other hand they both are associated with similar side effects, namely increased risk of serious dose-related Gl side effects.

There have been various attempts to enhance the permeability and bioavailability of naproxen. PCT/US1998/003388 uses nanoparticulate naproxen to have the effect of increased absorption. US 12/387,977 discloses an active ingredient having a particle size less than about 40 pm and a dissolution aid to increase the absorption of such an active ingredient including naproxen. Another study published by Mura et al. discloses a solid dispersion technique to increase the dissolution of naproxen but the manufacturing process either requires a complex micronization process for naproxen or requires a complex formulation process such as solid dispersion which complicates the manufacturing as it is known by one skilled in the art.(Mura et. Al, Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols (1996))

Delayed and extended release formulations of naproxen were also developed with the goal of improving the safety profile of naproxen and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of naproxen sodium salt were associated with faster absorption and rapid onset of pain relief. These include naproxen sodium immediate-release tablets, naproxen sodium liquid-filled soft gel capsules.

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. 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 A1 relates to a solid oral dosage form comprising a first portion comprising an NSA1D (preferably diclofenac); and a coating comprising an anti-ulcerative compound (preferably misoprostol); said coating at least partially surrounding said first NSA1D 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. Therefore a particular need exists in the art for a composition giving fast onset of action and long duration of treatment with decreased Gl side effects.

BR1EF DESCRIPTION OF THE INVENTION ln one aspect, the present invention provides a pharmaceutical composition comprising naproxen and a H2 receptor antagonist as a gastro protective agent for the treatment of inflammation or pain by reducing or treating gastrointestinal side effects and increasing the effect of both active ingredients; wherein H2 receptor antagonist is present in an amount of from 2 to 15% by weight of naproxen. ln another aspect, the present invention provides a pharmaceutical composition comprising naproxen and a H2 receptor antagonist as a gastro protective agent wherein the composition is a single unit pharmaceutical dosage form. The efficacy of the treatment regimen for both compounds would increase due to the increased patient compliance caused by the diminished side effects and the single unit dosage form administration of both compounds. Thus, because of the single unit use of both active ingredients combined rather than having two different medications, patient adherence would be increased. ln another aspect, the present invention is about a single unit pharmaceutical dosage form comprising naproxen and H2 receptor antagonist wherein the single unit pharmaceutical dosage form provides an immediate release profile in the gastrointestinal system. Therefore, both active ingredients increase each other's absorption through increased permeability across the gastro intestinal mucosa by decreasing the penetration barrier of the mucosa; therefore the single unit pharmaceutical dosage form of the present invention increases naproxen and H2 receptor antagonist concentration in blood after oral administration compared to their singular use.

The present invention also provides a single unit pharmaceutical dosage form of naproxen in combination with H2 receptor antagonist as a gastro protective agent, having a dual synergistic effect decreasing the Gl side effects of naproxen while inducing at least a 5% increase in the absorption of naproxen and at least 5% increase in the absorption of H2 receptor antagonist both at 30 minutes and 120 minutes under in-vitro assay conditions, proving that the combination of the present invention is superior both as a fast acting and long acting naproxen formulation. ln another aspect, the present invention also provides a pharmaceutical composition comprising naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and at least one carbonate for the treatment of inflammation or pain by reducing or treating gastrointestinal side effects. ln another aspect, the present invention provides a pharmaceutical composition comprising naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and at least one carbonate wherein the composition is a single unit pharmaceutical dosage form. ln another aspect, the present invention is about a single unit pharmaceutical dosage form comprising naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and at least one carbonate wherein the carbonate induce at least a 5% increase in the absorption of naproxen and at least 20% increase in the absorption of famotidine. ln another aspect, the present invention provides a method of manufacturing for the pharmaceutical composition comprising naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and optionally at least one carbonate, wherein the method is a simple and cost effective method of manufacturing. DETA1LED DESCRIPTION OF THE INVENTION

The present invention relates to an oral immediate release pharmaceutical composition in a single unit dosage form comprising naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and optionally at least one carbonate. The present invention relates to an oral immediate release pharmaceutical composition in a single unit dosage form comprising naproxen 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 2 to 15% by weight of naproxen. Thus, naproxen 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". lt has been surprisingly found that naproxen sodium 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 naproxen and H2 receptor antagonist. This dual synergistic effect provides a two-fold solution as the oral combination of naproxen and H2 receptor antagonist will decrease the Gl side effects associated with the use of naproxen and also increase the blood concentration of naproxen and H2 receptor antagonist which will create a new treatment modality when a stronger, faster action is needed without the undesired Gl side effects.

With the surprising dual synergistic effect added benefit of increased levels of naproxen sodium blood concentration, the combination of naproxen sodium 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.

According to the present invention, the pharmaceutical composition comprises naproxen 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 2 to 15% by weight of naproxen, wherein the total dose of naproxen administered within a 24 hour period is between 400 and 1250 mg and the total dose of famotidine administered within a 24 hour period is between 20 and 65mg. ln one embodiment of the present invention, the single unit pharmaceutical dosage form comprises naproxen in an amount from 200 to 700 mg or 200 to 750 mg, preferably 200 to 600 mg and more preferably 200 to 550 mg.

Naproxen according to the present invention may be in the form of a free acid or a pharmaceutically acceptable salt thereof; said naproxen is preferably naproxen sodium. ln another embodiment of the present invention, the pharmaceutical composition comprises naproxen sodium in an amount of 220mg, 225 mg, 275 mg or 550 mg. ln one embodiment of the present invention, the pharmaceutical composition comprises H2 receptor antagonist in an amount from 5 to 80 mg, preferably 10 to 60 mg and more preferably 10 to 40 mg. ln another embodiment of the present invention, H2 receptor antagonist is selected from the group including famotidine, ranitidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine, oxmetidine or a pharmaceutically acceptable salt thereof; said H2 receptor antagonist is preferably famotidine or a pharmaceutically acceptable salt thereof.

Bioavailability is a major issue with NSAIDs, including naproxen and naproxen sodium although naproxen is a BCS class 11 drug and has low solubility and high permeability, the surprising discovery of the present invention detailed in the study below discovered that naproxen and famotidine increase each others' permeability and absorption. Due to the increase in permeability and absorption of the active ingredients, rather than administering 1375 mg a day, which is the normal usage of naproxen, the present invention can provide a surprisingly higher level of naproxen and famotidine absorptionfas evidenced by the study below), to allow for a total daily dose under 1250mg when administered in a single unit dosage form with famotidine and pharmaceutically acceptable excipients. The twice a day administration method described above also increases patient compliance due to the decrease in dosing frequency and also diminishes the gastro- intestinal side effects due to the lower daily dose of naproxen sodium and the increase in permeability of famotidine also provides a higher level of gastro-intestinal protection, as it would be known by one with ordinary skill in the art and consequently the composition of the present invention only makes use of a maximum of 45 mg of famotidine per day rather than the use of 80 mg a day, due to the obvious synergies of the present invention. As used herein, "absorption" means penetration of the active ingredient through the oral mucosa and into systemic circulation.

According to the present invention, the pharmaceutical composition comprises naproxen and famotidine or a pharmaceutically acceptable salt thereof, wherein famotidine is present in an amount of from 2 to 15% by weight based on the weight of naproxen. ln one embodiment of the present invention, the pharmaceutical composition comprises naproxen and famotidine or a pharmaceutically acceptable salt thereof wherein the weight ratio of naproxen to famotidine is between 10:1 and 30:1. Specifically, for naproxen doses between 500 mg to 600 mg, the weight ratio of naproxen to famotidine is between 26:1 and 29:1 and for naproxen doses between 200 to 300 mg, same weight ratio is between 10:1 to 15:1. ln one embodiment of the present invention, the pharmaceutical composition comprises naproxen and famotidine or a pharmaceutically acceptable salt thereof, wherein famotidine is present in an amount of from 2 to 15% by weight of naproxen, wherein the total dose of naproxen administered within a 24 hour period is between 400 and 1250 mg and the total dose of famotidine administered within a 24 hour period is between 20 and 65mg and wherein the weight ratio of naproxen to famotidine is between 10:1 and 30:1.

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. ln another embodiment of the present invention, the pharmaceutical composition further comprises a carbonate.

The combination of an H2 receptor antagonist with Naproxen has the benefit of diminishing the gastro-intestinal side effects associated with Naproxen, and creates a treatment that can be used for longer periods of time due to the decreased side effects and it has been surprisingly discovered that the addition of a carbonate has further improved the pharmacokinetic profile of the gastro protective agent, whilst still providing a higher absorption for naproxen after administration compared to the singular administration of naproxen and also providing a higher AUC for naproxen within a 12 hour period after administration. Due to the above mentioned increase in efficiency, also detailed in the studies below, the compositions of the present invention can be ideally administered at a daily dose of 400mg to 1200mg rather than the maximum daily dose 1375mg for naproxen. As an example; a unit dose composition which includes 550mg naproxen sodium and 20mg famotidine and lOmg of a carbonate, will provide efficient pain and inflammation relief with diminished gasto intestinal side effects, if taken only twice within a 24 hour period. Which creates a great advantage as far as patient compliance is concerned and further decreases the gastro intestinal side effects due to the lower dose of naproxen employed within the composition of the present invention.

Carbonates are, but not limited to; sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate and lysine carbonate. ln the preferred embodiment of the present invention, the carbonate is selected from the group consisting of arginine carbonate or bicarbonate, lysine carbonate or bicarbonate, potassium carbonate or bicarbonate, sodium carbonate or bicarbonate and the mixture thereof. ln another most preferred embodiment of the present invention the carbonate is an alkali metal bicarbonate or amino acid based bicarbonate. ln the most preferred embodiment of the present invention the carbonate is selected from potassium bicarbonate or sodium bicarbonate. ln one embodiment of the present invention, the pharmaceutical composition comprises the carbonate in an amount of from 10 to lOOmg, preferably 20 to 80 mg. ln one embodiment of the present invention, the single unit pharmaceutical dosage form comprises the carbonate present in an amount of from 2 to 30% by weight based on the weight of naproxen. ln one embodiment of the present invention, the pharmaceutical composition for use in the treatment of inflammation or pain, wherein the pharmaceutical composition comprises, a) 500 to 600 mg of naproxen, 20 to 40 mg of famotidine and sodium or potassium bicarbonate, and 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. ln one embodiment of the present invention, the pharmaceutical composition for use in the treatment of inflammation or pain, wherein the pharmaceutical composition comprises, a) 200 to 300 mg of naproxen, 20 to 30 mg of famotidine and sodium or potassium bicarbonate, and b) at least one lubricant and at least one disintegrating agent as pharmaceutically acceptable excipients, and wherein the pharmaceutical composition is administered 2 or 3 times within a 24 hour period. ln one embodiment of the present invention, the pharmaceutical composition comprises naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and at least one carbonate wherein the AUC within 12 hours after administration of naproxenis at least 10% higher than its singular oral administration. ln another embodiment of the present invention, the pharmaceutical composition comprises naproxen or a pharmaceutically acceptable salt thereof, a H2 receptor antagonist as a gastro protective agent and at least one carbonate wherein the amount of gastro protective agent transported accross the Caco-2 cell membrane at 30 minutes under in-vitro assay conditions is at least 10% higher relative to the singular use of a gastro protective agent without naproxen and a carbonate. ln one embodiment of the present invention, the pharmaceutical composition may be an oral dosage form. This oral dosage form may be tablet, capsule, gel capsule, pellet, granule, tablet in tablet, tablet in capsule, powder or coated tablet, preferably being tablet, capsule or powder. The pharmaceutical composition may also be in the form of drop, pellet, granule, solution, suspension, syrup, powder. ln 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, glidants, 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 lauiyl 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, primaiy-secondary-tertiaiy amines, quaternary ammonium compounds, fatty alcohols, sugar esters of fatty acids, glycerides of fatty acids, polyoxy ethylene glycol alkyl ethers, polisorbates, 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. ln 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 1:1 and 1:40, preferably 1:1 and 1:10 and more preferably 1:1 and 1:5. ln one embodiment of the present invention, the pharmaceutical composition comprises magnesium stearate as lubricant and crospovidone as disintegrating agent. ln one embodiment of the present invention, the pharmaceutical composition comprises a) naproxen and famotidine or a pharmaceutically acceptable salt thereof as active ingredients and

b) at least one lubricant and disintegrating agent or binder, wherein the weight ratio of lubricant to disintegrating agent is between 1:1 and 1:40, preferably 1:1 and 1:10 and more preferably 1:1 and 1:7. ln one embodiment of the present invention, the pharmaceutical composition comprises a) naproxen, famotidine or a pharmaceutically acceptable salt thereof and a carbonate, and b) at least one lubricant and disintegrating agent or binder, wherein the weight ratio of lubricant to disintegrating agent is between 1:1 and 1:40, preferably 1:1 and 1:10 and more preferably 1:1 and 1:5. ln another embodiment of the present invention, the pharmaceutical composition comprises a) naproxen and famotidine or a pharmaceutically acceptable salt thereof as active ingredients, and b) magnesium stearate as a lubricant and crospovidone as a disintegrating agent. ln another embodiment of the present invention, the pharmaceutical composition comprises a) naproxen, famotidine or a pharmaceutically acceptable salt thereof and a carbonate, and b) magnesium stearate as a lubricant and crospovidone as a disintegrating agent. ln one embodiment of the present invention, the pharmaceutical composition comprises a)naproxen and famotidine or a pharmaceutically acceptable salt thereof 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 1:1 and 1:40, preferably 1:1 and 1:10 and more preferably 1:1 and 1:7. ln one embodiment of the present invention, the pharmaceutical composition comprises a) naproxen, famotidine or a pharmaceutically acceptable salt thereof and a carbonate, and b) magnesium stearate as a lubricant and crospovidone as a disintegrating agent, wherein the weight ratio of magnesium stearate to crospovidone is between 1:1 and 1:40, preferably 1:1 and 1:10 and more preferably 1:1 and 1:5. ln 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 1:1 and 1:40, preferably 1:1 and 1:10 and more preferably 1:1 and 1:7. Wherein the total amount of lubricant is less than 6% of the total weight of the composition. And preferably between 0,5 to 3% of the total weight of the composition. Thus, content uniformity problem of low dose famotidine and high dose naproxen sodium 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. ln yet another embodiment of the present invention, the pharmaceutical composition comprises magnesium stearate and crospovidone as pharmaceutically acceptable excipients wherein the weight ratio of magnesium stearate to crospovidone is between 1:1 and 1:20 and is preferably between 1:1 and 1:7. Thus, content uniformity problem of low dose famotidine and high dose naproxen sodium is decreased and flow and processability of the dosage form are increased, moreover the fast disintegration of the active ingredients is also made possible. ln one embodiment of the present invention, the pharmaceutical composition comprises naproxen and famotidine or a pharmaceutically acceptable salt thereof and crospovidone as a pharmaceutically acceptable excipient that acts both as a disintegrating agent and binder. Herein crosspovidone is in an amount of 1-20% by weight of the total dosage form. ln one embodiment of the present invention, the pharmaceutical composition comprises naproxen and famotidine or a pharmaceutically acceptable salt thereof, 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 the active ingredients, namely naproxen and famotidine, 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. ln one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulation the mixture of naproxen or a pharmaceutically acceptable salt thereof and famotidine with a granulation solution of distilled water and a binder in a high shear granulator. ln one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulation the mixture of naproxen or a pharmaceutically acceptable salt thereof and famotidine with a granulation solution of distilled water and polyvinylpyrrolidone (PVP) in a high shear granulator. ln one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulation the mixture of naproxen or a pharmaceutically acceptable salt thereof and famotidine with a granulation solution of distilled water and a binder in a high shear granulator, wherein the weight ratio of naproxen to famotidine is between 10:1 and 30:1. ln one embodiment to the present invention, the pharmaceutical composition is prepared by the method comprising the step of wet granulation the mixture of naproxen or a pharmaceutically acceptable salt thereof and famotidine with a granulation solution of distilled water and polyvinylpyrrolidone (PVP) in a high shear granulator, wherein the weight ratio of naproxen to famotidine is between 10:1 and 30:1. According to the present invention, the mixture used in wet granulation step further comprises at least one lubricant and at least one disintegrating agent, preferably magnesium stearate and crospovidone, providing a content uniformity between the range of 85% to 115% for both naproxen and famotidine in the pharmaceutical composition. The weight ratio of lubricant to disintegrating agent can be between 1:1 and 1:10. ln one embodiment, the present invention is related to a method for preparing said pharmaceutical composition which comprises the following steps: a) sieving together naproxen sodium, famotidine, lactose and crospovidone, b) granulating the mixture in step a) with granulation solution prepared with distilled water and polyvinylpyrrolidone in high shear granulator, c) drying the mixture in fluid-bed granulator and sieving through a 0.8 mm sieve, d) adding silicon dioxide, microcrystalline cellulose type 102, and mixing, e) adding magnesium stearate to the final mixture and mixing, f) compressing and coating.

Wet granulating famotidine and naproxen with polyvinylpyrrolidone and crospovidone provide better content uniformity, and the lubricant also helps with the flow and processability of final mixture and unit dosage. ln one embodiment, the present invention is related to a method for preparing said pharmaceutical composition which comprises the following steps: a) sieving together naproxen or a pharmaceutically acceptable salt thereof, H2 receptor antagonist, at least one binder and at least one disintegrating agent, b) granulating the mixture of a) with a granulation solution prepared by distilated water and polyvinylpyrrolidone in high shear granulator, c) drying the mixture of b), in fluid-bed granulator and passing through a 0.8-mm sieve, d) adding and mixing at least one glidant, one diluent and one disintegrating agent and the carbonate, e) adding and mixing at least one lubricant, f) optionally compressing and coating. ln 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 Gl side effects. ln 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. ln 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. ln 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) 500 to 600mg of naproxen and 20 to 30mg of famotidine as active ingredients, and 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 periodand wherein the total daily dose of naproxen administered is between 1000 and than 1250 mg. and wherein the total daily dose of famotidine administered is between 40 and 65 mg. ln 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) 200 to 300 mg of naproxen and 20 to 30mg of famotidine as active ingredients, and b) at least one lubricant and at least one disintegrating agent as pharmaceutically acceptable excipients, and wherein the pharmaceutical composition is administered 2 or 3 times within a 24 hour period and wherein the total daily dose of naproxen administered is between 400 and than 900 mg. and wherein the total daily dose of famotidine administered is between 40 and 65 mg.

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. ln 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

Example 1

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

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 550mg naproxen and 20mg famotidine were assayed by using HPLC, the method for the HPLC assay was based on; Haque et al, https: / /www.ncbi.nlm.nih.gov/pubmed/20884450 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 of the active ingredients Naproxen sodium and Famotidine separately and in combination using Caco-2 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.

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 lntegrity, 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

Naproxen sodium MW: 252.245 g/mol

Famotidin MW: 337.435 g/mol

Stock solution of Naproxen sodium was prepared in DMSO at 550 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 FaSSlF (Fasted State Simulated lntestinal 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 and 120 min) the samples were collected from plates and analyzed by HPLC to analyze both the short term and long term effects of both active ingredients.

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: lnertsil C8 250x4,6 mm ; 5 pm

Flow Rate: 1.0 ml/min Column Temperature: 35 °C

Autosampler Temperature: 5 °C

Wavelength: 254 nm

lnjection Volume: 50 mΐ

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 % of Naproxen sodium separately and in combination with famotidine.

Figure 2 shows intestinal permeability % of Famotidine separately and in combination with naproxen sodium.

Table 1. Permeability percentages of naproxen sodium separately and in combination with Famotidine.

Table 2. Permeability percentages of famotidine separately and in combination with naproxen sodium.

Table 3

Absorbed concentration of Naproxen sodium alone and in the presence of famotidine. (Also demonstrating the amount of naproxen transported across the Caco-2 cell membrane.)

Table 4

Absorbed concentration of Famotidine alone and in the presence of naproxen sodium. (Also demonstrating the amount of famotidine transported across the Caco-2 cell membrane.)

EVALUAT10N OF THE RESULTS Naproxen sodium is a BCS Class 11 medicinal product. BCS Class 11 medicinal products are characterized by low solubility and high permeability. Naproxen sodium alone showed 25,744% permeability at 30 minutes(min) and 35,146% permeability at 30 min in combination with famotidine. Naproxen sodium showed 56,557% permeability alone and 61,771% in combination with famotidine at 120 min. Based on the data obtained, Famotidine increases intestinal permeability and absorption of Naproxen sodium by at least 25% at 30 min which would equate to a faster onset of action as it would be known by one with ordinary skill in the art. And famotidine also increases the permeability and absorption of naproxen sodium by at least 5% at 120min which also shows that the fast onset of action has not eliminated the effect of naproxen still providing a long lasting effect. And the amount of naproxen sodium transported across the Caco-2 cell membrane has increased proportionally with the same percentages. These data also indicate that naproxen sodium increases the permeability and absorption of famotidine by at least 5% at 30 minutes and by at least 10% at 120 min. And the amount of famotidine transported across the Caco-2 cell membrane has increased proportionally with the same percentages. Which creates the dual synergistic effect of the present invention whereby both active compounds increase each others permeability and absorption, even more surprisingly considering that naproxen sodium is a BCS class 11 drug and already has high permeability, so to further increase this parameter was astonishing. Accordingly, permeability and absorption rate of naproxen sodium will increase in the presence of Famotidine under in- vivo conditions lt would be known by anyone with ordinary skill in the art, that the increase in the permeability and absorption of naproxen sodium and famotidine will also definitely increase the blood concentration of naproxen sodium and famotidine in-vivo and this increase is created by the combination of famotidine with naproxen sodium. Because longer acting NSAIDs which have more chronic use such as naproxen or naproxen sodium tend to have a higher 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 clearly demonstrate that the co-administration of naproxen and famotidine increase the amount of naproxen and famotidine transported across the Caco-2 cell membrane by at least between 1 and 10% at 30 and 120 minutes meaning that naproxen acts as a permeability and absorption enhancer for famotidine and famotidine acts as a permeability and absorption enhancer for naproxen, which was never reported before in the prior art or any other study.

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

Example 2

Study on permeability of the active ingredients naproxen sodium and Famotidine separately and in combination with potassium bicarbonate using 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 assay lntegrity, cell viability and permeability assays were carried out and cell viability was determined by MTT, and integrity was determined by using lucifer yellow methods.

Preparation of Stock and Test solutions

Naproxen sodium MW: 252.245 g/mol

Famotidin MW: 337.435 g/mol

Potassium bicarbonate MW: 100.115 g/mol

Stock solution of Naproxen sodium was prepared in DMSO at 550 mg/ml

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

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

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) supplemented 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 :

Flow Rate: 1.0 ml/min

Column Temperature: 35 °C

Autosampler Temperature: 5 °C

Wavelength: 254 nm

lnjection Volume: 50 pl

Run Time: 12 min

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

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

Figure 3 shows intestinal permeability of famotidine separately, in combination with naproxen sodium (NS+FAM) and in combination with naproxen sodium and potassium bicarbonate (NS+FAM+PB).

Table 5. Permeability percentages of Famotidine separately, in combination with naproxen sodium (NS+FAM) and in combination with naproxen sodium and potassium bicarbonate (NS+FAM+PB).

Table 6.Absorbed concentration of Famotidine separately, in combination with naproxen sodium (NS+FAM) and in combination with naproxen sodium and potassium bicarbonate (NS+FAM+PB).

EVALUAT10N OF THE RESULTS

Surprisingly it was found that the addition of a carbonate, namely potassium bicarbonate increased the absorption and permeability of famotidine in a combination with naproxen sodium. At least 20% higher permeability and absorption of famotidine was achievedfat least 20% more famotidine transported across the Caco-2 cell membrane under in-vitro assay conditions) at 30min and at least 10% higher permeability and absorption of famotidine was achieved (at least 10% more famotidine transported across the Caco-2 cell membrane under in-vitro assay conditions) at 120 min compared to the use of famotidine alone. The surprising results of the study demonstrate that a higher level of affectivity both in a short and long period with the combinations of the present invention are achievable providing a fast onset of action without compromising the longer term effect of famotidine.

Details of the study proving the synergistic effect between Naproxen, and famotidine with the addition a carbonate.

Study on the pharmacokinetics of combined effects of famotidine. Naproxen and potassium bicarbonate in rats.

ln this experimental study, the aim was to observe how the combination of Naproxen sodium, famotidine and potassium bicarbonate affected the Cmax, Tmax, and AUC of naproxen sodium and famotidine within a 12 hour period. MATERIALS AND METHODS

Chemicals and Reagents

Naproxen potassium, famotidine and 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.

Drug Administration

Bioavailability and pharmacokinetics of Naproxen sodium and famotidine were studied in all the normal state of rats following an oral administration of 55mg/kg Naproxen sodium, 2mg/kg famotidine and2mg/kg potassium bicarbonate in different combinations. A total of 24 rats were used in the study divided into 4 groups, each group was administered; famotidine or Naproxen alone, or 2 different combinations of Naproxen and Famotidine as outlined below.

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.

Results

Figure 4. Average Blood Concentrations of Naproxen sodium

Table 7. Pharmacokinetic Parameters of Naproxen sodium in blood

Figure 5. Average Blood Concentrations of Famotidine

Table 8. Pharmacokinetic Parameters of Famotidine in blood

Evaluation of the Results

Table 7 shows the AUC values of Naproxen, Naproxen + Famotidine and Naproxen + Famotidine Potassium bicarbonate. As it is seen, there is an evident increase in the AUC values of Naproxen when it is used in combination with famotidine and potassium bicarbonate. Similarly, Tmax values in Table 8 also show that combinations of the present invention provides a higher total systemic exposure to both the gastro protective agent (famotidine) and naproxen, providing a longer effective pain and inflammation relief whilst also providing a higher level of gastro intestinal protection due to the increased Cmax and AUC of famotidine. As it can be seen from the PK parameters described in table 8, , the AUC of famotidine is about 32% higher than the singular administration of famotidine with a Cmax about 65% higher than the singular administration of famotidine, while maintaining the same Tmax. Although it is of paramount importance to provide a significantly improved PK profile for famotidine to have an efficient gastro intestinal protection, it has been surprisingly discovered that the composition of the present invention also provides a significantly higher AUC for Naproxen sodium as well, even if it does not have the same Tmax or Cmax as naproxen’s singular administration, it has therapeutically effective levels of naproxen sodium as it would be known by one with ordinary skill in the art and higher total systemic exposure as it can be seen from Table 7, as the composition of the present invention provides about a 28% increase in the AUC of naproxen 12 hours within administration, which is ideally suited for twice a day dosing at the proportional dose of naproxen which would equate to about 550mg with the combination of the present invention.

And furthermore, it is more important for an NSA1D like naproxen sodium to provide efficient pain and inflammation relief over an extended period rather than having a short onset of action, which creates another major advantage of the present invention. The results of the study prove the superior treatment modality of the present invention with the surprising effect of longer lasting therapeutically effective blood concentrations (AUC) for pain and inflammation treatment, coupled with the diminished gastro intestinal side effects due to significant increase in the Cmax and AUC of famotidine as well, due to the novel combination of the present invention.

Claims

1. An oral immediate release pharmaceutical composition in a single unit dosage form comprising naproxen 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 2 to 15% by weight of naproxen, wherein the total dose of naproxen administered within a 24 hour period is between 400 and 1250 mg and the total dose of famotidine administered within a 24 hour period is between 20 and 65 mg.

2. The pharmaceutical composition according to claim 1, wherein naproxen or a pharmaceutically acceptable salt thereof is in an amount of 200 to 600 mg.

3. The pharmaceutical composition according to claim 2, wherein naproxen or a pharmaceutically acceptable salt thereof is in an amount of 200 to 550 mg.

4. The pharmaceutical composition according to any one of the preceeding claims, wherein the weight ratio of naproxen to famotidine is between 10:1 and 30:1.

5. An oral immediate release pharmaceutical composition in a single unit dosage form comprising naproxen or a pharmaceutically acceptable salt thereof, an H2 receptor antagonist as a gastro protective agent and at least one carbonate.

6. The pharmaceutical composition according to claim 5, wherein H2 receptor antagonist is present in an amount of from 2 to 20% by weight based on the weight of naproxen or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claims 5 or 6, wherein the carbonate is present in an amount of from 2 to 30% by weight based on the weight of naproxen.

8. The pharmaceutical composition according to any one of the preceding claims, wherein H2 receptor antagonist is selected from the group consisting of famotidine, ranitidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine, oxmetidine and pharmaceutically acceptable salts thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein naproxen is naproxen sodium.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein H2 receptor antagonist is famotidine or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10, wherein famotidine or a pharmaceutically acceptable salt thereof is in an amount of from 10 to 60 mg.

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

13. The pharmaceutical composition according to any one of the claims 5 to 12, wherein the carbonate is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate and lysine carbonate.

14. The pharmaceutical composition according to claim 13, wherein the carbonate is potassium or sodium bicarbonate.

15. The pharmaceutical composition according to claims 13 or 14, wherein the carbonate is in an amount of from 10 to 100 mg.

16. The pharmaceutical composition according to claim 1, 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.

17. The pharmaceutical composition according to claim 16, wherein the weight ratio of lubricant to disintegrating agent is between 1:1 and 1:10.

18. The pharmaceutical composition according to any one of claims 16 and 17, wherein the lubricant is magnesium stearate and the disintegrating agent is crospovidone.

19. A method for preparing the pharmaceutical composition according to any one of the preceding claims, comprising the step of wet granulating the mixture of naproxen and famotidine with a binder in a high shear granulator.

20. A method for preparing the pharmaceutical composition according to claim 19, comprising the step of wet granulating the mixture of naproxen and famotidine with a granulation solution prepared with distilled water and PVP in a high shear granulator.

21. The method according to any one of claims 19 and 20, wherein the weight ratio of naproxen to famotidine is between 10:1 and 30:1.

22. The method according to any one of claims 19 to 21, 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 naproxen and famotidine in the pharmaceutical composition.

23. The method according to claim 22, wherein the weight ratio of lubricant to disintegrating agent is between 1:1 and 1:10.

24. The method according to any one of the claims 22 and 23, wherein the lubricant is magnesium stearate and the disintegrating agent is crospovidone.

25. The pharmaceutical composition according to any one of the preceding claims for use in the treatment of inflammation and pain.

26. The pharmaceutical composition according to claim 1 for use in the treatment of inflammation and pain, wherein the pharmaceutical composition comprising

a) 500 to 600mg of naproxen and 20 to 30mg of famotidine, and

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 periodand wherein the total daily dose of naproxen administered is between 1000 and than 1250 mg. and wherein the total daily dose of famotidine administered is between 40 and 65 mg.

27. The pharmaceutical composition according to claim 1 for use in the treatment of inflammation and pain, wherein the pharmaceutical composition comprising

a) 200 to 300 mg of naproxen and 20 to 30 mg of famotidine, and

and wherein the pharmaceutical composition is administered 2 or 3 times within a 24 hour period and wherein the total daily dose of naproxen administered is between 400 and 900 mg and wherein the total daily dose of famotidine administered is between 40 and 65 mg.

28. The pharmaceutical composition according to claim 5 for use in the treatment of inflammation or pain, wherein the pharmaceutical composition comprising,

a) 500 to 600 mg of naproxen, 20 to 40 mg of famotidine and sodium or potassium bicarbonate,, and

and wherein the pharmaceutical composition is administered 2 times within a 24 hour period.

29. The pharmaceutical composition according to claim 5 for use in the treatment of inflammation or pain, wherein the pharmaceutical composition comprising, a) 200 to 300 mg of naproxen, 20 to 30 mg of famotidine and sodium or potassium bicarbonate, and

and wherein the pharmaceutical composition is administered 2 or 3 times within a 24 hour period.

30. The pharmaceutical composition for use according to any one of claims 25 to 29 in the treatment of 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.