WO2020167262A1

WO2020167262A1 - Immediate release formulations of gel forming polymers

Info

Publication number: WO2020167262A1
Application number: PCT/TR2019/050091
Authority: WO
Inventors: Mehmet Nevzat PISAK
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-02-12
Filing date: 2019-02-12
Publication date: 2020-08-20
Anticipated expiration: 2021-08-12

Abstract

The present invention relates to a pharmaceutical composition comprising an NSAID or a pharmaceutically acceptable salt thereof, famotidine as a gastroprotective agent and a gel forming polymer as a pharmaceutically acceptable excipient. Preferably, the gel forming polymer is a high molecular weight polymer 10 providing immediate release of active ingredients in a single unit dosage form.

Description

IMMEDIATE RELEASE FORMULATIONS OF GEL FORMING POLYMERS

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition comprising an NSAID or a pharmaceutically acceptable salt thereof, famotidine as a gastroprotective agent and a gel forming polymer as a pharmaceutically acceptable excipient.

BACKGROUND ART

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a diverse group of compounds that are mainly used for the treatment of mild to moderate pain. They are also used to reduce fever and inflammation. As being non-narcotic compared to opioids, NSAIDs are among the most frequently used classes of medications. They 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. Thus, the classification system of NSAIDs is based on their chemical structure and whether they inhibit the COX-1 and/or COX-2 enzymes.

Inhibition of COX-1 is also responsible, in part, for gastrointestinal side effects, which are the most frequent side effects of NSAIDs. These side effects result in decrease of mucous production in cells lining of the gastrointestinal tract and can be summarized as dyspepsia ,acid-reflux(heartburn), Nausea, Abdominal discomfort, Erosion, Ulcers(Upper and lower GI), Hemorrhage, Perforation, Obstruction, Occult and frank bleeding, Acute colitis and Exacerbation of existing colon disease. These side effects are generally related to the factors of dosage, dose frequency and duration of the therapy.

Due to the fact that NSAIDs can cause gastrointestinal side effects, 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 with increased efficacy and reduced GI side effects is needed. The co-therapy of famotidine as a gastro protective agent can reduce the GI side effects of NSAIDs. Famotidine is an H2 receptor antagonist which blocks the action of the histamine type 2 receptor (H2 receptor) reducing the acid secretion in the stomach and accordingly reduces the side effects of NSAIDs. However, because of the incompatibility between famotidine and NSAIDs, they are generally administered in two separate dosage forms and the patient compliance problem occurs.

In prior art, studies to overcome the chemical incompatibility and to formulate both active ingredients in single unit are disclosed. For example, W02013054352 is about a pharmaceutical composition in a single unit dosage form of ibuprofen found in the core and famotidine in the layer, wherein a barrier layer can be used to separate them. Another disclosure is EP2682112A1 which is about a capsule formulation comprising sustained release pellets of flurbiprofen and tablet of famotidine. As it is seen, the formulation of famotidine and NSAIDs in a single unit dosage form is problematic in the prior art.

However, there is still a need in the art for a single unit dosage form comprising NSAIDs and famotidine which is simple, cost effective and stable without any chemical compatibility while reducing GI side effects of NSAIDs.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition comprising an NSAID or a pharmaceutically acceptable salt thereof, famotidine as a gastroprotective agent and a gel forming polymer as a pharmaceutically acceptable excipient.

In one embodiment of the present invention, the pharmaceutical composition comprising an NSAID or a pharmaceutically acceptable salt thereof, famotidine and a gel forming polymer is an immediate release single unit dosage form.

It has been surprisingly found that gel forming polymers in the pharmaceutical composition of famotidine with NSAID provide an excellent instant release of active ingredients while providing a high level of bioavailability for both the NSA1D and famotidine. In prior art, gel forming polymers have been employed as excipients for controlled, delayed or sustained release oral formulations which would only release a small portion of the active ingredients within the first hours.

In one embodiment of the present invention, the pharmaceutical composition comprises famotidine or a pharmaceutically acceptable salt thereof in an amount from 10 to 40 mg, preferably 20 to 30 mg and more preferably 20 to 27 mg.

In one embodiment of the present invention, NSA1D is selected from the group consisting of 2-Arylpropionic acids group including alminoprofen, benoxaprofencarprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid; salicylates group including alicylamide, salicyl salicylate, methyl salicylate, magnesium salicylate, faislamine, ethenzamide, diflunisal, choline magnesium salicylate, benorylate/benorilatem and amoxiprin, aspirin; aiylalkanoic acids group including aceclofenac, acemetacin, alclofenac, bromfenac, diclofenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, and tolmetinor; and oxicams group including droxicam, lomoxicam, meloxicam, piroxicam, tenoxicam and pharmaceutically acceptable salts and derivatives thereof and their combinations. In one embodiment of the present invention, NSA1D is a non-selective COX inhibitor which is selected from the group consisting of ibuprofen, flurbiprofen, diclofenac, naproxen, meloxicam, piroxicam, acetyl salicylic acid, ketoprofen, dexketoprofen, ketorolac, lomoxicam, tenoxicam and pharmaceutically acceptable salts and/or derivatives thereof; preferably diclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, dexketoprofen and pharmaceutically acceptable salts and/or derivatives thereof and more preferably naproxen or ibuprofen.

In one embodiment of the present invention, the pharmaceutical composition comprises naproxen or a pharmaceutically acceptable salt thereof in an amount from 200 to 600 mg and preferably 350 to 600 mg. In one embodiment of the present invention, the pharmaceutical composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount from 400 to 810 mg and preferably 600 to 810 mg.

In one embodiment of the present invention, the pharmaceutical composition comprises dexketoprofen or a pharmaceutically acceptable salt thereof in an amount from 25 to 100 mg.

In one embodiment of the present invention, the gel forming polymer is high molecular weight polymer. As used herein, the term "high molecular weight" means a molecular weight of the polymer of not less than 250,000 Daltons. The polymer is selected from the group consisting of Chitosan, polyacrylic acid polymers (Carbopol®), crosslinked polyaciylic acid polymers, Cyanamer® polyacrylamides; cross-linked water swellable indenemaleic anhydride polymers; Good-rites polyaciylic acid; Aqua-Keeps® acrylate polymer polysaccharides composed of condensed glucose units, such as diester cross-linked polygluran and its combinations thereof. The polymer is preferably selected from the group consisting of chitosan, polyacrylic acid polymers, cross-linked polyacrylic acid polymers, cross-linked water swellable indenemaleic anhydride polymers, polysaccharides composed of condensed glucose units, such as diester cross-linked polygluran and its combinations thereof. The gel forming polymer is more preferably cross-linked polyaciylic acid polymers.

Some examples of the polymers of the preferred embodiment of the present invention are carbomer polymers selected from the group consisting of Carbomer interpolymer type A (Carbopol ® 5984 EP and Ultrez 10 NF ), Carbomer interpolymer type B (Carbopol ® 974P NF polymer), Carbopol ® 980 NF and Ultrez 10 NF polymers, Carbopol ® 71G NF, Carbomer homopolymer type A (Carbopol ®971P NF) and Carbopol ® 981 NF polymers, Pemulen™ TR-1 and TR- 2 NF polymers, preferably obtained with synthesis in either ethyl acetate or a co solvent ethyl acetate/cyclohexane mixture due to the unfavorable toxicological profile of polymers synthesized in benzene. In one embodiment of the present invention, the pharmaceutical composition comprises between 0.1 to 10% of gel forming polymer by weight of the total unit dosage form, preferably between 0.1 to 7% and more preferably between 0.2 to 5 % and most preferably between 0.4 to 4%. For the avoidance of doubt, if the unit dosage form is a capsule, the weight of capsule is included in the total weight of the unit dosage form.

It has been surprisingly found that when the gel forming polymer between the range according to the present invention provides immediate release of active ingredients instead of delaying their release and higher stability without any incompatibility of active ingredients and without requiring any intermediate layer between them.

In one embodiment of the present invention, the pharmaceutical composition further comprises a cellulose derivative as a pharmaceutically acceptable excipient.

The cellulose derivative can be selected from the group consisting of microcrystalline cellulose croscarmellose, hydroxypropylcellulose, methylcellulose, carboxy methyl cellulose, hydroxypropyl methyl cellulose and ethyl cellulose.

The use of cellulose derivative in combination with gel forming polymers in a composition comprising NSAID and famotidine may decrease the instant release potential of the pharmaceutical composition. Therefore, in one preferred embodiment of the present invention, the pharmaceutical composition comprises between 0,1 to 10% of cellulose derivative by weight of the unit dosage form.

In one embodiment, the present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising NSAID, famotidine and a gel forming polymer wherein at least 60% of NSAID and at least 60% of famotidine are released into a solution with a pH of about 6.8 to

7.4, (neutral pH conditions (e.g., an aqueous solution at about pH 6.8 to about pH

7.4, e.g., preferably at pH 7.2). within 20 minutes under in vitro assay conditions. Preferably at least 75% of famotidine is released into a solution with a pH of about 6.8 to 7.4, within 20 minutes under in vitro assay conditions. NSAID and famotidine dissolution and release rate from the formulation was measured in vitro using a USP type II dissolution apparatus (paddle) based on the US Pharmacopoeia.

In one embodiment, the present invention provides an oral immediate release pharmaceutical composition in a single unit dosage form comprising NSAID, famotidine and a gel forming polymer wherein at least 60%, preferably at least 70%, and most preferably at least 85% of famotidine is released, into with a pH of about 4.5 within 30 minutes under low pH assay conditions.

In one embodiment, the present invention provides a pharmaceutical composition comprising NSAID and famotidine or a pharmaceutically acceptable salt thereof, wherein at least 60% of famotidine is released within 20 minutes into a solution with a pH 7.2 when subjected to an in vitro dissolution test based on the US Pharmaceopoeia at about 50 rpm in 900 mL of a dissolution medium at 37.0°C. ± 0.5°C, and/or wherein at least 60% of famotidineis released within 20minutes into a solution with a pH 4.5 when subjected to an in vitro dissolution test based on the US Pharmaceopoeia at about 50 rpm in 900 mL of pH 4.5 phosphate buffer and at 37.0°C. ± 0.5°C. Thus, the pharmaceutical composition according to the present invention provides famotidine released independently of pH.

In one preferred embodiment, the pharmaceutical composition of the present invention is for use in a method for the treatment of inflammation or pain, preferably arthritis, wherein the composition is administered for more than 4 days. It is known that frequent NSAID usage which can be specified as "more than 4 days" can cause more significant and frequent gastrointestinal side effects compared to short-term or over-the-counter (OTC) administrations or dosages. Therefore, the pharmaceutical composition of the present invention which reduces the gastrointestinal side effects is preferably used for the therapies requiring an administration for more than 4 days. 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 is administered twice or three times a day and for a period longer than 4 days or preferably 7 days.

In one embodiment, the pharmaceutical composition of the present invention further comprises at least one carbonate. The use of carbonates have also specifically improved the stability of famotidine, when employed in the same oral dosage form with NSAIDs. The degradation of famotidine can be occured due to the acidic nature of the NSAID and the use of a carbonate as an excipient within the compositions of the present invention limits said degradation through decreasing the acidity induced by the NSAID thus the stability of both active ingredients and especially famotidine is within acceptable limits despite the stress conditions (Forced degradation) created in the stability studies below. The oral dosage forms of the present invention demonstrate a good stability for both active ingredients.

Carbonates are, but not limited to; sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, ammonium carbonate, ammonium bicarbonate, potassium carbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, arginine bicarbonate, lysine carbonate or derivatives thereof.

In the preferred embodiment of the present invention, the carbonate is magnesium carbonate or magnesium bicarbonate, potassium or sodium carbonate, or potassium or sodium bicarbonate, or calcium carbonate or calcium bicarbonate or derivatives thereof.

In another preferred embodiment of the present invention the carbonate is an alkali metal bicarbonate or amino acid based bicarbonate. In the most preferred embodiment of the present invention the carbonate is selected from an alkali metal bicarbonate; potassium bicarbonate or sodium bicarbonate or calcium bicarbonate or magnesium bicarbonate. In one embodiment of the present invention, the pharmaceutical composition comprises carbonate in an amount from 5 to 500 mg and preferably 10 to 300 mg and most preferably in an amount from 10 to 200mg.

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

Examples of pharmaceutically acceptable diluents include, but not limited to, magnesium stearate, lactose, microciystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose and dextrose. Examples of pharmaceutically acceptable binders include, but not limited to, starches, natural sugars, corn, sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP, polyethylene glycol, waxes, sodium alginate, alcohols and water.

Examples of pharmaceutically acceptable lubricants include, but not limited to, metallic stearates, metallic lauiyl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, sodium benzoate, sodium acetate, sodium chloride and talk.

Example of pharmaceutically acceptable glidants include, but not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide and silicon hydrogel.

Examples of pharmaceutically acceptable disintegrating agents include, but not limited to, starches, cellulose derivatives, PVP, crospovidone, clays, ion-exchange resins, alginic acid and sodium alginate. Examples of pharmaceutically acceptable surfactants of the present invention include, but not limited to, sulfates, sulfonates, phosphates, carboxylates, primary- secondary-tertiary amines, quaternary ammonium compounds, fatty alcohols, sugar esters of fatty acids, glycerides of fatty acids, polyoxy ethylene glycol alkyl ethers, polisorbates, sorbitan alkyl esters and poloxamers.

In one embodiment, the 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.

It has been also found that an homogenous composition with content uniformity is provided although the large dose difference among the active ingredients. In one embodiment, the composition of the present invention is prepared by a manufacturing method, wherein the active ingredients and gel forming polymer are mixed for at least 2 to 30 minutes in a dry mixer, high sheer granulator, tumbler mixer, V mixer, fluid bed dryer or the like. Herein the gel forming polymer is preferably polyacrylic acid polymer or carbomer. Preferably, the active ingredients and gel forming polymer are mixed with a carbonate for at least 2 to 30 minutes in a dry mixer, high sheer granulator, tumbler mixer, V mixer, fluid bed dryer, or the like. In another preferred embodiment, the pharmaceutical composition of the present invention is useful for the treatment of 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; muscle strain; toothache, muscular pain (myalgia, strain), back pain, knee pain, shoulder pain, bursitis, tendinitis or epicondylitis, inflammatory arthropathies, metastatic bone pain, headache and migraine and preferably rheumatoid arthritis, osteoarthritis, headaches, muscle aches, back pain, tendonitis, joint pain, and gout attacks. These indications require frequent use and hence the dosage forms of the present invention would be most beneficial for the patients of these indications that would have to take NSAlDs on a regular basis for periods definitively longer than 4 days. One aspect of the present invention is to provide a pharmaceutical composition comprising NSA1D, famotidine and a gel forming polymer in order to prevent upper gastrointestinal side effects caused by NSA1D, wherein these side effects include dyspepsia, acid-reflux(heartburn), Gastric(stomach) and duodenalfupper intestine) ulcers. EXAMPLES Example 1

MANUFACTURING PROCESS

1. lactose, Carbopol 971NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes.

2. Naproxen is added to this mixture and mixed for at least 3 minutes

3. The resulting particulate mixture, 625 mg, is filled into hard gelatin capsule shells. Example 2

MANUFACTURING PROCESS

1. Mix lactose, Carbopol 971NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes

2. Naproxen is added to this mixture and mixed well to achieve a uniform mixture and at least mixed for 3 minutes.

3. The resulting particulate mixture, 645 mg, is filled into hard gelatin capsule shells. Example 3

MANUFACTURING PROCESS

1. Mix lactose, Carbopol 971NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes. 2. Ibuprofen is added to this mixture and mixed for at least 3 minutes.

3. The resulting particulate mixture, 900 mg, is filled into hard gelatin capsule shells.

Example 4

MANUFACTURING PROCESS

1. Mix lactose, Carbopol 971 NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes

2. Ibuprofen is added to this mixture and mixed for at least 3 minutes 3. The resulting particulate mixture, 950 mg, is filled into hard gelatin capsule shells.

Example 5

MANUFACTURING PROCESS 1. Mix lactose, Carbopol 974 NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes

2. Ibuprofen is added to this mixture and mixed for at least 3 minutes.

3. The resulting particulate mixture,950 mg, is filled into hard gelatin capsule shells. Example 6

MANUFACTURING PROCESS

1. Carbopol 974 NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes 2. Flurbiprofen is added to this mixture and mixed at least for 3 minutes to achieve a uniform mixture.

3. The resulting particulate mixture,950 mg, is filled into hard gelatin capsule shells.

Example 7

Manufacturing Directions(Wet Granulation) 1. Sieve ibuprofen, Famotidine, Lactose monohydrate, Crospovidone (10mg) together 2. Granulate the mixture of items with granulation solution prepared by distilled water and PVP(20mg) in high shear granulator for at least 2 minutes. 3. Dry mix items in fluid-bed granulator and pass through a0.8-mm sieve, 4. Add colloidal silicon dioxide, crospovidone (15mg) and potassium bicarbonateandmixatleastfor3minutes. 5. Add magnesium stearate to the mixture and mix at least for 2 minutes. 6. Compress tablets, 7. Coat tablets with coating solution (Opadrywhite) Example8

Manufacturing Directions (Wet Granulation)

1. Sieve Naproxene sodium, Famotidine, Lactose monohydrate, Crospovidone (20mg) together

2. Granulate the mixture of items with granulation solution prepared by distilated water and Polyvinylpyrrolidone in high shear granulator for at least 2 minutes.

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

4. Add colloidal silicon dioxide, crospovidone (30mg) and potassium bicarbonate and mix at least for 3 minutes.

5. Add magnessium stearate to the mixture and mix at least for 2 minutes.

6. Compress tablets,

7. Coat tablets with coating solution (Preffered HSP BPP317053 Blue)

Example 9

MANUFACTURING PROCESS

1. Carbopol 974 NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 1 minute

2. Dexketoprofen is added to this mixture and mixed at least for 1 minute to achieve a uniform mixture.

3. The resulting particulate mixture is filled into hard gelatin capsule shells

Example 10

MANUFACTURING PROCESS

1. Carbopol 974 NF, Aerosil, talc, magnesium stearate, potassium bicarbonate and famotidine are combined in a mixer and mixed for at least 2 minutes

2. Diclofenac potassium is added to this mixture and mixed at least for 3 minutes to achieve a uniform mixture.

3. The resulting particulate mixture, 114 mg, is filled into hard gelatin capsule shells.

CONTENT UNIFORMITY TEST

The content uniformity of 10 dosage units were randomly chosen from each of the manufacturing examples, and were assessed according to the USP requirements for content uniformity. The amount of the active ingredients in each of the 10 unit dosage forms containing a NSA1D and famotidine were assayed by using HPLC. The formulations were prepared with the same method used in the manufacturing example, all of the HPLC results were well within the range of 85% to 115% for the content of the active ingredients present in the dosage forms.

STABILITY TEST

As described in prior art detailed above, substantial degradation of famotidine was observed in famotidine-NSAlD mixtures under stress conditions in the presence of NSAlDs unless a barrier layer, bilayer or tablet in tablet or other more complicated techniques that separate the NSA1D from famotidine is employed.

“Forced degradation” (Stress conditions) (e.g., 40° C.- 60° C and 75% relative humidity) are used to evaluate the long-term storage stability of a pharmaceutical ingredient or composition. In general terms, a stable composition is one which comprises the pharmaceutically active ingredients in an amount, for example 90%- 110% , relative to the amount initially present in the particular composition.

Stability may be determined, using forced degradation or other methods, for periods of 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, 36 months, longer.

Stability may also be determined by the presence and quantity of impurities. A principal degradant produced through the chemical interaction of famotidine and NSA1D in the oral dosage forms of the present invention is sulfamide. A quantitative determination of the presence of sulfamide in a unit dose form of the present invention held under forced degradation conditions for a period of even 1 week, yields valuable information about the long-term stability of the composition under normal (e.g., room temperature) storage conditions.

The term“stable,” as used herein, refers to a composition in which the active pharmaceutical ingredients (i.e., ibuprofen and famotidine) are present in an amount of at least 90%, and preferably at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the originally specified amount for each such ingredient, and no more than 3%, and preferably no more than 2%, no more than 1%, no more than 0.9%, no more than 0.8%, no more than 0.7%, or no more than 0.6% sulfamide is present after a specified period of time and under specified conditions.

Stability of a famotidine and ibuprofen formulations was evaluated under forced degradation“stress conditions” of 40° C- 60° C and 75% relative humidity to assess the viability of the different combinations of the active pharmaceutical ingredients. As it would be known by one with ordinary skill in the art, the forced degradation stability studies of the present invention presented below would demonstrate the stability of the dosage forms of the present invention for much longer periods of time (e.g. 2 years) under normal conditions (25° C. and 60% relative humidity.) Assays for evaluating the stability of a pharmaceutical composition, such as those described in the present invention, are known in the pharmaceutical art. For example, one can determine the percentage of active pharmaceutical ingredients present in a given composition, as well as the presence and percentage of impurities, through the use of standard analytical techniques as described below. Surprisingly, the compositions of the present invention with a high molecular weight gel forming polymer and a carbonate, in accordance with the present invention exhibited a very good stability profile even without requiring a layer between the active ingredients, as shown in the Table below.

*Famotidine and ibuprofen content were determined by analytical HPLC and expressed as a percentage of the initial control content analysis done before the stability tests.

*Famotidine and naproxen content were determined by analytical HPLC and expressed as a percentage of the initial control content analysis done before the stability tests.

Study for the effects of hydrogel forming polymers on the pharmacokinetics of naproxen and famotidine

Sprauge- Dawley rats (240-260 g) were used in the study. The rats were maintained in an air-conditioned animals 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 Naproxen sodium were studied in all the normal state of rats following an oral administration (gavages) of different combinations of 55 mg/kg Naproxen sodium ,2 mg/kg famotidine, 0,6 mg/kg and lmg/kg of Carbopol 971NF. Capsule formulations were applied to animals in size 5 capsules by gavage. Six male and/or female rats per group totaling 24 rats, were gavaged with singular naproxen or famotidine or their combinations with the doses and excipients 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

Blood samples were collected (Parasuman et. al., 2010) in corning tubes and kept on ice until 50 ml 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

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 ml

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

Conventional Ibuprofen/Famotidine and Conventional Naproxen/Famotidine Tablet:

Manufacturing Directions (Wet Granulation)

1. Sieve ibuprofen, Famotidin and mannitol together

2. Granulated the mixture of items with granulation solution prepared by distilated water and Crospovidone (20 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 (20 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 (Opadry)

5 Manufacturing Directions (Wet Granulation)

1. Sieve Naproxen sodium, Famotidine, Lactose monohydrate, Crospovidone together

2. Granulated the mixture of items with granulation solution prepared by distilated water and Polyvinylpyrrolidone in high shear granulator

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

4. Add colloidal silicon dioxide, microcrystalline cellulose type 102, polyvinylpyrrolidone and mix 15 minutes.

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

6. Compress tablets,

15 7. Coat tablets with coating solution (Preferred HSP BPP317053 Blue)

Evaluation of the results:

As it can be seen from Table 7, there is an evident increase in the AUC value of naproxen when it is used in combination with a hydrogel forming polymer, namely Carbopol 971NF. The 12 hour AUC of naproxen when used as a single active ingredient formulation is about 284 mg/ml, whereas it is about 492 and 504 mg/ml when administered in combination with famotidine and potassium bicarbonate and 1% or 2,5% of Carbopol 971NF. Table 8 also shows that combinations of the present invention provide a fast and consistent pain relief compared to naproxen alone due to the fact that the combination of the present invention provides a higher blood concentration.

As it can be seen in Table 7, when used in a fixed dose combination without a hydrogel forming polymer such as Carbopol, famotidine has substantially decreased the maximum blood concentration of naproxen from about 67mg/ml to about 39.9 mg/ml. Thus another beneficial advantage of the present invention is that famotidine has a detrimental effect to the blood concentrations of Naproxen which is countered by the formulation of the present invention reversing this effect to the opposite and further improving the PK profile of famotidine in the process.

As it can be seen in Table 8 there is an evident increase in the Cmax and AUC value of famotidine when it is used in combination with Naproxen and Carbopol 971NF at different concentrations. The Cmax of famotidine when used as a single active ingredient formulation is about 1 mg/ml, whereas it is about 1.6 to 1.7 mg/ml when administered in combination with Naproxen and carbopol showing an increase of more than 50% . This demonstrates that the 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 all of the 8 time points throughout the 12 hour period. Thus the combination of the present invention demonstrates a surprising dual synergistic effect increasing the Cmax and AUC of both Naproxen while providing therapeutically significant blood concentrations beginning within 15 minutes after oral administration, due to the instant release profile of the oral dosages detailed below. Dissolution study of Naproxen Sodium and Famotidine capsules with different variations of Carbopol 971NF compared to conventional instant release tablet formulations

Dissolution Apparatus: Apparatus 11 (Paddles)

Dissolution Medium: 50.0 mM Potassium Phosphate Buffer,

pH 7.2

Dissolution Medium Volume: 900 mL

Temperature in Vessel: 37.0° C. ± 0.5° C.

Speed: 50 RPM

Sampling Time: 5min, 10 min. 15min, 20 min., 30 min., 45 min.,

60 min

Sampling Volume: 1 mL analysed by HPLC

The unit dosage form is added to the vessel and dissolution is started. At the times specified above, a portion (e.g., 1ml) of medium is withdrawn and the amount of API in solution is determined using routine analytical methods (e.g., HPLC).

Evaluation of the results:

It was surprisingly demonstrated in the results of the dissolution study above, that the unit dosage forms of the present invention with a hydrogel forming polymer (e.g: Carbopol 971NF) have an instant release profile for both active ingredients under neutral and low pH conditions and the dosage forms significantly released both naproxen and famotidine in 20 minutes under in-vitro assay conditions.

Study for the effects of hydrogel forming polymers on the pharmacokinetics of ibuprofen and famotidine. Chemicals and Reagents

Test formulations are prepared according to Example 3, 4 and 5.

Animals

Sprauge- Dawley rats (240-260 g) were used in the study. The rats were maintained in an air-conditioned animals 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.

Bioavailability and pharmacokinetics of ibuprofen were studied in all the normal state of rats following an oral administration (gavage) of different combinations of 77 mg/kg or 80mg/kg ibuprofen, 2,4mg/kg and 2,66mg/kg famotidine and 0,9 or lmg/kg of Carbopol 971NF or 974 NF. Capsule formulations were applied to animals in size 5 capsules by gavage. The tablet formulation was administered through gavage as well. Six male and/or female rats per group totaling 24 rats, were gavaged with ibuprofen famotidine combinations with the doses and excipients 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

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°Cand supernatants were collected for HPLC analysis.

HPLC ANALYSIS

Chromatographic System :

Column: Inertsil C8 250x4,6 mm; 5 mm Flow Rate: 1.0 ml/min

Column Temperature: 35 °C

Autosampler Temperature: 5 °C Wavelength: 254 nm

Injection Volume: 50 ml

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 ± 0.2

5

Evaluation of the results: 0 As it can be seen from Table 14, there is an increase in the AUC value of ibuprofen when it is used in combination with a hydrogel forming polymer, namely Carbopol 971NF and 974NF. The 12 hour AUC of ibuprofen when formulated according to conventional immediate release dosage forms without a hydrogel forming polymer is about 611 mg/ml, whereas it is about 668 and 631 mg/ml with Carbopol 971 and 974 respectively. Table 14 also shows that combinations of the present invention would provide a fast and consistent pain relief compared to a conventional ibuprofen tablet formulation due to the fact that the combination of the present invention provides a higher Cmax, shorter or same Tmax and a higher AUC in the 12 hour period. As it can be seen in Table 16, there is an increase in the Cmax and AUC value of famotidine with the same Tmax, when it is used in combination with ibuprofen and Carbopol 971NF or 974NF at about 1%.

Furthermore it has been surprisingly demonstrated that lower dosages of ibuprofen and famotidine could be administered (eg: 770/24mg ibuprofen- famotidine) demonstrating highly similar blood concentrations to a conventional tablet formulation of ibuprofen-famotidine(800/26.6mg)

Thus the combination of the present invention demonstrates a surprising effect with hydrogel forming polymers, increasing the Cmax and AUC of both ibuprofen while maintaining the same or shorter Tmax, whilst still maintaining an instant release profile.

Dissolution study of Ibuprofen and Famotidine capsules with different carbomers (Carbopol 971NF and 974NF):

The capsules used were prepared according to the formulation and manufacturing process employed in manufacturing examples 3, 4 and 5.

Dissolution Apparatus: Apparatus 11 (Paddles)

Dissolution Medium: 50.0 mM Potassium Phosphate Buffer, pH 7.2

Dissolution Medium Volume: 900 mL

Temperature in Vessel: 37.0° C. ± 0.5° C.

Speed: 50 RPM Sampling Time: 5min, 10 min. 15min, 20 min., 30 min., 45 min.,

60 min

Sampling Volume: 1 mL analysed by HPLC

5 The unit dosage form is added to the vessel and dissolution is started. At the sampling times specified above, a portion (e.g., 1ml) of medium is withdrawn and the amount of API in solution is determined using routine analytical methods (e.g., HPLC).

5

Evaluation of the results:

It was surprisingly demonstrated in the results of the dissolution study above, that the unit dosage forms of the present invention with a gel forming polymer (eg: Carbopol 971NF or 974NF) have an instant release profile for both active ingredients under neutral and low pH conditions and the dosage forms significantly released at least both ibuprofen and famotidine, in 20 minutes under neutral pH conditions and significantly released both ibuprofen and famotidine under low pH conditions.

Dissolution study of Dexketoprofen Trometamol and Famotidine capsules with Carbopol 974 NF compared to a conventional instant release tablet formulation

The capsules used were prepared according to the formulation and manufacturing process employed in example 9.

Dissolution Apparatus: Apparatus 11 (Paddles)

Dissolution Medium: 50.0 mM Potassium Phosphate Buffer, pH 7.2 and 4.5

Dissolution Medium Volume: 900 mL

Temperature in Vessel: 37.0° C. ± 0.5° C. Speed: 50 RPM

Sampling Time: 5min, 10 min. 15min, 20 min., 30 min., 45 min., 60 min

Sampling Volume: 1 mL analysed by HPLC

The unit dosage form is added to the vessel and dissolution is started. At the sampling times specified above, a portion (e.g., 1ml) of medium is withdrawn and the amount of API in solution is determined using routine analytical methods (e.g., HPLC).

Evaluation of the results:

It was surprisingly demonstrated in the results of the dissolution study above, that the unit dosage forms of the present invention with a hydrogel forming polymer (e.g. Carbopol 974NF) have an instant release profile for both active ingredients under neutral and low pH conditions and the dosage forms significantly released both dexketoprofen and famotidine in 20 minutes under in-vitro assay conditions. Furthermore , the composition of the present invention (manufacturing example No.9) had a significantly higher release of dexketoprofen compared to the commercially available dexketoprofen tablet at pH 4.5

Claims

1. An oral, stable, immediate release pharmaceutical composition in a single unit dosage form comprising

a) NSAID and famotidine or a pharmaceutically acceptable salt thereof as active ingredients, and

b) a high molecular weight gel forming polymer.

2. The pharmaceutical composition according to claim 1, wherein the amount of gel forming polymer is between 0.1 to 10% by weight of the unit dosage form.

3. The pharmaceutical composition according to claim 2, wherein the amount of gel forming polymer is between 0.1 to 7% by weight of the unit dosage form.

4. The pharmaceutical composition according to claim 3, wherein the amount of gel forming polymer is between 0.2 to 5% by weight of the unit dosage form.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the gel forming polymer is a high molecular weight polymer which is selected from the group consisting of chitosan, polyacrylic acid polymers, cross- linked polyacrylic acid polymers, cross-linked water swellable indenemaleic anhydride polymers, polysaccharides composed of condensed glucose units, such as diester cross-linked polygluran and its combinations thereof.

6. The pharmaceutical composition according to claim 5, wherein the gel forming polymer is high-molecular weight cross-linked polyacrylic acid polymer.

7. The pharmaceutical composition according to claim 6, wherein high- molecular weight cross-linked polyacrylic acid polymer is carbomer polymer which is selected from carbomer interpolymer type A, carbomer interpolymer type B or carbomer homopolymer type A.

8. The pharmaceutical composition according to any one of the preceding claims, wherein NSAID is a non-selective COX inhibitor which is selected from the group consisting of ibuprofen, flurbiprofen, diclofenac, naproxen, meloxicam, piroxicam, acetyl salicylic acid, ketoprofen, dexketoprofen, ketorolac, lornoxicam, tenoxicam and pharmaceutically acceptable salts and/or derivatives thereof.

9. The pharmaceutical composition according to claim 8, wherein NSA1D is selected from the group consisting of diclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, dexketoprofen and pharmaceutically acceptable salts and/or derivatives thereof.

10. The pharmaceutical composition according to claim 9, wherein NSA1D is naproxen, ibuprofen or dexketoprofen.

11. The pharmaceutical composition according to claim 10, wherein naproxen is in an amount of from 200 to 600 mg.

12. The pharmaceutical composition according to claim 11, wherein naproxen is in an amount of from 350 to 600 mg.

13. The pharmaceutical composition according to claim 10, wherein ibuprofen is in an amount of from 400 to 810 mg.

14. The pharmaceutical composition according to claim 13, wherein ibuprofen is in an amount of from 600 to 810 mg.

15. The pharmaceutical composition according to claim 10, wherein

dexketoprofen is in an amount of from 25 to 100 mg.

16. The pharmaceutical composition according to any one of the preceding claims, wherein famotidine is in an amount of from 10 to 40 mg.

17. The pharmaceutical composition according to claim 16, wherein famotidine is in an amount of from 20 to 30 mg.

18. The pharmaceutical composition according to claim 17, wherein famotidine is in an amount of from 20 to 27 mg.

19. The pharmaceutical composition according to any one of the preceding claims, further comprising a cellulose derivative.

20. The pharmaceutical composition according to claim 19, wherein the cellulose derivative is selected from the group consisting of microcrystalline cellulose, croscarmellose, hydroxypropylcellulose, methylcellulose, carboxy methyl cellulose, hydroxypropyl methyl cellulose and ethyl cellulose.

21. The pharmaceutical composition according to claims 19 or 20, wherein the amount of cellulose derivative is between 0.1 to 10% by weight of the unit dosage form.

22. The pharmaceutical composition according to any one of the preceding claims, further comprising a carbonate.

23. The pharmaceutical composition according to claim 22, wherein the carbonate is in an amount of from 5 to 500 mg.

24. The pharmaceutical composition according to claim 23, wherein the carbonate is in an amount of from 10 to 300 mg.

25. The pharmaceutical composition according to claim 24, wherein the carbonate is in an amount of from 10 to 200 mg.

26. The pharmaceutical composition according to any one of claims 22 to 25, wherein the carbonate is magnesium carbonate, magnesium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, calcium carbonate or calcium bicarbonate or derivatives thereof.

27. The pharmaceutical composition according to any one of the preceding claims, wherein at least 60% of famotidine and at least 60% of NSA1D are released within 20 minutes into a solution with a pH 7.2 when subjected to an in vitro dissolution test based on the US Pharmaceopoeia at about 50 rpm in 900 mL of a dissolution medium at 37.0°C. ± 0.5°C.

28. The pharmaceutical composition according to any one of the preceding claims, wherein at least 60% of famotidine is released within 20 minutes into a solution with a pH 7.2 when subjected to an in vitro dissolution test based on the US Pharmaceopoeia at about 50 rpm in 900 mL of a dissolution medium at 37.0°C. ± 0.5°C and wherein at least 60% of famotidine is released within 20 minutes into a solution with a pH 4.5 when subjected to an in vitro dissolution test based on the US Pharmaceopoeia at about 50 rpm in 900 mL of pH 4.5 phosphate buffer and at 37.0°C. ± 0.5°C.