composition

Abstract

The present invention relates to oral tablets having an intra-granular component comprising naproxen and, more specifically, such oral tablets having enhanced disintegration times. The Invention further relates to granulation methods for preparation of such oral tablets.

Description

70234W001COMPOSITIONFIELD OF THE INVENTION

[0001] The present invention relates to oral tablets having an intra-granular component comprising naproxen and, more specifically, such oral tablets having enhanced disintegration times. The Invention further relates to granulation methods for preparation of such oral tabletsBACKGROUND TO THE INVENTION

[0002] Pain is a serious and prevalent clinical condition, affecting approximately 20% of adults worldwide. As pain can arise from various factors, a multimodal pain management strategy, which combines different approaches for treatment using different pharmacotherapeutic methods such as analgesics, anti-inflammatory drugs, adjuvant medications and combination therapies, can be particularly effective. This multimodal approach could offer good tolerability and overall safety, particularly when combining well characterised active ingredients.

[0003] Naproxen and paracetamol are commercially available drugs used in the treatment of pain. Each of these drugs has been described, individually and are available over-the-counter (OTC) for treatment of pain.

[0004] However, there remains a need for improved formulations for compressed pharmaceutical dosage forms for oral administration comprising paracetamol (APAP), naproxen or pharmaceutically acceptable salts thereof and improved methods for their production.SUMMARY OF THE INVENTION

[0005] In a First Aspect of the Invention, there is provided a compressed pharmaceutical dosage form for oral administration comprising paracetamol (APAP), naproxen or pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

[0006] In certain embodiments, the paracetamol, crosslinked polyvinyl pyrrolidone and calcium carbonate are present in the intragranular component and the alginic acid is present in an extra-granular component.70234W001

[0007] In other embodiments, the naproxen or pharmaceutically acceptable salt thereof is present in a first intragranular component, the paracetamol, crosslinked polyvinyl pyrrolidone and calcium carbonate are present in a second intragranular component and the alginic acid is present in an extra-granular component.

[0008] Particularly, compressed pharmaceutical dosage forms of the Invention from 250mg to lOOOmg of paracetamol and from 10050 mg to 300 500 mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof.

[0009] Particularly, compressed pharmaceutical dosage forms of the Invention comprise from 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone; and / or from 2% w / w to 30% w / w calcium carbonate; and / or from 0.5% w / w to 5% w / w alginic acid.

[0010] Particularly, compressed pharmaceutical dosage forms of the Invention further comprise one or more pharmaceutically acceptable excipients. More particularly, the one or more pharmaceutically acceptable excipients are selected from the group consisting of binders, lubricants and fillers.

[0011] The binder, where present, is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystal cellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers, and combinations thereof.

[0012] The lubricant, where present, is selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil, zinc stearate, and combinations thereof.

[0013] The filler, where present, is selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol, sugar, croscarmellose Sodium (cross-linked cellulose), Sodium Starch Glycolate (cross-linked starch), and combinations thereof.

[0014] In certain embodiments there is provided a compressed pharmaceutical dosage form comprising or consisting essentially of (1) an intragranular component comprising: (i) 250mg to lOOOmg of paracetamol, (ii) 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof, (iii) 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone, (iv) 2% w / w to 15% w / w calcium carbonate and (v) at least70234W001 one binder selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone, and methacrylic acid copolymers; and (2) an extra-granular component comprising (vi) 0.5% w / w to 2.5% w / w alginic acid, (vii) at least one lubricant selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil and zinc stearate, and (viii) at least one filler selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol and sugar.

[0015] In other embodiments, there is provided a compressed pharmaceutical dosage form comprising or consisting essentially of (1) a first intragranular component comprising: (i) 250mg to lOOOmg of paracetamol, (ii) 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone, (iii) 2% w / w to 15% w / w calcium carbonate and (iv) at least one binder selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone and methacrylic acid copolymers; (2) a second intragranular component comprising: (v) 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof and (vi) at least one binder selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone and methacrylic acid copolymers; and (3) an extra-granular component comprising: (vii) 0.5% w / w to 5% w / w alginic acid, (viii) at least one lubricant selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil and zinc stearate, and (ix) at least one filler selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol and sugar.

[0016] In a Second Aspect of the Invention, there is provided a process for preparing a compressed pharmaceutical dosage form of the First Aspect.

[0017] Thus, there is provided a process for preparing the compressed pharmaceutical dosage form of the First Aspect, comprising: (i) preparing a granulate by co-granulating70234W001 naproxen or pharmaceutically acceptable salt thereof with paracetamol, crosslinked polyvinyl pyrrolidone, calcium carbonate, water and one or more pharmaceutically acceptable excipients; (ii) powder blending the granulate with alginic acid and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; and (iii) compressing the resulting mixture into a unit dosage form such as a tablet or capsule.

[0018] There is also provided a process for preparing the compressed pharmaceutical dosage form of the First Aspect, comprising: (i) preparing a first granulate by granulating naproxen or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients; (ii) preparing a second granulate by granulating paracetamol, crosslinked polyvinyl pyrrolidone, calcium carbonate, water and one or more pharmaceutically acceptable excipients; (ii) powder blending the first and second granulate with alginic acid and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; and (iii) compressing the resulting mixture into a unit dosage form such as a tablet or capsule.

[0019] In some embodiments, the first granulate is prepared before the second granulate. In some embodiments, the second granulate is prepared before the first granulate. In some embodiments, the first granulate and second granulate are prepared in parallel, for example, at substantially the same time.

[0020] In a Third Aspect of the Invention, there is provided a compressed pharmaceutical dosage form of the First Aspect for use in treating or reducing pain in a subject. There is also provided a method of treating or reducing pain in a subject comprising administering to the subject a compressed pharmaceutical dosage form of the First Aspect.

[0021] Particularly, there is provided a compressed pharmaceutical dosage form for oral administration for use in treating or reducing pain in a subject, the compressed pharmaceutical dosage form comprising 250mg to lOOOmg of paracetamol (APAP), 50mg to 500mg of naproxen or pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

[0022] There is also provided a compressed pharmaceutical dosage form for oral administration for use in a method of treating or reducing pain in a subject, the method comprising administering a dose of lOOOmg of paracetamol and 250mg of naproxen or equivalent amount of pharmaceutically acceptable salt thereof twice daily, wherein the70234W001 compressed pharmaceutical dosage form comprises 500mg of paracetamol (APAP), 125mg of naproxen or equivalent amount of pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

[0023] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating or reducing dental pain and post operational pain in a subject.

[0024] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating or reducing dysmenorrhea / Period pain in a subject.

[0025] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating or reducing headache pain in a subject.

[0026] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating mild to moderate pain including headache, dental pain and toothache (postoperative), earache, period pain and cramps, pain after vaccination, acute pain states in which there is an inflammatory component, exertional or overload muscular and joint pain, back pain, acute musculoskeletal pain due to strains and sprains or minor injuries, respiratory tract infections including sore throat, cold and flu.

[0027] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating mild to moderate pain including chronic pain such as Osteoarthritis (OA) pain.DESCRIPTION OF FIGURES

[0028] FIGURE 1 : Shows the dissolution profile of paracetamol for the compositions of Examples 1 and 2 and a comparator 500mg paracetamol product.

[0029] FIGURE 2: Shows the dissolution profile of naproxen for the compositions of Examples 1 and 2 and a comparator 250mg naproxen product.DETAILED DESCRIPTION OF THE INVENTION

[0030] The present inventors have discovered that naproxen and its salts have a very cohesive property that causes issues with flow and handling during formulation and manufacturing processes. Indeed, dry -blending naproxen with other constituents of a formulation was found not to be a feasible route to produce a compressed pharmaceutical dosage70234W001 form. Similarly, granulating paracetamol and dry-blending naproxen as an extra-granular constituent also caused issues and the resulting blend could not be compressed into a tablet.

[0031] The Inventors have therefore discovered that naproxen needs to be granulated to solve the above issues. Thus, the present invention is directed to compressed pharmaceutical dosage forms for oral administration comprising paracetamol (APAP), naproxen or a pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component. Surprisingly, the dissolution of naproxen and paracetamol from the dosage forms of the Invention is substantially equivalent to the dissolution of naproxen and paracetamol from mono-products (products comprising either naproxen or paracetamol).

[0032] Pharmaceutical dosage forms are dosage forms comprising a safe and effective amount of at least one active ingredient and pharmaceutically acceptable excipients in final form suitable for administration to a patient. In the context of the present Invention, the dosage forms comprise a safe and effective amount of paracetamol and naproxen (or pharmaceutically acceptable salt thereof).Naproxen

[0033] Naproxen is a well-known drug that is widely used for its anti-inflammatory, analgesic and antipyretic properties. It is chemically known as (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid and has the following structure:

[0034] The term “naproxen” is generally used to refer to naproxen per se but may also include pharmaceutically acceptable salts thereof. Use of the term “pharmaceutically acceptable salts thereof’ refers to derivatives of naproxen wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Preferably the present invention may comprise naproxen sodium. When referring to pharmaceutically acceptable salts of naproxen, the term70234W001 “pharmaceutically equivalent amount” is used to refer to any dose amount of the salt that results in equivalent efficacy to the parent compound.

[0035] Naproxen is used for the reduction of pain, fever, inflammation, and stiffness caused by conditions including osteoarthritis, rheumatoid arthritis, menstrual cramps and the like.Paracetamol

[0036] Paracetamol, a well-known drug used to treat pain and fever, is also known as N-acetyl-p-aminophenol, acetaminophen and APAP. Paracetamol has the following structure:KW

[0037] The dosage forms are for oral administration, via the mouth, intended to be delivered to or released in the stomach and / or small intestine of a patient. The term “compressed pharmaceutical dosage form” refers to a non-liquid oral dosage form intended to be swallowed and having a sufficiently defined form to be coated, although for the avoidance of doubt, the dosage form may also be left uncoated. The dosage form is formed by compression methods known in the art using conventional equipment and processes, for example by compressing uniform volumes of powder, particles or particle aggregates produced by granulation methods. The dosage form may be of any size or shape known in the art, such as, by way of non-limiting example round, elliptical, oval, square or triangular.

[0038] The compressed pharmaceutical dosage form of the present invention comprises at least one intragranular component and an extra-granular component wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

[0039] The compressed tablets are prepared using a method which involves granulation wherein certain ingredients are combined and then formed into granules. The term “intragranular component” refers to the ingredients of the compressed tablet that are combined before the granulation step. The “extra-granular component” refers to those ingredients that are incorporated into the formulation after granulation. Thus, the term “Intragranular” refers to being or occurring within granules.

[0040] The compressed pharmaceutical dosage form may comprise an intragranular component and an extra-granular component.70234W001

[0041] Thus, in certain embodiments, the naproxen or pharmaceutically acceptable salt thereof, the paracetamol, crosslinked polyvinyl pyrrolidone and calcium carbonate are present in the intragranular component and the alginic acid is present in an extra-granular component.

[0042] The compressed pharmaceutical dosage form may comprise two intragranular components and an extra-granular component.

[0043] Thus, in other embodiments, the naproxen or pharmaceutically acceptable salt thereof is present in a first intragranular component, the paracetamol, crosslinked polyvinyl pyrrolidone and calcium carbonate are present in a second intragranular component and the alginic acid is present in an extra-granular component.

[0044] Particularly, compressed pharmaceutical dosage forms of the Invention comprise from 250mg to lOOOmg of paracetamol and from 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof.

[0045] Particularly, compressed pharmaceutical dosage forms of the Invention comprise from 250mg to lOOOmg of paracetamol, such as 250mg, 300mg, 350mg, 400mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg or lOOOmg. In certain preferred embodiments, the dosage form comprises 500mg paracetamol.

[0046] Particularly, compressed pharmaceutical dosage forms of the Invention comprise from 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof, such as 50mg, 75mg, lOOmg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, or 500mg. In certain embodiments, the dosage form comprises lOOmg to 300mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof. In certain preferred embodiments, the dosage form comprises 125mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof.

[0047] Particularly, the dosage form comprises 500mg paracetamol and 125mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof.

[0048] Particularly, compressed pharmaceutical dosage forms of the Invention comprise from 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone; and / or from 2% w / w to 30% w / w calcium carbonate; and / or from 0.5% w / w to 5% w / w alginic acid. More particularly, compressed pharmaceutical dosage forms of the Invention comprise from 0.2% w / w to 2% w / w70234W001 of crosslinked polyvinyl pyrrolidone; and / or from 2% w / w to 15% w / w calcium carbonate; and / or from 0.5% w / w to 2.5% w / w alginic acid.

[0049] Compressed pharmaceutical dosage forms of the Invention comprise cross-linked polyvinyl pyrrolidone, also referred to as crospovidone, in an amount from about 0.2% w / w to about 2% w / w, for example from 0.5% w / w to 1% w / w of crosslinked polyvinyl pyrrolidone. Suitable amounts may include 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w or 2.0% w / w of crospovidone. In certain embodiments, the dosage forms comprise 0.6% w / w to 0.8% w / w of crospovidone, such as 0.7% w / w.

[0050] Compressed pharmaceutical dosage forms of the Invention comprise calcium carbonate. Particularly calcium carbonate in an amount of from 2% w / w to 30% w / w calcium carbonate, particularly in an amount of from 2% w / w to 15% w / w calcium carbonate. Suitable amounts include 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w, 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 27% w / w, 28% w / w, 29% w / w or 30% w / w of calcium carbonate.

[0051] Particularly, compressed pharmaceutical dosage forms of the Invention further comprise one or more pharmaceutically acceptable excipients. More particularly, the one or more pharmaceutically acceptable excipients are selected from the group consisting of binders, dilutant, lubricants and fillers.

[0052] The binder, where present, is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers, and combinations thereof.

[0053] The lubricant, where present, is selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil, zinc stearate, and combinations thereof. The filler, where present, is selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol, sugar and combinations thereof.70234W001

[0054] For the avoidance of doubt, reference to “% by weight” (%w / w) means by weight of the total composition, the amount of each ingredient being selected so that total ingredients in the composition sum to 100 percent by weight.

[0055] Compressed pharmaceutical dosage forms of the present Invention may be prepared by co-granulation processes comprising: (i) preparing a granulate by co-granulating naproxen or pharmaceutically acceptable salt thereof with paracetamol, crosslinked polyvinyl pyrrolidone, calcium carbonate, water and one or more pharmaceutically acceptable excipients; (ii) powder blending the granulate with alginic acid and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; and (iii) compressing the resulting mixture into a unit dosage form such as a tablet or capsule.

[0056] Alternatively, the compressed pharmaceutical dosage forms may be prepared by double granulation comprising: (i) preparing a first granulate by granulating naproxen or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients; (ii) preparing a second granulate by granulating paracetamol, crosslinked polyvinyl pyrrolidone, calcium carbonate, water and one or more pharmaceutically acceptable excipients; (ii) powder blending the first and second granulate with alginic acid and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; and (iii) compressing the resulting mixture into a unit dosage form such as a tablet or capsule.

[0057] It will be apparent to the skilled person that certain steps of the double granulation process may be performed substantially in parallel, for example at substantially the same time or sequentially, for example, one after the other. Thus, the first granulate may be prepared before the second granulate or, the second granulate may be prepared before the first granulate or, the first granulate and second granulate may be prepared in parallel, for example, at substantially the same time.

[0058] Compressed pharmaceutical dosage forms of the Inventions are for use in treating or reducing pain in a subject, particularly for use in methods of treating or reducing pain in a subject comprising administering to the subject a compressed pharmaceutical dosage form of the First Aspect.

[0059] Particularly, there is provided a compressed pharmaceutical dosage form for oral administration for use in treating or reducing pain in a subject, the compressed pharmaceutical dosage form comprising 250mg to lOOOmg of paracetamol (APAP), 50mg to 500mg of naproxen70234W001 or pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component. More particularly, there is provided a compressed pharmaceutical dosage form for oral administration for use in treating or reducing pain in a subject, the compressed pharmaceutical dosage form comprising 250mg to lOOOmg of paracetamol (APAP), lOOmg to 300mg of naproxen or pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

[0060] There is also provided a compressed pharmaceutical dosage form for oral administration for use in a method of treating or reducing pain in a subject, the method comprising administering a dose of lOOOmg of paracetamol and 250mg of naproxen or equivalent amount of pharmaceutically acceptable salt thereof twice daily, wherein the compressed pharmaceutical dosage form comprises 500mg of paracetamol (APAP), 125mg of naproxen or equivalent amount of pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

[0061] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating or reducing dental pain in a subj ect.

[0062] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating or reducing dysmenorrhea / period pain in a subject.

[0063] Particularly, the compressed pharmaceutical dosage form for oral administration for use in treating or reducing headache pain in a subject.General

[0064] The term “comprising” encompasses “including” e.g. a composition “comprising” X may include something additional e.g. X + Y. In some implementations, the term “comprising” refers to the inclusion of the indicated active agent, such as recited compounds, as well as inclusion of other active agents, and carriers, excipients, emollients, stabilizers, etc., known in the consumer health industry and generally recognized as safe (GRAS). Use of the transitional phrase “consisting essentially of’ means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim, and those that do not70234W001materially affect the basic and novel characteristic(s) of the claimed invention. See, In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP § 2111.03. Thus, the term “consisting essentially of’ when used in a claim of this invention is not intended to be interpreted to be equivalent to “comprising”. The term “consisting of’ and variations thereof means including and limited to (for example, the specific recited constituents or steps). In certain territories, the term “comprising an active ingredient consisting of’ may be used in place of “consisting essentially”. The term “about” in relation to a numerical value x is optional and means, for example, that the numerical value may comprise some variance around the stated number to allow for routine experimental fluctuation, measurement variance or to encompass minor deviations that may achieve substantially the same results as the stated number, such as x±10%, x±5%, x±4%, x±3%, x±2% or x±l%. The word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention. All percentages and ratios used herein are by weight of total composition, unless otherwise indicated.

[0065] All references or patent applications cited within this patent specification are incorporated by reference herein.

[0066] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.EXAMPLESExample 1Ingredient Xanie I' ll net ion Mg / tab Granulate 11 Paracetamol, Ph. Eur active 5002 Pregelatinized Starch, Ph. Binder75Eur.3 Calcium Carbonate, Ph. Eur. Disintegrant 664 Povidone, Ph. Eur. binder 2.570234W001Ingredient Name l' ii net ion Mg / tal)Crospovidone, Ph. Eur. disintegrant 5.9 Granulate 26 Naproxen, Ph. Eur. active 2507 Pregelatinized Starch, Ph. Bindier47Eur.8 Povidone, Ph. Eur. Binder 10.0 Extra-granular9 Alginic Acid, Ph. Eur. Disintegrant 1510 Magnesium Stearate, Ph. lubricant5.0Eur.TOTAL 976.4 mg

[0067] Ingredients 1-6 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then passed through a 19-mesh sieve to give granulate 1 (white granules).Ingredients 6-8 were charged into a mixer and granulated with a suitable quantity of purified water to form fine to medium granules. The resulting granules were dried as before being milled and passed through a 1 ,27mm screen to give granulate 2 (white granules). Granulate 1 and 2 were mixed in a blender with the extra-granular excipients, ingredients 9-10. The resulting blend was then compressed into tablets using shaped tooling to give capsule shaped tablets.Example 2Ingredient Xante l' ii net ion Mg'lah Granulate 11 Paracetamol, Ph. Eur active 5002 Pregelatinized Starch, Ph. Binder75Eur.3 Calcium Carbonate, Ph. Eur. Disintegrant 6670234W001Ingredient Name I'Tinclion Mg / tab4 Povidone, Ph. Eur. binder 2.55 Crospovidone, Ph. Eur. disintegrant 5.9 Granulate 26 Naproxen, Ph. Eur. active 2507 Pregelatinized Starch, Ph. Binder0Eur.8 Povidone, Ph. Eur. Binder 10.0 Extra-granular9 Microcrystal celllulose Di sintegrant / dilutant 4710 Alginic Acid, Ph. Eur. Disintegrant 1511 Magnesium Stearate, Ph. lubricant5Eur.TOTAL 976.4 mg

[0068] Ingredients 1-6 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then passed through a 19-mesh sieve to give granulate 1. Ingredients 6-8 were charged into a mixer and granulated with a suitable quantity of purified water to form fine to medium granulates. After drying, the resulting dried granulates were then passed through a 1.27mm rough screen to give granulate 2. Granulates 1 and 2 were mixed in a blender with ingredients 9-11. The resulting blend was then compressed into tablets using suitable tooling to give capsule shaped tablets.Example 3Ingredient Name I'linction Mg / tab Granulate 11 Paracetamol, Ph. Eur active 50070234W001 Ingredient Name Hi net ion Mg / tab Pregelatinized Starch, Ph. Binder75 Eur.3 Calcium Carbonate, Ph. Eur. Disintegrant 664 Povidone, Ph. Eur. binder 2.55 Crospovidone, Ph. Eur. disintegrant 5.9 Granulate 26 Naproxen, Ph. Eur. active 2507 Pregelatinized Starch, Ph. Binder0 Eur.8 Povidone, Ph. Eur. Binder 10.09 Microcrystal celllulose Binder 47 Extra-granular10 Microcrystal celllulose Di sintegrant / dilutant 4911 Alginic Acid, Ph. Eur. Disintegrant 1512 Magnesium Stearate, Ph. lubricant5 Eur.TOTAL 1025.4 mg

[0069] Ingredients 1-6 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then passed through a 19-mesh sieve to give granulate 1. Ingredients 6-9 were charged into a mixer and granulated with a suitable quantity of purified water to form fine to medium granules. After drying, the resulting dried granules were milled and passed through a 1.27 mm screen to give granulate 2. Granulates 1 and 2 were mixed in a suitable blender with ingredients 10-12 and the resulting blend compressed into tablets using suitable tooling to give capsule shaped tablets.70234W001 Example 4Ingredient Name Hi net ion Mg / tab Granulate 11 Paracetamol, Ph. Eur active 5002 Pregelatinized Starch, Ph. Binder75Eur.3 Calcium Carbonate, Ph. Eur. Disintegrant 664 Povidone, Ph. Eur. binder 2.55 Crospovidone, Ph. Eur. disintegrant 5.9 Granulate 26 Naproxen, Ph. Eur. active 2507 Pregelatinized Starch, Ph. Binder0Eur.8 Povidone, Ph. Eur. Binder 10.09 Microcrystal celllulose Binder 47Extra-granular10 Microcrystal celllulose Di sintegrant / dilutant 9611 Alginic Acid, Ph. Eur. Disintegrant 1512 Magnesium Stearate, Ph. lubricant5.0Eur.TOTAL 1074.4 mg

[0070] Ingredients 1-6 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then passed through a 19-mesh sieve to give granulate 1. Ingredients 6-9 were charged into a suitable mixer and granulated with a suitable quantity of purified water to form fine to medium granules. After drying, the dried granulates were milled and passed through a 1.27 mm screen to give granulate 2. Granulate 1 and 2 were mixed in a blender with ingredients 10-12 and compressed into tablets using suitable tooling to give capsule shaped tablets.70234W001Example 5Ingredient Name l-'unction Mg / tab Granulate 11 Paracetamol, Ph. Eur active 5002 Pregelatinized Starch, Ph. Binder75Eur.3 Calcium Carbonate, Ph. Eur. Disintegrant 664 Povidone, Ph. Eur. binder 2.55 Crospovidone, Ph. Eur. disintegrant 5.9 Granulate 26 Naproxen, Ph. Eur. active 1257 Pregelatinized Starch, Ph. Binder23.5Eur.8 Povidone, Ph. Eur. Binder 5.0Extra-granular9 Alginic Acid, Ph. Eur. 1510 Magnesium Stearate, Ph. lubricant5.0Eur.11 Silica, Colloidal Anhydrous, Filler / dilutant5.0Ph. Eur.TOTAL 842.9 mg

[0071] Ingredients 1-6 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then passed through a 19-mesh sieve to give granulate 1. Ingredients 6-8 were charged into a mixer and granulated with a suitable quantity of purified water to form fine to medium granules. The resulting dried granules were then milled and passed through a 1 ,27mm screen to give granulate 2. Granulates 1 and 2 were mixed in a blender with extra granular ingredients 9-11. The resulting blend was then compressed into tablets using suitable tooling to give capsule shaped tablets.70234W001Example 6

[0072] The methodology of Example 5 was repeated except this time, granulate 2 was prepared by milling and passing through a 1.0 mm screen.Example 7

[0073] The methodology of Example 5 was repeated again, except this time granulate 2 was prepared by milling and passing through a 0.6 mm screen.Examples 8 and 9 (Co-granulation)Ingredient Xanie l‘ ii net ion Mg / tabExample 8 Example 9 Granulate 11 Paracetamol, Ph. Eur active 500 5002 Pregelatinized Starch, Binder100 100 Ph. Eur.3 Calcium Carbonate, Disintegrant66 66Ph. Eur.4 Povidone, Ph. Eur. binder 15 155 Crospovidone, Ph. Eur. disintegrant 5.9 5.96 Naproxen, Ph. Eur. active 125 125 Extra-granular7 Alginic Acid, Ph. Eur. 15 158 Microcrystal cellulose Binder 0 509 Magnesium Stearate, lubricant5.0 5.0Ph. Eur.10 Silica, Colloidal Filler / dilutant5.0 5.0 Anhydrous, Ph. Eur.TOTAL 836.9 mg 886.9 mg

[0074] Ingredients 1-6 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then milled and passed 1.27mm sieve to give a white granulate. The granulate was70234W001mixed in a blender with extra granular ingredients 7-10. The resulting blend was then compressed into tablets using suitable tooling to give capsule shaped tablets.Examples of 10-13Ingredient Xame 1-11110 ion Mg / tabExample Example Example Example 10 11 12 13 Granulate 11 Paracetamol, Ph. Eur active 500 500 500 500 2 Pregelatinized Starch, Binder100 100 100 100 Ph. Eur.3 Calcium Carbonate, Ph. Disintegran66 66 66 66 Eur. t4 Povidone, Ph. Eur. binder 15 15 15 15 5 Crospovidone, Ph. Eur. disintegrant 5.9 5.9 5.9 5.9 Extra-granular6 Naproxen, Ph. Eur. active 250 250 250 250 7 Alginic Acid, Ph. Eur. 15 15 15 15 8 Microcrystal cellulose Binder 90 48 1351371019 Magnesium Stearate, lubricants 0.5 0.48 5.31.0Ph. Eur.10 Silica, Colloidal Filler / diluta 3.0 1.93 5.33.0Anhydrous, Ph. Eur. ntTOTAL 1055 mg 1054 1008 1053

[0075] Ingredients 1-5 sieved were charged into a mixer and granulated with a suitable quantity of deionized water to form medium to heavy granules. The granules were dried in an oven at 40 - 50° C, until the moisture (water content) was around 2%. The resulting dried granules were then milled and passed 1.27mm sieve to give granulate 1. The granules were mixed in a suitable blender with extra granular ingredients 6-10. However, the naproxen was70234W001found to have very cohesive properties that caused flow and handling issues rendering this methodology unfeasible for large scale production. Similar issues were experienced when dry blending ingredients 1 to 10 without any granulation and the APAP Naproxen blend could not be compressed into tablets.Example 14

[0076] The properties of the tablets produced according to Examples 1-9 were tested using standard methods. The tablet dissolution was performed in a pH 7.4 phosphate buffer medium with USP apparatus II (paddle) at 50 rpm with 900 mL of 0.1M phosphate at 37° C. The collected samples were analyzed by UHPLC equipped with a Excel 2 super Cl 8, 100 x 2.1 (EXL-1011-1002U) column, a PDA detector:DissolutionI'lode 1 lardness Disintegration 1 'liability rale of APAPX (KP) (seconds)al ( 1 < > min)I'xample 1 20 0.79% 20.8 94% 177 Fxample 2 10 0.61% 23.6 95% 233 I'xample 3 16 0.53% 28.7 - 259 lixample 4 12 0.37% 29 - 286 I'xample 5 - 0.32 20 65% <180I 'xample b - <0.3 20 86% 135 I'xample 7 - <0.3 16 93% 120 I'xample 8 - 0.34 15 89% NAI 'xample b - 0.45 22 80% NA

[0077] Figures 1 and 2 compare the dissolution of compositions of Examples 1 and 2 with mono- API products containing either 500mg paracetamol or 250mg naproxen.The purpose of the above description is to illustrate some embodiments of the present invention without implying a limitation. It will be apparent to those skilled in the art that various modifications and variations may be made in the apparatus or procedure of the invention without departing from the scope or spirit of the invention.

Claims

70234W001 CLAIMS1. A compressed pharmaceutical dosage form for oral administration comprising paracetamol (APAP), naproxen or pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

2. The compressed pharmaceutical dosage form of claim 1, wherein the paracetamol, crosslinked polyvinyl pyrrolidone and calcium carbonate are present in the intragranular component and the alginic acid is present in an extra-granular component.

3. The compressed pharmaceutical dosage form of claim 1, wherein the naproxen or pharmaceutically acceptable salt thereof is present in a first intragranular component, the paracetamol, crosslinked polyvinyl pyrrolidone and calcium carbonate are present in a second intragranular component and the alginic acid is present in an extra-granular component.

4. The compressed pharmaceutical dosage form of any one of claims 1, 2 or 3 comprising from 250mg to lOOOmg of paracetamol and from 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof.

5. The compressed pharmaceutical dosage form of claim 4, comprising from 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone; and / or from 2% w / w to 30% w / w calcium carbonate; and / or from 0.5% w / w to 5% w / w alginic acid.

6. The compressed pharmaceutical dosage form of claim 4 or 5, further comprising one or more pharmaceutically acceptable excipients.

7. The compressed pharmaceutical dosage form of claim 6, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of binders, dilutant, lubricants and fillers.70234W001 8. The compressed pharmaceutical dosage form of claim 7, wherein the binder is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, microcrystal cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers, and combinations thereof.

9. The compressed pharmaceutical dosage form of claim 7 or 8, wherein the lubricant is selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil, zinc stearate, and combinations thereof.

10. The compressed pharmaceutical dosage form of claim 7, 8 or 9, wherein the filler or dilutant is selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol, sugar, croscarmellose Sodium (cross-linked cellulose), Sodium Starch Glycolate (cross-linked starch), and combinations thereof.

11. The composition of any one of claims 1 to 10 comprising 500mg paracetamol and 250mg naproxen.

12. The composition of any one of claims 1 to 10 comprising 500mg paracetamol and 125mg naproxen.

13. The compressed pharmaceutical dosage form of any one of claims 1 to 10 comprising or consisting essentially of an intragranular component comprising: (i) 250mg to lOOOmg of paracetamol, (ii) 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof, (iii) 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone, (iv) 2% w / w to 30% w / w calcium carbonate and (v) at least one binder selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone and methacrylic acid copolymers; and an extra-granular component comprising (vi) 0.5% w / w to 5%70234W001 w / w alginic acid, (vii) at least one lubricant selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil and zinc stearate, and (viii) at least one filler selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol and sugar.

14. The compressed pharmaceutical dosage form of any one of claims 1 to 12 comprising or consisting essentially of a first intragranular component comprising: (i) 250mg to lOOOmg of paracetamol, (ii) 0.2% w / w to 2% w / w of crosslinked polyvinyl pyrrolidone, (iii) 2% w / w to 30% w / w calcium carbonate and (iv) at least one binder selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone and methacrylic acid copolymers; a second intragranular component comprising: (v) 50mg to 500mg of naproxen or pharmaceutically equivalent amount of pharmaceutically acceptable salt thereof and (vi) at least one binder selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl alcohol, hydrocolloids, sugars, polyvinyl pyrrolidone, copovidone and methacrylic acid copolymers; and an extra-granular component comprising: (vii) 0.5% w / w to 5% w / w alginic acid, (viii) at least one lubricant selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil and zinc stearate, and (ix) at least one filler selected from the group consisting of silica, anhydrous silica, microcrystalline cellulose, lactose, maltose, mannitol and sugar.

15. A process for preparing the compressed pharmaceutical dosage form of any one of claims 1 to 13, comprising: (i) preparing a granulate by co-granulating naproxen or pharmaceutically acceptable salt thereof with paracetamol, crosslinked polyvinyl pyrrolidone, calcium carbonate, water and one or more pharmaceutically acceptable excipients; (ii) powder blending the granulate with alginic acid and at least one pharmaceutically acceptable excipient in70234W001 a mixer to form a mixture; and (iii) compressing the resulting mixture into a unit dosage form such as a tablet or capsule.

16. A process for preparing the compressed pharmaceutical dosage form of any one of claims 1 to 12 and 14, comprising: (i) preparing a first granulate by granulating naproxen or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients; (ii) preparing a second granulate by granulating paracetamol, crosslinked polyvinyl pyrrolidone, calcium carbonate, water and one or more pharmaceutically acceptable excipients; (ii) powder blending the first and second granulate with alginic acid and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; and (iii) compressing the resulting mixture into a unit dosage form such as a tablet or capsule.

17. A compressed pharmaceutical dosage form for oral administration for use in the treatment of pain, the compressed pharmaceutical dosage form comprising 250mg to lOOOmg of paracetamol (APAP), 50mg to 500mg of naproxen or pharmaceutically acceptable salt thereof, crosslinked polyvinyl pyrrolidone, calcium carbonate and alginic acid, wherein the naproxen or pharmaceutically acceptable salt thereof is present in an intragranular component.

18. The compressed pharmaceutical dosage form for oral administration of claim 17 for use in the treatment of pain associated with menstruation (dysmenorrhea).

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