WO2023281089A2

WO2023281089A2 - Pharmaceutical composition comprising naproxen and paracetamol

Info

Publication number: WO2023281089A2
Application number: PCT/EP2022/069158
Authority: WO
Inventors: Marko Benkovic; Kristina DEBELJAK SIMONCIC; Nastja BAŠELJ; Maja KINCL SKUBE; Klemen KORASA; Nina BRVAR
Original assignee: Krka, D.D., Novo Mesto
Priority date: 2021-07-08
Filing date: 2022-07-08
Publication date: 2023-01-12
Also published as: WO2023281089A3; WO2023281089A4

Abstract

The invention relates to a multilayer tablet comprising (i) a naproxen layer containing naproxen or a physiologically acceptable salt thereof and providing immediate release of the naproxen or the physio- logically acceptable salt thereof; and (ii) a paracetamol layer containing paracetamol and providing im- mediate release of the paracetamol. The multilayer tablet is preferably prepared by wet granulation such that the naproxen layer and the paracetamol layer both comprise an extragranular phase and an intragranular phase. Preferably, both extragranular phases contain microcrystalline cellulose. Preferably, the intragranular phase and the extragranular phase of the paracetamol layer both contain a disintegrant, whereas the naproxen layer does not contain disintegrant in any phase. The total content of excipients in both intragranular phases is particularly low.

Description

PHARMACEUTICAL COMPOSITION COMPRISING NAPROXEN AND PARACETAMOL

FIELD OF THE INVENTION

[0001] The invention relates to a multilayer tablet comprising (i) a naproxen layer containing naproxen or a physiologically acceptable salt thereof and providing immediate release of the naproxen or the physiologically acceptable salt thereof; and (ii) a paracetamol layer containing paracetamol and provid ing immediate release of the paracetamol. The multilayer tablet is preferably prepared by wet granula tion such that the naproxen layer and the paracetamol layer both comprise an extragranular phase and an intragranular phase. Preferably, both extragranular phases contain microcrystalline cellulose. Prefer ably, the intragranular phase and the extragranular phase of the paracetamol layer both contain a disin- tegrant, whereas the naproxen layer does not contain disintegrant in any phase. The total content of excipients in both intragranular phases is particularly low.

BACKGROUND OF THE INVENTION

[0002] Naproxen and its sodium salt are a nonsteroidal anti-inflammatory drugs (NS AID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, and fever. Naproxen has a structure shown in formula (I):

[0003] Paracetamol, also known as acetaminophen, is a drug used to treat pain and fever. Paracetamol has a structure shown in formula (II):

[0004] Naproxen, naproxen sodium and paracetamol are well known drugs with established efficacy and safety.

[0005] Several pharmaceutical compositions have been proposed that contain paracetamol in combina tion with other pharmacologically active ingredients.

[0006] For example, compositions comprising paracetamol in combination with ibuprofen are disclosed in WO 2006 004449 A2, WO 2010 44681 Al, WO 2012 05605 Al, WO 2012 060719 Al, EP 1 781 277 A2, EP 2089013 Al and US 2009264530 Al. [0007] S.S. Tomar et al., Int. Journal of Advances in Pharmaceutics, 5(4), 2016, 101-106 relates to formulation and evaluation of a modified release bilayer tablet of paracetamol and diclofenac sodium.

[0008] Combination preparations comprising naproxen and paracetamol in intimate admixture with one another are also known from the prior art. Combinations in a single dosage form were put on the market, for example, under the tradenames Febrax^®, Proxalin^® Plus, Brunadol^®, Flaxenol^®, Naprosyn^® P, Movex^® and Dafloxen^® F.

[0009] EP 0 012 621 A1 discloses pharmaceutical compositions comprising selected NSAIDs and pa racetamol. Example 10 relates to tablets comprising 90 mg of naproxen and 425 mg of paracetamol which are prepared by mixing the finely powdered ingredients with starch paste and compressing the granulation after drying into tablets.

[0010] WO 2006 016126 Al relates to a pharmaceutical composition comprising a granular component comprising a plurality of solidified melt granules of a sugar alcohol having a salt of a non-steroidal anti inflammatory drug (NSAID salt) and paracetamol contained therein. Examples 11 to 14 relate to com binations of naproxen sodium with paracetamol.

[0011] WO 2007 034135 Al relates to a process for producing a granular composition comprising a plurality of solidified melt granules including a non-steroidal anti-inflammatory drug (NSAID) and pa racetamol. Examples 9 to 12 relate to combinations of naproxen with paracetamol.

[0012] J.A. Palma-Aguirre et al., Clinical Therapeutics, 31(2), 2009, 399-410 relates to single dose randomized open-label two-period crossover study in healthy Mexican adult subjects comparing bioa vailability of two oral-tablet and two oral-suspension formulations of naproxen sodium/paracetamol. [0013] K.B. Singh et al., IJPSR, 3(10), 2012, 4045-4049 relates to a validated RP-HPLC method for the simultaneous estimation of paracetamol and naproxen in tablet formulations.

[0014] V.H. Pansara et al. JPR:BioMedRx: An International Journal, 1(7), 2013, 633-636 relates to the development and validation of RP-HPLC method for simultaneous estimation of naproxen and parace tamol in their combined solid dosage forms.

[0015] J.R. Medina et al., Int. Journal of Pharmacy and Pharm. Sciences, 7(5), 2015, 183-188 relates to dissolution studies by first-order derivative spectroscopy concerning naproxen sodium and aceta minophen fixed-dose combination formulations.

[0016] J.R. Medina et al., Int. Journal of Pharmacy and Pharm. Sciences, 8(2), 2016, 239-243 relates to an in vitro evaluation of naproxen sodium and acetaminophen from fixed-dose combinations using the flow-through cell method.

[0017] WO 2016 127221 Al describes pharmaceutical combinations comprising paracetamol and/or NSAID. Example 6 relates to formulations comprising 500 mg of paracetamol and 330 mg of naproxen.

[0018] CN 110 354 111 A relates to binary mixtures of naproxen and paracetamol.

[0019] MX 2014 008985 A relates to tablets comprising a ternary combination of naproxen, paraceta mol and pamabrom. [0020] The thesis of J.R. Santamaria Aguirre, Central University of Ecuador, Quito, April 2013 relates to the development of a formulation, using the fluid bed granulation method, which allows paracetamol and naproxen sodium tablets to be obtained with adequate resistance to abrasion.

[0021] Clinical trial CTRI/2010/091/001495 studies the effects of a fixed dose combination (naproxen 500 mg + paracetamol 500 mg) in patients with acute painful/inflammatory conditions.

[0022] Clinical trial NCT 04447040 relates to an acetaminophen/naproxen sodium dose ranging study.

[0023] Clinical trial NCT 03879408 relates to a naproxen sodium/acetaminophen proof of concept dos ing study.

[0024] However, pharmaceutical dosage forms that contain both pharmacologically active ingredients in admixture with one another have disadvantages. It has been found that there is an undesirable inter action between naproxen sodium and paracetamol that has a negative impact on dissolution of parace tamol. Naproxen or its physiologically acceptable salts, particularly naproxen sodium, when formulated with paracetamol and made into tablets, can significantly decrease the dissolution rate of paracetamol, especially at those low pH values that exist in the stomach, i.e. that are relevant immediately after in gestion. This retardant effect with respect to dissolution of paracetamol is outlasting such that even after considerable periods of time, e.g. after 30 minutes and more, no significant amounts of paracetamol are dissolved. Such outlasting effect cannot be explained on the basis of preceding tablet disintegration but involves subsequent dissolution from the disintegrated formulation.

[0025] A decreased dissolution rate of paracetamol in the time window of 15-30 minutes (and more) after administration is particularly disadvantageous, since it would be desirable for the patient to provide rapid onset of analgesic effects after administration in order to provide rapid pain relief.

[0026] Combination preparations comprising naproxen and paracetamol in separate units providing different release kinetics are also known from the prior art.

[0027] US 2008 0166407 A1 discloses, inter alia, bilayer tablets comprising a slow-releasing base layer comprising paracetamol and fast-releasing layer comprising naproxen sodium.

[0028] WO 2010 138441 A1 relates to pharmaceutical compositions comprising immediate release layer (IR) and extended release layer (ER) ofNSAID and/or paracetamol.

[0029] However, providing different release kinetics for the two pharmacologically active ingredients is not desirable for every therapeutic application and there is a demand for pharmaceutical dosage forms that provide immediate release for both pharmacologically active ingredients.

[0030] WO 2021 127546 A1 relates to oral naproxen sodium tablets comprising roller-compacted gran ules. The naproxen sodium tablets are formulated for and prepared by dry granulation methods, specif ically roller compaction. The combination of dry granulation compatible excipients with roller compac tion methods is said to result in naproxen sodium tablets that exhibit an enhanced dissolution profile and shorter disintegration time as compared to commercially available oral naproxen sodium tablets pre pared by standard wet granulation methods. [0031] However, providing accelerated dissolution of naproxen sodium (e.g., greater initial dissolution rates, shorter disintegration times, and the like) has a negative impact on bioequivalence with respect to existing formulations and is thus not always desirable. In particular, many patients are used to achieve comedication by simultaneously taking existing and approved mono preparations providing immediate release of naproxen (or naproxen sodium) and existing and approved mono preparations providing im mediate release of paracetamol. It would be desirable to provide pharmaceutical dosage forms compris ing fixed-dose combinations of naproxen (or naproxen sodium) and paracetamol that are bioequivalent to both said existing and approved mono preparations. Such pharmaceutical dosage forms comprising fixed-dose combinations would provide convenience and thus improved compliance to those patients because they can simply substitute two tablets (mono preparations) for one tablet (bioequivalent com bination preparation).

[0032] Further, dry granulation, especially roller compaction, has several disadvantages. Dry granula tion is comparatively laborious and requires specialized equipment. In the course of dry granulation considerable amounts of dust may be generated that may cause cross contamination. Segregation of the components may occur after mixing and powder flow may not be satisfactory. Dry granulation leads to low flowability, compressibility, and cohesiveness of the powder. Tablets manufactured by dry granu lation tend to be comparatively soft rendering them more difficult to process using post-tableting tech niques, e.g. film coating.

[0033] Particular problems arise when oral pharmaceutical dosage forms shall be provided that contain comparatively high doses of naproxen or a physiologically acceptable salt thereof (e.g. 275 mg) and comparatively high doses of paracetamol (e.g. 500 mg). Under these circumstances, the two pharmaco logically active ingredients of the combination already have a considerable volume after compaction that needs to be swallowed by the patient upon oral administration. A considerable number of patients have problems with taking large dosage forms exceeding a certain total volume. Thus, when formulating fixed-dose combinations of this type, the total content of excipients should be minimized in order to keep the total volume (an weight) of the oral pharmaceutical dosage forms acceptable.

[0034] There is a demand for pharmaceutical dosage forms that contain a combination of naproxen or a physiologically acceptable salt thereof and paracetamol and that provide immediate release of both pharmacologically active ingredients.

[0035] It is an object of the invention to provide a pharmaceutical dosage form for oral administration that comprises a combination of naproxen or a physiologically acceptable salt thereof and paracetamol and that has advantages compared to the pharmaceutical dosage forms of the prior art. The pharmaceu tical dosage form should provide immediate release of naproxen or the physiologically acceptable salt thereof and immediate release of paracetamol thereby providing a rapid onset of therapeutic effect, par ticularly analgesic effect. Preferably, the pharmaceutical dosage form should be easy to manufacture, have satisfactory properties such as mechanical strength (hardness, friability and the like) and storage stability, provide improved patient compliance, should be bioequivalent compared to commercial mono preparations of naproxen or a physiologically acceptable salt thereof providing immediate release, and should be bioequivalent compared to commercial mono preparations of paracetamol providing immedi ate release.

[0036] These objects have been achieved by the subject-matter of the patent claims.

SUMMARY OF THE INVENTION

[0037] A first aspect of the invention relates to a multilayer tablet, preferably a bilayer tablet, compris ing

- a naproxen layer containing naproxen or a physiologically acceptable salt thereof, preferably naproxen sodium, and providing immediate release of the naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium; and

- a paracetamol layer containing paracetamol and providing immediate release of the paracetamol. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 and 2 depict dissolution profiles of paracetamol from tablets of Comparative Example, Inventive Example and commercial Panadol^® tablets.

[0039] Figure 3 depicts dissolution profiles of naproxen from tablets of Comparative Example, In ventive Example and commercial Apranax^® tablets.

[0040] Dissolution testing for Figure 1 was performed using the USP I (basket) apparatus at 100 rpm and in 900 mL 0.1 M hydrochloric acid at 37 °C.

[0041] Dissolution testing for Figure 2 and 3 was performed using the USP I (basket) apparatus at 100 rpm and in 900 mL phosphate buffer with pH 6.8 at 37 °C.

DETAILED DESCRIPTION OF THE INVENTION

[0042] It has been surprisingly found that when naproxen or its physiologically acceptable salts and paracetamol are separated from one another and compressed into a multilayer tablet according to the invention, the dissolution rate of paracetamol is not significantly affected by naproxen. The influence of naproxen sodium on the dissolution rate of paracetamol in acidic biorelevant medium (0.1 M HC1) is shown in Figure 1. When the dissolution rate is determined at higher pH (Figure 2, pH 6.8), then it appears that naproxen sodium has negligible influence on dissolution rate of paracetamol. However, pH 6.8 is less relevant for the immediate release multilayer tablet which will typically dissolve the entire doses of naproxen or the physiologically acceptable salt thereof and paracetamol while it is in the stom ach (pH ~1), i.e. prior to transition into the intestine (pH ~6.8). It has been surprisingly found that the multilayer tablet according to the invention overcome this drawback in acidic biorelevant medium.

[0043] Further, it has been surprisingly found that immediate release of paracetamol can be achieved in a robust manner when the intragranular phase and preferably also the extragranular phase of the pa racetamol layer contains a disintegrant, whereas the naproxen layer does not need to contain disintegrant in any phase. Immediate release of naproxen can thus be achieved without a disintegrant. Omission of a disintegrant is advantageous, as the disintegrant would otherwise contribute to the total volume of the dosage form thereby negatively influencing patient compliance.

[0044] Still further, it has been surprisingly found that naproxen or a physiologically acceptable salt thereof as well as paracetamol can both be separately formulated by granulation, preferably wet granu lation, whereas the total content of excipients in the naproxen granulate (intragranular phase) as well as the total content of excipients in the paracetamol granulate (intragranular phase) can be kept low. Keep ing the content of intragranular excipients low is likewise advantageous, as higher contents of intragran ular excipients would otherwise contribute to the total volume of the dosage form thereby negatively influencing patient compliance.

[0045] The multilayer tablet according to the invention comprises an immediate release naproxen layer and an immediate release paracetamol layer.

[0046] The term " immediate release " as used herein means a formulation that releases at least 75% of the pharmacologically active ingredient within 45 minutes, when determined with USP I (basket) appa ratus at 100 rpm in 900 mL of phosphate buffer with pH 6.8 at 37 °C. The pharmacologically active ingredients in the multilayer tablet according to the invention are paracetamol and naproxen or a physi ologically acceptable salt thereof.

[0047] The term "naproxen layer", as used herein, refers to a layer in a multilayer tablet that comprises naproxen or its salt, preferably naproxen sodium.

[0048] The term "paracetamol layer", as used herein, refers to a layer in a multilayer tablet which com prises paracetamol.

[0049] As used herein, the term " multilayer tablet " refers to a tablet in which different active ingredients and pharmaceutical excipients are stacked in separate layers in a stepwise manner and then compressed into a single dosage form.

[0050] Preferably, the multilayer tablet according to the invention contains no additional pharmacolog ically active ingredient besides the naproxen or the physiologically acceptable salt thereof and the para cetamol.

[0051] In preferred embodiments, the multilayer tablet according to the invention releases at least 75% of the naproxen or physiologically acceptable salt thereof, preferably naproxen sodium, within 50 minutes, preferably within 45 minutes, more preferably within 40 minutes, still more preferably within 35 minutes, yet more preferably within 30 minutes, even more preferably within 25 minutes, most pref erably within 20 minutes, and in particular within 15 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL phosphate buffer pH 6.8 at 37 °C.

[0052] In preferred embodiments, the multilayer tablet according to the invention releases at least 75% of the paracetamol within 45 minutes, preferably within 40 minutes, more preferably within 35 minutes, still more preferably within 30 minutes, yet more preferably within 25 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, and in particular within 10 minutes, when deter mined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C.

[0053] In preferred embodiments, the multilayer tablet according to the invention releases at least 75% of the paracetamol within 45 minutes, preferably within 40 minutes, more preferably within 35 minutes, still more preferably within 30 minutes, yet more preferably within 25 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, and in particular within 10 minutes, when deter mined with USP I (basket) apparatus at 100 rpm in 900 mL phosphate buffer pH 6.8 at 37 °C.

[0054] The multilayer tablet according to the invention of the invention is preferably in the form of a three layer or bilayer tablet, more preferably the multilayer tablet according to the invention is a bilayer tablet.

[0055] The multilayer tablet according to the invention is preferably film coated, typically with con ventional materials used for film coating. Film coatings can preferably serve different purposes, e.g. achieving smoother and/or colored tablet surfaces resulting in an easier swallowing of the tablets and or distinguishing among different pharmaceutical products.

[0056] Each layer in the multilayer tablet according to the invention preferably comprises at least one pharmaceutically acceptable excipient, preferably selected from the group consisting of diluents, bind ers, disintegrants, glidants, pigments and/or lubricants.

[0057] Binders are preferably selected from the group consisting of povidone (polyvinylpyrrolidone, PVP, povidone), copovidone, hydroxypropyl methyl cellulose (HPMC, hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), polyvinyl alcohol, polyethylene glycol (PEG, macrogol), starch and/or pregelatinized starch and combinations thereof not specifically listed herein.

[0058] Preferably, the binder is copovidone and/or povidone, most preferably the binder is povidone. Preferably, the naproxen layer and paracetamol layer comprise povidone. The amount of povidone in each layer is preferably in the range of 1 to 10 %, preferably 1 to 5 %, and most preferably 2 to 4 % by weight of the tablet.

[0059] Diluents are preferably selected from the group consisting of starch and its derivatives (e.g., com starch, pregelatinized starch), cellulose, microcrystalline cellulose, co-processed microcrystalline cellulose such as silicified microcrystalline cellulose, carbohydrates or their derivatives such as manni tol, xylitol, sorbitol, isomalt, lactose, dextrose, dextrates, dextrin, sucrose, metal salts of phosphoric acid (e.g., calcium hydrogen phosphate in anhydrous or hydrated form) or other diluents and combinations thereof not specifically listed herein.

[0060] Preferably, the diluent is microcrystalline cellulose. Preferably, the naproxen layer and parace tamol layer comprise microcrystalline cellulose. The amount of microcrystalline cellulose in the naproxen layer is preferably in the range of 1 to 20 %, preferably 5 to 15 %, and most preferably 6 to 12 % by weight of the layer. The amount of microcrystalline cellulose in the paracetamol layer is preferably in the range of 10 to 30 %, preferably 15 to 25 %, and most preferably 18 to 22 % by weight of the layer.

[0061] Disintegrants are preferably selected from the group consisting of crospovidone, starch, prege latinized starch, croscarmellose sodium, carmellose sodium or calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin such as potassium polacrilin, and silicate deriva tives such as calcium silicate or other disintegrants or combinations thereof not specifically listed herein. Preferably, the disintegrant is crospovidone. Preferably, the paracetamol layer comprises crospovidone. The amount of crospovidone in the paracetamol layer is preferably in the range of 1 to 10 %, preferably 1 to 5 % and most preferably 2 to 4 % by weight of the layer.

[0062] Preferably, the naproxen layer comprises no disintegrant.

[0063] Lubricants are preferably selected from the group consisting of metallic stearates (e.g. magne sium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegeta ble oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, mag nesium lauryl sulfate), sodium chloride, sodium benzoate and/or sodium acetate and combinations thereof not specifically listed herein. The lubricant is preferably present in each layer of the multilayer tablet according to the invention in an amount of 0.1 to 5 %, preferably in a range of 0.25 to 3 %, and most preferably 0.25 to 1.5 % by weight of the layer. Preferably, the lubricant is magnesium stearate and most preferably, naproxen layer and paracetamol layer comprise magnesium stearate.

[0064] Glidants are preferably selected from silicon dioxide, talc, magnesium trisilicate, magnesium silicate, calcium phosphate, powdered cellulose, starch, talc, and/or magnesium oxide.

[0065] Pigments are preferably selected from water insoluble pigments such as titanium oxide, iron oxide, iron sesquioxide, yellow iron sesquioxide or yellow No. 5 aluminum lake talc and/or water solu ble pigments such as indigo carmine El 32.

[0066] Polymers which can be used for film coating are preferably selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, copovidone and/or povidone. For example, com mercially available film coating sold under the trade name Opadry® can be used.

[0067] The multilayer tablet according to the invention can comprise from 200 mg to 600 mg of naproxen, preferably the amount of naproxen is 200 mg, 250 mg, 375 mg, 400 mg, 500 mg or 600 mg, and most preferably the amount of naproxen is 250 mg. In case naproxen salt is used, the amount of the salt is correspondingly higher so that the dosage of naproxen (naproxen acid) remains the same.

[0068] Preferably, the multilayer tablet according to the invention comprises naproxen sodium. The amount of naproxen sodium in the multilayer tablet according to the invention is preferably in the range from 220 mg to 660 mg, preferably the amount of naproxen sodium is 220 mg, 275 mg, 375 mg, 440 mg, 550 mg or 660 mg, and most preferably the amount of naproxen sodium is 275 mg. [0069] Preferably, the amount of naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium, in the naproxen layer is in the range of 75±15 %, preferably 75±10 %, and most preferably 75±5 %, by weight of the naproxen layer.

[0070] Preferably, the amount of naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium, in the multilayer tablet according to the invention is in the range of 25±15 %, prefer ably 25±10 %, and most preferably 25±5 %, by weight of the multilayer tablet according to the inven tion.

[0071] Preferably, the naproxen layer comprises essentially the total amount of the naproxen or the physiologically acceptable salt thereof that is contained in the multilayer tablet according to the inven tion.

[0072] Preferably, the naproxen layer has been prepared by granulation, preferably by wet granulation, more preferably with an aqueous granulation liquid, and comprises an intragranular phase and an extra- granular phase.

[0073] Preferably essentially the total amount of the naproxen or the physiologically acceptable salt thereof that is contained in the naproxen layer is contained in the intragranular phase of the naproxen layer.

[0074] Preferably, the intragranular phase of the naproxen layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pre gelatinized starch, and combinations thereof; more preferably povidone.

[0075] Preferably, the amount of binder, preferably povidone, in the naproxen layer is in the range of 9.0±8.0 %, preferably 9.0±5.0 %, and most preferably 9.0±2.0 % by weight of the naproxen layer.

[0076] Preferably, the total amount of all excipients in the intragranular phase of the naproxen layer is at most 15 %, preferably at most 13 %, and most preferably at most 11 % by weight of the intragranular phase of the naproxen layer.

[0077] Preferably, the total amount of all excipients in the intragranular phase of the naproxen layer is at most 14 %, preferably at most 12 %, and most preferably at most 10 % by weight of the naproxen layer.

[0078] Preferably, the total amount of all excipients in the intragranular phase of the naproxen layer is at most 8.0 %, preferably at most 6.0 %, and most preferably at most 4.0 % by weight of the multilayer tablet according to the invention.

[0079] Preferably, the intragranular phase of the naproxen layer essentially consists of the naproxen or physiologically acceptable salt thereof, the binder, and optionally a pigment. [0080] Preferably, the extragranular phase of the naproxen layer comprises a diluent; preferably se lected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, car bohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellulose.

[0081] Preferably, the amount of diluent, preferably microcrystalline cellulose, in the naproxen layer is in the range of 8.0±7.0 %, preferably 8.0±5.0 %, and most preferably 8.0±3.0 % by weight of the naproxen layer.

[0082] Preferably, the extragranular phase of the naproxen layer comprises a lubricant; preferably se lected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyc eryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, me tallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.

[0083] Preferably, the amount of lubricant, preferably magnesium stearate, in the naproxen layer is in the range of 1.0±0.9 %, preferably 1 0±0.6 %, and most preferably 1.0±0.3 % by weight of the naproxen layer.

[0084] Preferably, the extragranular phase of the naproxen layer essentially consists of the diluent and the lubricant.

[0085] The amount of paracetamol in the multilayer tablet according to the invention is preferably in the range from 100 mg to 1000 mg, preferably the amount of paracetamol is 250 mg, 300 mg, 500 mg or 750 mg, and most preferably the amount of paracetamol is 500 mg.

[0086] Preferably, the amount of paracetamol in the paracetamol layer is in the range of 70±15 %, preferably 70±10 %, and most preferably 70±5 %, by weight of the paracetamol layer.

[0087] Preferably, the amount of paracetamol in the multilayer tablet according to the invention is in the range of 45±15 %, preferably 45±10 %, and most preferably 45±5 %, by weight of the multilayer tablet according to the invention.

[0088] Preferably, the paracetamol layer comprises essentially the total amount of the paracetamol that is contained in the multilayer tablet according to the invention.

[0089] Preferably, the paracetamol layer has been prepared by granulation, preferably by wet granula tion, more preferably with an aqueous granulation liquid, and comprises an intragranular phase and an extragranular phase.

[0090] Preferably, essentially the total amount of the paracetamol that is contained in the paracetamol layer is contained in the intragranular phase of the paracetamol layer.

[0091] Preferably, the intragranular phase of the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose so dium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably cro- spovidone.

[0092] Preferably, the amount of disintegrant, preferably crospovidone, in the intragranular phase of the paracetamol layer is in the range of 2.0±1.5 %, preferably 2.0±1.0 % and most preferably 2.0±0.5 % by weight of the paracetamol layer.

[0093] Preferably, the extragranular phase of the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose so dium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably cro spovidone.

[0094] Preferably, the amount of disintegrant, preferably crospovidone, in the extragranular phase of the paracetamol layer is in the range of 2.0±1.5 %, preferably 2.0±1.0 % and most preferably 2.0±0.5 % by weight of the paracetamol layer.

[0095] Preferably, the intragranular phase as well as the extragranular phase of the paracetamol layer comprises a disintegrant; preferably independently selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low sub stituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone.

[0096] Preferably, the total amount of disintegrant, preferably crospovidone, in the extragranular phase and the intragranular phase of the paracetamol layer is in the range of 4.0±3.0 %, preferably 4.0±2.0 % and most preferably 4.0±1.0 % by weight of the paracetamol layer.

[0097] Preferably, the intragranular phase of the paracetamol layer comprises a binder; preferably se lected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone.

[0098] Preferably, the amount of binder, preferably povidone, in the intragranular phase of the parace tamol layer is in the range of 4.0±3.0 %, preferably 4.0±2.0 % and most preferably 4.0±1.0 % by weight of the paracetamol layer.

[0099] Preferably, the total amount of all excipients in the intragranular phase of the paracetamol layer is at most 12 %, preferably at most 10 %, and most preferably at most 8 % by weight of the intragranular phase of the paracetamol layer.

[0100] Preferably, the total amount of all excipients in the intragranular phase of the paracetamol layer is at most 11 %, preferably at most 9.0 %, and most preferably at most 7.0 % by weight of the paraceta mol layer. [0101] Preferably, the total amount of all excipients in the intragranular phase of the paracetamol layer is at most 8.0 %, preferably at most 6.0 %, and most preferably at most 4.0 % by weight of the multilayer tablet according to the invention.

[0102] Preferably, the intragranular phase of the paracetamol layer essentially consists of the paraceta mol, the disintegrant and the binder.

[0103] Preferably, the extragranular phase of the paracetamol layer comprises a diluent; preferably se lected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, car bohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellulose.

[0104] Preferably, the amount of diluent, preferably microcrystalline cellulose, in the paracetamol layer is in the range of 20±15 %, preferably 20±10 %, and most preferably 20±5 % by weight of the parace tamol layer.

[0105] Preferably, the extragranular phase of the paracetamol layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.

[0106] Preferably, the amount of lubricant, preferably magnesium stearate, in the paracetamol layer is in the range of 0.5±0.4 %, preferably 0.5±0.3 %, and most preferably 0.5±0.2 % by weight of the naproxen layer.

[0107] Preferably, the extragranular phase of the naproxen layer essentially consists of the disintegrant, the diluent and the lubricant.

[0108] In preferred embodiments of the multilayer tablet according to the invention, the amount of the naproxen layer in the multilayer tablet according to the invention is in the range of 33±15 %, preferably 33±10 %, and most preferably 33±5 %, by weight of the multilayer tablet according to the invention.

[0109] In preferred embodiments of the multilayer tablet according to the invention, the amount of the paracetamol layer in the multilayer tablet according to the invention is in the range of 67±15 %, prefer ably 67±10 %, and most preferably 67±5 %, by weight of the multilayer tablet according to the inven tion.

[0110] Preferably, the multilayer tablet according to the invention comprises 275 mg of naproxen so dium and 500 mg of paracetamol. Most preferably, the multilayer tablet according to the invention is a bilayer tablet comprising 275 mg of naproxen sodium and 500 mg of paracetamol.

[0111] In a preferred aspect of the invention, naproxen layer and paracetamol layer in the multilayer tablet according to the invention comprise microcrystalline cellulose, povidone and magnesium stearate, and paracetamol layer comprises crospovidone. [0112] Preferably, the extragranular phase of the naproxen layer and the extragranular phase of the paracetamol layer both contain microcrystalline cellulose.

[0113] Preferably the intragranular phase of the paracetamol layer and the extragranular phase of the paracetamol layer both contain a disintegrant, whereas the naproxen layer does not contain disintegrant in any phase.

[0114] Preferably, the total amount of all excipients contained in the intragranular phase of the naproxen layer and in the intragranular phase of the paracetamol layer is at most 10 %, more preferably at most 9.0 %, still more preferably at most 8.0 % by weight of the multilayer tablet according to the invention.

[0115] Preferably, the multilayer tablet according to the invention has a total weight of at most 1200 mg, preferably at most 1150 mg, more preferably at most 1100 mg.

[0116] Preferably, the total amount of all excipients is at most 35 %, preferably at most 30 % by weight of the multilayer tablet according to the invention.

[0117] Preferably, the multilayer tablet according to the invention is fdm coated. Preferably, the mul tilayer tablet according to the invention is a scored tablet.

[0118] In a more preferred aspect of the invention, the multilayer tablet according to the invention comprises 275 mg of naproxen sodium and 500 mg of paracetamol, and naproxen layer and paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate, and paracetamol layer comprises crospovidone.

[0119] In the most preferred aspect of the invention, the multilayer tablet according to the invention is a bilayer tablet which releases at least 75% of the paracetamol within 45 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C, and wherein the tablet comprises 275 mg of naproxen sodium and 500 mg of paracetamol, and wherein naproxen layer and paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate, and wherein paracetamol layer comprises crospovidone.

[0120] Naproxen layer and paracetamol layer in the multilayer tablet according to the invention can be prepared by conventional methods such as wet granulation or direct compression. Preferably, naproxen layer and paracetamol layer are prepared by wet granulation.

[0121] The multilayer tablet according to the invention is useful for treating of a condition or disorder selected from pain, fever and inflammation. Thus, another aspect of the invention relates to the multi layer tablet according to the invention as described above for use in the treatment of a condition or disorder selected from pain, fever and inflammation. This aspect likewise relates to the use of naproxen or a physiologically acceptable salt thereof and paracetamol for the manufacture of the multilayer tablet according to the invention as described above for use in the treatment of a condition or disorder selected from pain, fever and inflammation. Further, this aspect likewise relates to a method for the treatment of a condition or disorder selected from pain, fever and inflammation, the comprising administration of the multilayer tablet according to the invention as described above to a subject in need thereof.

[0122] Preferably, the pain is selected from nociceptive pain, inflammatory pain, pathological pain, neuropathic pain, idiopathic pain, chronic pain, acute pain, subacute pain, thermal pain, mechanical pain, chemical pain, visceral pain, deep somatic pain, superficial somatic pain, somatoform pain, psychogenic pain, and psychalgia pain; preferably from arthritis pain, rheumatoid pain, muscular pain, back pain, menstrual pain, headache, orofacial pain, tooth pain.

[0123] In preferred embodiments, the multilayer tablet according to the invention is orally administered once daily, twice daily, thrice daily or more frequently.

[0124] Particularly preferred embodiments of the invention are compiled as clauses 1 to 15 hereinafter:

Clause 1. A multilayer tablet comprising an immediate release naproxen layer and an immediate release paracetamol layer.

Clause 2. The multilayer tablet according to clause 1, wherein the tablet releases at least 75% of the paracetamol within 45 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C.

Clause 3. The multilayer tablet according to clause 1 or 2, wherein the multilayer tablet is a bilayer tablet.

Clause 4. The multilayer tablet according to clause 1, 2 or 3, comprising from 220 mg to 660 mg of naproxen sodium.

Clause 5. The multilayer tablet according to clause 4, comprising 220 mg, 275 mg, 375 mg, 440 mg, 550 mg or 660 mg of naproxen sodium.

Clause 6. The multilayer tablet according to any one of the previous clauses, comprising from 100 mg to 1000 mg of paracetamol.

Clause 7. The multilayer tablet according to clause 6, comprising 275 mg, 300 mg, 500 mg or 750 mg of paracetamol.

Clause 8. The multilayer tablet according to clause 7, comprising 275 mg of naproxen sodium and 500 mg of paracetamol.

Clause 9. The multilayer tablet according to any one of the previous clauses, wherein naproxen layer and paracetamol layer comprise microcrystalline cellulose.

Clause 10. The multilayer tablet according to any one of the previous clauses, wherein naproxen layer and paracetamol layer comprise povidone.

Clause 11. The multilayer tablet according to any one of the previous clauses, wherein paracetamol layer comprises crospovidone.

Clause 12. The multilayer tablet according to any one of the previous clauses, wherein naproxen layer and paracetamol layer comprise magnesium stearate. Clause 13. The multilayer tablet according to any one of the previous clauses, wherein naproxen layer and paracetamol layer are prepared by wet granulation.

Clause 14. The multilayer tablet according to any one of the previous clauses, wherein naproxen layer and paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate, and pa racetamol layer comprises crospovidone.

Clause 15. The multilayer tablet according to any one of the previous clauses, wherein the multilayer tablet is a bilayer tablet that releases at least 75 % of the paracetamol within 45 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C, and wherein the tablet comprises 275 mg of naproxen sodium and 500 mg of paracetamol, and wherein naproxen layer and paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate, and pa racetamol layer comprises crospovidone.

EXAMPLES

[0125] The following examples further illustrate the invention but are not to be construed as limiting its scope.

Comparative Example 1 :

[0126] Film coated tablets were prepared comprising naproxen sodium and paracetamol together in the same layer:

¹ Evaporates during manufacturing process

Granulation:

[0127] The tablets in Comparative Example 1 were prepared by adding the contents of the intragranular phase in a high shear mixer. The contents were mixed in the mixer for 1 to 3 minutes. Afterwards the contents were granulated with water while mixing for 1 to 10 minutes. After the granulation, the granu late was kneaded for 1 to 3 minutes. The contents were transferred to a fluid bed dryer and dried until the product reached a temperature of 35 to 50 °C. The loss on drying was determined after the drying was complete (2-4 %). The dried granulate was sieved through a sieve with openings between 0.6 and 2.0 mm.

Preparation of tableting mixture:

[0128] Extragranular components (crospovidone and microcrystalline cellulose) were added to the granulate and mixed in a container mixer for 5 to 20 minutes. Afterwards magnesium stearate was added to the mixture and mixed in a container mixer for additional 1 to 3 minutes.

Tableting:

[0129] The tablet cores were prepared using a rotary tablet press.

Film coating:

[0130] Tablet cores were coated in automatic coating pan with water-based film coating suspension, prepared by suspending of ready-to-use mixture. The theoretical weight of the film coated tablets was 27 mg higher than the core weight.

Inventive Examples 2 to 11:

[0131] Film coated bilayer tablets were prepared comprising naproxen sodium in a naproxen layer and paracetamol in a paracetamol layer:

¹ Evaporates during manufacturing process

¹ Evaporates during manufacturing process

Preparation of the naproxen layer tableting mixture:

[0132] Naproxen sodium and binder (copovidone, povidone, hydroxypropyl cellulose) were added into a high shear mixer. Separately, a granulation fluid was prepared by mixing purified water and pigment (indigo carmine). The granulation fluid was sprayed onto naproxen sodium and binder (copovidone, povidone, hydroxypropyl cellulose) during mixing of the ingredients. The duration of this step was be tween 2 and 20 minutes. After the spraying was complete the ingredients were kneaded for 15 to 120 seconds. Afterwards the granulate was transferred into a fluid bed dryer, where it was dried until the granulate reached a temperature of 35 - 50 °C. Loss on drying was determined after the temperature was reached. Loss on drying should be between 5 and 7 % to achieve optimal compression characteris tics of the layer. The dried granulate was sieved through a sieve with openings between 0.6 and 2.0 mm. Diluent (microcrystalline cellulose, mannitol) was added to the granulate and mixed in a container mixer for 5 to 20 minutes. Afterwards lubricant (magnesium stearate, glyceryl behenate) was added to the mixture and mixed in a container mixer for additional 1 to 3 minutes.

Preparation of the paracetamol layer tahleting mixture:

[0133] Paracetamol and half of disintegrant (crospovidone, croscarmellose sodium, sodium starch gly- colate) were added to the fluid bed dryer, mixed and heated to 25 - 40 °C. Separately, a granulation fluid was prepared by mixing water and binder (copovidone, povidone, hydroxypropyl cellulose). Then, granulation liquid was sprayed onto the mixture in the fluid bed dryer. During the granulation the tem perature of the granulate was maintained at 20 - 32 °C. After the granulation, the granulate was dried to a temperature of 23 to 32 °C. After the drying was finished loss on drying was determined. The loss on drying should be below 3% for optimal compression characteristics of the mixture. The dried granulate was sieved through a sieve with openings between 0.6 and 2.0 mm. Diluent (microcrystalline cellulose, mannitol) and the second half of disintegrant (crospovidone, croscarmellose sodium, sodium starch gly- colate) were added to the granulate and mixed in a container mixer for 5 to 20 minutes. Afterwards lubricant (magnesium stearate, glyceryl behenate) was added to the mixture and mixed in a container mixer for additional 1 to 3 minutes.

Tahleting:

[0134] The tablet cores were prepared using a rotary tablet press. The naproxen layer tahleting mixture and the paracetamol layer tahleting mixture were compressed into bilayer tablets wherein the bottom layer comprises paracetamol and the top layer comprises naproxen sodium.

Film coating:

[0135] Tablet cores were coated in automatic coating pan with water-based film coating suspension, prepared by suspending of ready-to-use mixture. The theoretical weight of the film coated tablets was 30 mg higher than the core weight.

[0136] Dissolution testing was performed using the USP I (basket) apparatus at 37 °C at 100 rpm and in 900 mL dissolution medium, either 0.1 M hydrochloric acid (Figure 1) or phosphate buffer (Figures 2 and 3). The dissolution profiles of paracetamol from tablets of Comparative Example, Inventive Ex ample and commercial Panadol^® tablets are shown in Figures 1 and 2. The dissolution profiles of naproxen from tablets of Comparative Example, Inventive Example and commercial Apranax^® tablets are shown in Figure 3.

Bioequivalence Data:

[0137] In a single dose, randomized, 2-way (2-period, 2-treatment) crossover study under fasting conditions on 40 healthy male and female volunteers, film coated bilayer tablets according to Inventive Example (275 mg naproxen sodium, 500 mg paracetamol) were compared with the following two reference products administered concomitantly:

- Apranax^® 275 mg film-coated tablets (naproxen sodium), batch no. E0158E2, expiry date: 04-2023 (Atnahs Pharma); and - Panadol^® 500 mg film-coated tablets (paracetamol), batch no. TS7H, expiry date: 10-2023 (GSK Healthcare).

[0138] Results confirm bioequivalence between the test product and reference products.

Claims

Patent claims:

1. A multilayer tablet comprising

- a naproxen layer containing naproxen or a physiologically acceptable salt thereof and provid ing immediate release of the naproxen or the physiologically acceptable salt thereof; and

- a paracetamol layer containing paracetamol and providing immediate release of the paraceta mol.

2. The multilayer tablet according to claim 1, which is a bilayer tablet.

3. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer com prises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellu lose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phos phoric acid, and combinations thereof; more preferably microcrystalline cellulose.

4. The multilayer tablet according to claim 3, wherein the amount of diluent, preferably microcrys talline cellulose, in the naproxen layer is in the range of 1 to 20 %, preferably 5 to 15 %, and most preferably 6 to 12 % by weight of the naproxen layer.

5. The multilayer tablet according to any of the preceding claims, wherein the naproxen comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more pref erably povidone.

6. The multilayer tablet according to claim 5, wherein the amount of binder, preferably povidone, in the naproxen layer is in the range of 1 to 10 %, preferably 1 to 5 %, and most preferably 2 to 4 % by weight of the multilayer tablet.

7. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer com prises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegeta ble oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.

8. The multilayer tablet according to claim 7, wherein the amount of lubricant, preferably magne sium stearate, in the naproxen layer is in the range of 0.1 to 5 %, preferably 0.25 to 3 %, and most preferably 0.25 to 1.5 % by weight of the naproxen layer.

9. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer com prises no disintegrant.

10. The multilayer tablet according to any of the preceding claims, which comprises from 220 mg to 660 mg of naproxen or a physiologically acceptable salt thereof; preferably naproxen sodium; more preferably 220 mg, 275 mg, 375 mg, 440 mg, 550 mg or 660 mg of naproxen sodium.

11. The multilayer tablet according to any of the preceding claims, wherein the amount of naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium, in the naproxen layer is in the range of 75±15 %, preferably 75±10 %, and most preferably 75±5 %, by weight of the naproxen layer.

12. The multilayer tablet according to any of the preceding claims, wherein the amount of naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium, in the multilayer tablet is in the range of 25±15 %, preferably 25±10 %, and most preferably 25±5 %, by weight of the multilayer tablet.

13. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer has been prepared by wet granulation.

14. The multilayer tablet according to any of the preceding claims, wherein the tablet releases at least 75% of the naproxen or physiologically acceptable salt thereof, preferably naproxen sodium, within 50 minutes, preferably within 45 minutes, more preferably within 40 minutes, still more preferably within 35 minutes, yet more preferably within 30 minutes, even more preferably within 25 minutes, most preferably within 20 minutes, and in particular within 15 minutes, when deter mined with USP I (basket) apparatus at 100 rpm in 900 mL phosphate buffer pH 6.8 at 37 °C.

15. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer com prises essentially the total amount of the naproxen or the physiologically acceptable salt thereof that is contained in the multilayer tablet.

16. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer has been prepared by granulation, preferably by wet granulation, more preferably with an aqueous granulation liquid, and comprises an intragranular phase and an extragranular phase.

17. The multilayer tablet according to claim 16, wherein essentially the total amount of the naproxen or the physiologically acceptable salt thereof that is contained in the naproxen layer is contained in the intragranular phase of the naproxen layer.

18. The multilayer tablet according to claim 16 or 17, wherein the intragranular phase of the naproxen layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellu lose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone.

19. The multilayer tablet according to claim 18, wherein the amount of binder, preferably povidone, in the intragranular phase of the naproxen layer is in the range of 9.0±8.0 %, preferably 9.0±5.0 %, and most preferably 9.0±2.0 % by weight of the naproxen layer.

20. The multilayer tablet according to any of claims 16 to 19, wherein the intragranular phase of the naproxen layer contains no disintegrant.

21. The multilayer tablet according to any of claims 16 to 20, wherein the total amount of all excipi ents in the intragranular phase of the naproxen layer is at most 15 %, preferably at most 13 %, and most preferably at most 11 % by weight of the intragranular phase of the naproxen layer.

22. The multilayer tablet according to any of claims 16 to 21, wherein the total amount of all excipi ents in the intragranular phase of the naproxen layer is at most 14 %, preferably at most 12 %, and most preferably at most 10 % by weight of the naproxen layer.

23. The multilayer tablet according to any of claims 16 to 22, wherein the total amount of all excipi ents in the intragranular phase of the naproxen layer is at most 8.0 %, preferably at most 6.0 %, and most preferably at most 4.0 % by weight of the multilayer tablet.

24. The multilayer tablet according to any of claims 16 to 23, wherein the intragranular phase of the naproxen layer essentially consists of the naproxen or physiologically acceptable salt thereof, the binder, and optionally a pigment.

25. The multilayer tablet according to any of claims 16 to 24, wherein the extragranular phase of the naproxen layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellulose.

26. The multilayer tablet according to claim 25, wherein the amount of diluent, preferably microcrys talline cellulose, in the extragranular phase of the naproxen layer is in the range of 8.0±7.0 %, preferably 8.0±5.0 %, and most preferably 8.0±3.0 % by weight of the naproxen layer.

27. The multilayer tablet according to any of claims 16 to 26, wherein the extragranular phase of the naproxen layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chlo ride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.

28. The multilayer tablet according to claim 27, wherein the amount of lubricant, preferably magne sium stearate, in the extragranular phase of the naproxen layer is in the range of 1.0±0.9 %, pref erably 1 0±0.6 %, and most preferably 1.0±0.3 % by weight of the naproxen layer.

29. The multilayer tablet according to any of claims 16 to 28, wherein the extragranular phase of the naproxen layer contains no disintegrant.

30. The multilayer tablet according to any of claims 16 to 29, wherein the extragranular phase of the naproxen layer essentially consists of the diluent and the lubricant.

31. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phos phoric acid, and combinations thereof; more preferably microcrystalline cellulose.

32. The multilayer tablet according to claim 31, wherein the amount of diluent, preferably microcrys talline cellulose, in the paracetamol layer is in the range of 10 to 30 %, preferably 15 to 25 %, and most preferably 18 to 22 % by weight of the paracetamol layer.

33. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hy- droxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone.

34. The multilayer tablet according to claim 33, wherein the amount of binder, preferably povidone, in the paracetamol layer is in the range of 1 to 10 %, preferably 1 to 5 %, and most preferably 2 to 4 % by weight of the multilayer tablet.

35. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.

36. The multilayer tablet according to claim 35, wherein the amount of lubricant, preferably magne sium stearate, in the paracetamol layer is in the range of 0.1 to 5 %, preferably 0.25 to 3 %, and most preferably 0.25 to 1.5 % by weight of the paracetamol layer.

37. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low sub stituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone.

38. The multilayer tablet according to claim 37, wherein the amount of disintegrant, preferably cro spovidone, in the paracetamol layer is in the range of 1 to 10 %, preferably 1 to 5 % and most preferably 2 to 4 % by weight of the paracetamol layer.

39. The multilayer tablet according to any of the preceding claims, which comprises from 100 mg to 1000 mg of paracetamol; preferably 275 mg, 300 mg, 500 mg or 750 mg of paracetamol.

40. The multilayer tablet according to any of the preceding claims, wherein the amount of paraceta mol in the paracetamol layer is in the range of 70±15 %, preferably 70±10 %, and most preferably 70±5 %, by weight of the paracetamol layer.

41. The multilayer tablet according to any of the preceding claims, wherein the amount of paraceta mol in the multilayer tablet is in the range of 45±15 %, preferably 45±10 %, and most preferably 45±5 %, by weight of the multilayer tablet.

42. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer has been prepared by wet granulation.

43. The multilayer tablet according to any of the preceding claims, wherein the tablet releases at least 75% of the paracetamol within 45 minutes, preferably within 40 minutes, more preferably within 35 minutes, still more preferably within 30 minutes, yet more preferably within 25 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, and in particular within 10 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydro chloric acid at 37 °C.

44. The multilayer tablet according to any of the preceding claims, wherein the tablet releases at least 75% of the paracetamol within 45 minutes, preferably within 40 minutes, more preferably within 35 minutes, still more preferably within 30 minutes, yet more preferably within 25 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, and in particular within 10 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL phosphate buffer pH 6.8 at 37 °C.

45. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises essentially the total amount of the paracetamol that is contained in the multilayer tablet.

46. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer has been prepared by granulation, preferably by wet granulation, more preferably with an aqueous granulation liquid, and comprises an intragranular phase and an extragranular phase.

47. The multilayer tablet according to claim 46, wherein essentially the total amount of the paraceta mol that is contained in the paracetamol layer is contained in the intragranular phase of the para cetamol layer.

48. The multilayer tablet according to claim 46 or 47, wherein the intragranular phase of the parace tamol layer comprises a disintegrant; preferably selected from the group consisting of cro- spovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone.

49. The multilayer tablet according to claim 48, wherein the amount of disintegrant, preferably cro- spovidone, in the intragranular phase of the paracetamol layer is in the range of 2.0± 1.5 %, pref erably 2.0±1.0 % and most preferably 2.0±0.5 % by weight of the paracetamol layer.

50. The multilayer tablet according to any of claims 46 to 49, wherein the extragranular phase of the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of cro- spovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone.

51. The multilayer tablet according to claim 50, wherein the amount of disintegrant, preferably cro spovidone, in the extragranular phase of the paracetamol layer is in the range of 2.0±1.5 %, pref erably 2.0±1.0 % and most preferably 2.0±0.5 % by weight of the paracetamol layer.

52. The multilayer tablet according to any of claims 46 to 51, wherein the intragranular phase as well as the extragranular phase of the paracetamol layer comprises a disintegrant; preferably inde pendently selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone.

53. The multilayer tablet according to claim 52, wherein the total amount of disintegrant, preferably crospovidone, in the extragranular phase and the intragranular phase of the paracetamol layer is in the range of 4.0±3.0 %, preferably 4.0±2.0 % and most preferably 4.0±1.0 % by weight of the paracetamol layer.

54. The multilayer tablet according to any of claims 46 to 53, wherein the intragranular phase of the paracetamol layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and com binations thereof; more preferably povidone.

55. The multilayer tablet according to claim 54, wherein the amount of binder, preferably povidone, in the intragranular phase of the paracetamol layer is in the range of 4.0±3.0 %, preferably 4.0±2.0 % and most preferably 4.0±1.0 % by weight of the paracetamol layer.

56. The multilayer tablet according to any of claims 46 to 55, wherein the total amount of all excipi ents in the intragranular phase of the paracetamol layer is at most 12 %, preferably at most 10 %, and most preferably at most 8 % by weight of the intragranular phase of the paracetamol layer.

57. The multilayer tablet according to any of claims 46 to 56, wherein the total amount of all excipi ents in the intragranular phase of the paracetamol layer is at most 11 %, preferably at most 9.0 %, and most preferably at most 7.0 % by weight of the paracetamol layer.

58. The multilayer tablet according to any of claims 46 to 57, wherein the total amount of all excipi ents in the intragranular phase of the paracetamol layer is at most 8.0 %, preferably at most 6.0 %, and most preferably at most 4.0 % by weight of the multilayer tablet.

59. The multilayer tablet according to any of claims 46 to 58, wherein the intragranular phase of the paracetamol layer essentially consists of the paracetamol, the disintegrant and the binder.

60. The multilayer tablet according to any of claims 46 to 59, wherein the extragranular phase of the paracetamol layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellu lose.

61. The multilayer tablet according to claim 60, wherein the amount of diluent, preferably microcrys talline cellulose, in the extragranular phase of the paracetamol layer is in the range of 20±15 %, preferably 20±10 %, and most preferably 20±5 % by weight of the paracetamol layer.

62. The multilayer tablet according to any of claims 46 to 61, wherein the extragranular phase of the paracetamol layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chlo ride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.

63. The multilayer tablet according to claim 62, wherein the amount of lubricant, preferably magne sium stearate, in the extragranular phase of the paracetamol layer is in the range of 0.5±0.4 %, preferably 0.5±0.3 %, and most preferably 0.5±0.2 % by weight of the naproxen layer.

64. The multilayer tablet according to any of claims 46 to 63, wherein the extragranular phase of the naproxen layer essentially consists of the disintegrant, the diluent and the lubricant.

65. The multilayer tablet according to any of claims 46 to 64, wherein the extragranular phase of the naproxen layer and the extragranular phase of the paracetamol layer both contain microcrystalline cellulose.

66. The multilayer tablet according to any of claims 46 to 65, wherein the intragranular phase of the paracetamol layer and the extragranular phase of the paracetamol layer both contain a disinte grant, whereas the naproxen layer does not contain a disintegrant in any phase.

67. The multilayer tablet according to any of claims 16 to 66, wherein the total amount of all excipi ents contained in the intragranular phase of the naproxen layer and in the intragranular phase of the paracetamol layer is at most 10 %, more preferably at most 9.0 %, still more preferably at most 8.0 % by weight of the multilayer tablet.

68. The multilayer tablet according to any of the preceding claims, which besides the naproxen or the physiologically acceptable salt thereof and the paracetamol contains no additional pharmacolog ically active ingredient.

69. The multilayer tablet according to any of the preceding claims, which comprises 275 mg of naproxen sodium and 500 mg of paracetamol.

70. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer and the paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate; and wherein the paracetamol layer comprises crospovidone.

71. The multilayer tablet according to any of the preceding claims,

- wherein the multilayer tablet is a bilayer tablet;

- which releases at least 75% of the paracetamol within 45 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C;

- wherein the tablet comprises 275 mg of naproxen sodium and 500 mg of paracetamol,

- wherein the naproxen layer and the paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate; and

- wherein the paracetamol layer comprises crospovidone.

72. The multilayer tablet according to any of the preceding claims, wherein the amount of the naproxen layer in the multilayer tablet is in the range of 33±15 %, preferably 33±10 %, and most preferably 33±5 %, by weight of the multilayer tablet.

73. The multilayer tablet according to any of the preceding claims, wherein the amount of the para cetamol layer in the multilayer tablet is in the range of 67±15 %, preferably 67±10 %, and most preferably 67±5 %, by weight of the multilayer tablet.

74. The multilayer tablet according to any of the preceding claims, which has atotal weight of at most 1200 mg, preferably at most 1150 mg, more preferably at most 1100 mg.

75. The multilayer tablet according to any of the preceding claims, wherein the total amount of all excipients is at most 35 %, preferably at most 30 % by weight of the multilayer tablet.

76. The multilayer tablet according to any of the preceding claims, which is fdm coated.

77. The multilayer tablet according to any of the preceding claims, which is a scored tablet.

78. The multilayer tablet according to any of the preceding claims for use in the treatment of a con dition or disorder selected from pain, fever and inflammation.

79. The multilayer tablet for use according to claim 78, wherein the pain is selected from nociceptive pain, inflammatory pain, pathological pain, neuropathic pain, idiopathic pain, chronic pain, acute pain, subacute pain, thermal pain, mechanical pain, chemical pain, visceral pain, deep somatic pain, superficial somatic pain, somatoform pain, psychogenic pain, and psychalgia pain; prefera bly from arthritis pain, rheumatoid pain, muscular pain, back pain, menstrual pain, headache, orofacial pain, tooth pain.

80. The multilayer tablet for use according to claim 78 or 79, wherein the multilayer tablet is orally administered once daily.

81. The multilayer tablet for use according to claim 78 or 79, wherein the multilayer tablet is orally administered twice daily.

82. The multilayer tablet for use according to claim 78 or 79, wherein the multilayer tablet is orally administered thrice daily or more frequently.