Ibuprofen arginate oral solution

Abstract

The present invention relates to an ibuprofen arginate oral solution comprising xanthan gum as sole viscosizing agent, liquid maltitol and purified water as sole solvent. The oral solution is physicochemically stable and has optimal viscosity and organoleptic properties. The invention also relates to said composition for use in therapy.

Description

[0001] IBUPROFEN ARGINATE ORAL SOLUTION

[0002] Technical field

[0003] The present invention relates to an ibuprofen oral solution, more particularly, to an ibuprofen arginate oral solution.

[0004] State of the art

[0005] Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), belonging to the family of propionic acid derivatives. Ibuprofen is the most commonly used NSAID and the most frequently prescribed by doctors worldwide for the treatment of pain, inflammation and / or fever in patients of all ages, including paediatric patients. It exerts its analgesic action by inhibiting the enzyme cyclooxygenase (COX), which is mainly responsible for the synthesis of prostaglandins, and, although ibuprofen is safer than other NSAIDs, it can also give rise to some undesirable adverse effects, for example, gastric lesions and gastric bleeding, among others.

[0006] Ibuprofen is a relatively weak acid, it is practically insoluble in water, and has a characteristic bitter taste. Although the bioavailability of ibuprofen is high, due to its poor solubility, the drug reaches the bloodstream relatively slowly and, consequently, its therapeutic effects are not manifested immediately, but rather generally start from 45 minutes to one hour after oral administration.

[0007] An alternative to achieve a faster therapeutic effect, that is, both a more rapid onset of analgesia and also superior analgesic effect, is to use an ibuprofen salt, which has the advantage of being water soluble (Moore et al., Faster, higher, stronger? Evidence for formulation and efficacy for ibuprofen in acute pain, Pain, 2014, 155 (1), 14-21). A particularly preferred salt of ibuprofen is the salt with arginine, also known as ibuprofen arginate (Cajarville J.P., Ibuprofen arginate for rapid-onset pain relief in daily practice: a review of its use in different pain conditions, J. Pain Res., 2021 , 25 (14), 117-126). Furthermore, ibuprofen arginine has been reported to cause fewer gastric endoscopic lesions and to be associated with significantly lower rate of clinical adverse effects than ibuprofen, which could be explained by the increase in NO synthesis induced by arginine (Gallego-Sandin et. al., Effect of ibuprofen on cyclooxygenase and nitric oxide synthase of gastric mucosa: correlation with endoscopic lesions and adverse reactions, Dig. Dis. Sci. , 2004, 49 (9), 1538-44). Ibuprofen arginate is available from the company Zambon in the form of tablets or as a granulate for oral solution, that must be previously dissolved in water, under the tradenames Espidifen®, Spedifen® or Spidifen®.

[0008] A solubilized dosage form of ibuprofen arginate, in the form of oral solution, would provide several advantages, namely, a rapid bioavailability of solubilized ibuprofen, better suitability for paediatric population, and more convenient administration also for the general adult population, specially including elderly people.

[0009] Solid forms, such as tablets, may be inconvenient for patients with swallowing difficulties and, even for patients without difficulties, generally require water for swallowing the medicament. On the other hand, commercially available granulate for oral solution also has disadvantages for the patient, due to the high amount of water required for solubilizing the granules and the unsuitability for customizing the dose.

[0010] An oral solution would overcome such drawbacks. However, the development of an ibuprofen arginate oral solution raises several challenges, namely, an efficient masking of the bitter ibuprofen taste, a suitable concentration and viscosity of the solution, suitable for bottles with syringe and mono-dose stick forms, and long-lasting chemical and physical stability, avoiding, for example, crystal formation.

[0011] Some ibuprofen arginate oral solutions are disclosed in the prior art.

[0012] Several prior art documents disclose fairly concentrated ibuprofen solutions, of reduced viscosity, suitable for oral drops.

[0013] For example, the international patent application W095 / 00134 discloses ibuprofen aqueous solutions comprising 20% w / v ibuprofen and 18.5% arginine, as well as sweeteners (preferably sodium saccharin), flavours and preservatives. The international patent application W002 / 083118 discloses low viscosity ibuprofen aqueous solutions, as oral drops, comprising 30-60% w / v ibuprofen, sodium hydroxide and ethanol. Analogously, the international patent application W02007 / 142707 discloses ibuprofen arginate aqueous solutions for oral administration, comprising about 25% w / v ibuprofen, a strong base (sodium hydroxide), a sweetener (saccharin), flavours and colouring agents.

[0014] Other prior art documents particularly face the problem of ibuprofen bitter taste masking.

[0015] For example, the Korean patent application KR-A- 10-2005-0071889 discloses aqueous ibuprofen arginate oral solutions comprising beta-cyclodextrins, aspartame and / or acesulfame potassium, 55-85 wt% of a sugar alcohol sweetener (such as isomalt, maltitol, sorbitol or erythritol), and a viscosizing agent selected from sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, gelatin and polyvinylpyrrolidone.

[0016] In the international patent application WO2018 / 053423, 4% w / v ibuprofen oral solutions, comprising sodium ibuprofen salt, are disclosed, further comprising sodium bicarbonate and povidone for taste masking. Other ingredients include EDTA (sequestrant), sorbitol (crystallization inhibitor), propylene glycol (co-solvent) and sucrose, as well as sweeteners, flavours, colourants and preservatives.

[0017] The Chinese patent application CN-A-109381426 discloses ibuprofen oral solutions comprising L-arginine, L-histidine or L-lysine as solubilizers, sweeteners (sucralose, stevioside or aspartame) and a taste-masking agent, such as glycerin or tartaric acid.

[0018] On the other hand, the international patent application WO2021 / 105524 discloses ibuprofen oral solutions comprising a viscosizing system to provide an optimally viscose solution, suitable to be dispensed, for example, with a dosing syringe. In particular, it is taught that only the combination of xanthan gum and povidone provides satisfactory results, while, conversely, when only xanthan gum was used, the solutions were not stable, with the appearance of needle-shaped crystals, and when only povidone was used, the viscosity of the solution was insufficient. The compositions disclosed also included propylene glycol and polyethylene glycol as co-solvents, a buffering agent, a preservative, maltitol and sorbitol as sugar alcohol sweeteners, sucralose and saccharin as high intensity sweeteners, sodium chloride as taste-masking agent, as well as preservatives, and flavours.

[0019] Despite the different approaches available so far, there is still the need to provide ibuprofen arginate oral solutions, which are chemically and physically stable, in particular, which remain transparent, without precipitation, crystallization or aggregate formation, and having optimal concentration and viscosity to be dosed, for example, with syringe dosing from a bottle or in mono-dose sticks, also having good taste and requiring less formulation excipients. Furthermore, it would be also an advantage to provide an ibuprofen arginate oral solution bioequivalent to the present commercial forms, namely, bioequivalent to Espidifen®, Spedifen® or Spidifen® granules for oral solution.

[0020] Object of the invention

[0021] The object of the invention is an ibuprofen oral solution.

[0022] Another aspect of the invention is said oral solution for use in therapy.

[0023] Detailed description of the invention The object of the present invention is an ibuprofen oral solution comprising: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1 ; c) a viscosizing agent consisting of xanthan gum in an amount comprised between 0.05% w / v and 1 .5% w / v; d) a sugar alcohol consisting of liquid maltitol in an amount comprised between 10% w / v and 50% w / v; and e) a solvent consisting of water.

[0024] The authors of the present invention have developed an ibuprofen arginate oral solution which solves the above stated problems.

[0025] Along the present description, as well as in the claims, the singular expressions, generally preceded by the articles “a”, “an” or “the”, are meant to include also the plural forms, unless the context clearly indicates otherwise. Furthermore, numeric values preceded by the term “about” or “approximately” are meant to include the exact stated value and also a certain variation around such value, namely a variation or ±5% of the stated amount. Numeric ranges defined by lower and upper endpoints are meant to include also said stated endpoints, as well as all sub-ranges.

[0026] Unless otherwise stated, the percentages disclosed for each component of the composition are weight / volume (% w / v), i.e., grams of each component in 100 ml of the solution.

[0027] The excipients used for preparing the composition of the present invention are well known in the art, and widely available, and are described, for example, in the reference book R.C. Rowe, P.J. Sheskey and P.J. Weller, Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, 2009 [ISBN 978 0 85369 792 3], Also, common excipients and procedures for preparing the compositions are described in the book J.P Remington and A. R. Genaro, Remington The Science and Practice of Pharmacy, 20thedition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472] or in the book M.E. Aulton and K.M.G. Taylor, Aulton’s Pharmaceutics, the design and manufacture of medicines, 4thedition, Churchill Livingstone Elsevier, 2013 [ISBN: 978-0-7020-4290-4],

[0028] Ibuprofen arginate

[0029] Ibuprofen arginate (CAS number 57469-82-6), also known as ibuprofen arginine, or ibuprofen L-arginine, is the ibuprofen salt with arginine, with a 1 :1 molar ratio. Within the context of the present invention, an ibuprofen arginate oral solution means either a solution prepared dissolving the previously formed salt of ibuprofen and arginine, or a solution prepared using ibuprofen and arginine independently, as separate ingredients of the composition, in particular, wherein the proportion of arginine in the composition is defined by a molar ratio ibuprofemarginine comprised between about 0.7:1 and about 1.3:1.

[0030] Therefore, in the context of the present invention, ibuprofen arginate oral solution means an oral solution comprising dissolved ibuprofen and arginine, independently of how ibuprofen and arginine are added to the composition. Preferably, the compositions are prepared using ibuprofen and arginine as separate substances, rather than the pre-formed salt.

[0031] When ibuprofen arginate is used in the form of the previously formed salt, said salt is commercially available or can be prepared by methods well known to those skilled in the art, for example, as described in US4279926.

[0032] Arginine is an a-amino acid, which is found in nature in its enantiomeric form L. In the context of this invention, the term arginine includes any of its enantiomeric forms: L- arginine, D-arginine and mixtures thereof. Preferably, arginine is in the form of L-arginine.

[0033] On the other hand, ibuprofen is the International Nonproprietary Name (INN) corresponding to the compound (R,S)-2-(4-isobutylphenyl)propionic acid (CAS number 15687-27-1). In the context of the present invention, the term ibuprofen includes the racemic form ((R,S)-ibuprofen), the (S) enantiomer of ibuprofen ((S)-ibuprofen) and a mixture of the enantiomers (R) and (S) of ibuprofen, preferably enriched in the (S) form. Preferably, ibuprofen is selected from (R,S)-ibuprofen and (S)-ibuprofen, and more preferably ibuprofen is the racemic (R.S)-ibuprofen form.

[0034] The ibuprofen arginate oral solution according to the present invention comprises from about 2.0% w / v to about 6.0% w / v of ibuprofen. Preferably, the composition comprises from about 2.5% w / v to about 5.5% w / v of ibuprofen, more preferably comprises from about 3.0% w / v to about 5.0% w / v, more preferably comprises from about 3.5% w / v to about 4.5% w / v of ibuprofen, still more preferably comprises from about 3.7% w / v to about 4.3% w / v of ibuprofen, and still more preferably comprises about 4.0% w / v of ibuprofen.

[0035] The amount of arginine in the oral solution is defined relative to the amount of ibuprofen. In particular, the composition comprises an amount of arginine corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1. Preferably, the molar ratio ibuprofen:arginine in the ibuprofen oral solution according to the present invention is comprised between 0.75:1 and 1.2:1 , more preferably is comprised between 0.8:1 and 1.1 :1 , still more preferably is comprised between 0.85:1 and 1 :1 , and still more preferably is about 0.9:1.

[0036] Viscosizinq agent

[0037] The ibuprofen arginate oral solution according to the present invention is a transparent, viscose solution, optimal to be accurately dispensed from a multidose container using a suitable measuring device, such as, for example, a dosing syringe or a graduated cup. The ibuprofen arginate oral solution according to the present invention has also optimal viscose characteristics for intake from oral mono-dose sticks.

[0038] It was found that xanthan gum as the sole viscosizing agent provides optimal ibuprofen arginate solution, with the required viscosity, and which remains stable, transparent and without agglomerates or crystal formation in the stability assays performed.

[0039] The ibuprofen oral solution according to the present invention comprises xanthan gum as the only viscosizing agent and, therefore, it does not comprise any other viscosizing agent. In particular, the ibuprofen oral solution does not comprise povidone.

[0040] The results obtained were unexpected, in view of the teaching of WO2021 / 105524, where only the combination of xanthan gum and povidone provided optimal results for an ibuprofen sodium oral solution.

[0041] Xanthan gum is a well-known pharmaceutical excipient used as thickening agent. Xanthan gum can be described as a high molecular weight polysaccharide gum. It contains D-glucose and D-mannose as the dominant hexose units, along with D-glucuronic acid, and is available as the sodium, potassium, or calcium salt. Xanthan gum is usually obtained by fermentation of carbohydrates using the bacteria Xanthomonas campestris. The main characteristics of xanthan gum are described, for example, in Rowe et al., op.cit.

[0042] Xanthan gum is commercially available from various suppliers, for example, the companies CP Kelco (Keltrol®, Xantural®), DuPont (Grindsted®), or Vanderbilt Minerals (Vanzan®), among many others. Xanthan gum is available in different grades, corresponding to different particle sizes, and all of them are suitable for use in the compositions of the present invention.

[0043] The content of xanthan gum in the ibuprofen oral solution according to the present invention is comprised between 0.05% w / v and 1.5% w / v, preferably comprised between 0.1 % w / v and 1.0% w / v, more preferably comprised between 0.15% w / v and 0.8% w / v, still more preferably comprised between 0.2% w / v and 0.6% w / v, still more preferably comprised between 0.25% w / v and 0.4% w / v, and still more preferably is about 0.3% w / v.

[0044] The viscosity of the ibuprofen oral solution according to the present invention is generally comprised between 50 and 350 mPa s, preferably comprised between 100 and 300 mPa s, more preferably comprised between 150 and 250 mPa s, and still more preferably comprised between 200 and 230 mPa s.

[0045] The viscosity of the solution may be measured according to standard procedures, typically, using a viscometer (or viscosimeter), as are well-known in the art. Typically, a rotary viscometer may be used.

[0046] For example, the rotary Visco Star-L viscometer may be used (JP Selecta S.A., Spain). Another example is the Brookfield viscometer.

[0047] The viscosity can be typically determined according to the method described in Ph. Eur. (2.2.70.), directly on a representative sample of the solution of approximately 20 ml, with a rotary viscometer at a temperature comprised between 22-25°C, with TL7 spindle and a speed of 100 rpm.

[0048] Liquid maltitol

[0049] The ibuprofen oral solution according to the present invention comprises a sugar alcohol, which is liquid maltitol.

[0050] In an embodiment, the ibuprofen oral solution according to the present invention comprises liquid maltitol and does not comprise any other additional sugar alcohol.

[0051] Maltitol is a disaccharide (4-O-a-D-Glucopyranosyl-D-glucitol). Liquid maltitol, also known as maltitol solution, is an aqueous solution consisting predominantly of D-maltitol together with minor amounts of sorbitol and other hydrogenated saccharides. In accordance with the European Pharmacopoeia, liquid maltitol has not less than 68% w / w and not more than 85% w / w of solid matter (anhydrous substance), the content of D-maltitol is > 50% w / w (anhydrous substance) with a 95.0% to 105.0% of the content stated on the label, it contains no more than 8% w / w of sorbitol (anhydrous substance), and it further contains minor amounts of hydrogenated oligo- and polysaccharides. According to the US Pharmacopeia, maltitol solution comprises not less than 50% w / w of D-maltitol on the anhydrous basis, and not more than 8.0% w / w of D-sorbitol.

[0052] Accordingly, as used herein, “liquid maltitol” refers to an aqueous solution of D- maltitol comprising at least 50% w / w of D-maltitol, referred to the total weight of anhydrous matter (dry basis). Typically, the content of D-maltitol is from about 50% w / w to about 60% w / w, or from about 52% w / w to about 58% w / w on dry basis.

[0053] Additionally, typically, liquid maltitol contains no more than 8% w / w of sorbitol, preferably from about 2% w / w to about 7% w / w of sorbitol, and more preferably from about 2% w / w to about 5% w / w of sorbitol, on dry basis.

[0054] Additionally, typically, the total solid matter in liquid maltitol ranges from about 68% w / w to about 85% w / w, preferably from about 70% w / w to about 80% w / w, and the water content is typically in the range 15-32% w / w, preferably in the range 20-30% w / w, referred to the total weight of the solution.

[0055] Liquid maltitol is therefore a commonly used and well-characterized excipient and it is extensively described in authoritative reference works such as the Handbook of Pharmaceutical Excipients op. cit. (under the entry “Maltitol solution”).

[0056] Suitable liquid maltitol, as above defined, meeting the requirements of the European Pharmacopoeia, is commercially widely available, for example, from companies such as Roquette Pharmaceutical or Zhejiang Huakang, among other sources.

[0057] Liquid maltitol is typically produced by hydrogenation of a high-maltose syrup obtained from starch by enzymatic hydrolysis (Handbook of Pharmaceutical Excipients, op. cit.).

[0058] Liquid maltitol is a bulk sweetening agent. It was found that the ibuprofen oral solution according to the present invention, comprising liquid maltitol and xanthan gum, was not only physicochemically stable but also had optimal organoleptic properties, with effective masking of ibuprofen bitter taste.

[0059] The content of liquid maltitol in the composition is comprised between 10% w / v and 50% w / v, preferably comprised between 15% w / v and 40% w / v, more preferably comprised between 20% w / v and 30% w / v, and still more preferably is about 25% w / v.

[0060] Optional components

[0061] The ibuprofen oral solution may comprise one or more of the following additional components. pH regulating agent

[0062] The composition may additionally comprise a pH regulating agent, in order to adjust the pH value of the solution in a suitable pH range. The pH of the composition is generally comprised between 7 and 9, and preferably is comprised between 7.5 and 8.5. The pH regulating agent may comprise an acidic substance such as acetic acid, boric acid, citric acid, hydrochloric acid, fumaric acid, nitric acid, propionic acid, succinic acid, sulfuric acid, or phosphoric acid, for example, and / or an alkaline substance, such as sodium / potassium / ammonium acetate, bicarbonate, borate, carbonate, citrate, phosphate, hydrogen phosphate, hydroxide or propionate, among others; said acidic and alkaline substances are generally used in combination, in the form of buffer systems which are formed, as is well known, of an acid and its conjugate base, for example citrate, acetate, borate, phosphate or carbonate buffers.

[0063] The person skilled in the art will have no difficulty in selecting a suitable pH regulator, and choosing the appropriate amount thereof, to provide the desired pH to the composition.

[0064] The pH regulating agent in the present composition may advantageously comprise a buffering agent. The buffer is, for example, carbonate buffer or phosphate buffer.

[0065] A preferred buffer is a phosphate buffer, more preferably consisting of a mixture of monobasic dihydrogen phosphate and dibasic monohydrogen phosphate.

[0066] These buffers are commercially available or can be readily prepared by one of ordinary skill in the art.

[0067] Preservative

[0068] The composition may comprise a preservative to ensure its protection against microbial contamination. Suitable preservatives are, for example, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, benzoic acid, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, cresol, domiphen bromide, imidurea, phenol, sodium benzoate, sorbic acid, thimerosal, for example, among others.

[0069] The amount of preservative generally depends on the particular preservative used, as is well known in the art, and typically may range from about 0.001% to about 5%, expressed as w / v percentage. The skilled in the art will have no difficulties in selecting the suitable amount in each case, as disclosed in reference books in the field.

[0070] In an embodiment of the invention, the composition comprises a preservative. Preferably, the preservative is selected from butyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and domiphen bromide. In an embodiment, the preservative is domiphen bromide, which is typically used in an amount in the range 0.005-0.5% w / v.

[0071] Sweetening agents Optionally, the composition may comprise a sweetening agent to reinforce the sweetening effect liquid maltitol, particularly an intense sweetening agent may be used. Intense sweetening agents are generally meant those non-nutritive, high-intensity sweeteners, which are generally from about 100 to about 13000 times sweeter than sucrose.

[0072] Suitable intense sweetening agents for use in the present composition are, for example, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, saccharin sodium, sucralose, thaumatin, or mixtures thereof.

[0073] The amount of the sweetening agent may widely vary depending on the sweetening intensity of the agent, but generally is comprised in the range 0.0001% to 0.5% w / v.

[0074] In an embodiment, the composition comprises saccharin sodium, typically in an amount comprised between 0.01% w / v and 0.5% w / v.

[0075] In an embodiment, the composition comprises thaumatin, typically in an amount comprised between 0.0005% w / v and 0.05% w / v, preferably comprised between 0.001% w / v and 0.025% w / v.

[0076] In an embodiment, the composition comprises sucralose, typically in an amount comprised between 0.5% w / v and 3.0% w / v, preferably between 0.5% w / v and 2.5% w / v.

[0077] In an embodiment, the sweetening agent is selected from thaumatin, sucralose and mixtures thereof. In an embodiment, the composition comprises thaumatin and sucralose.

[0078] Flavouring agents

[0079] The composition may optionally also comprise a flavouring agent for providing a pleasant flavour and / or odour to the composition. Suitable flavouring agents include natural and artificial flavours. Natural flavours include natural oils, and extracts from plants, leaves, flowers and fruits. Some suitable flavours are, for example, menthol, cinnamon, clove, anise, eucalyptus, glycyrrhizin or ammonium glycyrrhizate, peppermint, spearmint, thyme, vanilla, chocolate, fruit flavours, such as cherry flavour, grape flavour, orange flavour, banana flavour, strawberry flavour, lemon flavour, apple flavour, peach flavour, raspberry flavour, pineapple flavour and apricot flavour among many others, and combinations thereof.

[0080] The amount of flavouring agent will be easily adjusted by the skilled formulator, depending on the specific flavouring agent and the desired organoleptic effect. Typically, the amount of flavouring agent, if present in the composition, ranges from about 0.001% w / v to about 0.5% w / v, preferably from about 0.005% w / v to about 0.2% w / v. Colouring agent

[0081] The ibuprofen oral solution according to the present invention may also additionally comprise a colouring agent, in order to improve its appearance and make it more organoleptically appealing.

[0082] Any pharmaceutically acceptable natural or artificially synthesized colouring agent may be used, as are well known in the art, for example, those disclosed under the section “Coloring Agents” in the book “Handbook of Pharmaceutical Ingredients” op. cit.

[0083] When a colouring agent is used in the composition, its amount is generally comprised between 0.001% w / v and 0.05% w / v, preferably comprised between 0.001 % w / v and 0.025% w / v.

[0084] Anti-foaming agent

[0085] The ibuprofen oral solution according to the present invention may also additionally comprise an anti-foaming agent in order to reduce or prevent the formation of foam during manufacturing and filling of the product.

[0086] Suitable anti-foaming agents include, for example, propylene glycol, simethicone, dimethicone, or poloxamers. A preferred anti-foaming agent is propylene glycol.

[0087] The anti-foaming agent may be present in the composition in an amount typically ranging from about 0.01% w / v to about 5% w / v, preferably from about 0.1 % w / v to about 4.5% w / w and more preferably from about 1 % w / v to about 4% w / v.

[0088] Ibuprofen arginate oral solution

[0089] The ibuprofen composition according to the present invention is a solution. As is well known for the skilled in the art, a solution may be defined as a mixture of two or more components that form a single phase that is homogeneous down to the molecular level, wherein the component that determines the phase of the solution is the solvent (Aulton et.al., op. cit.).

[0090] The ibuprofen oral solution according to the present invention is an aqueous solution, wherein water is the main solvent, preferably is the sole solvent. In particularly preferred embodiments, the ibuprofen solution according to the present invention does not contain any additional co-solvent, namely, it does not contain any organic solvent. Typically, purified water for pharmaceutical use is used, which is available commercially, commonly obtained by distillation, ion exchange or any other suitable method from drinkable water.

[0091] In an embodiment, the ibuprofen oral solution consists of: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1 ; c) xanthan gum in an amount comprised between 0.05% w / v and 1 .5% w / v; d) liquid maltitol in an amount comprised between 10% w / v and 50% w / v; e) optionally, one or more additional ingredients selected from the group consisting of: a pH regulating agent, a preservative, a sweetening agent, a flavouring agent, a colouring agent, and an anti-foaming agent; and f) water; wherein the characteristics and preferred percentages of each component are as hereinabove described.

[0092] The ibuprofen arginate oral solution can be prepared according to conventional methods, by dissolving the components in purified water, using conventional mixing processes, for example, in a stainless-steel reactor provided with agitation system and, preferably, also with heating jacket.

[0093] The ibuprofen oral solution according to the present invention may be filled in suitable containers, typically, in polyethylene terephthalate (PET) bottles or in glass bottles, provided with a suitable cap, preferably, a children-proof cap, typically of high-density polyethylene (HDPE) with or without a stopper, typically of low-density polyethylene (LDPE). The package typically also includes a measuring device to dispense the required dose of the composition, for example, a graduated cup or oral syringe.

[0094] Alternatively, the composition may be filled into mono-dose sticks, adding a suitable volume to deliver the required dose, for example, volumes typically comprised between about 5 ml and about 15 ml, such as 5 ml, 7.5 ml, 10 ml, 12.5 ml or 15 ml may be used. Other volumes may also be suitable, depending on the desired dose and the concentration of the composition. Preferred unit doses of ibuprofen are 200 mg, 400 mg or 600 mg.

[0095] Suitable sachets / sticks for liquid compositions may be made, for example, of laminated materials, for example, Polyester / Aluminium / Polyester / Polyethylene (PET / Alu / PET / PE). The composition according to the present invention has optimal organoleptic properties, so the bitter taste of ibuprofen as well as the burning sensation commonly associated to ibuprofen are completely masked. Therefore, the good palatability of this formulation is remarkable.

[0096] Additionally, as disclosed in Example 3, the stability tests performed confirm that the composition according to the present invention is outstandingly stable, both chemically and physically. The ibuprofen oral solution according to the present invention has optimal viscosity, is transparent and remains stable, without any precipitation, crystallization or aggregate formation and without changes in the viscosity. This is important to ensure that a correct dose of the active substances is administered along the whole shelf-life of the medicinal product.

[0097] Furthermore, as shown in Example 2 and in Figure 1 , the ibuprofen arginate oral solution according to the present invention, provides a solubility profile which is analogous to that of the commercial Espidifen® granules for oral solution, despite their different dosage forms. This in vitro comparative dissolution assay is predictive of in vivo bioequivalence. Therefore, the present invention is capable of providing the same therapeutic effects as Espidifen®, but in a more convenient and advantageous dosage form.

[0098] Indeed, the availability of ibuprofen arginate in the form of an oral solution has several advantages over the granulate form for oral solution.

[0099] On the one hand, it allows for better customizing the drug dose to the specific requirements, based on measuring the volume of the solution to be administered, using a simple and accurate measuring device, such as a syringe or a graduated cup, for example.

[0100] Additionally, the mono-dose sticks allow for the convenient and quick administration of a given dose.

[0101] In both cases, furthermore, the ibuprofen oral solution according to the present invention avoids the need of previously dissolving the granules in an important volume of external water for preparing the solution and, therefore, the volume of liquid medicine to be ingested is drastically reduced, which is an important advantage, particularly for the paediatric patient and elderly people with swallowing difficulties.

[0102] Additionally, the oral solution of the invention is even safer than the granulate for solution due to the fact that the water used in the oral solution is purified water, microbiologically tested, while in the granulate it is the patient who needs to add noncontrolled water for solubilizing it, therefore raising a possible health risk. The viscosity of the present composition, based on the sole use of xanthan gum, proves to be optimal for both delivery types, either from an oral dose syringe or from monodose sticks.

[0103] Additionally, as shown in Example 4, other single viscosizing agents failed to achieve all the advantages shown in the present invention.

[0104] Another aspect of the invention is the ibuprofen arginate oral solution according to the present invention for use in therapy.

[0105] The ibuprofen oral solution according to the present invention is suitable for the treatment of any disease or medical condition susceptible to be treated with ibuprofen, particularly those involving pain, fever and / or inflammation. The patients susceptible to being treated with the ibuprofen oral solution of the invention are all those suffering from pain, fever and / or inflammation, of all ages, including elderly people, adults and paediatric patients.

[0106] In the context of the present invention, the paediatric patient includes children from approximately 3 months to 12 years of age. Adults include adolescents from 12 years and beyond.

[0107] Therefore, another aspect of the invention is the composition of the invention for use for the treatment of pain, inflammation and / or fever.

[0108] Or, alternatively, another aspect of the invention is the use of the composition of the invention for the preparation of a medicament for the treatment of pain, inflammation and / or fever.

[0109] Or, alternatively, another aspect of the invention is a method of treating pain, inflammation and / or fever in a patient in need thereof, comprising the administration of a therapeutically effective amount of the ibuprofen oral solution according to the invention.

[0110] The recommended dose of ibuprofen to be administered may vary depending on the specific indication and the severity of the condition as well as depending on age and body weight, in case of paediatric patients, as is well-known in the art.

[0111] Therefore, the skilled practitioner will have no difficulty in prescribing the most suitable dose in each case. Thus, for example, for paediatric patients the recommended daily dose of ibuprofen generally ranges from about 20 mg to about 30 mg per kg of body weight, divided into three or four individual doses. For adults, suitable doses are, for example, between about 600 mg and about 1800 mg per day, divided into three or four individual doses. Single doses of ibuprofen are generally of about 200 mg, 400 mg or 600 mg. The present invention may be defined by the following embodiments:

[0112] 1.- Ibuprofen oral solution comprising: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1 ; c) a viscosizing agent consisting of xanthan gum in an amount comprised between 0.05% w / v and 1.5% w / v; d) a sugar alcohol consisting of liquid maltitol in an amount comprised between 10% w / v and 50% w / v; and e) a solvent consisting of water.

[0113] 2.- Ibuprofen oral solution according to embodiment 1 , wherein the solution consists of: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1 ; c) xanthan gum in an amount comprised between 0.05% w / v and 1 .5% w / v; d) liquid maltitol in an amount comprised between 10% w / v and 50% w / v; e) optionally, one or more additional ingredients selected from the group consisting of: a pH regulating agent, a preservative, a sweetening agent, a flavouring agent, a colouring agent and an anti-foaming agent; and f) water.

[0114] 3.- Ibuprofen oral solution according to embodiments 1 or 2, wherein the amount of ibuprofen is comprised between 2.5% w / v and 5.5% w / v, preferably between 3.0% w / v and 5.0% w / v, more preferably between 3.5% w / v and 4.5% w / v, still more preferably between 3.7% w / v and 4.3% w / v, and still more preferably is about 4.0% w / v.

[0115] 4.- Ibuprofen oral solution according to any one of embodiments 1 to 3, wherein the molar ratio ibuprofen:arginine is comprised between 0.75:1 and 1.2:1 , preferably between 0.8:1 and 1.1 :1 , more preferably between 0.85:1 and 1 :1 , and still more preferably is about 0.9:1.

[0116] 5.- Ibuprofen oral solution according to any one of embodiments 1 to 4, wherein the amount of xanthan gum is comprised between 0.1 % w / v and 1.0% w / v, preferably between 0.15% w / v and 0.8% w / v, more preferably between 0.2% w / v and 0.6% w / v, still more preferably between 0.25% w / v and 0.4% w / v, and still more preferably is about 0.3% w / v.

[0117] 6.- Ibuprofen oral solution according to any one of embodiments 1 to 5, wherein the viscosity of the solution is comprised between 50 mPa-s and 350 mPa s, preferably comprised between 100 mPa s and 300 mPa s, more preferably comprised between 150 mPa s and 250 mPa s, and still more preferably comprised between 200 mPa s and 230 mPa s, wherein the viscosity is measured with a rotary viscometer at a temperature comprised between 22-25°C, preferably with TL7 spindle and a speed of 100 rpm.

[0118] 7.- Ibuprofen oral solution according to any one of embodiments 1 to 6, wherein the amount of liquid maltitol is comprised between 15% w / v and 40% w / v, preferably between 20% w / v and 30% w / v, and more preferably is about 25% w / v.

[0119] 8.- Ibuprofen oral solution according to any one of embodiments 1 to 7, wherein the solution also comprises a pH regulating agent to adjust the pH to a value comprised between 7 and

[0120] 9. preferably comprised between 7.5 and 8.5.

[0121] 9.- Ibuprofen oral solution according to embodiment 8, wherein the oral solution comprises a phosphate buffer.

[0122] 10.- Ibuprofen oral solution according to embodiments 8 or 9, wherein the oral solution comprises mixture of monobasic dihydrogen phosphate and dibasic monohydrogen phosphate.

[0123] 11.- Ibuprofen oral solution according to any one of embodiments 1 to 10, wherein the oral solution also comprises a preservative.

[0124] 12.- Ibuprofen oral solution according to embodiment 11 , wherein the preservative is selected from butyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and domiphen bromide, and preferably is domiphen bromide.

[0125] 13.- Ibuprofen oral solution according to any one of embodiments 1 to 12, wherein the oral solution also comprises a sweetening agent. 14.- Ibuprofen oral solution according to embodiment 13, wherein the sweetener is selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, saccharin sodium, sucralose, thaumatin, and mixtures thereof.

[0126] 15.- Ibuprofen oral solution according to embodiment 14, wherein the sweetener is selected from thaumatin, sucralose and mixtures thereof, preferably the sweetener is a mixture of thaumatin and sucralose.

[0127] 16.- Ibuprofen oral solution according to any one of embodiments 1 to 15, wherein the oral solution also comprises a flavouring agent.

[0128] 17.- Ibuprofen oral solution according to any one of embodiments 1 to 16, wherein the oral solution also comprises a colouring agent.

[0129] 18.- Ibuprofen oral solution according to any one of embodiments 1 to 17, wherein the oral solution also comprises an anti-foaming agent.

[0130] 19.- Ibuprofen oral solution according to embodiment 19, wherein the anti-foaming agent is selected from the group consisting of propylene glycol, simethicone, dimethicone, poloxamers, and mixtures thereof, and preferably is propylene glycol.

[0131] 20.- Ibuprofen oral solution according to any one of embodiments 1 to 17 for use in therapy.

[0132] 21 .- Ibuprofen oral solution for use according to embodiment 18, wherein it is for use for the treatment of pain, inflammation and / or fever.

[0133] The present invention can be further defined by the following embodiments:

[0134] 1.- Ibuprofen oral solution comprising: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofen:arginine comprised between 0.7:1 and 1.3:1 ; c) a viscosizing agent consisting of xanthan gum in an amount comprised between 0.05% w / v and 1.5% w / v; d) a sugar alcohol consisting of liquid maltitol in an amount comprised between 10% w / v and 50% w / v; and e) a solvent consisting of water.

[0135] 2.- Ibuprofen oral solution according to embodiment 1 , wherein the solution consists of: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofen:arginine comprised between 0.7:1 and 1.3:1 ; c) xanthan gum in an amount comprised between 0.05% w / v and 1 .5% w / v; d) liquid maltitol in an amount comprised between 10% w / v and 50% w / v; e) optionally, one or more additional ingredients selected from the group consisting of: a pH regulating agent, a preservative, a sweetening agent, a flavouring agent and a colouring agent; and f) water.

[0136] 3.- Ibuprofen oral solution according to embodiments 1 or 2, wherein the amount of ibuprofen is comprised between 2.5% w / v and 5.5% w / v, preferably between 3.0% w / v and 5.0% w / v, more preferably between 3.5% w / v and 4.5% w / v, still more preferably between 3.7% w / v and 4.3% w / v, and still more preferably is about 4.0% w / v.

[0137] 4.- Ibuprofen oral solution according to any one of embodiments 1 to 3, wherein the molar ratio ibuprofen:arginine is comprised between 0.75:1 and 1.2:1 , preferably between 0.8:1 and 1.1 :1 , more preferably between 0.85:1 and 1 :1 , and still more preferably is about 0.9:1.

[0138] 5.- Ibuprofen oral solution according to any one of embodiments 1 to 4, wherein the amount of xanthan gum is comprised between 0.1 % w / v and 1.0% w / v, preferably between 0.15% w / v and 0.8% w / v, more preferably between 0.2% w / v and 0.6% w / v, still more preferably between 0.25% w / v and 0.4% w / v, and still more preferably is about 0.3% w / v.

[0139] 6.- Ibuprofen oral solution according to any one of embodiments 1 to 5, wherein the viscosity of the solution is comprised between 50 cPs and 350 cPs, preferably comprised between 100 cPs and 300 cPs, more preferably comprised between 150 cPs and 250 cPs, and still more preferably comprised between 200 cPs and 230 cPs.

[0140] 7.- Ibuprofen oral solution according to any one of embodiments 1 to 6, wherein the amount of liquid maltitol is comprised between 15% w / v and 40% w / v, preferably between 20% w / v and 30% w / v, and more preferably is about 25% w / v.

[0141] 8.- Ibuprofen oral solution according to any one of embodiments 1 to 7, wherein the solution also comprises a pH regulating agent to adjust the pH to a value comprised between 7 and

[0142] 9. preferably comprised between 7.5 and 8.5.

[0143] 9.- Ibuprofen oral solution according to embodiment 8, wherein the oral solution comprises a phosphate buffer.

[0144] 10.- Ibuprofen oral solution according to any one of embodiments 1 to 9, wherein the oral solution also comprises a preservative selected from butyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and domiphen bromide, and preferably is domiphen bromide.

[0145] 11.- Ibuprofen oral solution according to any one of embodiments 1 to 10, wherein the oral solution also comprises a sweetening agent selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, saccharin sodium, sucralose, thaumatin, and mixtures thereof.

[0146] 12.- Ibuprofen oral solution according to embodiment 11 , wherein the sweetener is selected from thaumatin, sucralose and mixtures thereof, preferably the sweetener is a mixture of thaumatin and sucralose.

[0147] 13.- Ibuprofen oral solution according to any one of embodiments 1 to 12, wherein the oral solution also comprises a flavouring agent.

[0148] 14.- Ibuprofen oral solution according to any one of embodiments 1 to 13 for use in therapy.

[0149] 15.- Ibuprofen oral solution for use according to embodiment 14, wherein it is for use for the treatment of pain, inflammation and / or fever. Examples

[0150] Example 1 : Ibuprofen arqinate oral solution according to the invention

[0151] A 4% ibuprofen solution according to the present invention was prepared using the ingredients listed in the following table:

[0152] All ingredients were dissolved in purified water, in a stainless-steel reactor equipped with agitation system and heating jacket, to obtain a clear orange solution. The pH of the final product was about 8.0.

[0153] The obtained ibuprofen arginate solution was filled into PET amber bottles of 150 ml provided with a LDPE stopper and closed with a HDPE child-resistant screw cap, equipped with oral syringe for dosing.

[0154] Example 2: Comparative dissolution assay of the product of the invention vs. Espidifen® 400 granules for oral solution.

[0155] Comparative dissolution assays were performed for the ibuprofen arginate oral solution according to the invention, compared to Espidifen® 400 mg granules for oral solution. According to the official Summary of Product Characteristics published by the Agenda Espanola de Medicamentos y Productos Sanitarios (AEMPS), this product contains, in addition to the active ingredient, the following excipients: L-arginine, sodium saccharin, aspartame (E951), sucrose, sodium hydrogen carbonate, mint flavour, and aniseed flavour containing butylhydroxyanisole (E-320). The product should be administered by dissolving the contents of a sachet in a glass of water and ingesting the resulting solution immediately after preparation.

[0156] 10 ml of the product of Example 1 were compared to one dose of Espidifen®400 mg. The product of the invention was placed in a vessel and, for each assay, 900 ml of dissolution medium was used. For the reference, the content of a sachet, previously dissolved in 150 ml of water, was added to the vessel with 750 ml of dissolution medium. Both according to in-use instructions.

[0157] The dissolution assays were performed with 3 different dissolution media (at pH values of 1.2, 4.5 and 6.8) and, for each media, the assay was repeated 12 times, i.e. , in 12 different vessels, and the average of the 12 measures was calculated for each time point. Samples were taken at the following time points: 0, 5, 10 15, 20, 30 and 45 minutes.

[0158] The dissolution media were prepared using purified water and adjusting the pH to the following values 1.2, 4.5 and 6.8, using HCI (pH 1.2) or phosphate buffer (pHs 4.5 and 6.8), for example, as disclosed in in the European Pharmacopoeia 6.0 (Eur. Phar. 6.0), Chapter 2.9.3: Dissolution Test for Solid Dosage Forms. The dissolution assays were performed with stirring at 50 rpm with Eur. Ph. Apparatus II at 37°C ± 0.5°C.

[0159] The amount of ibuprofen dissolved in each sample was analysed using HPLC, using the equipment and conditions as disclosed below:

[0160] Column Sunfire C18, dimensions 150 x 4.6 mm, 5 pm,

[0161] Waters

[0162] Temperature 25 °C Mobile phase flow 2.0 ml / minute Detection UV absorption - = 235 nm

[0163] Injection volume 10 pl

[0164] Duration of the chromatogram 8 minutes

[0165] Mobile phase (A / B) 40:60

[0166] A: 40%: HPLC grade water adjusting to pH 2.5 with orthophosphoric acid at 85%

[0167] B: 60%: HPLC grade acetonitrile

[0168] The percentage of ibuprofen dissolved at each time point, at the three pH conditions is summarized in the following table:

[0169] These profiles are represented in Figure 1. The y-axis represents the percentage of ibuprofen dissolved and the x-axis represents the time.

[0170] For quantitatively comparing the dissolution similarity between the reference compound (Espidifen® 400 granules for oral solution) and the ibuprofen solution according to the present invention, the similarity factor f2, was used, as disclosed in Moore et al., Mathematical comparison of curves with an emphasis on in vitro dissolution profiles, Pharm. Tech., 1996, 20(6), 64-74 or in Helmy et al., In vitro dissolution similarity as a surrogate for in vivo bioavailability and therapeutic equivalence, Dissolution Technologies, August 2016, 32-39, and in the Guideline on the investigation of bioequivalence CM PM / EWP / QWP / 1401 / 98 Rev. 1.

[0171] As is well known in the art, the factor f2is a measure of the similarity between the dissolution curves obtained from the test and reference products. This factor is calculated from the mean of the dissolution profiles at each of the sampling times using the following equation: where:

[0172] • n = number of sampling times

[0173] • Rt = average percentage dissolved at time t of the reference drug

[0174] • Pt = average percentage dissolved at time t of the test drug

[0175] Those points where the percentage of dissolved drug exceeds 85% are not taken into account for f2calculation. The comparison was performed for each sample vs. the reference compound at each pH value (1.2, 4.5 and 6.8)

[0176] The value of f2varies from 0 to 100. If the value is equal to or greater than 50, the product is considered to meet the similarity factor in relation to the reference product.

[0177] The following table summarizes the value of the similarity factor f2at the different pH values:

[0178] (*) Some dissolution mean values at pH=1.2 had a coefficient of variation higher than that required in the “Guideline on the investigation of bioequivalence”. Therefore, the Bootstrap similarity factor f2has also been carried out, with the following result: mean 63.9 with lower and upper confidence interval for expected f2of 63.3 and 64.5, respectively.

[0179] So, it can be observed that the value of the similarity factor f2is more than 50 for all pH conditions assayed.

[0180] Example 3: Stability data

[0181] The product of Example 1 , stored in 150 ml PET amber bottles provided with a LDPE stopper and closed with a HDPE child-resistant screw cap, was tested for stability according to ICH Guidelines. Data are available up to 12 months, with sampling at 0, 3, 6, 9 and 12 months under 25 °C ± 2°C / RH, 60% ± 5% and 30 °C ± 2 °C / RH 65% ± 5%, and, at 0, 3 and 6 months also under 40 °C ± 2 °C / RH 75% ± 5% conditions.

[0182] The following parameters were tested: appearance (description, clarity and colour of the solution), pH, viscosity, uniformity of mass of delivered doses from multidose containers (oral syringe), assay of ibuprofen (HPLC), assay of arginine (HPLC), assay of domiphen bromide (HPLC), related substances of ibuprofen (HPLC) and microbiological quality.

[0183] The results obtained are compliant for all the assessed parameters, with no relevant changes in the appearance, pH or viscosity of the solution, or for the assayed substances. The analysis of impurities related to ibuprofen showed very low levels of all impurities with no reportable amounts in all conditions (<0.0.05%).

[0184] The stability of the product is confirmed for all conditions. Example 4: Comparative examples

[0185] Comparative ibuprofen solutions were prepared using the composition of Example 1 , but substituting xanthan gum with alternative viscosizing agents, namely with maize starch, carrageenan and hypromellose (HPMC). Each viscosizing agent was tested at the minimum and maximum proportions recommended for every substance, as disclosed in the following table: The characteristics observed for the obtained formulations are summarized in the following table:

[0186] The solutions prepared with maize starch and with carrageenan were physically unstable, showing visible sedimentation, such that homogeneous solutions could not be obtained with these substances. In addition, the viscosity of the resulting compositions was below the level required for acceptable performance.

[0187] The solutions prepared with HPMC were initially physically stable and exhibited suitable viscosity. However, in stability studies performed at 40 °C ± 2 °C and 75% ± 5% RH, whitish thread-like precipitates were observed after 1 month, which are believed to result from a chemical incompatibility of HPMC with certain ingredients of the composition.

[0188] Nevertheless, comparative dissolution assays were also performed with the solutions prepared with HPMC (Examples 3A and 3B) in comparison with Espidifen® 400 mg granules for oral solution, using the same procedure and comparison criteria described in Example 2.

[0189] The following tables summarize the value of the similarity factor R values obtained for the comparison of 3A and 3B with Espidifen®, at different pH values:

[0190] It is observed that the compositions prepared with HPMC do not meet the similarity criteria, because f2is less than 50 relative to the reference product at pH 1 .2 and at pH 4.5.

Claims

- 26 -CLAIMS1.- Ibuprofen oral solution comprising: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1 ; c) a viscosizing agent consisting of xanthan gum in an amount comprised between 0.05% w / v and 1.5% w / v; d) a sugar alcohol consisting of liquid maltitol in an amount comprised between 10% w / v and 50% w / v; and e) a solvent consisting of water.2.- Ibuprofen oral solution according to claim 1 , wherein the solution consists of: a) ibuprofen in an amount comprised between 2.0% w / v and 6.0% w / v; b) arginine in an amount corresponding to a molar ratio ibuprofemarginine comprised between 0.7:1 and 1.3:1 ; c) xanthan gum in an amount comprised between 0.05% w / v and 1 .5% w / v; d) liquid maltitol in an amount comprised between 10% w / v and 50% w / v; e) optionally, one or more additional ingredients selected from the group consisting of: a pH regulating agent, a preservative, a sweetening agent, a flavouring agent, a colouring agent and an anti-foaming agent; and f) water.3.- Ibuprofen oral solution according to claims 1 or 2, wherein the amount of ibuprofen is comprised between 2.5% w / v and 5.5% w / v, preferably between 3.0% w / v and 5.0% w / v, more preferably between 3.5% w / v and 4.5% w / v, still more preferably between 3.7% w / v and 4.3% w / v, and still more preferably is about 4.0% w / v.4.- Ibuprofen oral solution according to any one of claims 1 to 3, wherein the molar ratio ibuprofemarginine is comprised between 0.75:1 and 1.2:1 , preferably between 0.8:1 and 1.1 :1 , more preferably between 0.85:1 and 1 :1 , and still more preferably is about 0.9:1.5.- Ibuprofen oral solution according to any one of claims 1 to 4, wherein the amount of xanthan gum is comprised between 0.1% w / v and 1.0% w / v, preferably between 0.15% w / vand 0.8% w / v, more preferably between 0.2% w / v and 0.6% w / v, still more preferably between 0.25% w / v and 0.4% w / v, and still more preferably is about 0.3% w / v.6.- Ibuprofen oral solution according to any one of claims 1 to 5, wherein the viscosity of the solution is comprised between 50 mPa-s and 350 mPa s, preferably comprised between 100 mPa s and 300 mPa s, more preferably comprised between 150 mPa s and 250 mPa s, and still more preferably comprised between 200 mPa s and 230 mPa s, wherein the viscosity is measured with a rotary viscometer at a temperature comprised between 22°C and 25°C.7.- Ibuprofen oral solution according to any one of claims 1 to 6, wherein the amount of liquid maltitol is comprised between 15% w / v and 40% w / v, preferably between 20% w / v and 30% w / v, and more preferably is about 25% w / v.8.- Ibuprofen oral solution according to any one of claims 1 to 7, wherein the solution also comprises a pH regulating agent to adjust the pH to a value comprised between 7 and 9, preferably comprised between 7.5 and 8.5.9.- Ibuprofen oral solution according to claim 8, wherein the oral solution comprises a phosphate buffer.10.- Ibuprofen oral solution according to any one of claims 1 to 9, wherein the oral solution also comprises a preservative selected from butyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and domiphen bromide, and preferably is domiphen bromide.11.- Ibuprofen oral solution according to any one of claims 1 to 10, wherein the oral solution also comprises a sweetening agent selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, saccharin sodium, sucralose, thaumatin, and mixtures thereof.12.- Ibuprofen oral solution according to claim 11 , wherein the sweetener is selected from thaumatin, sucralose and mixtures thereof, preferably the sweetener is a mixture of thaumatin and sucralose.13.- Ibuprofen oral solution according to any one of claims 1 to 12, wherein the oral solution also comprises a flavouring agent.14.- Ibuprofen oral solution according to any one of claims 1 to 13, wherein the oral solution also comprises an anti-foaming agent, preferably selected from the group consisting of propylene glycol, simethicone, dimethicone, poloxamers, and mixtures thereof.15.- Ibuprofen oral solution according to any one of claims 1 to 14 for use in therapy, preferably for the treatment of pain, inflammation and / or fever.

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