ES2775648A1 - Pharmaceutical composition in the form of an oral solution of ibuprofen salt with lysine (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

The present invention relates to a pharmaceutical composition in the form of an oral solution of the ibuprofen salt with lysine, which comprises a viscosifying system comprising the combination of xanthan gum and a second agent chosen from povidone, hypromellose and carbomers, together with a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, as cosolvents. The combination of these excipients allows obtaining a liquid composition of the ibuprofen salt with lysine of great stability and good organoleptic characteristics. The invention also relates to the use of said composition for the treatment of pain, inflammation and/or fever, particularly in the pediatric patient. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

PHARMACEUTICAL COMPOSITION OF IBUPROFEN SALT WITH LYSINE IN THE FORM OF AN ORAL SOLUTION

Technical field

The present invention relates to a pharmaceutical composition of ibuprofen salt with Usine in the form of an aqueous solution for oral administration, which is remarkably stable and particularly suitable for pediatric administration.

Prior state of the art

Ibuprofen is a drug belonging to the group of non-steroidal anti-inflammatory drugs, commonly called NSAIDs, specifically to the family of propionic acid derivatives. It is a non-selective inhibitor of cyclooxygenase 1 (COX-1) and clclooxygenase 2 (COX-2) that has analgesic, anti-pyretic and anti-inflammatory activity.

Ibuprofen is the most commonly used NSAID and the most frequently prescribed worldwide. Chemically, the ibuprofen molecule is a relatively weak acid, with a pKa value of 5.3, and is practically insoluble in water.

There is a direct correlation between the plasma levels of ibuprofen and its analgesic activity, as well as between the speed of absorption after oral administration and the triggering of its therapeutic effects.

Although the bioavailability of ibuprofen is high, its low solubility determines that the drug reaches the bloodstream relatively slowly, which also means that its therapeutic effects do not manifest immediately, but do not begin to be observed until after 45 minutes and one hour after oral administration of the dose.

An alternative to achieve a faster therapeutic effect is to use ibuprofen salts, in particular the salt with lysine (or ibuprofen lysine) which provides a faster absorption than ibuprofen in the free acid form, as described, for example, in the articles Geisslinger et al., Therapeutically relevant differences in the pharmacokinetical and pharmaceutical behavior of ibuprofen lysinate as compared to ibuprofen acid., Int. J. Clin. Pharmacol. Ther. Toxlcol., 1989, 27 (7), 324-8, and Portolés et al., Comparative single-dose bioavailability study of two oral formulations of ibuprofen in healthy volunteers, Clin. Drug Invest., 2001, 21 (5), 383-389.

Therefore, ibuprofen formulations in the form of its salt with lysine are especially advantageous in providing rapid pain relief.

Ibuprofen is also widely used in pediatrics for the treatment of pain, inflammation and / or fever in children, generally as early as 3 months of age. In the context of pediatric administration, liquid formulations are particularly preferred, since they allow the dose to be adjusted more precisely according to the weight of each child and, furthermore, they are more convenient from the organoleptic point of view. In this framework, therefore, it is desirable to have liquid ibuprofen lysine compositions in order to provide rapid relief from pain, fever and inflammation in the pediatric patient.

However, the preparation of liquid compositions with ibuprofen salts, particularly with the ibuprofen salt with lysine, is not trivial.

A first challenge is to mask the characteristic bitter taste of lysine ibuprofen, whose organoleptic characteristics are more unpleasant than those of acidic ibuprofen. In the state of the art, this problem has been solved for liquid compositions of acid ibuprofen by preparing formulations in suspension form, taking advantage of the low solubility in water of the drug in acid form and its practically total insolubility at pH values below 4; in this way its bitter effect is diminished as it is in undissociated form.

This strategy, however, is not applicable for the formulation of aqueous compositions of the ibuprofen salt with lysine, since it is a water-soluble salt, which is administered in a totally dissociated form and, therefore, inevitably manifests its flavor. bitter.

On the other hand, although the ibuprofen salt with lysine is soluble in water, it is not trivial to obtain liquid compositions with said product that remain perfectly stable physically and chemically over time, for example, without the appearance of aggregates or precipitates from the beginning. active, particularly for relatively high concentrations of the drug.

It is also complex to obtain a liquid formulation with the ibuprofen salt with lysine whose physical properties, in terms of uniformity, transparency and viscosity, for example, are optimal and that allow a sufficiently wide range of concentrations of the active ingredient to be available, which facilitates an adequate dosage thereof.

In the European patent application EP-A-2253329 liquid compositions of buprofen lysin are described in oral suspension form that are prepared according to a process that comprises the previous encapsulation of said salt in cyclodextrins, by means of sieving and ultra-rapid mixing of ibuprofen lysine and the cyclodextrins, and the subsequent incorporation of this complex into a suspension prepared with a colloidal agent, generally a combination of microcrystalline cellulose and sodium carboxymethylcellulose, in water or in propylene glycol. The compositions described contain a proportion of lysine ibuprofen between 3 and 5%.

The need therefore persists for alternative liquid formulations of ibuprofen salt with lysine, which are easy to prepare, which are stable and have adequate physico-chemical characteristics, which allow to efficiently mask the bitter taste of this drug and which allow to have relatively high concentrations of the active principle.

Object of the invention

The object of the present invention is a composition of the ibuprofen salt with lysine in the form of an aqueous solution.

Another aspect of the invention is the use of said composition for the preparation of a medicament for the treatment of pain, inflammation and fever, or alternatively, the composition for use in treating pain, inflammation and / or fever, or alternatively, a method for the treatment of pain, inflammation and / or fever comprising the administration of said composition.

Detailed description of the invention

The object of the present invention is an aqueous pharmaceutical composition for oral administration characterized in that it comprises:

- salt of ibuprofen with lysine in a proportion comprised between 1% (w / v) and 30% (w / v), expressed as an equivalent percentage of buprofen in acid form;

- a viscosizing system comprising xanthan gum and a second agent chosen from the group consisting of povidone, hypromellose and carbomers; - a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, in a proportion between 1% (w / v) and 10% (w / v); and

- a pH regulating agent to adjust the pH of the composition to a value between 5.5 and 8.

The authors of the present invention have developed a pharmaceutical composition of the ibuprofen salt with lysine for oral use, in the form of an aqueous solution that has optimal physicochemical characteristics and excellent stability, as well as good organoleptic characteristics. The present inventors found that, surprisingly, the combination of xanthan gum and a second viscosifying agent chosen from among povidone, hypromellose and carbomers gave the composition improved properties, simultaneously providing good viscosity and completely inhibiting the formation of crystals in the solution, thus obtaining a stable composition with good organoleptic properties.

This composition makes it possible to have, by means of a simple formulation, liquid compositions of the ibuprofen salt with lysine of very different concentrations, up to 30% (expressed as an equivalent concentration of acid ibuprofen, which represents a real concentration of up to 51% of ibuprofen salt with lysine), without any impairment of its stability.

Said compositions, therefore, are particularly suitable for use in pediatrics, since they contain the active ingredient in the ideal proportions to facilitate correct administration in children and with excellent organoleptic qualities for acceptance by the pediatric patient.

This invention provides an effective therapeutic tool for the treatment of pain, inflammation and / or fever, especially in the pediatric patient, capable of providing a rapid therapeutic effect.

Definitions

Throughout the present description, unless expressly indicated otherwise, the proportions of the components of the composition of the invention are expressed as percentages by weight / volume (w / v), that is, expressed as grams of each component for every 100 mL of composition.

Throughout the present description, any numerical figure preceded by the term "approximately" indicates that said figure also includes a variation of ± 5% from the indicated value.

Throughout the present description, as well as in the claims, expressions in the singular, usually preceded by the articles "a", "an", "the" or "the" also implicitly include the reference to the plural, unless the context clearly indicates otherwise.

Ibuprofen salt with lysine

The ibuprofen salt with lysine (CAS number 57469-77-9) is also commonly called ibuprofen lysine, ibuprofen lysinate or ibuprofen lysinate, and corresponds to the ibuprofen salt with lysine with a 1: 1 molar ratio between the two, and their empirical formula is Ci ⁹ H ³² N2 ⁰ 4.

For its part, ibuprofen is the International Common Denomination (INN) by which (R, S) -2- (4-isobutylphenyl) propionic acid is commonly known. In the context of the present invention, the lysine salt of ibuprofen includes ibuprofen in its racemic form ((RS) -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, the lysine salt of ibuprofen comprises ibuprofen which is selected from (RS) -ibuprofen and (S) -ibuprofen. Most preferably the salt of (RS) -ibuprofen is used.

For its part, lysine is an a-amino acid found in nature in its L-enantiomeric form. In the context of this invention, the lysine salt of ibuprofen includes lysine in any of its enantiomeric forms: L-lysine, D- lysine and its mixtures. Preferably the lysine is in the form of L-lysine.

Thus, within the scope of the present invention, the ibuprofen salt with lysine includes the combination of the possible enantiomeric forms and their mixtures for each of its two components. In a particularly preferred embodiment of the invention, the salt of ibuprofen with lysine refers to the salt of (R, S) -ibuprofen with L-lysine. In another also preferred embodiment, the lysine salt of ibuprofen refers to the (S) -ibuprofen with L-lysine salt.

On the other hand, the name ibuprofen salt with lysine also includes the possible solvated forms of this salt, including hydrated forms, and particularly the monohydrate.

Ibuprofen constitutes the active ingredient of the composition, that is, the one responsible for its pharmacological effect, and that is why throughout the present description the content of the ibuprofen salt with lysine of the compositions is usually expressed as the content ibuprofen equivalent in form of free acid. The person skilled in the art will have no difficulty in converting the values appropriately, based on the molecular weights of said substances. Thus, for example, a solution of the ibuprofen salt with lysine of 2% (w / v) expressed as an equivalent proportion of ibuprofen in the free acid form, would correspond to a real concentration of 3.4% (w / v) of ibuprofen lysine.

The ibuprofen salt with lysine is commercially available, or it can be prepared by methods well known to those skilled in the art, for example, as described in patent GB1497044.

Alternatively, the ibuprofen and lysine salt could be formed in situ by separately adding ibuprofen in its acid form and the amino acid lysine to the composition, in an approximately 1: 1 molar ratio.

The ibuprofen salt with lysine in the composition of the invention is in a proportion comprised between 1% (w / v) and 30% (w / v), where the percentages are expressed as equivalent percentage of ibuprofen in acid form.

In one embodiment of the invention, the ibuprofen salt with lysine is in a proportion between 1% (w / v) and 10% (w / v), more preferably between 1% (w / v) and 6% ( w / v), expressed as an equivalent percentage of ibuprofen in acid form.

In another embodiment of the invention, the ibuprofen salt with lysine is in a proportion between 10% (w / v) and 30% (w / v), more preferably between 10% (w / v) and 20% ( w / v), expressed as an equivalent percentage of ibuprofen in acid form.

In a preferred embodiment of the invention, the ibuprofen salt with lysine is in a proportion between 1% (w / v) and 3% (w / v), preferably between 1.5% (w / v) and 2 , 5% (w / v), and more preferably about 2% (w / v), expressed as an equivalent percentage of ibuprofen in acid form.

In another preferred embodiment of the invention, the ibuprofen salt with lysine is in a proportion between 3% (w / v) and 6% (w / v), preferably between 3.5% (w / v) and 5 % (w / v), and more preferably about 4% (w / v), expressed as an equivalent percentage of ibuprofen in acid form.

Viscosizing system

The composition according to the present invention comprises a viscosifying system comprising xanthan gum and a second viscosifying agent selected from the group consisting of povidone, hypromellose and carbomers.

The authors of the present invention have found that, surprisingly, the combination of both viscosifying agents confers optimum properties to the composition, especially good uniformity, viscosity and stability, without observing the formation of agglomerates, crystals or precipitates.

In a particularly preferred embodiment of the invention the viscosizing system comprises xanthan gum and povidone. With this particular combination of viscosifiers, the composition obtained is a totally limpid and transparent solution, and it remains stable in this same way over time.

Thus, as shown in Table 4 of Example 4, if no viscosizing agent is added, the solutions obtained not only lack the desirable viscosity for an oral liquid formulation, but are unstable and give rise to aggregates of the active principle. , which are macroscopically visible. On the other hand, if only xanthan gum is added, the composition acquires a suitable viscosity, but remains unstable, since the formation of elongated, needle-shaped crystals is observed in the solution, which are visible to the naked eye. If only povidone is used, no precipitates or agglomerates appear, but the solution has insufficient viscosity. Only when both viscosifiers are used at the same time is a clear solution with good viscosity, stable over time, obtained.

In another embodiment of the invention, the viscosizing system comprises xanthan gum and hypromellose.

In another embodiment of the invention, the viscosifying system comprises xanthan gum and carbomer.

When the second viscosifier is hypromellose or carbomer, the composition obtained is a colloidal solution, opaque whitish in color, with a particle size less than one micron. As described in Example 4, said formulations in the form of a colloidal solution also constitute a stable composition, since the formation of crystals, agglomerates and / or precipitates of the active principle is avoided.

Xanthan gum (CAS number 11138-66-2), as is well known in the field of pharmaceutical formulation, is a high molecular weight polysaccharide, whose repeating unit is a pentasaccharide comprising D-glucose, D-mannose and D-glucuronide acid in a ratio (2: 2: 1), and which can be obtained in the form of the sodium, potassium or calcium salt. Xanthan gum is usually obtained by fermentation of carbohydrates using the bacterium Xanthomonas campestris.

The main characteristics of xanthan gum are described, for example, in the manual Rowe et al., Handbook of Pharmaceutical Excipients, Sixth edition, 2009, Pharmaceutical Press [ISBN 9780853697923],

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

The composition of the present invention comprises xanthan gum generally in a proportion between 0.05% (w / v) and 2% (w / v), preferably between 0.1% (w / v) and 1% (p / v) and more preferably it is in a proportion of about 0.2% (w / v).

Povidone (CAS number 9003-39-8), also known as polyvinylpyrrolidone, polyvidone, or PVP, corresponds to the homopolymer of 1-vinyl-2-pyrrolidone.

Povidone is commercially available from various suppliers, for example from Ashland (Plasdone®) or BASF (Kollidon®), among others.

Povidone can have different degrees of polymerization and therefore different molecular weights. Usually the different grades of povidone are quantified with the "K" value, which generally ranges between 10 and 120 and is related to the viscosity provided in an aqueous solution, the lower the K value, the lower the molecular weight, and vice versa.

Povidone of any viscosity grade can be used. Preferably the povidone is chosen from among the povidones with a K value between 12 and 90, more preferably it is chosen from among povidone K-17, povidone K-25 and povidone K-30, and even more preferably, the povidone is povidone K-25.

The main characteristics and different grades of povidone are described, for example, in the manual Rowe et al. aforesaid.

When the composition of the present invention contains povidone, it is generally in a proportion comprised between 0.5% (w / v) and 8% (w / v), preferably comprised between 1% (w / v) and 6% ( w / v), more preferably between 1.5% (w / v) and 5% (w / v) and more preferably it is in a proportion of about 2% (w / v).

Hypromellose (CAS number 9004-65-3), is also called hydroxypropyl methylcellulose, cellulose hydroxypropyl methyl ether or HPMC and, as is well known, it is a derivative of cellulose, where it is partially O-methylated and partially 0- ( 2-hydroxypropylated).

Hypromellose is also widely commercially available from various suppliers, such as Dow Chemical Company (Methocel®).

Hypromellose can be present in various grades that can vary depending on the degree of viscosity and the degree of substitution. In general, all of them are suitable for the present composition.

In the Rowe et al. The main characteristics of this product are described above.

When the composition of the present invention contains hypromellose, it is generally in a proportion between 0.05% (w / v) and 5% (w / v), preferably between 0.1% (w / v) and 3 % (w / v), more preferably between 0.2% (w / v) and 1% (w / v) and more preferably in a proportion of about 0.3% (w / v).

Carbomers (CAS number 9003-01-04) are polymers of acrylic acid cross-linked with allylsucrose or allyl ethers of pentaerythritol. There are carbomers of various degrees, for example, depending on their chemical structure, or their degree of crosslinking, which gives them various theological characteristics, for example, as described in the manual Rowe et al. already quoted. In general, all of them are suitable for the present invention.

Carbomers are commercially available, for example under the designation Carbopol® (Lubrizol).

When the composition of the present invention contains carbomers, these are generally in a proportion between 0.05% (w / v) and 4% (w / v), preferably between 0.1% (w / v) and 2 % (w / v), more preferably between 0.1% (w / v) and 0.5% (w / v), and more preferably in a proportion of about 0.3% (w / v).

Cosolvent

The aqueous composition of the invention contains a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, in a proportion comprised between 1% (w / v) and 10% (w / v). This proportion refers to the total amount of polyol, which can be only propylene glycol {also called PG), or only polyethylene glycol (also called PEG), or only glycerin, or a mixture of propylene glycol and polyethylene glycol, or a mixture of propylene glycol and glycerin, or a mixture of polyethylene glycol and glycerin, or a mixture of propylene glycol, polyethylene glycol and glycerin.

Although the ibuprofen salt with lysine is soluble in water, the incorporation of a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, as a cosolvent can contribute to improving the stability of the compositions. long-term aqueous and can also improve the palatability of the final composition.

Preferably, the total amount of polyol is between 2% (w / v) and 9% (w / v), more preferably between 4% (w / v) and 8% (w / v), even more preferably between between 6% (p / v) and 7.5% (p / v).

In one embodiment of the invention the polyol is propylene glycol.

In another embodiment of the invention the polyol is polyethylene glycol.

In another embodiment of the invention the polyol is glycerin.

In another particularly preferred embodiment of the invention, a mixture of propylene glycol and polyethylene glycol is added, in any proportion between the two. Preferably, when a mixture of PG and PEG is used, the PG: PEG weight ratio is between 0.5: 1 and 1: 5, more preferably between 1: 1 and 1: 3, and more preferably is about 1 : 2.5.

As is well known, polyethylene glycol (PEG) can have different molecular weights, depending on the average number of ethylene oxide units it contains.

In one embodiment of the invention, the polyethylene glycol used in the compositions is selected from among PEG-200, PEG-300, PEG-400, PEG-600 and their mixtures. In a preferred embodiment of the invention, the polyethylene glycol is PEG-400.

PH regulator

The composition contains a pH regulating agent to adjust the pH of the composition to a value between 5.5 and 8, preferably between 6.0 and 7.5.

To regulate the pH, acid substances such as acetic acid, boric acid, citric acid, hydrochloric acid, fumaric acid, nitric acid, propionic acid, succinic acid, sulfuric acid, or sodium or potassium dihydrogen phosphate, among others, and / or substances can be used. alkaline, such as sodium or potassium acetate, sodium or potassium bicarbonate, sodium borate, ammonium or sodium carbonate, sodium or potassium citrate, ammonium, sodium or potassium phosphate, sodium or potassium hydrogen phosphate, ammonium or sodium hydroxide or sodium 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 conjugated base, for example, citrate, acetate, borate, phosphate or carbonate buffers.

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.

A preferred example of a pH regulator comprises citric acid and sodium citrate. For example, citric acid in a proportion generally comprised between 0.005-0.1% (w / v), and sodium citrate in a proportion generally comprised between 0.1 and 1% (w / v) can be used.

Other components

The composition of the invention is an aqueous composition, that is, the main solvent is water in which the Usine salt of buprofen is dissolved and where the cosolvent, the viscosity agent and, optionally, other optional additional components are added.

Purified water is usually used, according to the specifications, for example, of the European Pharmacopoeia (Ph Eur) or the United States Pharmacopoeia (USP).

In addition to water, the active ingredient, the cosolvent, the viscosifier and the pH regulator, the composition of the invention can optionally contain other additional components, such as preservatives, sweeteners, flavorings, colorants, flavor masks or chelating agents, among others.

The characteristics of some of these excipients are described, for example, in the manual Rowe et al. already quoted.

The composition of the invention generally comprises a preservative agent to ensure the microbiological stability of the preparation since it, by containing a high proportion of water, could be susceptible to microbiological contamination.

Any suitable preservative can be used to achieve the microbiological stability of pharmaceutical solutions for oral administration, as are well known to the person skilled in pharmaceutical technology, and used in proportions that are also usual in the art, for example, as indicated in the Chapter 39 (Crowley MM, Solutions, Emulsiona, Suspensions and Extracts) of the renowned Remington handbook of pharmaceutical technology The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, 2005 [ISBN: 0-683-306472]; or in the manual Handbook of Preservatives, Michael and Irene Ash, Synapse Information Resources, 2004, [ISBN 1-890595-66-7],

Thus, among the suitable preservative agents to be incorporated into the compositions of the present invention are, for example, parabens, or esters of! p-hydroxybenzoic acid, in particular methyl paraben, ethyl paraben, propyl paraben or butyl paraben, cetylpyridinium chloride, chlorhexidine acetate, chloramine T, or mixtures of the foregoing. Preferably a paraben or a mixture of parabens is used. More preferably a mixture of methyl paraben and propyl paraben is used.

The proportion in which said preservatives are added will be adjusted as a function of the particular preservative or mixture of preservatives employed, as is well known to those skilled in pharmaceutical technology.

As an indication, butylparaben can be added in a proportion usually between 0.1% and 0.4%, methylparaben and ethylparaben can be added in a proportion between 0.1% and 0.25%, propylparaben can be In a proportion generally comprised between 0.01% and 0.1%, cetylpyridinium chloride is added in concentrations that generally vary between 0.1% and 1.5%, chlorhexidine acetate in concentrations that generally vary between 0, 01% and 0.5%, and chloramine T in concentrations generally ranging from 0.001% to 0.1, where the percentages are expressed in weight / volume.

Usually, the composition of the invention also comprises a sugar alcohol that provides a sweet taste to the composition, which is suitable for the purpose of its oral administration, especially in pediatrics.

Thus, the composition generally contains a sugar alcohol that can be chosen from maltitol, mannitol, sorbitol, xylitol, and mixtures thereof. When the composition contains a sugar alcohol, it is added in a proportion generally comprised between 5% (w / v) and 60% (w / v).

In one embodiment of the invention, the composition comprises a mixture of maltitol and sorbitol, preferably in a maltitol: sorbitol weight ratio of between about 30: 1 and 45: 1.

Optionally, the composition can include a sweetening agent to enhance its sweet taste.

Among the suitable sweeteners to be used in the compositions of the present invention are, for example, sodium saccharin, sucralose, aspartame, potassium acesulfame, cyclamate, neohesperidin, thaumatin and mixtures of the above, among others.

The person skilled in pharmaceutical technology will have no difficulty in choosing a suitable amount of the sweetening substance or substances to be incorporated into the composition.

As an indication, saccharin, sucralose, aspartame, acesulfame potassium, neohesperidin and cyclamate are generally used in proportions between 0.05% and 1.0%, or thaumatin is generally used in a proportion between 0.001% and 0.25%, where the percentages are expressed in weight / volume.

Additionally, the composition of the invention may contain other substances to help mask the bitter taste of the active ingredient. For this purpose, the composition may optionally contain, for example, sodium chloride, generally in a proportion comprised between 0.1% (p / v) and 2% (p / v).

Additionally, the composition may contain flavoring agents to improve palatability. Said flavoring substances can be, for example, essential oils of natural origin such as peppermint, arvensis, curly mint, eucalyptus, lime or lemon, among others, or their mixtures. The flavoring can also be of synthetic origin, of different flavors, for example, strawberry, banana, pineapple, caramel, vanilla, cinnamon, apricot or orange, among others. Water soluble flavoring substances are preferably used.

The flavoring, or mixture of flavorings, are used in suitable concentrations, adapted to the particular substance chosen, usually between 0.05% (w / v) and 3.0% (w / v).

Optionally, the composition of the invention may contain a sequestering agent or chelating agent, which has a stabilizing function of the solution due to its ability to bind to the metal ions present and, thus, avoid the possible oxidation of the active ingredient catalyzed by said ions.

Among the suitable sequestering agents to be incorporated in the composition of the invention are, for example, ethylenediaminetetraacetic acid (EDTA) or edetic acid, edetate disodium, citric acid, fumaric acid, malic acid, or their mixtures. Edetate disodium is preferably used.

The sequestering agent is added in a suitable proportion, as is well known to those skilled in the art. For example, edetate disodium can be used in concentrations that generally vary between 0.05% and 0.2%, citric acid in concentrations generally comprised between 0.1% and 3.0%, edetic acid in concentrations usually between 0.05% and 0.2%, fumaric acid in concentrations generally varying between 0.1% and 3.0% and malic acid in concentrations generally between 0.1% and 3.0%, where the percentages They are expressed in weight / volume.

In a particularly preferred embodiment, the composition of the invention consists essentially of:

- Ibuprofen salt with lysine in a proportion between 1% (w / v) and 30% (w / v), preferably between 1% (w / v) and 10% (w / v), more preferably between 1% (w / v) and 6% (w / v), and more preferably about 2% (w / v) or about 4% (w / v), expressed as an equivalent percentage of ibuprofen in acid form;

- a viscosifying system consisting of xanthan gum and a second agent chosen from the group consisting of povidone, hypromellose and carbomers; preferably it consists of xanthan gum and povidone; and more preferably where the xanthan gum is in a proportion comprised between 0.05% (w / v) and 2% (w / v), more preferably comprised between 0.1% (w / v) and 1% (p / v); and wherein the povidone is in a proportion comprised between 0.5% (w / v) and 8% (w / v), more preferably comprised between 1% (w / v) and 6% (w / v), plus preferably between 1.5% (w / v) and 5% (w / v) and more preferably it is in a proportion of about 2% (w / v);

- a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, in a proportion between 1% (w / v) and 10% (w / v), preferably between 2% (w / v) and 9% (w / v), more preferably between 4% (w / v) and 8% (w / v), and even more preferably between 6% (w / v) and 7.5% (p / v); wherein preferably a mixture of propylene glycol and polyethylene glycol is used with a weight ratio PG: PEG comprised between 0.5: 1 and 1: 5, more preferably comprised between 1: 1 and 1: 3, and more preferably of approximately 1: 2 ,5;

- a pH regulating agent to adjust the pH of the composition to a value between 5.5 and 8, preferably between 6.0 and 7.5; preferably a buffering agent chosen from citrate, acetate, borate, phosphate or carbonate buffer is used;

- optionally a preservative agent, preferably a paraben or a mixture of parabens, more preferably a mixture of methyl paraben and propyl paraben;

- optionally between 5% (w / v) and 60% (w / v) of a sugar alcohol chosen from the group consisting of maltitol, mannitol, sorbitol, xylitol and their mixtures; preferably a mixture of maltitol and sorbitol with a maltitol: sorbitol weight ratio of between approximately 30: 1 and 45: 1.

- optionally a sweetening agent chosen from the group consisting of saccharin sodium, sucralose, aspartame, acesulfame potassium, cyclamate, neohesperidin, thaumatin and mixtures of the above;

- optionally between 0.1% (w / v) and 2% (w / v) of sodium chloride;

- optionally a flavoring; and

- Water.

In another particularly preferred embodiment, the composition of the invention consists essentially of:

- Ibuprofen salt with lysine in a proportion between 1% (w / v) and 30% (w / v), preferably between 1% (w / v) and 10% (w / v), more preferably between 1% (w / v) and 6% (w / v), and more preferably about 2% (w / v) or about 4% (w / v), expressed as an equivalent percentage of ibuprofen in acid form;

- a viscosizing system consisting of xanthan gum and a second agent chosen from the group consisting of povidone, hypromellose and carbomers; preferably it consists of xanthan gum and povidone; and more preferably where the xanthan gum is in a proportion comprised between 0.05% (w / v) and 2% (w / v), more preferably comprised between 0.1% (w / v) and 1% (p / v); and wherein the povidone is in a proportion comprised between 0.5% (w / v) and 8% (w / v), more preferably comprised between 1% (w / v) and 6% (w / v), plus preferably between 1.5% (w / v) and 5% (w / v) and more preferably it is in a proportion of about 2% (w / v);

- a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, in a proportion between 1% (w / v) and 10% (w / v), preferably between 2% (w / v) and 9% (w / v), more preferably between 4% (w / v) and 8% (w / v), and even more preferably between 4% (w / v) and 7% (w / v ); wherein glycerin is preferably used;

- a pH regulating agent to adjust the pH of the composition to a value between 5.5 and 8, preferably between 6.0 and 7.5; preferably a buffering agent chosen from citrate, acetate, borate, phosphate or carbonate buffer is used;

- optionally a preservative agent, preferably a paraben or a mixture of parabens, more preferably a mixture of methyl paraben and propyl paraben;

- optionally between 5% (w / v) and 60% (w / v) of a sugar alcohol chosen from the group consisting of maltitol, mannitol, sorbitol, xylitol and their mixtures; preferably a mixture of maltitol and sorbitol with a maltitofsorbitol weight ratio of between approximately 30: 1 and 45: 1.

- optionally a sweetening agent chosen from the group consisting of saccharin sodium, sucralose, aspartame, acesulfame potassium, cyclamate, neohesperidin, thaumatin and mixtures of the above;

- optionally between 0.1% (w / v) and 2% (w / v) of sodium chloride;

- optionally a flavoring; and

- Water.

Using the composition

The liquid composition of the ibuprofen salt with lysine according to the present invention remains stable over time, without observing any precipitation of the active principle, even at high concentrations of the itself, up to 51% (w / v) (or 30% expressed as ibuprofen acid equivalent), so that it remains in solution and is evenly distributed. Therefore, this composition is particularly useful as a ready-to-use preparation, which allows a variable dosage, suitable to adapt it to the body weight of each patient.

Thus, for example, for a given concentration of the active ingredient in the composition, it is trivial to administer an adequate volume to provide the required weight of the drug. To this end, the composition can be dispensed into bottles provided with a suitable device for measuring a certain volume, for example a syringe, a dosing container or a dropper.

Furthermore, the combination of the two viscosifiers, together with the co-solvents and, possibly, other components of the composition, for example, sugar alcohols and sweeteners, is particularly effective in masking the unpleasant bitter taste of ibuprofen lysinate, which is why it The composition is also attractive from an organoleptic point of view to the patient, including the pediatric patient.

The developed composition, which contains ibuprofen in the form of its salt with lysine, allows a very rapid absorption of the active principle and, therefore, a rapid therapeutic approach to diseases or pathological states that can be treated with ibuprofen, particularly those that they present with pain, fever and / or inflammation. The patients susceptible to be treated with the composition of the invention are all those suffering from said diseases or pathological states and, very particularly, pediatric patients.

In the context of the present invention, the pediatric patient encompasses children from approximately 3 months to 12 years of age.

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

Or formulated in another way, 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.

Or formulated still in another way, another aspect of the invention is a method for the treatment of pain, inflammation and / or fever in a patient in need thereof, comprising the administration of a therapeutically effective amount of the composition of the invention .

A preferred embodiment of the invention relates to said use or method of treatment in the pediatric patient.

The dose of active principle administered may vary according to the specific indication and the severity of the affectation and, particularly in pediatric patients, depending on body weight.

Thus, for pediatric patients the recommended daily dose of ibuprofen is generally between 20 and 30 mg per kg of body weight, divided into three or four individual doses.

Orlentatively, the recommended dosage of ibuprofen in adults usually varies between 800 mg and 1800 mg per day, divided into three doses, and it is recommended not to exceed 2400 mg daily.

Some examples are provided below to illustrate the present invention, but they should not be construed as limiting it,

Examples

Example 1.- Aqueous composition of ibuprofen 4% Usine

100 mL of composition were prepared using the components and the quantities that are detailed in the following table:

TABLE 1

c.s.p. = sufficient quantity for

For the preparation of the composition, firstly the xanthan gum and povidone were solubilized in 20 mL of water. Once dissolved, maltitol, sorbitol, the pH regulator (sodium dihydrogen phosphate and sodium hydrogen phosphate) and sodium chloride were mixed consecutively with constant stirring until dissolution. Ibuprofen lysinate, previously dissolved in a mixture containing PG and PEG-400 in 20 mL of purified water, was then added.

Subsequently, the rest of the components were incorporated, that is, sucralose and saccharin, which had previously been dissolved in 4 mL of purified water, methyl paraben, propyl paraben, and flavoring, and finally water was added to the final volume of 100 me.

The composition obtained was a clear solution, pale yellow in color mainly due to the presence of PVP in the formula.

Example 2, - Aqueous composition of 10% ibuprofen lysine

100 mL of composition were prepared using the components and the quantities that are detailed in the following table:

TABLE 2

The composition was prepared substantially analogously to that described in Example 1, and a clear pale yellow solution was also obtained.

Example 3.- Aqueous composition of 2% buprofen lysine

100 ml of composition (Example 3A) were prepared using the components and quantities detailed in the following table:

TABLE 3

The composition was prepared substantially analogously to that described in Example 1. A clear, pale yellow solution was obtained.

Other solutions were prepared with the same composition, but substituting HPMC (0.3% w / v, Example 3B) or by carbopol 974 (0.2% w / v, Example 3C) for povidone. In both cases, a colloidal, opaque, whitish solution was obtained.

Example 4.- Stability of the compositions

A composition was prepared containing the same components as detailed in Table 3, but without adding any viscosifier (Comparative Example 1), or by adding only xanthan gum (Comparative Example 2), or only povidone, but not xanthan gum (Example comparative 3).

In all cases, the compositions obtained were clear and limpid solutions. The stability of the composition of Example 3A and those of Comparative Examples 1,2 and 3 was studied comparatively. For this, the compositions were stored for 15 days at room temperature and the appearance of the compositions was observed after said period. The result of these observations is summarized in Table 4.

TABLE 4

It is observed that with the combination of xanthan gum and povidone an optimal composition is obtained, of adequate viscosity, totally transparent and limpid and that remains stable, maintaining said properties over time.

Stability tests were also carried out on the compositions of Examples 3B and 3C and it was found that they also remained stable, without detecting the formation of aggregates, precipitates or crystals of the active principle.

Example 5.- Aqueous composition of ibuprofen 2% lysine

100 ml of composition were prepared, the components and the quantities that are detailed in the following table:

TABLE 5

The composition was prepared substantially analogously to that described in Example 1. A clear, pale yellow solution was obtained.

Claims (18)

1. - Aqueous pharmaceutical composition for oral administration characterized in that it comprises: - salt of buprofen with lysine in a proportion comprised between 1% (w / v) and 30% (w / v), expressed as an equivalent percentage of ibuprofen in acid form; - a viscosizing system comprising xanthan gum and a second agent chosen from the group consisting of povidone, hypromellose and carbomers; - a polyol selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, in a proportion comprised between 1% (w / v) and 10% (w / v); and - a pH regulating agent to adjust the pH of the composition to a value between 5.5 and 8. 2. - Composition according to claim 1, characterized in that the salt of buprofen with lysine is in a proportion of 2% (w / v), expressed as an equivalent percentage of ibuprofen in acid form. 3. - Composition according to claim 1, characterized in that the ibuprofen salt with Usine is in a proportion of 4% (w / v), expressed as an equivalent percentage of ibuprofen in acid form. 4. - Composition according to any of claims 1 to 3, characterized in that the xanthan gum is in a proportion between 0.05% (w / v) and 2% (w / v). 5. - Composition according to any of claims 1 to 4, characterized in that the second viscosifying agent is povidone. 6. - Composition according to claim 5, characterized in that the povidone is in a proportion between 0.5% (p / v) and 8% (p / v). 7. - Composition according to any of claims 1 to 4, characterized in that the second viscosifying agent is hypromellose. 8. - Composition according to claim 7, characterized in that the hypromellose is in a proportion between 0.05% (p / v) and 5% (p / v). 9. - Composition according to any of claims 1 to 4, characterized in that the second viscosifying agent is a carbomer. 10. - Composition according to claim 9, characterized in that the carbomer is in a proportion between 0.05% (w / v) and 4% (w / v). 11. - Composition according to any of claims 1 to 10, characterized in that a mixture of propylene glycol and polyethylene glycol is used, where the weight ratio propylene glycol: polyethylene glycol is between 0.5: 1 and 1: 5. 12. - Composition according to any of claims 1 to 10, characterized in that the polyol is glycerin. 13. - Composition according to any of claims 1 to 12, characterized in that e! pH is adjusted to a value between 6.0 and 7.5. 14. - Composition according to any of claims 1 to 13, characterized in that it also comprises a sugar alcohol that is selected from the group consisting of maltitol, mannitol, sorbitol, xylitol and their mixtures. 15. - Composition according to any of claims 1 to 14, characterized in that it also comprises a sweetener selected from the group consisting of sodium saccharin, sucralose, aspartame, potassium acesulfame, cyclamate, neohesperidin, thaumatin and their mixtures. 16. - Composition according to any of claims 1 to 15, characterized in that it also comprises sodium chloride in a proportion between 0.1% (w / v) and 2% (w / v). 17. - Composition according to any of claims 1 to 16 for use for the treatment of pain, inflammation and / or fever. 18. Composition according to claim 17, for use for the treatment of a pediatric patient