GB2490840A

GB2490840A - Liquid ibuprofen/codeine pharmaceutical composition for oral administration, the method for preparation thereof and use thereof

Info

Publication number: GB2490840A
Application number: GB1215436.5A
Authority: GB
Inventors: Ana Maria Jima Nez Redondo; Angel Mua Oz Ruiz; Nuria Sanz Mena Ndez; Femando Martinez-Alzamora Garcia; Antonia Gomez Calvo; Gonzalo Hernandez Herrero
Original assignee: Farmalider SA
Current assignee: Farmalider SA
Priority date: 2010-03-01
Filing date: 2010-03-01
Publication date: 2012-11-14
Anticipated expiration: 2030-03-01
Also published as: GB2490840B; GB201215436D0; WO2011107617A1

Abstract

The present invention relates to a novel liquid pharmaceutical composition that contains ibuprofen in the form of a salt formed with a basic amino acid and codeine or a pharmaceutically acceptable codeine salt, for oral administration, and in particular the composition contains an ibuprofen salt or a basic amino acid such as arginine, lysine or mixtures thereof. Furthermore, the invention relates to a method for preparing said pharmaceutical composition and also the use thereof, preferably in paediatrics, for the manufacture of a drug that can be used to treat moderate-to-severe pain, inflammation, fever and/or other illnesses in which ibuprofen and/or codeine are traditionally used principally as analgesic. The composition of the invention exhibits good stability after three years under different temperature and relative humidity conditions.

Description

LIQUID IBUPROFEN/CODEINE PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION, THE METHOD FOR PREPARATION THEREOF

AND USE THEREOF

Technical field

The present invention relates to a novel liquid pharmaceutical composition that oontains ibuprofen in the form of a salt formed with a basio amino aoid and oodeine or a pharmaoeutioally aooeptable oodeine salt, for oral administration. Furthermore, the invention relates to a method for preparinq said liquid pharmaceutical composition and also the use thereof, preferably in paediatrics, for the manufacture of a drug that can be used to treat moderate-to-severe pain, inflammation, fever and/or other illnesses wherein ibuprofen and/or codeine are traditionally used, principally as an analgesic.

Prior state of the art Ibuprofen salts with basic amino acids are known at least since the year 1976, when Spanish patent ES 435416 was published, which disclosed a method for preparing an ibuprofen salt with L-arginine and an ibuprofen salt with L-lysine.

Ibuprofen is a non-steroidal anti-inflammatory drug ("NSAID'T), which is used in medicine because of its analgesic, antipyretic and anti-inflammatory activity.

In the state of the art, solid and liquid pharmaceutical forms that contain ibuprofen as the active principle have been disclosed. Thus, for example, patent application PCT WO-A-95/00134 discloses a liquid pharmaceutical composition for oral administration that contains ibuprofen, arginine, sweetening agents, preservative agents and water as a solvent. Said composition presents an ibuprofen content of at least mg/ml and it is necessary to dilute it at the time of use.

Codeine is an alkaloid that was isolated from the opium poppy in 1830. Although it may be obtained by extraotion from said plant, it is primarily obtained by the methylation of morphine. Different codeine salts are known, for example the hydrochloride, sulfate and phosphate thereof. Codeine and its salts have an application in medicine because of their analgesic, antitussive and anti-diarrhoeal properties.

European patent application EP-A-0388125 discloses that the combination of ibuprofen and codeine is known since the early 1980s and that said combination presents a greater analgesic effect than that of ibuprofen or codeine by themselves. In the state of the art, it has been disclosed that ibuprofen and codeine may interact when they are present in the same pharmaceutical composition, and said interaction may affect the stability of these active principles. A study designed to separate ibuprofen, codeine phosphate and the degradation products and impurities thereof by capillary electrophoresis (see the article by Persson-Stubberud et al., J. Chromatogr., 1998, A 798, 307-314) describes a codeine-ibuprofen ester as a probable degradation product of those pharmaceutical combinations that contain both active principles. In order to prevent said interaction, persons skilled in the art have been forced to design complex administration forms that keep the two active principles separate and which reguire more complex processes for the industrial manufacture thereof. Thus, for example, European patent application EP-A-0159852 discloses an ibuprofen/codeine composition that is directly compressible. In said composition, the codeine is granulated and separate from the ibuprofen, jointly with polyvinylpyrrolidone and lactose, in order to prevent intimate contact between the two active components, since this contact may adversely affect the stability thereof. EP-A-0159852 also discloses that the joint wet granulation of ibuprofen and codeine salts leads to the formation of colorations during said process and during the subsequent drying of the granules.

European patent applications EP-A-0220805 and EP-A- 0535841 disclose bi-layer tablets wherein, in order to prevent the interaction between ibuprofen and codeine, both active principles are found in separate layers.

European patent application EP-A-0274845 discloses a stable solid pharmaceutical composition of ibuprofen and codeine which contains an effective quantity of carboxymethylcellulose calcium salt. It is indicated that the presence of this disaggregating agent confers stability to the compositions, whereas the presence of other disaggregating agents leads to the formation of colorations when the compositions are stored at a temperature of 50°C. Patent application PCT WO-A-96/05834 discloses solid ibuprofen/codeine pharmaceutical compositions which include a hydrogenated vegetable oil in order to prevent the stability problems associated with the formulations that contain ibuprofen and codeine and which are observed during the storage thereof.

In another approach, the ibuprofen is kept substantially in suspension, as described in European patent application EP-A-041317l, which develops pharmaceutical compositions for the treatment of severe states of pain. Said patent application discloses a suspension of finely-divided ibuprofen and codeine phosphate in a mixture of PLURONIC® L35, CIREMOPHOR® RH4O and 1,2-propylene glycol. Said suspension is encapsulated in soft gelatin capsules in order to prevent potential sedimentation problems and inaccuracies in the dosing.

Another technical solution involves using mixtures of several solvents to prepare liquid compositions with relatively low contents of the active principles. Thus, European patent application EP-A-0429856 discloses various liquid compositions that contain an ibuprofen magnesium salt and codeine hydrochloride, both dissolved in a mixture of 1,2-propanediol, water and glycerin, the latter being the main solvent. This combination of solvents makes it possible to prepare solutions with a relatively low content of active principles.

Therefore, it is still necessary to have available a liguid ibuprofen/codeine pharmaceutical formulation that exhibits good stability and a substantially high content of active principles.

Object of the invention The object of the present invention is a liquid pharmaceutical composition for oral administration which comprises ibuprofen in the form of a salt with a basic amino acid and codeine or a codeine salt.

Also a part of the object of the invention is a method for preparing said pharmaceutical composition.

Also a part of the object of the invention is the use of said composition, preferably in paediatrics, for the manufacture of a drug designed for the oral treatment of pain, inflammation, fever and/or other illnesses of those traditionally relieved by means of ibuprofen and/or codeine.

Detailed description of the invention

One object of the present invention is a liquid pharmaceutical composition for oral administration which comprises: -ibuprofen and a basic amino acid selected from the group formed by arginine, lysine and mixtures thereof, in a molar ratio of ibuprofen:amino acid ranging between 0.9:1 and 1.1:1; -codeine or a pharmaceutically acceptable codeine salt and -at least one pharmaceutically acceptable excipient, where the ibuprofen content is equal to or greater than 20 mg/mi and the content of codeine or a pharmaceuticaiiy acceptabie codeine sait is equai to or greater than 0.92 mg/mi.

The authors of this invention have now deveioped a iiquid pharmaceuticai composition that contains an ibuprofen sait and a basic amino acid, seiected from arginine, iysine and/or mixtures thereof, and codeine phosphate; this pharmaceuticai composition may be easiiy administered and, surprisingiy, exhibits good stabiiity iO despite the fact that it inciudes a considerabiy high quantity of the active principies.

The authors of the invention have geared their research efforts towards the deveiopment of iiquid forms, since these offer many advantages with respect to soiid compositions. Amongst these advantages, it is worth highiighting that iiquid forms generaiiy have a better bioavaiiabiiity than soiid forms, due to the fact that the active principie is aiready dissoived when it reaches the stomach, which transiates into a rapid onset of the pharmacoiogicai action. Liquids may be easiiy administered to chiidren or persons incapabie of swaiiowing capsuies or tabiets, and provide an exceiient vehicie for the uniform administration of drugs.

Within the context of the invention, Tiiquid pharmaceuticai composition" is understood to mean that the composition is a fiuid at room temperature and that, in generai, it presents a viscosity of iess than 5,000 cps at a temperature of 20°C.

Ibvprofen Ibuprofen is a compound that has a chirai carbon atom in its moiecuie and, consequently, has two enantiomers. It is well-known that, in medicine, racemic ibuprofen, i.e. (RS)-ibuprofen, is primariiy used. It is aiso weii-known that the active enantiomer is the enantiomer with the S-configuration at the chiralL centre, i.e. (5)-ibuprofen. However, the other enantiomer, (1<)-ibuprofen, with the R-configuration at the chiral centre, also contributes to the pharmacological activity of racemic ibuprofen, since it is partially converted into the (S) enantiomer in the body.

Within the context of the present invention, the term "ibuprofen" refers indistinctly to racemic ibuprofen (RS), as well as to (S)-ibuprofen and (R)-ibuprofen.

Preferably, the ibuprofen used in the pharmaceutical composition of the present invention is selected from the group formed by (RS)-ibuprofen and (S)-ibuprofen.

The ibuprofen may be prepared in accordance with the process described in patent application GB-A-971700. The resolution of ibuprofen into its enantiomers is described in the article by Brushan et al., IBiomed. Chromatogr., 1998, 12, 309.

The quantity of ibuprofen present in the composition of the invention is equal to or greater than 20 mg/ml, preferably equal to or greater than 50 mg/ml, especially equal to or greater than 100 mg/ml, especially preferably equal to or greater than 150 mg/ml, in particular equal to or greater than 200 mg/ml and, particularly preferably, it is equal to 200 mg/mi.

Basic amino acids The composition of the invention comprises a basic amino acid selected from the group formed by arginine, lysine and mixtures thereof. The structure of said amino acids has at least one additional amino group which confers a basic character upon them, such that aqueous solutions of said amino acids present a pH within the alkaline range. Many amino acids are available in the D-form or the L-form, which is the natural one. Within the context of this invention, the terms "arginine'T and "lysine" refer to the D-form, the L-form or mixtures of both forms, L and D. Preferably, the composition of the invention uses the basic amino acid arginine, in particular the amino acid in its natural form, L-arginine.

The molar ratio of ibuprofen:basic amino acid ranges between 0.9:1 and 1.1:1, preferably between 0.92:1 and 1.07:1, especially between 0.95:1 and 1.05:1, especially preferably between 0.98:1 and 1.02:1 and, in particular, it is 1:1.

In general, the pH of the liguid composition obtained ranges between 7 and 8. It is possible for the pH to be adjusted within this range by using corrective agents that are well-known to persons skilled in the art.

It is also possible to use previously formed arginine or lysine salts of ibuprofen. Said salts may be prepared, for example, in accordance with the method described in Spanish patent E5435516.

Codeine The composition of the present invention comprises codeine or a pharmaceutically acceptable codeine salt.

Within the context of the invention, the expression "codeine" refers to codeine base or a pharmaceutically acceptable codeine salt, and the expression "pharmaceutically acceptable codeine salt" also includes the hydrates and soivates thereof.

The pharmaceutically acceptable codeine salt may be selected from the group formed by hydrochloride, hydroiodide, hydrobromide, bitartrate, citrate, acetate, sulfate and phosphate.

Preferably, the composition of the invention uses codeine phosphate as the codeine salt, in particular codeine phosphate hemihydrate.

The guantity of codeine or the pharmaceutically acceptable codeine salt present in the composition of the invention is egual to or greater than 0.92 mg/ml, preferably equal to or greater than 2.5 mg/ml, especially equal to or greater than 3.0 mg/mi, especially preferably equal to or greater than 10 mg/mI and, in particular, it is 10 mg/ml.

In certain embodiments of the composition of the invention, the quantity of codeine or the pharmaceutically acceptable codeine salt may reach mg/ml.

The weight ratio between ibuprofen and codeine or the pharmaceutically acceptable codeine salt is not critical, and different proportions of both may be designed in order to define compositions according to the invention which have different degrees of analgesic potency.

Thus, for example, when codeine phosphate hemihydrate is used, compositions may be prepared which contain 200 mg/ml of ibuprofen and 30 mg/ml of codeine phosphate hemihydrate, or 200 mg/ml of ibuprofen and 10 mg/ml of codeine phosphate hemihydrate, or 50 mg/ml of ibuprofen and 3.17 mg/mi of codeine phosphate hemihydrate, always maintaining the aforementioned proportions of the active principles.

Excipien ts The pharmaceutical compositions of the invention include at least one pharmaceutically acceptable excipient, which may be selected from the group formed by preservatives, appetising agents, flavouring agents, sweeteners and/or mixtures thereof.

Examples of preservatives that may be used in the pharmaceutical composition of the invention are those selected from the group formed by domiphen bromide, butylparaben, propyiparaben, ethylparaben, methyiparaben, benzyl alcohol, sodium acetate, glycerin, xylitoi and/or mixtures thereof, preservatives selected from the group formed by domiphen bromide, butylparaben, propylparaben, ethylparaben, methyiparaben and/or mixtures thereof being especially preferred.

Preferably, the pharmaceutical composition of the invention includes, as a preservative, domiphen bromide, since the latter exhibits good anti-microbial efficacy in the pH range wherein the composition of the invention is found. In this case, the guantity of domiphen bromide as a preservative agent present in the composition of the invention ranges between 0.05 mg/mi and 0.5 mg/mi, preferabiy between 0.07 mg/mi and 0.2 mg/mi, and, especiaiiy, between 0.09 mg/mi and 0.11 mg/mi.

The aikyiparaben derivatives may be used by themseives or combined in order to obtain a greater anti-microbiai effectiveness. Said compounds are commerciaiiy avaiiabie in acid form or in the form of a sait, such that they may be used in any of these presentations. In the event that a mixture of methyiparaben and propyiparaben is used, the quantity of methyiparaben habituaiiy ranges between 1.2 mg/mi and 2.0 mg/mi, preferabiy between 1.4 mg/mi and 1.8 mg/mi, and especiaiiy between 1.5 mg/mi and 1.7 mg/mi; and the quantity of propyiparaben generaiiy ranges between 0.12 mg/mi and 0.26 mg/mi, preferabiy between 0.15 mg/mi and 0.23 mg/mi, and especiaiiy between 0.18 mg/mi and 0.20 mg/mi.

As exampies of appetising agents, we may mention sodium chioride, ethyi maitoi, ethyl vaniiia, vaniiia and menthoi. Exampies of fiavouring agents inciude mint aroma, caramei aroma and iemon aroma, although any other adequate aroma may aiso be present. Said aromas may be commerciaiiy found in the form of mixtures with other substances in order to facilitate the dosing thereof. For example, caramel aroma may contain flavouring substances that are identical to natural ones, natural flavouring substances, maltodextrin, sugar, vegetable oil, silicon dioxide and lecithin. On the other hand, mint aroma may contain natural flavouring preparations, natural flavouring substances, flavouring substances that are identical to natural ones, maltodextrin, modified corn starch, glycerin triacetate and puleqone.

Examples of sweeteners that may be present in the composition of the invention are those selected from the group formed by maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomaltose, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate and/or mixtures thereof. Preferably, a sweetener selected from the group formed by maltitol, sucrose, glucose, thaumatin, sodium saccharin and/or mixtures thereof is used; in particular, the sweetener is selected from the group formed by maltitol, sodium saccharin, thaumatin and/or mixtures thereof.

In the composition of the present invention, the pharmaceutically acceptable excipients may be used in solid or liquid form. For example, maltitol may be commercially found in solid form or in the form of an aqueous solution containing between 68% and 85% by weight of maltitol. The physical-chemical characteristics of the excipients, as well as the names of the commercial products wherewith they are commercialised, may be found in the book by R.C. Rowe et al., "Handbook of Pharmaceutical Excipients'T, 4th edition, Pharmaceutical Press, London, 2003 [ISBN: 0-85369-472-9] In one embodiment of the liquid pharmaceutical composition of the present invention, the latter comprises the following components: -200 mg/mi of ibuprofen, -10 mg/ml of codeine phosphate hemihydrate, -170 mg/ml of L-arginine, -0.10 mg/mi of domiphen bromide, -100 mg/mi of liquid maltitol, -1.7 mg/mi of sodium saccharin and -0.05 mg/mi of thaumatin.

Preferably, this composition further includes flavouring agents.

Alternatively, in another, especially preferred embodiment of the liquid pharmaceutical composition of the invention, the latter comprises the following components: -200 mg/ml of ibuprofen, -10 mg/mi of codeine phosphate hemihydrate, -170 mg/ml of L-arginine, -1.67 mg/mi of methylparaben, -0.19 mg/mi of propylparaben, -100 mg/mi of sucrose, -1.7 mg/mi of sodium saccharin and -0.05 mg/mi of thaumatin.

Preferably, this composition further includes flavouring agents.

The pharmaceutical composition of the present invention is substantially aqueous. This means that the solvent thereof is substantially made up of water and that it is a composition which is substantially free of solvents other than water. However, it is not excluded that some of the pharmaceutically acceptable excipients which may be a part of said composition include some water-miscible solvent.

In general, 90% by weight of the solvents present in the composition of the invention is water, and it may reach up to 95% by weight or even 99% by weight.

Another object of the invention involves a method for preparing the liquid ibuprofen/codeine composition of the present invention, which comprises the following steps: a)diluting the ibuprofen salt with the basic amino acid in a part of water, b)adding the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient to the solution obtained in step a), stirring until complete dissolution and adjusting to the final volume with water, or, alternatively, c)dissoiving the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of water, d)adding the ibuprofen salt with the basic amino acid to the solution obtained in step c) and stirring until complete dissolution, e)filling to the final volume with water, or, alternatively, f)dispersing the basic amino acid in a part of water, g)adding the ibuprofen to the dispersion obtained in step f) and stirring until complete dissolution, h)adding the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient to the solution obtained in step g), stirring until complete dissolution and adjusting to the final volume with water, or, alternatively, i)dissolving the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of water, j)dispersing the basic amino acid in the solution obtained in step I), k)adding the ibuprofen to the dispersion obtained in step j) and stirring until complete dissolution, and l)filling to the final volume with water.

Preferably, the ibuprofen salt with the basic amino acid is diluted in a part of water that is equivalent to half of the volume of the manufacture batch; alternatively, the basic amino acid is dispersed in a part of water that is equivalent to half of the volume of the manufacture batch; alternatively, the codeine or the pharmaceutically acceptable codeine salt and at least one acceptable excipient are dissolved in a part of water that is equivalent to half of the volume of the manufacture batch.

In the event that the ibuprofen salt is not directly used with the basic amino acid, prior dispersion of the basic amino acid provides an appropriate alkaline pH which facilitates the subsequent dissolution of ibuprofen.

The liquid composition of the invention obtained by means of the method of the invention is a substantially transparent solution. Optionally, any precipitate which may potentially form during the manufacture process may be separated by filtration or centrifugation. For this reason, it is preferred that, following the addition of codeine or the pharmaceutically acceptable codeine salt, and of at least one pharmaceutical excipient, there be sufficient stirring in order to obtain a solution after the addition of each new component. In the event that the pharmaceutical composition of the invention includes several excipients, in the method of the invention, following the addition of each of them, the mixture is preferably stirred until the complete dissolution thereof.

The aforementioned excipients may be added in step b) of the method of the invention or, alternatively, following step d) and prior to filling to the final volume with water (step e)), or, alternatively, in step h) or, alternatively, following step k) and prior to filling to the final volume with water (step 1)) The method of the invention for preparing the pharmaceutical composition of the invention may be performed at a temperature ranging between 15°C and 50°C, preferably at a temperature close to room temperature.

In the method of the invention, the excipients may be added in solid form or in the form of a substantially aqueous solution, previously prepared, in a separate container, with a part of the water which is a part of the formulation. For example, when domiphen bromide is used, it has been observed that foam may form when adding said preservative in pulverulent form to the aqueous solution of the pharmaceutically acceptable codeine salt.

For this reason, it is preferred to prepare a solution of domiphen bromide in a part of the water in the formulation prior to adding it to said solution.

The method of the invention for preparing the composition of the invention includes the step of filling to the final volume with water, a step that is well-known to persons skilled in the art and which refers to the addition of sufficient water to the container where the composition has been prepared, in order to obtain the desired concentration of active principles.

Stability assays The pharmaceutical composition of the invention was subjected to stability assays under the following temperature and relative humidity (RH) conditions: -25°C and 60% RH -30°C and 65% RH -40°C and 75% RH, and -5°C to 8°C under refrigeration.

The liquid composition of the invention exhibited good stability and the contents of ibuprofen and codeine remained substantially unaltered after 36 months of storage at 25°C and 60% relative humidity, at 30°C and 65% relative humidity, as well as after 6 months at a temperature of 40°C and 75% relative humidity, and after 6 months under refrigeration at a temperature ranging between 5°C and 8°C. At this temperature, no turbidity whatsoever or precipitates were observed. The stability results are shown in the Examples.

The content of active principles present in the composition of the invention may be analysed by means of HPLC (high-performance liquid chromatography) techniques, which are well-known to persons skilled in the art, adjusting the operating conditions by means of routine assays typical of laboratories where pharmaceutical active principles are analysed.

Surprisingly, the pharmaceutical composition of the invention is stable even when it includes considerable quantities of ibuprofen and codeine dissolved in a substantially aqueous liquid composition.

The composition of the invention was also subjected to a photostability assay, and it was observed that the contents of ibuprofen and codeine remained substantially unaltered in the bulk solution following said assay. The photostability assay was performed in accordance with the

specifications contained in the 1CM (International

Conference on Harmonization) document according to Stability Testing: Photostability Testing of New Drug Substances and Products QlB. The results of said assay are shown in the Examples section.

Use of the pharmaceutical composition of the invention Also a part of the object of the invention is the use of the pharmaceutical composition of the invention, preferably in paediatrics, for the manufacture of a drug designed for the oral treatment of moderate-to-severe pain, inflammation, fever and/or other illnesses that may be relieved with ibuprofen and/or codeine. The illnesses that may be relieved with ibuprofen include, for example, Alzheimer's disease, arthritis and primary dysmenorrhoea.

The pharmaceutical composition of the invention is characterised by its high efficacy and the rapid onset of the pharmacological effect, for which reason it is especially adequate as an analgesic designed to rapidly relieve pain.

The pharmaceutical composition of the invention may be administered diluted in a liquid at the time of use, for example in water.

The dose to be administered to the subjects may vary according to their body weight, the indication and the severity of the condition. In general, the dose of the composition of the invention to be orally administered to the subjects is that which makes it possible to provide them with a quantity of ibuprofen ranging between 100 and 800 mg every 4 to 6 hours, preferably between 200 and 400 mg, the maximum daily dose ranging between 800 and 1,200 mg of ibuprofen. In some cases, a maximum daily dose of up to 2,400 mg of ibuprofen may be reached.

The pharmaceutical composition of the invention is also appropriate for paediatric use. In general, the paediatric dose of ibuprofen to be orally administered to the subjects by means of the composition of the invention ranges between 5 mg/kg and 10 mg/kg of ibuprofen every 4 to 6 hours. Likewise, the paediatric dose of codeine to be orally administered to the subjects by means of the composition of the invention ranges between 0.5 and 1 mg/kg every 4 to 6 hours, with a maximum of 60 mg/dose, reaching in some cases a daily dose of 120 mg.

The following examples serve to illustrate the invention, but do not limit it in any way.

Examples

Example 1

Preparation of a concentrated liquid formulation with mg/ml of ibuprofen and 10 mg/ml of codeine phosphate hemihydrate litres of purified water are introduced into a stainless steel reactor equipped with a stirrer and 1.0 kg of codeine phosphate hemihydrate is dissolved therein by means of stirring. Subsequently, 0.17 kg of sodium saccharin, 0.25 kg of caramel aroma and 1.60 kg of mint aroma are added and it is stirred to complete dissolution. Thereafter, 0.005 kg of the sweetener thaumatin are added and it is stirred to complete dissolution. 17.0 kg of L-arginine are dispersed in this solution under stirring. Subsequently, 20.0 kg of ibuprofen are added and the stirring is maintained until complete dissolution. 10.0 kg of a solution of liquid maltitol are added to this solution and it is stirred until complete homogenisation is achieved. Finally, 0.01 kg of domiphen bromide dissolved in 1 litre of purified water are added, it is adjusted to 100 litres with water and stirred until a homogeneous solution is obtained. The liquid composition is packed in 30-ml and 60-ml bottles.

The liquid formulation for oral administration thus obtained has the following composition: Component mg/mi Active ingredients ____________________ Ibuprofen 200.00 Codeine phosphate hemihydrate 10.00 Excipients ____________________ L-arginine 170.00 Domiphen bromide 0.10 Liquid maltitol 100.00 Sodium saccharin 1.70 Caramel aroma 2.50 Mint aroma 16.00 Thaumatin 0.05 Purified water s.q.

The concentrated liquid composition thus obtained contained 200 mg of ibuprofen per ml, 10 mg of codeine phosphate hemihydrate per ml, the solids content being greater than 400 mg per ml. This composition exhibited high stability and the contents of ibuprofen and codeine phosphate hemihydrate remained substantially unaltered after 36 months of storage at 25°C and 60% relative humidity, at 30°C and 65% relative humidity, as well as after 6 months at a temperature of 40°C and 75% relative humidity, and also after 6 months under refrigeration at a temperature ranging between 5°C and 8°C. At this temperature, no turbidity or precipitates were observed.

Table 1 below shows the stability data corresponding to the contents of ibuprofen, L-arginine and codeine phosphate hemihydrate:

TABLE 1

Time, L-Codeine Temperature/RH Ibuprofen Arginine phosphate ________________________ ____________ ___________ hemihydrate Initial 100.4% 100.0% 98.9% 36 months, 25°C/60% 100 6% 98 8% 98 6% 36 months, 30°C/65% 100.3% 99.1% 99.5% 6 months, 40°C/75% 100.2% 100.2% 100.5% RH = relative humidity The active principles were analysed by means of HPLC techniques.

The composition obtained in Example 1 was also subjected to a photostability assay in accordance with the method mentioned above, and it was observed that the contents of ibuprofen, arginine and codeine phosphate hemihydrate remained substantially unaltered in the bulk solution after said assay, as shown in Table 2:

TABLE 2

Bulk in the Bulk in the _________________________ dark light Ibuprofen 99.7% 100.9% Arginine 99.7% 100.5% Codeine phosphate 97.9% 104.1% hemihydrate _________________ ________________

Examples 2 to 4

Preparation of concentrated liquid formulations of ibuprofen and codeine phosphate hemihydrate Following a process analogous to that used in Example 1, other concentrated liquid formulations were prepared, with the compositions shown in Tables 3 to 5:

TABLE 3

Component Example 2 (mg/ml) Active ingredients ____________________ Ibuprofen 200.00 Codeine phosphate hemihydrate 30.00 Excipients _____________________ L-arginine 170.00 Domiphen bromide 0.10 Liquid glucose 100.00 Sodium cyclamate 1.70 Menthol 10.00 Mint aroma 16.00 Purified water s.q.

TABLE 4

Component Example 3 (mg/mi) Active ingredients ____________________ Ibuprofen 200.00 Codeine phosphate hemihydrate 10.00 Excipients _____________________ L-arginine 170.00 Methylparaben 1. 67 Propylparaben 0.19 Sucrose 100.00 Sodium saccharin 1.70 Caramel aroma 2.50 Mint aroma 4.00 Thaumatin 0.05 Purified water s.q.

TABLE 5

Component Example 4 (mg/mi) Active ingredients ____________________ Ibuprofen 50.00 Codeine phosphate hemihydrate 3.17 Excipients _____________________ L-arginine 42.50 Methylparaben 1. 67 Propylparaben 0.19 Sucrose 350.00 Lemon aroma 1.00 Mint aroma 4.00 Thaumatin 0.05 Purified water s.g.

Claims

CLAIMS1. Liquid pharmaceutical composition for oral administration characterised in that it comprises: -one ibuprofen salt and one basic amino acid selected from the group formed by arginine, lysine and mixtures thereof, in a molar ratio of ibuprofen:amino acid ranging between 0.9:1 and 1.1:1, -codeine or a pharmaceutically acceptable codeine salt and -at least one pharmaceutically acceptable excipient where the ibuprofen content is equal to or greater than 20 mg/ml and the content of codeine or the pharmaceutically acceptable codeine salt is equal to or greater than 0.92 mg/ml.
2. Composition according to claim 1, characterised in that the ibuprofen is selected from the group formed by (RS)-ibuprofen and (S)-ibuprofen.
3. Composition according to claims 1 or 2, characterised in that the ibuprofen content is equal to or greater than 50 mg/ml.
4. Composition according to claim 3, characterised in that the ibuprofen content is equal to or greater than mg/ml.
5. Composition according to claim 4, characterised in that the ibuprofen content is equal to or greater than mg/ml.
6. Composition according to claim 5, characterised in that the ibuprofen content is equal to 200 mg/mi.
7. Composition according to any of claims 1 to 6, characterised in that the basic amino acid is arginine.
8. Composition according to claim 7, characterised in that the basic amino acid is the amino acid in its natural form, L-arginine.
9. Composition according to any of claims 1 to 8, characterised in that the molar ratio between ibuprofen and the basic amino acid ranges between 0.92:1 and 1.07:1.
10. Composition according to claim 9, characterised in that the molar ratio between ibuprofen and the basic amino acid ranges between 0.95:1 and 1.05:1.
11. Composition according to claim 10, characterised in that the molar ratio between ibuprofen and the basic amino acid ranges between 0.98:1 and 1.02:1.
12. Composition according to claim 11, characterised in that the molar ratio between ibuprofen and the basic amino acid is 1:1.
13. Composition according to any of claims 1 to 12, characterised in that it comprises codeine.
14. Composition according to any of claims 1 to 12, characterised in that it comprises a pharmaceutically acceptable codeine salt.
15. Composition according to claim 14, characterised in that the pharmaceutically acceptable codeine salt is selected from the group formed by codeine hydrochloride, codeine hydroiodide, codeine hydrobromide, codeine bitartrate, codeine citrate, codeine acetate, codeine sulfate and codeine phosphate.
16. Composition according to claim 15, characterised in that the pharmaceutically acceptable codeine salt is codeine phosphate.
17. Composition according to claim 16, characterised in that the pharmaceutically acceptable codeine salt is codeine phosphate hemihydrate.
18. Composition according to any of claims 1 to 17, characterised in that the content of codeine or the pharmaceutically acceptable codeine salt is equal to or greater than 2.5 mg/ml.
19. Composition according to claim 18, characterised in that the content of codeine or the pharmaceutically acceptable codeine salt is equal to or greater than 3.0 mg/ml.
20. Composition according to claim 19, characterised in that the content of codeine or the pharmaceutically acceptable codeine salt is equal to 10 mg/ml.
21. Composition according to claim 19, characterised in that the content of codeine or the pharmaceutically acceptable codeine salt is equal to 30 mg/mi.
22. Composition according to any of claims 1 to 21, characterised in that the pharmaceutically acceptable excipient is selected from the group formed by preservatives, appetising agents, flavouring agents, sweeteners and/or mixtures thereof.
23. Composition according to claim 22, characterised in that the preservative is selected from the group formed by domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben and/or mixtures thereof.
24. Composition according to claim 23, characterised in that the preservative is domiphen bromide.
25. Composition according to claim 22, characterised in that the sweetener is selected from the group formed by maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomaltose, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate and/or mixtures thereof.
26. Composition according to claim 25, characterised in that the sweetener is selected from the group formed by maltitol, sucrose, glucose, thaumatin, sodium saccharin and/or mixtures thereof.
27. Composition according to claim 26, characterised in that the sweetener is selected from the group formed by maltitol, sodium saccharin, thaumatin and/or mixtures thereof.
28. Liguid pharmaceutical composition for oral administration, characterised in that it comprises: -200 mg/ml of ibuprofen -10 mg/ml of codeine phosphate hemihydrate -170 mg/ml of L-arginine -0.10 mg/mi of domiphen bromide -100 mg/mi of liguid maltitol -1.7 mg/mi of sodium saccharin and -0.05 mg/ml of thaumatin.
29. Composition according to claim 28, characterised in that it further comprises flavouring agents.
30. Liquid pharmaceutical composition for oral administration, characterised in that it comprises: -200 mg/ml of ibuprofen -10 mg/mi of codeine phosphate hemihydrate -170 mg/mi of L-arginine -1.67 mg/mi of methylparaben -0.19 mg/ml of propylparaben -100 mg/mi of sucrose -1.7 mg/mi of sodium saccharin and -0.05 mg/ml of thaumatin.
31. Composition according to claim 30, characterised in that it further comprises flavouring agents.
32. Method for preparing a composition according to any of claims 1 to 31, characterised in that it comprises the following steps: a)diluting the ibuprofen salt with the basic amino acid in a part of water, b)adding the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient to the solution obtained in step a), stirring until complete dissolution and adjusting to the final volume with water, or, alternatively, c)dissoiving the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of water, d)adding the ibuprofen salt with the basic amino acid to the solution obtained in step c) and stirring until complete dissolution, e)filling to the final volume with water, or, alternatively, f)dispersing the basic amino acid in a part of water, g)adding the ibuprofen to the dispersion obtained in step f) and stirring until complete dissolution, h)adding the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient to the solution obtained in step g), stirring until complete dissolution and adjusting to the final volume with water, or, alternatively, i)dissolving the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of water, j)dispersing the basic amino acid in the solution obtained in step i), k)adding the ibuprofen to the dispersion obtained in step j) and stirring until complete dissolution, and 1) filling to the final volume with water.
33. Use of a pharmaceutical composition according to any of claims 1 to 31 for the manufacture of a drug designed for the oral treatment of moderate-to-severe pain, inflammation, fever and/or other illnesses that may be relieved with ibuprofen and/or codeine.
34. Use according to claim 33, characterised in that the other illnesses mentioned above are selected from the group formed by Alzheimer's disease, arthritis and primary dysmenorrhoea.
35. Use according to claim 33, for paediatric use.