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WO2011107617A1 - Liquid ibuprofen/codeine pharmaceutical composition for oral administration, the method for preparation thereof and use thereof - Google Patents

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

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Publication number
WO2011107617A1
WO2011107617A1 PCT/ES2010/000078 ES2010000078W WO2011107617A1 WO 2011107617 A1 WO2011107617 A1 WO 2011107617A1 ES 2010000078 W ES2010000078 W ES 2010000078W WO 2011107617 A1 WO2011107617 A1 WO 2011107617A1
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WO
WIPO (PCT)
Prior art keywords
codeine
ibuprofen
composition according
pharmaceutically acceptable
salt
Prior art date
Application number
PCT/ES2010/000078
Other languages
Spanish (es)
French (fr)
Inventor
Ana María JIMÉNEZ REDONDO
Ángel Muñoz Ruiz
Nuria SANZ MENÉNDEZ
Femando Martinez-Alzamora Garcia
Antonia GÓMEZ CALVO
Gonzalo HERNÁNDEZ HERRERO
Original Assignee
Farmalider, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Farmalider, S.A. filed Critical Farmalider, S.A.
Priority to GB1215436.5A priority Critical patent/GB2490840B/en
Priority to PCT/ES2010/000078 priority patent/WO2011107617A1/en
Publication of WO2011107617A1 publication Critical patent/WO2011107617A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a new liquid pharmaceutical composition containing ibuprofen in the form of a salt formed with a basic amino acid and codeine or a pharmaceutically acceptable codeine salt, for oral administration.
  • the invention relates to a process for the preparation of said liquid pharmaceutical composition, as well as its use, preferably in pediatrics, for the manufacture of a medicament useful in the treatment of moderate to severe pain, inflammation, fever and / or other medical conditions in which ibuprofen and / or codeine are traditionally used, mainly as an analgesic.
  • Ibuprofen salts with basic amino acids have been known at least since 1976, when Spanish patent ES 435416 was published where a procedure for the preparation of an ibuprofen salt with L-arginine and a salt of ibuprofen with L-lysine.
  • Ibuprofen is a non-steroidal anti-inflammatory drug (in English "NSAID", in Spanish "NSAID") that is used in medicine for its analgesic, antipyretic and anti-inflammatory activity.
  • Solid and liquid pharmaceutical forms containing ibuprofen as active ingredient have been described in the state of the art. So by for example, in the PCT patent application WO-A-95/00134 a liquid pharmaceutical composition for oral administration containing ibuprofen, arginine, sweetening agents, preservatives and water as solvent is described. Said composition has an ibuprofen content of at least 200 mg / ml and must be diluted at the time of use.
  • Codeine is an alkaloid that was isolated in 1830 from the opium plant. Although it can be obtained by extracting said plant, it is mostly obtained by morphine methylation.
  • Different codeine salts are known, for example their hydrochloride, sulfate and phosphate. Codeine and its salts find their application in medicine for their analgesic, antitussive and antidiarrheal properties.
  • European patent application EP-A-0388125 describes that the combination ibuprofen and codeine has been known since the early 1980s and that this combination has an analgesic effect superior to that of ibuprofen or codeine alone.
  • ibuprofen and codeine can interact when they are present in the same pharmaceutical composition, said interaction being able to affect the stability of these active ingredients.
  • codeine phosphate and its degradation products and impurities by capillary electrophoresis describe an ibuprofen and codeine ester as a probable degradation product of those pharmaceutical combinations that contain both active ingredients.
  • EP-A-0159852 a composition of ibuprofen and codeine is described which is directly compressible.
  • codeine is granulated and separately from ibuprofen, together with polyvinylpyrrolidone and lactose, to avoid intimate contact between the two active components, contact that can adversely affect their stability.
  • the wet wet granulation of ibuprofen and codeine salts leads to the formation of colorations during said process and in the subsequent drying of the granulate.
  • Bilayer tablets are described in European patent applications EP-A-0220805 and EP-A-0535841 where, in order to avoid the interaction between ibuprofen and codeine, both active ingredients are found in separate layers.
  • European patent application EP-A-0274845 describes a stable solid pharmaceutical composition of ibuprofen and codeine containing an effective amount of carboxymethyl cellulose calcium salt. It is indicated that the presence of such a disintegrating agent confers stability to the compositions, while the presence of other different disintegrating agents leads to the formation of colorations when the compositions are stored at a temperature of 50 ° C.
  • ibuprofen is substantially suspended, as described in European Patent Application EP-A-0413171, where pharmaceutical compositions are developed for the treatment of serious pain states.
  • the object of the present invention is a liquid pharmaceutical composition for oral administration comprising ibuprofen in the form of a salt with a basic amino acid and codeine or a codeine salt. Also part of the object of the invention is a process for preparing said pharmaceutical composition.
  • composition preferably in pediatrics, for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other ailments of those traditionally relieved by buprofen and / or codeine.
  • An object of the present invention is a liquid pharmaceutical composition for oral administration comprising: - buprofen and a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof, in a molar ratio ibuprofen: amino acid between 0.9: 1 and 1, 1: 1;
  • - codeine or a pharmaceutically acceptable codeine salt and - at least one pharmaceutically acceptable excipient where the content of buprofen is equal to or greater than 20 mg / ml and the content of codeine or a pharmaceutically acceptable codeine salt is equal to or greater at 0.92 mg / ml.
  • liquid forms generally have a better bioavailability than solid forms, because the active substance is already dissolved when it reaches the stomach, which translates into a rapid onset of pharmacological action.
  • Liquids can be easily administered to children or people unable to swallow capsules or tablets and provide an excellent vehicle for uniform administration of drugs.
  • liquid pharmaceutical composition means that the composition is fluid at room temperature and, in general, has a viscosity of less than 5,000 cps at a temperature of 20 ° C.
  • Ibuprofen is a compound that has a chiral carbon atom in its molecule and, consequently, has two enantiomers. It is known that in medicine mainly racemic ibuprofen is used, that is (RS) -ibuprophen. It is also known that the active enantiomer is the enantiomer having the S configuration in the chiral center, that is (S) -ibuprofen. However, the other enantiomer, (R) -ibuprofen, with the R configuration in the chiral center, also contributes to the pharmacological activity of racemic ibuprofen, since it is partially converted to the enantiomer (S) in the body. In the context of the present invention, the term “ibuprofen” refers interchangeably to racemic ibuprofen (RS), as well as to (S) - buprofen and (R) -ibuprofen.
  • the ibuprofen used in the pharmaceutical composition of the present invention is selected from the group consisting of (RS) -ibuprofen and (S) -ibuprofen.
  • Ibuprofen can be prepared according to the procedure described in patent application GB-A-971700. The resolution of ibuprofen in its enantiomers is described in the article by Brushan et al., Biomed. Chromatogr., 1998, 12, 309.
  • the amount 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 with particular preference is equal to 200 mg / ml.
  • Basic amino acids preferably 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 with particular preference is equal to 200 mg / ml.
  • the composition of the invention comprises a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof.
  • Said amino acids have in their structure at least one additional amino group which gives them a basic character, so that the aqueous solutions of said amino acids have a pH in the alkaline range.
  • Many amino acids are available in form D or form L, which is the natural one.
  • the terms "arginine” and lysine "refer to form D, form L or mixtures of both forms L and D.
  • the basic amino acid arginine is used in the composition of the invention and in particular the naturally occurring amino acid L-arginine.
  • the ibuprofen: basic amino acid molar ratio is 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, with special preference between 0.98: 1 and 1, 02: 1 and in particular is 1: 1.
  • the pH of the liquid composition obtained is between 7 and 8.
  • the pH can be adjusted within this range by means of the use of corrective agents well known to those skilled in the art.
  • the previously formed ibuprofen arginine or lysine salts can also be used.
  • Said salts can be prepared, for example, in accordance with the procedure described in Spanish patent ES435516.
  • the composition of the present invention comprises codeine or a pharmaceutically acceptable codeine salt.
  • codeine refers to codeine base or a pharmaceutically acceptable salt of codeine and the term “pharmaceutically acceptable salt of codeine” also includes the hydrates and solvates thereof.
  • the pharmaceutically acceptable codeine salt may be selected from the group consisting of hydrochloride, iodhydrate, hydrobromide, bitartrate, citrate, acetate, sulfate and phosphate.
  • codeine salt is used, in particular codeine phosphate hemihydrate.
  • the amount of codeine or the pharmaceutically acceptable codeine salt present in the composition of the invention is equal 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 / ml, especially preferably equal to or greater than 10 mg / ml and in particular is 10 mg / ml.
  • the amount of codeine or the pharmaceutically acceptable salt of codeine may reach 30 mg / ml.
  • the weight ratio between ibuprofen and codeine or the pharmaceutically acceptable codeine salt is not critical, and different proportions can be designed between them to define compositions according to the invention with different degrees of analgesic potency.
  • compositions containing 200 mg / ml of ibuprofen and 30 mg / ml of codeine phosphate hemihydrate, or 200 mg / ml of ibuprofen and 10 mg / ml can be prepared of codeine phosphate hemihydrate, or 50 mg / ml of ibuprofen and 3.17 mg / ml of codeine phosphate hemihydrate, always maintaining the proportions of active ingredients mentioned above.
  • compositions of the invention include at least one pharmaceutically acceptable excipient, which can be selected from the group consisting of preservatives, flavorings, flavorings, sweeteners and / or mixtures thereof.
  • preservatives that can be used in the pharmaceutical composition of the invention are those selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben, benzyl alcohol, sodium acetate, glycerin, xylitol and / or mixtures of the same, the preservatives selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben and / or mixtures thereof being especially preferred.
  • the pharmaceutical composition of the invention includes, as a preservative, domifene bromide, because it has a good antimicrobial efficacy in the pH range in which the composition of the invention is found.
  • the amount of domifen bromide as a preservative present in the composition of the invention is between 0.05 mg / ml and 0.5 mg / ml, preferably between 0.07 mg / ml and 0.2 mg. / ml and especially between 0.09 mg / ml and 0.11 mg / ml.
  • Alkylparaben derivatives can be used alone or in combination to obtain greater antimicrobial effectiveness. Such compounds are commercially available in acidic or salt form, so that they can be used in any of these presentations.
  • the amount of methylparaben is between 1.2 mg / ml and 2.0 mg / ml, preferably between 1.4 mg / ml and 1.8 mg / ml and especially between 1.5 mg / ml and 1.7 mg / ml; and the amount of propylparaben is generally between 0.12 mg / ml and 0.26 mg / ml, preferably between 0.15 mg / ml and 0.23 mg / ml and especially between 0.18 mg / ml and 0 , 20 mg / ml.
  • flavorings sodium chloride, ethylmaltol, ethyl vanilla, vanilla and menthol can be mentioned.
  • flavorings are mint aroma, caramel aroma and lemon aroma, although any other suitable aroma may also be present. Said aromas can be found commercially in the form of mixtures with other substances to facilitate their dosage.
  • caramel aroma may contain flavoring substances identical to natural ones, natural flavoring substances, maltodextrin, sugar, vegetable oil, silicon dioxide and lecithin.
  • the mint aroma may contain natural flavoring preparations, natural flavoring substances, flavoring substances identical to natural ones, maltodextrin, modified corn starch, glycerin triacetate and pulegone.
  • sweeteners that may be present in the composition of the invention are those selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatine, sodium cyclamate, and / or mixtures thereof.
  • a sweetener selected from the group consisting of maltitol, sucrose, glucose, thaumatine, sodium saccharin and / or mixtures thereof is used; in particular the Sweetener is selected from the group consisting of maltitol, sodium saccharin, thaumatine and / or mixtures thereof.
  • composition of the present invention pharmaceutically acceptable excipients can be used in solid or liquid form.
  • maltitol can be found commercially in solid form or in the form of an aqueous solution containing between 68% and 85% by weight of maltitol.
  • Physico-chemical properties of excipients as well as the name of the commercial products under which they are marketed, features can be found in the book of RC Rowe et al, "Handbook of Pharmaceutical Excipients", 4th edition, Pharmaceutical Press, London , 2003 [ISBN: 0-85369-472-9].
  • liquid pharmaceutical composition of the present invention it comprises the following components:
  • this composition additionally includes flavoring agents.
  • liquid pharmaceutical composition of the invention comprises the following components: - 200 mg / ml ibuprofen,
  • this composition additionally includes flavoring agents.
  • the pharmaceutical composition of the present invention is substantially aqueous. This means that the solvent thereof is substantially water and that it is a composition substantially free of solvents other than water. While it is not excluded that some of the pharmaceutically acceptable excipients that may eventually be part of said composition may include some water miscible solvent.
  • 90% by weight of the solvents present in the composition of the invention is water, which can reach up to 95% by weight or up to 99% by weight.
  • Another object of the invention is a process for preparing the liquid composition of ibuprofen and codeine of the present invention, a process comprising the steps of: a) dilute the ibuprofen salt with the basic amino acid in a part of the water,
  • step b) add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step a), stir until complete dissolution and adjust with water to the final volume, or alternatively c) dissolve the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of the water,
  • step d) add the ibuprofen salt with the basic amino acid in the solution obtained in step c) and stir until completely dissolved,
  • step f) add ibuprofen to the dispersion obtained in step f) and stir until completely dissolved
  • step g add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step g), stir until completely dissolved and adjust with water to the final volume, or alternatively i) dissolve the codeine or pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a portion of the water,
  • step j) add ibuprofen to the dispersion obtained in step j) and stir until completely dissolved and
  • the ibuprofen salt with the basic amino acid is diluted in a part of water equivalent to half the volume of the manufacturing batch; alternatively, the basic amino acid is dispersed in a part of the water equivalent to half the volume of the manufacturing batch; alternatively, the codeine or the pharmaceutically acceptable salt of codeine and the at least one acceptable excipient are dissolved in a part of the water equivalent to half the volume of the manufacturing batch.
  • the previous dispersion of the basic amino acid provides an appropriate alkaline pH that facilitates the subsequent dissolution of ibuprofen.
  • the liquid composition of the invention obtained by the process of the invention is a substantially transparent solution.
  • any precipitate that could have formed during the manufacturing process can be separated by filtration or centrifugation. Therefore, it is preferred that after the addition of the codeine or the pharmaceutically acceptable salt of codeine, and of the at least one pharmaceutical excipient, is sufficiently stirred to achieve a solution after the addition of each new component.
  • the pharmaceutical composition of the invention includes several excipients, in the process of the invention, after the addition of each of them, the mixture is preferably stirred until it is completely dissolved.
  • step b) of the process of the invention can be added in step b) of the process of the invention or alternatively after step d) and before filling with water to the final volume (step e)) or alternatively in step h) or alternatively, after from stage k) and before completing with water to the final volume (stage I))
  • the process of the invention for the preparation of the pharmaceutical composition of the invention can be carried out at a temperature between 15 ° C and 50 ° C, preferably at a temperature close to room temperature.
  • the excipients can 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 that forms part of the formulation.
  • a substantially aqueous solution previously prepared in a separate container with a part of the water that forms part of the formulation.
  • foam can be formed by adding said preservative in powder form to the aqueous solution of the pharmaceutically acceptable codeine salt. Therefore, it is preferable to prepare a solution of domifene bromide in a part of the water of the formulation before proceeding with its addition to said solution.
  • the process of the invention for preparing the composition of the invention includes the step of completing with water to a final volume, a stage well known to the person skilled in the art and which refers to adding sufficient water to the container where the preparation of the composition has been carried out to obtain the desired concentration of active ingredients.
  • the pharmaceutical composition of the invention was subjected to stability tests under the following conditions of temperature and relative humidity (H.R.):
  • the liquid composition of the invention exhibited good stability and the contents of ibuprofen and codeine remained substantially unchanged after 36 months of storage at 25 ° C and under a relative humidity of 60%, at 30 ° C and under a relative humidity of 65 %, as well as after 6 months at a temperature of 40 ° C under a relative humidity of 75% and after 6 months under refrigeration at a temperature between 5 o C and 8 o C. At this temperature no appearance of some turbidity or precipitates.
  • the results corresponding to stability are presented in the Examples.
  • the content of active ingredients present in the composition of the invention can be analyzed by means of HPLC (high performance liquid chromatography) techniques, well known to the person skilled in the art, and adjusting the operating conditions by means of routine laboratory tests of analysis of pharmaceutical active ingredients.
  • the pharmaceutical composition of the invention is stable even when it includes appreciable amounts of ibuprofen and codeine dissolved in a substantially aqueous liquid composition.
  • the composition of the invention was also subjected to a photostability test, observing that the contents of ibuprofen and codeine remained substantially unchanged in the bulk solution after said test.
  • the photostability test was carried out in accordance with the specifications described in the document of the ICH (International Conference on Harmonization) according to Stability Testing: Photostability testing of New Drug Substances and Products Q1B. The results of this test are presented in the Examples section.
  • Also part of the object of the invention is the use of the pharmaceutical composition of the invention, preferably in pediatrics, for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other medical conditions. They can be relieved with ibuprofen and / or codeine. Conditions that can be relieved with ibuprofen include, for example, Alzheimer's disease, arthritis and primary dysmenorrhea.
  • the pharmaceutical composition of the invention is characterized by its high efficacy and the rapid onset of the pharmacological effect, so it is especially suitable as an analgesic to quickly relieve pain.
  • the pharmaceutical composition of the invention can be administered diluted in a liquid at the time of use, for example in water.
  • the dose to be administered to the subject may vary according to his body weight, the indication and the severity of the condition.
  • the dose of the composition of the invention to be administered to the subject orally is that which allows a quantity of buprofen of between 100 and 800 mg to be given every 4 to 6 hours, preferably between 200 and 400 mg, with the maximum daily dose between 800 and 1,200 mg of ibuprofen. In some cases, a maximum daily dose of 2,400 mg of ibuprofen can be reached.
  • the pharmaceutical composition of the invention is also suitable for pediatric use.
  • the pediatric dose of ibuprofen to be administered to the subject orally through the composition of the invention is between 5 mg / kg and 10 mg / kg of buprofen every 4 to 6 hours.
  • the pediatric dose of codeine to be administered orally to the subject through the composition of the invention is between 0.5 and 1 mg / kg every 4 to 6 hours, with a maximum of 60 mg / dose, reaching some cases at a daily dose of 120 mg.
  • the oral oral liquid formulation thus obtained has the following composition:
  • Purified water is.
  • 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 unchanged after 36 months of storage at 25 ° C and under a relative humidity of 60%, at 30 ° C and under a relative humidity of 65% , as well as after 6 months at a temperature of 40 ° C with a relative humidity of 75%, and also after 6 months under refrigeration at a temperature between 5 ° C and 8 ° C. At this temperature the temperature was not observed. occurrence of turbidity or precipitates.
  • Table 1 shows the stability data corresponding to the contents of ibuprofen, L-arginine and codeine phosphate hemihydrate: Table 1
  • the active substances were analyzed by means of HPLC techniques.
  • Example 2 The composition obtained in Example 1 was also subjected to a photostability test according to the above-mentioned method, observing that the contents of ibuprofen, arginine and codeine phosphate hemihydrate remained substantially unchanged in the bulk solution after said test, as shown in Table 2:
  • Purified water is.
  • Purified water is.
  • Purified water is.

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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

COMPOSICIÓN FARMACÉUTICA LÍQUIDA DE IBUPROFENO Y CODEÍNA PARA SU ADMINISTRACIÓN POR VÍA ORAL, SU PROCEDIMIENTO DE PREPARACIÓN Y UTILIZACIÓN DE LA MISMA Campo de la técnica  IBUPROFEN AND CODEINE LIQUID PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION, ITS PREPARATION AND USE PROCEDURE OF THE SAME Field of Technology
La presente invención se refiere a una nueva composición farmacéutica líquida que contiene ibuprofeno en forma de una sal formada con un aminoácido básico y codeína o una sal de codeína farmacéuticamente aceptable, para su administración vía oral. Igualmente, la invención se refiere a un procedimiento para la preparación de dicha composición farmacéutica líquida, así como a su utilización, preferentementemente en pediatría, para la fabricación de un medicamento útil en el tratamiento del dolor moderado a severo, la inflamación, la fiebre y/u otras dolencias en las que tradicionalmente se emplea ibuprofeno y/o codeína, principalmente como analgésico. The present invention relates to a new liquid pharmaceutical composition containing ibuprofen in the form of a salt formed with a basic amino acid and codeine or a pharmaceutically acceptable codeine salt, for oral administration. Likewise, the invention relates to a process for the preparation of said liquid pharmaceutical composition, as well as its use, preferably in pediatrics, for the manufacture of a medicament useful in the treatment of moderate to severe pain, inflammation, fever and / or other medical conditions in which ibuprofen and / or codeine are traditionally used, mainly as an analgesic.
Estado de la técnica anterior Las sales de ibuprofeno con aminoácidos básicos son conocidas al menos desde el año 1976, cuando se publicó la patente española ES 435416 donde se describía un procedimiento para la preparación de una sal de ibuprofeno con L-arginina y una sal de ibuprofeno con L-lisina. El ibuprofeno es un fármaco antiinflamatorio no esteroideo (en inglés "NSAID", en español "AINE") que se emplea en medicina por su actividad analgésica, antipirética y antiinflámatoria. State of the prior art Ibuprofen salts with basic amino acids have been known at least since 1976, when Spanish patent ES 435416 was published where a procedure for the preparation of an ibuprofen salt with L-arginine and a salt of ibuprofen with L-lysine. Ibuprofen is a non-steroidal anti-inflammatory drug (in English "NSAID", in Spanish "NSAID") that is used in medicine for its analgesic, antipyretic and anti-inflammatory activity.
En el estado de la técnica se han descrito formas farmacéuticas sólidas y líquidas que contienen ibuprofeno como principio activo. Así, por ejemplo, en la solicitud de patente PCT WO-A-95/00134 se describe una composición farmacéutica líquida para la administración vía oral que contiene ibuprofeno, arginina, agentes edulcorantes, agentes conservantes y agua como disolvente. Dicha composición presenta un contenido en ibuprofeno de al menos 200 mg/ml y es necesario diluirla en el momento de su utilización. Solid and liquid pharmaceutical forms containing ibuprofen as active ingredient have been described in the state of the art. So by For example, in the PCT patent application WO-A-95/00134 a liquid pharmaceutical composition for oral administration containing ibuprofen, arginine, sweetening agents, preservatives and water as solvent is described. Said composition has an ibuprofen content of at least 200 mg / ml and must be diluted at the time of use.
La codeína es un alcaloide que fue aislado en 1830 de la planta del opio. Si bien se puede obtener por extracción de dicha planta, mayoritariamente se obtiene por metilación de la morfina. Son conocidas diferentes sales de codeína, por ejemplo su clorhidrato, sulfato y fosfato. La codeína y sus sales encuentran su aplicación en medicina por sus propiedades analgésicas, antitusivas y antidiarreicas. En la solicitud de patente europea EP-A-0388125 se describe que la combinación ibuprofeno y codeína es conocida desde principios de los años '80 y que dicha combinación presenta un efecto analgésico superior al del ibuprofeno o al de la codeína por sí solos. En el estado de la técnica se ha descrito que el ibuprofeno y la codeína pueden interaccionar cuando se encuentran presentes en una misma composición farmacéutica, pudiendo dicha interacción afectar a la estabilidad de estos principios activos. En el marco de un estudio para separar ibuprofeno, fosfato de codeína y sus productos de degradación e impurezas por electroforesis capilar (véase el artículo de Persson-Stubberud y col., J. Chromatogr., 1998, A 798, 307-314) se describe un éster de ibuprofeno y codeína como probable producto de degradación de aquellas combinaciones farmacéuticas que contienen ambos principios activos. Para evitar tal interacción, los técnicos se han visto obligados a diseñar formas de administración complejas que mantienen los dos principios activos separados y que requieren procesos más complejos para su fabricación industrial. Así, por ejemplo, en la solicitud de patente europea EP-A-0159852 se describe una composición de ibuprofeno y codeína que es directamente compresible. En dicha composición, la codeína se encuentra granulada y por separado del ibuprofeno, junto con polivinilpirrolidona y lactosa, para evitar el contacto íntimo entre los dos componentes activos, contacto que puede afectar adversamente a la estabilidad de los mismos. También se describe en la EP-A-0159852 que la granulación conjunta en húmedo de ibuprofeno y sales de codeína conduce a la formación de coloraciones durante dicho proceso y en el secado posterior del granulado. Codeine is an alkaloid that was isolated in 1830 from the opium plant. Although it can be obtained by extracting said plant, it is mostly obtained by morphine methylation. Different codeine salts are known, for example their hydrochloride, sulfate and phosphate. Codeine and its salts find their application in medicine for their analgesic, antitussive and antidiarrheal properties. European patent application EP-A-0388125 describes that the combination ibuprofen and codeine has been known since the early 1980s and that this combination has an analgesic effect superior to that of ibuprofen or codeine alone. In the state of the art it has been described that ibuprofen and codeine can interact when they are present in the same pharmaceutical composition, said interaction being able to affect the stability of these active ingredients. Within the framework of a study to separate ibuprofen, codeine phosphate and its degradation products and impurities by capillary electrophoresis (see article by Persson-Stubberud et al., J. Chromatogr., 1998, A 798, 307-314) describes an ibuprofen and codeine ester as a probable degradation product of those pharmaceutical combinations that contain both active ingredients. To avoid such interaction, technicians have been forced to design complex forms of administration that keep the two active principles separate and that require more complex processes for their industrial manufacturing Thus, for example, in the European patent application EP-A-0159852 a composition of ibuprofen and codeine is described which is directly compressible. In said composition, codeine is granulated and separately from ibuprofen, together with polyvinylpyrrolidone and lactose, to avoid intimate contact between the two active components, contact that can adversely affect their stability. It is also described in EP-A-0159852 that the wet wet granulation of ibuprofen and codeine salts leads to the formation of colorations during said process and in the subsequent drying of the granulate.
En las solicitudes de patente europeas EP-A-0220805 y EP-A- 0535841 se describen comprimidos bicapa donde, para evitar la interacción entre el ibuprofeno y la codeína, ambos principios activos se encuentran en capas separadas. En la solicitud de patente europea EP-A- 0274845 se describe una composición farmacéutica sólida estable de ibuprofeno y codeína que contiene una cantidad efectiva de sal cálcica de carboximetilcelulosa. Se indica que la presencia de tal agente disgregante confiere estabilidad a las composiciones, mientras que la presencia de otros agentes disgregantes distintos conduce a la formación de coloraciones cuando las composiciones se almacenan a una temperatura de 50° C. En la solicitud de patente PCT WO-A-96/05834 se describen composiciones farmacéuticas sólidas de ibuprofeno y , codeína que incluyen un aceite vegetal hidrogenado para evitar los problemas de estabilidad asociados a las formulaciones que contienen ibuprofeno y codeína y que se observan durante su almacenamiento. Bilayer tablets are described in European patent applications EP-A-0220805 and EP-A-0535841 where, in order to avoid the interaction between ibuprofen and codeine, both active ingredients are found in separate layers. European patent application EP-A-0274845 describes a stable solid pharmaceutical composition of ibuprofen and codeine containing an effective amount of carboxymethyl cellulose calcium salt. It is indicated that the presence of such a disintegrating agent confers stability to the compositions, while the presence of other different disintegrating agents leads to the formation of colorations when the compositions are stored at a temperature of 50 ° C. In the PCT WO patent application -A-96/05834 describes solid pharmaceutical compositions of ibuprofen and , codeine that include a hydrogenated vegetable oil to avoid the stability problems associated with formulations containing ibuprofen and codeine and that are observed during storage.
En otra aproximación, el ibuprofeno se mantiene sustancialmente en suspensión, tal como se describe en la solicitud de patente europea EP-A-0413171 , donde se desarrollan composiciones farmacéuticas para el tratamiento de estados de dolor graves. En dicha solicitud de patente se describe una suspensión de ibuprofeno finamente dividido y fosfato de codeína en una mezcla de PLURONIC® L35, CREMOPHOR® RH40 y 1 ,2- propilenglicol. Dicha suspensión se encapsula en cápsulas de gelatina blanda con el fin de evitar eventuales problemas de sedimentación e imprecisiones en la dosificación. In another approach, ibuprofen is substantially suspended, as described in European Patent Application EP-A-0413171, where pharmaceutical compositions are developed for the treatment of serious pain states. In said patent application a suspension of finely divided ibuprofen and codeine phosphate in a mixture of Pluronic ® L35, CREMOPHOR RH40 ® and 1, 2- propylene glycol described. Said suspension is encapsulated in soft gelatin capsules in order to avoid possible sedimentation problems and inaccuracies in the dosage.
Otra solución técnica consiste en emplear mezclas de varios disolventes para preparar las composiciones líquidas con contenidos relativamente bajos de principios activos. Así, en la solicitud de patente europea EP-A-0429856 se describen diversas composiciones líquidas que contienen una sal magnésica de ibuprofeno y clorhidrato de codeína, ambos disueltos en una mezcla de 1 ,2-propanodiol, agua y glicerina, siendo ésta última el disolvente principal. Esta combinación de disolventes permite preparar soluciones con un contenido relativamente bajo de principios activos. Another technical solution consists in using mixtures of various solvents to prepare liquid compositions with relatively low contents of active ingredients. Thus, in the European patent application EP-A-0429856 various liquid compositions are described which contain a magnesium salt of ibuprofen 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 allows solutions with a relatively low content of active ingredients to be prepared.
Por tanto, sigue siendo necesario poder disponer de una formulación farmacéutica líquida de ibuprofeno y codeína que presente una buena estabilidad y un contenido sustancialmente elevado de principios activos. Therefore, it is still necessary to have a liquid pharmaceutical formulation of ibuprofen and codeine that has good stability and a substantially high content of active ingredients.
Objeto de la invención El objeto de la presente invención es una composición farmacéutica líquida para la administración por vía oral que comprende ibuprofeno en forma de sal con un aminoácido básico y codeína o una sal de codeína. También forma parte del objeto de la invención un procedimiento para preparar dicha composición farmacéutica. Object of the invention The object of the present invention is a liquid pharmaceutical composition for oral administration comprising ibuprofen in the form of a salt with a basic amino acid and codeine or a codeine salt. Also part of the object of the invention is a process for preparing said pharmaceutical composition.
Forma parte también del objeto de la invención, la utilización de dicha composición, preferentemente en pediatría, para la fabricación de un medicamento para el tratamiento por vía oral del dolor moderado a severo, la inflamación, la fiebre y/u otras dolencias de las tradicionalmente aliviadas mediante ¡buprofeno y/o codeína. Descripción detallada de la invención Also part of the object of the invention is the use of said composition, preferably in pediatrics, for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other ailments of those traditionally relieved by buprofen and / or codeine. Detailed description of the invention
Un objeto de la presente invención es una composición farmacéutica líquida para la administración por vía oral que comprende: - ¡buprofeno y un aminoácido básico seleccionado de entre el grupo consistente en arginina, lisina y mezclas de los mismos, en una relación molar ibuprofeno:aminoácido comprendida entre 0,9:1 y 1 ,1 :1 ; An object of the present invention is a liquid pharmaceutical composition for oral administration comprising: - buprofen and a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof, in a molar ratio ibuprofen: amino acid between 0.9: 1 and 1, 1: 1;
- codeína o una sal de codeína farmacéuticamente aceptable y - al menos un excipiente farmacéuticamente aceptable, donde el contenido de ¡buprofeno es igual o superior a 20 mg/ml y el contenido de la codeína o una sal farmacéuticamente aceptable de codeína es igual o superior a 0,92 mg/ml.  - codeine or a pharmaceutically acceptable codeine salt and - at least one pharmaceutically acceptable excipient, where the content of buprofen is equal to or greater than 20 mg / ml and the content of codeine or a pharmaceutically acceptable codeine salt is equal to or greater at 0.92 mg / ml.
Los autores de esta invención han desarrollado ahora una composición farmacéutica líquida que contiene una sal de ¡buprofeno y un aminoácido básico, seleccionado de entre arginina, lisina y/o mezclas los mismos, y fosfato de codeína, composición farmacéutica que se puede administrar fácilmente y que, sorprendentemente, presenta una buena estabilidad a pesar de incluir una cantidad de los principios activos considerablemente elevada. The authors of this invention have now developed a liquid pharmaceutical composition containing a buprofen salt and a basic amino acid, selected from arginine, lysine and / or mixtures thereof, and codeine phosphate, a pharmaceutical composition that can be easily administered and which, surprisingly, presents a good stability despite including a considerably high amount of active ingredients.
Los autores de la invención han dirigido sus esfuerzos investigadores hacia el desarrollo de formas líquidas, ya que éstas ofrecen muchas ventajas con respecto a las composiciones sólidas. Entre tales ventajas se puede destacar que las formas líquidas generalmente presentan una mejor biodisponibilidad que las formas sólidas, debido a que el principio activo ya se encuentra disuelto cuando llega al estómago, lo cual se traduce en un rápido inicio de la acción farmacológica. Los líquidos se pueden administrar fácilmente a niños o a personas incapaces de tragar cápsulas o comprimidos y proporcionan un excelente vehículo para la administración uniforme de los fármacos. En el contexto de la invención, por "composición farmacéutica líquida" se entiende que la composición es fluida a temperatura ambiente y que, en general, presenta una viscosidad inferior a 5.000 cps a una temperatura de 20° C. Ibuprofeno The authors of the invention have directed their research efforts towards the development of liquid forms, since they offer many advantages over solid compositions. Among these advantages, it should be noted that liquid forms generally have a better bioavailability than solid forms, because the active substance is already dissolved when it reaches the stomach, which translates into a rapid onset of pharmacological action. Liquids can be easily administered to children or people unable to swallow capsules or tablets and provide an excellent vehicle for uniform administration of drugs. In the context of the invention, "liquid pharmaceutical composition" means that the composition is fluid at room temperature and, in general, has a viscosity of less than 5,000 cps at a temperature of 20 ° C. Ibuprofen
El ibuprofeno es un compuesto que tiene un átomo de carbono quiral en su molécula y, consecuentemente, presenta dos enantiómeros. Es conocido que en medicina se emplea principalmente ibuprofeno racémico, es decir (RS)-ibuprófeno. También es conocido que el enantiómero activo es el enantiómero que tiene la configuración S en el centro quiral, es decir (S)-ibuprofeno. No obstante, el otro enantiómero, (R)-ibuprofeno, con la configuración R en el centro quiral, también contribuye a la actividad farmacológica del ibuprofeno racémico, ya que es parcialmente convertido al enantiómero (S) en el organismo. En el contexto de la presente invención, el término "ibuprofeno" se refiere indistintamente al ibuprofeno racémico (RS), así como al (S)- ¡buprofeno y al (R)-ibuprofeno. Ibuprofen is a compound that has a chiral carbon atom in its molecule and, consequently, has two enantiomers. It is known that in medicine mainly racemic ibuprofen is used, that is (RS) -ibuprophen. It is also known that the active enantiomer is the enantiomer having the S configuration in the chiral center, that is (S) -ibuprofen. However, the other enantiomer, (R) -ibuprofen, with the R configuration in the chiral center, also contributes to the pharmacological activity of racemic ibuprofen, since it is partially converted to the enantiomer (S) in the body. In the context of the present invention, the term "ibuprofen" refers interchangeably to racemic ibuprofen (RS), as well as to (S) - buprofen and (R) -ibuprofen.
Preferiblemente, el ibuprofeno empleado en la composición farmacéutica de la presente invención se selecciona de entre el grupo formado por (RS)-ibuprofeno y (S)-ibuprofeno. Preferably, the ibuprofen used in the pharmaceutical composition of the present invention is selected from the group consisting of (RS) -ibuprofen and (S) -ibuprofen.
El ibuprofeno se puede preparar de acuerdo con el procedimiento descrito en la solicitud de patente GB-A-971700. La resolución del ibuprofeno en sus enantiomeros se describe en el artículo de Brushan y col., Biomed. Chromatogr., 1998, 12, 309.  Ibuprofen can be prepared according to the procedure described in patent application GB-A-971700. The resolution of ibuprofen in its enantiomers is described in the article by Brushan et al., Biomed. Chromatogr., 1998, 12, 309.
La cantidad de ibuprofeno presente en la composición de la invención es igual o superior a 20 mg/ml, preferiblemente igual o superior a 50 mg/ml, en especial igual o superior a 100 mg/ml, con especial preferencia igual o superior a 150 mg/ml, en particular igual o superior a 200 mg/ml y con particular preferencia es igual a 200 mg/ml. Aminoácidos básicos The amount 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 with particular preference is equal to 200 mg / ml. Basic amino acids
La composición de la invención comprende un aminoácido básico seleccionado de entre el grupo formado por arginina, lisina y mezclas de los mismos. Dichos aminoácidos tienen en su estructura al menos un grupo amino adicional que les confiere un carácter básico, de modo que las soluciones acuosas de dichos aminoácidos presentan un pH en el rango alcalino. Muchos aminoácidos se encuentran disponibles en la forma D o en la forma L, que es la natural. En el contexto de esta invención, los términos ~arginina " y lisina " se refieren a la forma D, a la forma L o a mezclas de ambas formas L y D. Preferiblemente, en la composición de la invención se emplea el aminoácido básico arginina y en particular el aminoácido en su forma natural L-arginina. The composition of the invention comprises a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof. Said amino acids have in their structure at least one additional amino group which gives them a basic character, so that the aqueous solutions of said amino acids have a pH in the alkaline range. Many amino acids are available in form D or form L, which is the natural one. In the context of this invention, the terms "arginine" and lysine "refer to form D, form L or mixtures of both forms L and D. Preferably, the basic amino acid arginine is used in the composition of the invention and in particular the naturally occurring amino acid L-arginine.
La relación molar ibuprofeno:aminoácido básico está comprendida entre 0,9:1 y 1 ,1 :1 , preferiblemente entre 0,92:1 y 1 ,07:1", én especial entre 0,95:1 y 1 ,05:1 , con especial preferencia entre 0,98:1 y 1 ,02:1 y en particular es 1 :1 . The ibuprofen: basic amino acid molar ratio is 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, with special preference between 0.98: 1 and 1, 02: 1 and in particular is 1: 1.
En general, el pH de la composición líquida obtenida está comprendido entre 7 y 8. Eventualmente se puede ajustar el pH dentro de este rango mediante el empleo de agentes correctores bien conocidos por el experto en la materia. Eventualmente también se pueden emplear las sales de arginina o de lisina del ibuprofeno previamente formadas. Dichas sales se pueden preparar, por ejemplo, de acuerdo con el procedimiento descrito en la patente española ES435516. Codeína  In general, the pH of the liquid composition obtained is between 7 and 8. The pH can be adjusted within this range by means of the use of corrective agents well known to those skilled in the art. Eventually, the previously formed ibuprofen arginine or lysine salts can also be used. Said salts can be prepared, for example, in accordance with the procedure described in Spanish patent ES435516. Codeine
La composición de la presente invención comprende codeína o una sal farmacéuticamente aceptable de codeína. En el contexto de la invención, la expresión "codeína " se refiere a codeína base o una sal farmacéuticamente aceptable de codeína y la expresión ~sal farmacéuticamente aceptable de codeína " incluye también los hidratos y solvatos de la misma. La sal de codeína farmacéuticamente aceptable se puede seleccionar de entre el grupo consistente en clorhidrato, yodhidrato, bromhidrato, bitartrato, citrato, acetato, sulfato y fosfato. Preferiblemente, en la composición de la invención, como sal de codeína, se emplea fosfato de codeína, en particular hemihidrato de fosfato de codeína. The composition of the present invention comprises codeine or a pharmaceutically acceptable codeine salt. In the context of the invention, the term " codeine" refers to codeine base or a pharmaceutically acceptable salt of codeine and the term "pharmaceutically acceptable salt of codeine" also includes the hydrates and solvates thereof. The pharmaceutically acceptable codeine salt may be selected from the group consisting of hydrochloride, iodhydrate, hydrobromide, bitartrate, citrate, acetate, sulfate and phosphate. Preferably, in the composition of the invention, as codeine salt, codeine phosphate is used, in particular codeine phosphate hemihydrate.
La cantidad de codeína o de la sal farmacéuticamente aceptable de codeína presente en la composición de la invención es igual o superior a 0,92 mg/ml, preferiblemente igual o superior a 2,5 mg/ml, en especial igual o superior a 3,0 mg/ml, con especial preferencia igual o superior a 10 mg/ml y en particular es 10 mg/ml. En determinadas realizaciones de la composición de la invención, la cantidad de codeína o de la sal farmacéuticamente aceptable de codeína puede llegar a 30 mg/ml. The amount of codeine or the pharmaceutically acceptable codeine salt present in the composition of the invention is equal 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 / ml, especially preferably equal to or greater than 10 mg / ml and in particular is 10 mg / ml. In certain embodiments of the composition of the invention, the amount of codeine or the pharmaceutically acceptable salt of codeine may reach 30 mg / ml.
La relación ponderal entre el ibuprofeno y la codeína o la sal farmacéuticamente aceptable de codeína no es crítica, pudiéndose diseñar diferentes proporciones entre ambos para definir composiciones según la invención con diferentes grados de potencia analgésica. The weight ratio between ibuprofen and codeine or the pharmaceutically acceptable codeine salt is not critical, and different proportions can be designed between them to define compositions according to the invention with different degrees of analgesic potency.
Así, por ejemplo, cuando se emplea hemihidrato de fosfato de codeína se pueden preparar composiciones que contienen 200 mg/ml de ibuprofeno y 30 mg/ml de hemihidrato de fosfato de codeína, o bien 200 mg/ml de ibuprofeno y 10 mg/ml de hemihidrato de fosfato de codeína, o bien 50 mg/ml de ibuprofeno y 3,17 mg/ml de hemihidrato de fosfato de codeína, siempre manteniendo las proporciones de principios activos mencionadas anteriormente. - ιυ - Thus, for example, when using codeine phosphate hemihydrate, compositions containing 200 mg / ml of ibuprofen and 30 mg / ml of codeine phosphate hemihydrate, or 200 mg / ml of ibuprofen and 10 mg / ml can be prepared of codeine phosphate hemihydrate, or 50 mg / ml of ibuprofen and 3.17 mg / ml of codeine phosphate hemihydrate, always maintaining the proportions of active ingredients mentioned above. - ιυ -
Excipientes Excipients
Las composiciones farmacéuticas de la invención incluyen al menos un excipiente farmacéuticamente aceptable, el cual se puede seleccionar de entre el grupo consistente en conservantes, saborizantes, aromatizantes, edulcorantes y/o mezclas de los mismos. The pharmaceutical compositions of the invention include at least one pharmaceutically acceptable excipient, which can be selected from the group consisting of preservatives, flavorings, flavorings, sweeteners and / or mixtures thereof.
Ejemplos de conservantes que se pueden emplear en la composición farmacéutica de la invención son aquellos seleccionados de entre el grupo formado por bromuro de domifeno, butilparabén, propilparabén, etilparabén, metilparabén, alcohol bencílico, acetato de sodio, glicerina, xilitol y/o mezclas de los mismos, siendo especialmente preferentes los conservantes seleccionados de entre el grupo formado por bromuro de domifeno, butilparabén, propilparabén, etilparabén, metilparabén y/o mezclas de los mismos. Examples of preservatives that can be used in the pharmaceutical composition of the invention are those selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben, benzyl alcohol, sodium acetate, glycerin, xylitol and / or mixtures of the same, the preservatives selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben and / or mixtures thereof being especially preferred.
Preferiblemente, la composición farmacéutica de la invención incluye, como conservante, bromuro de domifeno, debido a que éste presenta una buena eficacia antimicrobiana en el rango de pH en el que se encuentra la composición de la invención. En este caso, la cantidad de bromuro de domifeno como agente conservante presente en la composición de la invención está comprendida entre 0,05 mg/ml y 0,5 mg/ml, preferiblemente entre 0,07 mg/ml y 0,2 mg/ml y en especial entre 0,09 mg/ml y 0,11 mg/ml. Preferably, the pharmaceutical composition of the invention includes, as a preservative, domifene bromide, because it has a good antimicrobial efficacy in the pH range in which the composition of the invention is found. In this case, the amount of domifen bromide as a preservative present in the composition of the invention is between 0.05 mg / ml and 0.5 mg / ml, preferably between 0.07 mg / ml and 0.2 mg. / ml and especially between 0.09 mg / ml and 0.11 mg / ml.
Los derivados de alquilparabén se pueden emplear solos o en combinación para obtener una mayor efectividad antimicrobiana. Dichos compuestos están disponibles comercialmente en forma ácida o en forma de sal, de modo que pueden emplearse en cualquiera de estas presentaciones. En el caso de emplear una mezcla de metilparabén y propilparabén, habitualmente la cantidad de metilparabén está comprendida entre 1 ,2 mg/ml y 2,0 mg/ml, preferiblemente entre 1 ,4 mg/ml y 1 ,8 mg/ml y en especial entre 1 ,5 mg/ml y 1 ,7 mg/ml; y la cantidad de propilparabén está comprendida generalmente entre 0,12 mg/ml y 0,26 mg/ml, preferiblemente entre 0,15 mg/ml y 0,23 mg/ml y en especial entre 0,18 mg/ml y 0,20 mg/ml. Alkylparaben derivatives can be used alone or in combination to obtain greater antimicrobial effectiveness. Such compounds are commercially available in acidic or salt form, so that they can be used in any of these presentations. In the case of using a mixture of methylparaben and propylparaben, usually the amount of methylparaben is between 1.2 mg / ml and 2.0 mg / ml, preferably between 1.4 mg / ml and 1.8 mg / ml and especially between 1.5 mg / ml and 1.7 mg / ml; and the amount of propylparaben is generally between 0.12 mg / ml and 0.26 mg / ml, preferably between 0.15 mg / ml and 0.23 mg / ml and especially between 0.18 mg / ml and 0 , 20 mg / ml.
Como ejemplos de saborizantes se pueden mencionar cloruro sódico, etilmaltol, etilvainilla, vainilla y mentol. Ejemplos de aromatizantes son aroma de menta, aroma de caramelo y aroma de limón, aunque también puede estar presente cualquier otro aroma adecuado. Dichos aromas se pueden encontrar comercialmente en forma de mezclas con otras sustancias para facilitar su dosificación. Por ejemplo, el aroma de caramelo puede contener sustancias aromatizantes idénticas a las naturales, sustancias aromatizantes naturales, maltodextrina, azúcar, aceite vegetal, dióxido de silicio y lecitina. Por su parte, el aroma de menta puede contener preparaciones aromatizantes naturales, sustancias aromatizantes naturales, sustancias aromatizantes idénticas a las naturales, maltodextrina, almidón de maíz modificado, triacetato de glicerina y pulegona. As examples of flavorings, sodium chloride, ethylmaltol, ethyl vanilla, vanilla and menthol can be mentioned. Examples of flavorings are mint aroma, caramel aroma and lemon aroma, although any other suitable aroma may also be present. Said aromas can be found commercially in the form of mixtures with other substances to facilitate their dosage. For example, caramel aroma may contain flavoring substances identical to natural ones, natural flavoring substances, maltodextrin, sugar, vegetable oil, silicon dioxide and lecithin. On the other hand, the mint aroma may contain natural flavoring preparations, natural flavoring substances, flavoring substances identical to natural ones, maltodextrin, modified corn starch, glycerin triacetate and pulegone.
Ejemplos de edulcorantes que pueden estar presentes en la composición de la invención son aquellos seleccionados de entre el grupo consistente en maltitol, sacarosa, dextrosa, fructosa, glucosa, glicerina, inulina, isomaltosa, lactitol, maltosa, maltol, manitol, sucralosa, trehalosa, xilitol, propilenglicol, sorbitol, sacarina sódica, taumatina, ciclamato sódico, y/o mezclas de los mismos. Preferiblemente se emplea un edulcorante seleccionado de entre el grupo consistente en maltitol, sacarosa, glucosa, taumatina, sacarina sódica y/o mezclas de los mismos; en particular, el edulcorante se selecciona de entre el grupo formado por maltitol, sacarina sódica, taumatina y/o mezclas de los mismos. Examples of sweeteners that may be present in the composition of the invention are those selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatine, sodium cyclamate, and / or mixtures thereof. Preferably a sweetener selected from the group consisting of maltitol, sucrose, glucose, thaumatine, sodium saccharin and / or mixtures thereof is used; in particular the Sweetener is selected from the group consisting of maltitol, sodium saccharin, thaumatine and / or mixtures thereof.
En la composición de la presente invención, los excipientes farmacéuticamente aceptables se pueden emplear en forma sólida o líquida. Por ejemplo, el maltitol se puede encontrar comercialmente en forma sólida o en forma de solución acuosa conteniendo entre un 68% y un 85% en peso de maltitol. Las características físico-químicas de los excipientes, así como el nombre de los productos comerciales bajo los que se comercializan, se pueden encontrar en el libro de R.C. Rowe y col, "Handbook of Pharmaceutical Excipiente", 4a edición, Pharmaceutical Press, Londres, 2003 [ISBN: 0-85369-472-9]. In the composition of the present invention, pharmaceutically acceptable excipients can be used in solid or liquid form. For example, maltitol can be found commercially in solid form or in the form of an aqueous solution containing between 68% and 85% by weight of maltitol. Physico-chemical properties of excipients as well as the name of the commercial products under which they are marketed, features can be found in the book of RC Rowe et al, "Handbook of Pharmaceutical Excipients", 4th edition, Pharmaceutical Press, London , 2003 [ISBN: 0-85369-472-9].
En un ejemplo de la realización de la composición farmacéutica líquida de la presente invención, ésta comprende los siguientes componentes: In an example of the embodiment of the liquid pharmaceutical composition of the present invention, it comprises the following components:
- 200 mg/ml de ibuprofeno,  - 200 mg / ml ibuprofen,
- 10 mg/ml de fosfato de codeína hemihidrato,  - 10 mg / ml codeine phosphate hemihydrate,
- 170 mg/ml de L-arginina,  - 170 mg / ml of L-arginine,
- 0,10 mg/ml de bromuro de domifeno,  - 0.10 mg / ml domifen bromide,
- 100 mg/ml de maltitol líquido ,  - 100 mg / ml liquid maltitol,
- 1 ,7 mg/ml de sacarina sódica y  - 1, 7 mg / ml of sodium saccharin and
- 0,05 mg/ml de taumatina. Preferiblemente, esta composición incluye adicionalmente agentes aromatizantes.  - 0.05 mg / ml of thaumatine. Preferably, this composition additionally includes flavoring agents.
Alternativamente, en otra forma de realización especialmente preferente de la composición farmacéutica líquida de la invención, ésta comprende los siguientes componentes: - 200 mg/ml de ibuprofeno, Alternatively, in another especially preferred embodiment of the liquid pharmaceutical composition of the invention, it comprises the following components: - 200 mg / ml ibuprofen,
- 10 mg/ml de fosfato de codeína hemihidrato,  - 10 mg / ml codeine phosphate hemihydrate,
- 170 mg/ml de L-arginina,  - 170 mg / ml of L-arginine,
- 1 ,67 mg/ml de metilparabén,  - 1, 67 mg / ml methylparaben,
- 0,19 mg/ml de propilparabén,  - 0.19 mg / ml propylparaben,
- 00 mg/ml de sacarosa,  - 00 mg / ml sucrose,
- 1 ,7 mg/ml de sacarina sódica y  - 1, 7 mg / ml of sodium saccharin and
- 0,05 mg/ml de taumatina.  - 0.05 mg / ml of thaumatine.
Preferiblemente, esta composición incluye adicionalmente agentes aromatizantes. Preferably, this composition additionally includes flavoring agents.
La composición farmacéutica de la presente invención es sustancialmente acuosa. Esto significa que el disolvente de la misma está constituido sustancialmente por agua y que se trata de una composición sustancialmente exenta de otros disolventes que no sean agua. Si bien no se excluye que algunos de los excipientes farmacéuticamente aceptables que eventualmente puedan formar parte de dicha composición puedan incluir algún disolvente miscible en agua. The pharmaceutical composition of the present invention is substantially aqueous. This means that the solvent thereof is substantially water and that it is a composition substantially free of solvents other than water. While it is not excluded that some of the pharmaceutically acceptable excipients that may eventually be part of said composition may include some water miscible solvent.
En general, el 90% en peso de los disolventes presentes en la composición de la invención es agua, pudiendo llegar hasta el 95% en peso o hasta el 99% en peso. In general, 90% by weight of the solvents present in the composition of the invention is water, which can reach up to 95% by weight or up to 99% by weight.
Otro objeto de la invención consiste en un procedimiento para la preparación la composición líquida de ibuprofeno y codeína de la presente invención, procedimiento que comprende las etapas de: a) diluir la sal de ibuprofeno con el aminoácido básico en una parte del agua, Another object of the invention is a process for preparing the liquid composition of ibuprofen and codeine of the present invention, a process comprising the steps of: a) dilute the ibuprofen salt with the basic amino acid in a part of the water,
b) añadir la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable a la solución obtenida en la etapa a), agitar hasta disolución completa y ajustar con agua hasta el volumen final, o alternativamente c) disolver la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable en una parte del agua, b) add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step a), stir until complete dissolution and adjust with water to the final volume, or alternatively c) dissolve the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of the water,
d) añadir la sal de ibuprofeno con el aminoácido básico en la disolución obtenida en la etapa c) y agitar hasta disolución completa, d) add the ibuprofen salt with the basic amino acid in the solution obtained in step c) and stir until completely dissolved,
e) completar con agua hasta el volumen final, o alternativamente f) dispersar el aminoácido básico en una parte del agua, e) complete with water to the final volume, or alternatively f) disperse the basic amino acid in a part of the water,
g) añadir el ibuprofeno a la dispersión obtenida en la etapa f) y agitar hasta disolución completa, g) add ibuprofen to the dispersion obtained in step f) and stir until completely dissolved,
h) añadir la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable a la solución obtenida en la etapa g), agitar hasta disolución completa y ajustar con agua hasta el volumen final, o alternativamente i) disolver la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable en una parte del agua, h) add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step g), stir until completely dissolved and adjust with water to the final volume, or alternatively i) dissolve the codeine or pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a portion of the water,
j) dispersar el aminoácido básico en la disolución obtenida en la etapa i),  j) dispersing the basic amino acid in the solution obtained in step i),
k) añadir el ibuprofeno a la dispersión obtenida en la etapa j) y agitar hasta disolución completa y  k) add ibuprofen to the dispersion obtained in step j) and stir until completely dissolved and
I) completar con agua hasta el volumen final. Preferiblemente la sal de ibuprofeno con el aminoácido básico se diluye en una parte de agua equivalente a la mitad del volumen del lote de fabricación; alternativamente, el aminoácido básico se dispersa en una parte del agua equivalente a la mitad del volumen del lote de fabricación; alternativamente, la codeína o la sal farmacéuticamente aceptable de codeína y del al menos un excipiente aceptable se disuelven en una parte del agua equivalente s la mitad del volumen del lote de fabricación.  I) complete with water to the final volume. Preferably the ibuprofen salt with the basic amino acid is diluted in a part of water equivalent to half the volume of the manufacturing batch; alternatively, the basic amino acid is dispersed in a part of the water equivalent to half the volume of the manufacturing batch; alternatively, the codeine or the pharmaceutically acceptable salt of codeine and the at least one acceptable excipient are dissolved in a part of the water equivalent to half the volume of the manufacturing batch.
En caso de no usar directamente la sal de ibuprofeno con el aminoácido básico, la dispersión previa del aminoácido básico proporciona un pH alcalino apropiado que facilita la disolución subsiguiente del ibuprofeno. If the ibuprofen salt is not used directly with the basic amino acid, the previous dispersion of the basic amino acid provides an appropriate alkaline pH that facilitates the subsequent dissolution of ibuprofen.
La composición líquida de la invención obtenida mediante el procedimiento de la invención es una solución sustancialmente transparente. Opcionalmente se puede separar por filtración o centrifugación cualquier precipitado que se hubiera podido formar durante el proceso de fabricación. Por ello, resulta preferente que después de la adición de la codeína o la sal farmacéuticamente aceptable de codeína, y del al menos un excipiente farmacéutico, se agite suficientemente para conseguir una solución después de la adición de cada nuevo componente. En el caso de que la composición farmacéutica de la invención incluya varios excipientes, en el procedimiento de la invención, después de la adición de cada uno de ellos, preferiblemente se agita la mezcla hasta conseguir su completa disolución. The liquid composition of the invention obtained by the process of the invention is a substantially transparent solution. Optionally, any precipitate that could have formed during the manufacturing process can be separated by filtration or centrifugation. Therefore, it is preferred that after the addition of the codeine or the pharmaceutically acceptable salt of codeine, and of the at least one pharmaceutical excipient, is sufficiently stirred to achieve a solution after the addition of each new component. In the event that the pharmaceutical composition of the invention includes several excipients, in the process of the invention, after the addition of each of them, the mixture is preferably stirred until it is completely dissolved.
Los excipientes mencionados se pueden añadir en la etapa b) del procedimiento de la invención o alternativamente después de la etapa d) y antes de completar con agua hasta el volumen final (etapa e)) o alternativamente en la etapa h) o alternativamente, después de la etapa k) y antes de completar con agua hasta el volumen final (etapa I)) The mentioned excipients can be added in step b) of the process of the invention or alternatively after step d) and before filling with water to the final volume (step e)) or alternatively in step h) or alternatively, after from stage k) and before completing with water to the final volume (stage I))
El procedimiento de la invención para la preparación de la composición farmacéutica de la invención se puede llevar a cabo a una temperatura comprendida entre 15° C y 50° C, preferiblemente a una temperatura cercana a la temperatura ambiente. The process of the invention for the preparation of the pharmaceutical composition of the invention can be carried out at a temperature between 15 ° C and 50 ° C, preferably at a temperature close to room temperature.
En el procedimiento de la invención, los excipientes se pueden añadir en forma sólida o bien en forma de solución sustancialmente acuosa, previamente preparada en un recipiente aparte con una parte del agua que forma parte de la formulación. Por ejemplo, cuando se emplea bromuro de domifeno, se ha observado que se puede formar espuma al añadir dicho conservante en forma pulverulenta a la solución acuosa de la sal farmacéuticamente aceptable de codeína. Por ello, es preferible preparar una solución de bromuro de domifeno en una parte del agua de la formulación antes de proceder a su adición a dicha solución. In the process of the invention, the excipients can 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 that forms part of the formulation. For example, when domifen bromide is used, it has been found that foam can be formed by adding said preservative in powder form to the aqueous solution of the pharmaceutically acceptable codeine salt. Therefore, it is preferable to prepare a solution of domifene bromide in a part of the water of the formulation before proceeding with its addition to said solution.
El procedimiento de la invención para preparar la composición de la invención incluye la etapa de completar con agua hasta un volumen final,etapa bien conocida por el experto en la materia y que se refiere a añadir el agua suficiente al recipiente donde se ha efectuado la preparación de la composición para obtener la concentración de principios activos deseada. The process of the invention for preparing the composition of the invention includes the step of completing with water to a final volume, a stage well known to the person skilled in the art and which refers to adding sufficient water to the container where the preparation of the composition has been carried out to obtain the desired concentration of active ingredients.
Ensayos de estabilidad Stability tests
La composición farmacéutica de la invención se sometió a ensayos de estabilidad bajo las siguientes condiciones de temperatura y de humedad relativa (H.R.): The pharmaceutical composition of the invention was subjected to stability tests under the following conditions of temperature and relative humidity (H.R.):
- 25° C y 60% H.R.  - 25 ° C and 60% H.R.
- 30° C y 65% H.R.  - 30 ° C and 65% H.R.
- 40° C y 75% H.R., y  - 40 ° C and 75% H.R., and
- 5o C a 8o C bajo refrigeración. - 5 o C to 8 o C under refrigeration.
La composición líquida de la invención presentó una buena estabilidad y los contenidos de ibuprofeno y codeína permanecieron sustancialmente inalterados después de 36 meses de almacenamiento a 25° C y bajo una humedad relativa del 60%, a 30° C y bajo una humedad relativa del 65%, así como después de 6 meses a una temperatura de 40° C bajo una humedad relativa del 75% y después de 6 meses bajo refrigeración a una temperatura comprendida entre 5o C y 8o C. A esta temperatura no se observó aparición de turbidez alguna o de precipitados. Los resultados correspondientes a la estabilidad se presentan en los Ejemplos. El contenido en principios activos presente en la composición de la invención se puede analizar por medio de técnicas HPLC (cromatografía líquida de alta resolución), bien conocidas por el experto en la materia, y ajusfando las condiciones operatorias mediante ensayos de rutina propios de un laboratorio de análisis de principios activos farmacéuticos. Sorprendentemente, la composición farmacéutica de la invención es estable incluso cuando incluye cantidades apreciables de ibuprofeno y codeína disueltos en una composición líquida sustancialmente acuosa. La composición de la invención se sometió también a un ensayo de fotoestabilidad, observándose que los contenidos de ibuprofeno y codeína permanecían sustancialmente inalterados en la solución a granel después de dicho ensayo. El ensayo de fotoestabilidad se llevó a cabo de acuerdo con las especificaciones descritas en el documento de la ICH (International Conference on Harmonization) según Stability Testing: Photostability testing of New Drug Substances and Products Q1B. Los resultados de dicho ensayo se presentan en el apartado de Ejemplos. The liquid composition of the invention exhibited good stability and the contents of ibuprofen and codeine remained substantially unchanged after 36 months of storage at 25 ° C and under a relative humidity of 60%, at 30 ° C and under a relative humidity of 65 %, as well as after 6 months at a temperature of 40 ° C under a relative humidity of 75% and after 6 months under refrigeration at a temperature between 5 o C and 8 o C. At this temperature no appearance of some turbidity or precipitates. The results corresponding to stability are presented in the Examples. The content of active ingredients present in the composition of the invention can be analyzed by means of HPLC (high performance liquid chromatography) techniques, well known to the person skilled in the art, and adjusting the operating conditions by means of routine laboratory tests of analysis of pharmaceutical active ingredients. Surprisingly, the pharmaceutical composition of the invention is stable even when it includes appreciable amounts of ibuprofen and codeine dissolved in a substantially aqueous liquid composition. The composition of the invention was also subjected to a photostability test, observing that the contents of ibuprofen and codeine remained substantially unchanged in the bulk solution after said test. The photostability test was carried out in accordance with the specifications described in the document of the ICH (International Conference on Harmonization) according to Stability Testing: Photostability testing of New Drug Substances and Products Q1B. The results of this test are presented in the Examples section.
Utilización de la composición farmacéutica de la invención Use of the pharmaceutical composition of the invention
Forma parte también del objeto de la invención la utilización de la composición farmacéutica de la invención, preferentemente en pediatría, para la fabricación de un medicamento para el tratamiento vía oral del dolor moderado a severo, la inflamación, la fiebre y/u otras dolencias que se pueden aliviar con ibuprofeno y/o codeína. Entre las dolencias que se pueden aliviar con ibuprofeno se incluyen, por ejemplo, la enfermedad de Alzheimer, la artritis y la dismenorrea primaria. Also part of the object of the invention is the use of the pharmaceutical composition of the invention, preferably in pediatrics, for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other medical conditions. They can be relieved with ibuprofen and / or codeine. Conditions that can be relieved with ibuprofen include, for example, Alzheimer's disease, arthritis and primary dysmenorrhea.
La composición farmacéutica de la invención se caracteriza por su alta eficacia y por el rápido inicio del efecto farmacológico, por lo que es especialmente adecuada como analgésico para aliviar rápidamente el dolor. La composición farmacéutica de la invención se puede administrar diluida en un líquido en el momento de su utilización, por ejemplo en agua. La dosis a administrar al sujeto puede variar según su peso corporal, la indicación y la gravedad de la afección. En general, la dosis de la composición de la invención a administrar al sujeto vía oral es aquella que permite suministrarle una cantidad de ¡buprofeno de entre 100 y 800 mg cada 4 a 6 horas, preferiblemente de entre 200 y 400 mg, estando comprendida la dosis diaria máxima entre 800 y 1.200 mg de ibuprofeno. En algunos casos se puede llegar incluso a una dosis diaria máxima de 2.400 mg de ibuprofeno. The pharmaceutical composition of the invention is characterized by its high efficacy and the rapid onset of the pharmacological effect, so it is especially suitable as an analgesic to quickly relieve pain. The pharmaceutical composition of the invention can be administered diluted in a liquid at the time of use, for example in water. The dose to be administered to the subject may vary according to his body weight, the indication and the severity of the condition. In general, the dose of the composition of the invention to be administered to the subject orally is that which allows a quantity of buprofen of between 100 and 800 mg to be given every 4 to 6 hours, preferably between 200 and 400 mg, with the maximum daily dose between 800 and 1,200 mg of ibuprofen. In some cases, a maximum daily dose of 2,400 mg of ibuprofen can be reached.
La composición farmacéutica de la invención también es apropiada para el uso pediátrico. En general, la dosis pediátrica de ibuprofeno a administrar al sujeto vía oral medíante la composición de la invención se sitúa entre 5 mg/kg y 10 mg/kg de ¡buprofeno cada 4 a 6 horas. De igual forma, la dosis pediátrica de codeína a administrar vía oral al sujeto mediante la composición de la invención está comprendida entre 0,5 y 1 mg/Kg cada 4 a 6 horas, con un máximo de 60 mg/dosis, llegando en algunos casos a una dosis diaria de 120 mg. The pharmaceutical composition of the invention is also suitable for pediatric use. In general, the pediatric dose of ibuprofen to be administered to the subject orally through the composition of the invention is between 5 mg / kg and 10 mg / kg of buprofen every 4 to 6 hours. Similarly, the pediatric dose of codeine to be administered orally to the subject through the composition of the invention is between 0.5 and 1 mg / kg every 4 to 6 hours, with a maximum of 60 mg / dose, reaching some cases at a daily dose of 120 mg.
Los ejemplos siguientes sirven para ilustrar la invención, pero no la limitan en modo alguno. The following examples serve to illustrate the invention, but do not limit it in any way.
Ejemplos Examples
Ejemplo 1 : Preparación de una formulación líquida concentrada con Example 1: Preparation of a concentrated liquid formulation with
200 mg/ml de ibuprofeno y 10 mg/ml de fosfato de codeína hemihidrato En un reactor de acero inoxidable equipado con agitador se introducen 50 litros de agua purificada y se disuelve en ella 1 ,0 kg de fosfato de codeína hemihidrato mediante agitación. A continuación, se añaden 0,17 kg de sacarina sódica, 0,25 kg de aroma de caramelo y 1 ,60 kg de aroma de menta y se agita hasta disolución total. Seguidamente se añaden 0,005 kg del edulcorante taumatina y se agita hasta disolución total. En esta solución se dispersan 17,0 kg de L-arginina bajo agitación. A continuación, se añaden 20,0 kg de ibuprofeno y se mantiene la agitación hasta disolución completa. A esta solución se añaden 10,0 kg de una solución de maltitol líquido y se agita hasta conseguir la completa homogeneización. Finalmente, se añaden 0,01 kg de bromuro de domifeno disueltos en 1 litro de agua purificada, se ajusta con agua hasta 100 litros y se agita hasta conseguir una solución homogénea. La composición líquida se envasa en frascos de 30 mi y 60 mi. 200 mg / ml ibuprofen and 10 mg / ml codeine phosphate hemihydrate In a stainless steel reactor equipped with a stirrer, 50 liters of purified water are introduced and 1.0 kg of codeine phosphate hemihydrate is dissolved therein by stirring. Next, 0.17 kg of sodium saccharin, 0.25 kg of caramel aroma and 1.60 kg of mint aroma are added and stirred until completely dissolved. Then 0.005 kg of the thaumatine sweetener is added and stirred until completely dissolved. 17.0 kg of L-arginine is dispersed in this solution under stirring. Then, 20.0 kg of ibuprofen are added and stirring is maintained until complete dissolution. To this solution, 10.0 kg of a liquid maltitol solution are added and stirred until complete homogenization is achieved. Finally, 0.01 kg of domifen bromide dissolved in 1 liter of purified water is added, adjusted with water to 100 liters and stirred until a homogeneous solution is achieved. The liquid composition is packaged in 30 ml and 60 ml bottles.
La formulación líquida de administración oral así obtenida tiene la siguiente composición: The oral oral liquid formulation thus obtained has the following composition:
Componente mg/ml Mg / ml component
Inqredientes activos Active ingredients
Ibuprofeno 200,00 Ibuprofen 200.00
Fosfato de codeína hemihidrato 10,00Codeine phosphate hemihydrate 10.00
Excipientes Excipients
L-arginina 170,00 L-arginine 170.00
Bromuro de domifeno 0,10Domiphene Bromide 0.10
Maltitol líquido 100,00Liquid Maltitol 100.00
Sacarina de sodio 1 ,70Sodium Saccharin 1, 70
Aroma de caramelo 2,50Candy Aroma 2.50
Aroma de menta 16,00Mint Aroma 16.00
Taumatina 0,05Thaumatine 0.05
Agua purificada es. Purified water is.
La composición líquida concentrada así obtenida contenía 200 mg de ibuprofeno por mi, 10 mg de fosfato de codeína hemihidrato por mi, siendo el contenido de sólidos superior a 400 mg por mi. Esta composición presentaba una alta estabilidad y los contenidos de ibuprofeno y fosfato de codeína hemihidrato permanecieron sustancialmente inalterados después de 36 meses de almacenamiento a 25° C y bajo una humedad relativa del 60%, a 30° C y bajo una humedad relativa del 65%, así como después de 6 meses a una temperatura de 40° C con una humedad relativa del 75%, y también después de 6 meses bajo refrigeración a una temperatura comprendida entre 5° C y 8° C. A esta temperatura no se observó la aparición de turbidez o de precipitados. En la Tabla 1 siguiente se muestran los datos de estabilidad correspondientes a los contenidos de ibuprofeno, L-arginina y fosfato de codeína hemihidrato: Tabla 1 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 unchanged after 36 months of storage at 25 ° C and under a relative humidity of 60%, at 30 ° C and under a relative humidity of 65% , as well as after 6 months at a temperature of 40 ° C with a relative humidity of 75%, and also after 6 months under refrigeration at a temperature between 5 ° C and 8 ° C. At this temperature the temperature was not observed. occurrence of turbidity or precipitates. The following Table 1 shows the stability data corresponding to the contents of ibuprofen, L-arginine and codeine phosphate hemihydrate: Table 1
Figure imgf000023_0001
Figure imgf000023_0001
H.R. = humedad relativa  H.R. = relative humidity
Los principios activos se analizaron por medio de técnicas HPLC. The active substances were analyzed by means of HPLC techniques.
La composición obtenida en el Ejemplo 1 se sometió también a un ensayo de fotoestabilidad de acuerdo con el método mencionado anteriormente, observándose que los contenidos de ibuprofeno, arginina y de fosfato de codeína hemihidrato permanecían sustancialmente inalterados en la solución a granel después de dicho ensayo, tal como se muestra en la Tabla 2: The composition obtained in Example 1 was also subjected to a photostability test according to the above-mentioned method, observing that the contents of ibuprofen, arginine and codeine phosphate hemihydrate remained substantially unchanged in the bulk solution after said test, as shown in Table 2:
Tabla 2 Table 2
Granel en Granel a la luz oscuridad  Bulk bulk in the dark light
Ibuprofeno 99,7% 100,9% Ibuprofen 99.7% 100.9%
Arginina 99,7% 100,5% Arginine 99.7% 100.5%
Fosfato de codeíná hemihidrato 97,9% 104,1 % Ejemplos 2 a 4: Preparación de formulaciones líquidas Codeine phosphate hemihydrate 97.9% 104.1% Examples 2 to 4: Preparation of liquid formulations
concentradas de ibuprofeno y fosfato de codeína hemihidrato  ibuprofen and codeine phosphate hemihydrate concentrates
Siguiendo un procedimiento análogo al empleado en el Ejemplo 1 , se prepararon otras formulaciones líquidas concentradas con las composiciones mostradas en la Tablas 3 a 5:  Following a procedure analogous to that used in Example 1, other concentrated liquid formulations were prepared with the compositions shown in Tables 3 to 5:
Tabla 3 Table 3
Componente Ejemplo 2 (mg/ml)  Component Example 2 (mg / ml)
Ingredientes activos Active ingredients
Ibuprofeno 200,00 Ibuprofen 200.00
Fosfato de codeína hemihidrato 30,00Codeine phosphate hemihydrate 30.00
Excipientes Excipients
L-arginina 170,00 L-arginine 170.00
Bromuro de domifeno 0,10Domiphene Bromide 0.10
Glucosa líquida 100,00Liquid glucose 100.00
Ciclamato de sodio 1 ,70Sodium Cyclamate 1, 70
Mentol 10,00Menthol 10.00
Aroma de menta 16,00Mint Aroma 16.00
Agua purificada es. Purified water is.
Tabla 4 Table 4
Componente Ejemplo 3 (mg/ml) lnqredient.es activos  Component Example 3 (mg / ml) active lnqredient.es
Ibuprofeno 200,00 Ibuprofen 200.00
Fosfato de codeína hemihidrato 10,00Codeine phosphate hemihydrate 10.00
Excipientes Excipients
L-arginina 170,00 L-arginine 170.00
Metilparabén 1 ,67Methylparaben 1, 67
Propilparabén 0,19Propyparaben 0.19
Sacarosa 100,00Sucrose 100.00
Sacarina de sodio 1 ,70Sodium Saccharin 1, 70
Aroma de caramelo 2,50Candy Aroma 2.50
Aroma de menta 4,00Mint Aroma 4.00
Taumatina 0,05Thaumatine 0.05
Agua purificada es. Purified water is.
Tabla 5 Table 5
Componente Ejemplo 4 (mg/ml)  Component Example 4 (mg / ml)
Inqredientes activos Active ingredients
Ibuprofeno 50,00 Ibuprofen 50.00
Fosfato de codeína hemihidrato 3,17Codeine phosphate hemihydrate 3.17
Excipientes Excipients
L-arginina 42,50 L-Arginine 42.50
Metilparabén 1 ,67Methylparaben 1, 67
Propilparabén 0,19Propyparaben 0.19
Sacarosa 350,00Sucrose 350.00
Aroma de limón 1 ,00Lemon Aroma 1, 00
Aroma de menta 4,00Mint Aroma 4.00
Taumatina 0,05Thaumatine 0.05
Agua purificada es. Purified water is.

Claims

REIVINDICACIONES
Composición farmacéutica líquida para su administración por vía oral caracterizada porque comprende: Liquid pharmaceutical composition for oral administration characterized in that it comprises:
una sal de ibuprofeno y un aminoácido básico seleccionado de entre el grupo consistente en arginina, lisina y mezclas de los mismos, en una relación molar ibuprofeno:aminoácido comprendida entre 0,9:1 y 1 ,1 :1 ,  an ibuprofen salt and a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof, in a molar ratio ibuprofen: amino acid between 0.9: 1 and 1, 1: 1,
codeína o una sal de codeína farmacéuticamente aceptable y al menos un excipiente farmacéuticamente aceptable donde el contenido de ibuprofeno es igual o superior a 20 mg/ml y el contenido de codeína o de la sal farmacéuticamente aceptable de codeína es igual o superior a 0,92 mg/ml.  codeine or a pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient where the content of ibuprofen is equal to or greater than 20 mg / ml and the content of codeine or the pharmaceutically acceptable salt of codeine is equal to or greater than 0.92 mg / ml
Composición según la reivindicación 1 , caracterizada porque el ibuprofeno se selecciona de entre el grupo formado por (RS)- ibuprofeno y (S)-ibuprofeno. Composition according to claim 1, characterized in that ibuprofen is selected from the group consisting of (RS) - ibuprofen and (S) -ibuprofen.
Composición según las reivindicaciones 1 ó 2, caracterizada porque el contenido de ibuprofeno es igual o superior a 50 mg/ml. Composition according to claims 1 or 2, characterized in that the ibuprofen content is equal to or greater than 50 mg / ml.
Composición según la reivindicación 3, caracterizada porque el contenido de ibuprofeno es igual o superior a 100 mg/ml. Composition according to claim 3, characterized in that the ibuprofen content is equal to or greater than 100 mg / ml.
Composición según la reivindicación 4, caracterizada porque el contenido de ibuprofeno es igual o superior a 150 mg/ml. Composition according to claim 4, characterized in that the ibuprofen content is equal to or greater than 150 mg / ml.
Composición según la reivindicación 5, caracterizada porque el contenido de ibuprofeno es igual a 200 mg/ml. Composition according to claim 5, characterized in that the ibuprofen content is equal to 200 mg / ml.
7. Composición según cualquiera de las reivindicaciones 1 a 6, caracterizada porque el aminoácido básico es arginina. 8. Composición según la reivindicación 7, caracterizada porque el aminoácido básico es el aminoácido en su forma natural L-arginina. 7. Composition according to any one of claims 1 to 6, characterized in that the basic amino acid is arginine. 8. Composition according to claim 7, characterized in that the basic amino acid is the naturally occurring amino acid L-arginine.
9. Composición según cualquiera de las reivindicaciones 1 a 8, caracterizada porque la relación molar entre el ibuprofeno y el aminoácido básico está comprendida entre 0,92:1 y 1 ,07:1. 9. Composition according to any of claims 1 to 8, characterized in that the molar ratio between ibuprofen and the basic amino acid is between 0.92: 1 and 1, 07: 1.
10. Composición según la reivindicación 9, caracterizada porque la relación molar entre el ibuprofeno y el aminoácido básico está comprendida entre 0,95:1 y 1 ,05:1. 10. Composition according to claim 9, characterized in that the molar ratio between ibuprofen and the basic amino acid is between 0.95: 1 and 1: 05: 1.
11. Composición según la reivindicación 10, caracterizada porque la relación molar entre el ibuprofeno y el aminoácido básico está comprendida entre 0,98:1 y 1 ,02:1. 12. Composición según la reivindicación 11 , caracterizada porque la relación molar entre el ibuprofeno y el aminoácido básico es :1. 11. Composition according to claim 10, characterized in that the molar ratio between ibuprofen and the basic amino acid is between 0.98: 1 and 1, 02: 1. 12. Composition according to claim 11, characterized in that the molar ratio between ibuprofen and the basic amino acid is: 1.
13. Composición según cualquiera de las reivindicaciones 1 a 12, caracterizada porque comprende codeína. 13. Composition according to any of claims 1 to 12, characterized in that it comprises codeine.
14. Composición según cualquiera de las reivindicaciones 1 a 12, caracterizada porque comprende una sal de codeína farmacéuticamente aceptable. Composición según la reivindicación 14, caracterizada porque la sal farmacéuticamente aceptable de codeína se selecciona de entre el grupo consistente en clorhidrato de codeína, yodhidrato de codeína, bromhidrato de codeína, bitartrato de codeína, citrato de codeína, acetato de codeína, sulfato de codeína y fosfato de codeína. 14. Composition according to any one of claims 1 to 12, characterized in that it comprises a pharmaceutically acceptable codeine salt. Composition according to claim 14, characterized in that the pharmaceutically acceptable codeine salt is selected from the group consisting of codeine hydrochloride, codeine hydrochloride, codeine hydrobromide, codeine bitartrate, codeine citrate, codeine acetate, codeine sulfate and codeine phosphate
Composición según la reivindicación 15, caracterizada porque la sal farmacéuticamente aceptable de codeína es fosfato de codeína. Composition according to claim 15, characterized in that the pharmaceutically acceptable codeine salt is codeine phosphate.
Composición según la reivindicación 16, caracterizada porque la sal farmacéuticamente aceptable de codeína es hemihidrato de fosfato de codeína. Composition according to claim 16, characterized in that the pharmaceutically acceptable codeine salt is codeine phosphate hemihydrate.
Composición según cualquiera de las reivindicaciones 1 a 17, caracterizada porque el contenido de codeína o de la sal farmacéuticamente aceptable de codeína es igual o superior a 2,5 mg/ml. Composition according to any one of claims 1 to 17, characterized in that the content of codeine or the pharmaceutically acceptable salt of codeine is equal to or greater than 2.5 mg / ml.
Composición según la reivindicación 18, caracterizada porque el contenido de codeína o de la sal farmacéuticamente aceptable de codeína es igual o superior a 3,0 mg/ml. Composition according to claim 18, characterized in that the content of codeine or the pharmaceutically acceptable salt of codeine is equal to or greater than 3.0 mg / ml.
Composición según la reivindicación 19, caracterizada porque el contenido de codeína o de la sal farmacéuticamente aceptable de codeína es igual a 10 mg/ml. Composition according to claim 19, characterized in that the content of codeine or the pharmaceutically acceptable salt of codeine is equal to 10 mg / ml.
21. Composición según la reivindicación 19, caracterizada porque el contenido de codeína o de la sal farmacéuticamente aceptable de codeína es igual a 30 mg/ml. Composición según cualquiera de las reivindicaciones 1 a 21 , caracterizada porque el excipiente farmacéuticamente aceptable se selecciona de entre el grupo consistente en conservantes, saborizantes, aromatizantes, edulcorantes y/o mezclas de los mismos. 21. Composition according to claim 19, characterized in that the content of codeine or the pharmaceutically acceptable salt of codeine is equal to 30 mg / ml. Composition according to any one of claims 1 to 21, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of preservatives, flavorings, flavorings, sweeteners and / or mixtures thereof.
Composición según la reivindicación 22, caracterizada porque el conservante se selecciona de entre el grupo consistente en bromuro de domifeno, butilparabén, propilparabén, etilparabén, metilparabén y/o mezclas de los mismos. Composition according to claim 22, characterized in that the preservative is selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben and / or mixtures thereof.
24. Composición según la reivindicación 23, caracterizada porque el conservante es bromuro de domifeno. 24. Composition according to claim 23, characterized in that the preservative is domifen bromide.
25. Composición según la reivindicación 22, caracterizada porque el edulcorante se selecciona de entre el grupo consistente en maltitol, sacarosa, dextrosa, fructosa, glucosa, glicerina, inulina, isomaltosa, lactitol, maltosa, maltol, manitol, sucralosa, trehalosa, xilitol, propilenglicol, sorbitol, sacarina sódica, taumatina, ciclamato sódico y/o mezclas de los mismos. 25. Composition according to claim 22, characterized in that the sweetener is selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatine, sodium cyclamate and / or mixtures thereof.
26. Composición según la reivindicación 25, caracterizado porque el edulcorante se selecciona de entre el grupo consistente en maltitol, sacarosa, glucosa, taumatina, sacarina sódica y/o mezclas de los mismos. 26. Composition according to claim 25, characterized in that the sweetener is selected from the group consisting of maltitol, sucrose, glucose, thaumatine, sodium saccharin and / or mixtures thereof.
27. Composición según la reivindicación 26, caracterizado porque el edulcorante se selecciona de entre el grupo consistente en maltitol, sacarina sódica, taumatina y/o mezclas de los mismos. 27. Composition according to claim 26, characterized in that the sweetener is selected from the group consisting of maltitol, sodium saccharin, thaumatine and / or mixtures thereof.
28. Composición farmacéutica líquida para su administración por vía oral, caracterizada porque comprende: 28. Liquid pharmaceutical composition for oral administration, characterized in that it comprises:
200 mg/ml de ibuprofeno  200 mg / ml ibuprofen
- 10 mg/ml de fosfato de codeína hemihidrato  - 10 mg / ml codeine phosphate hemihydrate
170 mg/ml de L-arginina  170 mg / ml L-arginine
0,10 mg/ml de bromuro de domifeno  0.10 mg / ml domifen bromide
100 mg/ml de maltitol líquido  100 mg / ml liquid maltitol
1 ,7 mg/ml de sacarina sódica y  1.7 mg / ml sodium saccharin and
- 0,05 mg/ml de taumatina.  - 0.05 mg / ml of thaumatine.
29. Composición según la reivindicación 28, caracterizada porque comprende adicionalmente agentes aromatizantes. 30. Composición farmacéutica líquida para su administración por vía oral, caracterizada porque comprende: 29. Composition according to claim 28, characterized in that it further comprises flavoring agents. 30. Liquid pharmaceutical composition for oral administration, characterized in that it comprises:
200 mg/ml de ibuprofeno  200 mg / ml ibuprofen
10 mg/ml de fosfato de codeína hemihidrato  10 mg / ml codeine phosphate hemihydrate
170 mg/ml de L-arginina  170 mg / ml L-arginine
- 1 ,67 mg/ml de metilparabén  - 1, 67 mg / ml methylparaben
0,19 mg/ml de propilparabén  0.19 mg / ml propylparaben
100 mg/ml de sacarosa  100 mg / ml sucrose
1 ,7 mg/ml de sacarina sódica y  1.7 mg / ml sodium saccharin and
0,05 mg/ml de taumatina.  0.05 mg / ml of thaumatine.
31. Composición según la reivindicación 30, caracterizada porque comprende adicionalmente agentes aromatizantes. Composition according to claim 30, characterized in that it further comprises flavoring agents.
32. Procedimiento para la preparación de una composición según cualquiera de las reivindicaciones 1 a 31 , caracterizado porque comprende las etapas de: 32. Method for preparing a composition according to any of claims 1 to 31, characterized in that it comprises the steps of:
a) diluir la sal de ibuprofeno con el aminoácido básico en una parte del agua,  a) dilute the ibuprofen salt with the basic amino acid in a part of the water,
b) añadir la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable a la solución obtenida en la etapa a), agitar hasta disolución completa y ajusfar con agua hasta el volumen final, o alternativamente c) disolver la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable en una parte del agua,  b) add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step a), stir until complete dissolution and adjust with water to the final volume, or alternatively c) dissolve the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of the water,
d) añadir la sal de ibuprofeno con el aminoácido básico en la disolución obtenida en . la etapa c) y agitar hasta disolución completa,  d) add the ibuprofen salt with the basic amino acid in the solution obtained in. step c) and stir until complete dissolution,
e) completar con agua hasta el volumen final, o alternativamente f) dispersar el aminoácido básico en una parte del agua,  e) complete with water to the final volume, or alternatively f) disperse the basic amino acid in a part of the water,
g) añadir el ibuprofeno a la dispersión obtenida en la etapa f) y agitar hasta disolución completa,  g) add ibuprofen to the dispersion obtained in step f) and stir until completely dissolved,
h) añadir la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable a la solución obtenida en la etapa g), agitar hasta disolución completa y ajustar con agua hasta el volumen final, o alternativamente i) disolver la codeína o la sal farmacéuticamente aceptable de codeína y al menos un excipiente farmacéuticamente aceptable en una parte del agua, h) add the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient to the solution obtained in step g), stir until completely dissolved and adjust with water to the final volume, or alternatively i) dissolve the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of the water,
j) dispersar el aminoácido básico en la disolución obtenida en la etapa i),  j) dispersing the basic amino acid in the solution obtained in step i),
k) añadir el ibuprofeno a la dispersión obtenida en la etapa j) y agitar hasta disolución completa y  k) add ibuprofen to the dispersion obtained in step j) and stir until completely dissolved and
I) completar con agua hasta el volumen final.  I) complete with water to the final volume.
Utilización de una composición farmacéutica según cualquiera de las reivindicaciones 1 a 31 para la fabricación de un medicamento para el tratamiento por vía oral del dolor moderado a severo, de la inflamación, de la fiebre y/o de otras dolencias que pueden aliviarse con ibuprofeno y/o codeína. Use of a pharmaceutical composition according to any of claims 1 to 31 for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other conditions that can be relieved with ibuprofen and / or codeine.
Utilización según la reivindicación 33, caracterizada porque las mencionadas otras dolencias se seleccionan de entre el grupo consistente en la enfermedad de Alzheimer, la artritis y la dismenorrea primaria. Use according to claim 33, characterized in that said other ailments are selected from the group consisting of Alzheimer's disease, arthritis and primary dysmenorrhea.
35. Utilización según la reivindicación 33 para uso pediátrico. 35. Use according to claim 33 for pediatric use.
PCT/ES2010/000078 2010-03-01 2010-03-01 Liquid ibuprofen/codeine pharmaceutical composition for oral administration, the method for preparation thereof and use thereof WO2011107617A1 (en)

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Citations (5)

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EP0388125A1 (en) * 1989-03-14 1990-09-19 Beecham Group Plc Medicament
CA2030140A1 (en) * 1989-11-17 1991-05-18 Manfred Lohner Medicament preparations containing a metal salt of ibuprofen and process for preparing same
US5164398A (en) * 1991-04-01 1992-11-17 Merck & Co., Inc. Ibuprofen-antitussive combinations
WO1995007103A1 (en) * 1993-09-07 1995-03-16 The Procter & Gamble Company Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussive
EP1226831A1 (en) * 2001-01-30 2002-07-31 Leandro Baiocchi Aqueous pharmaceutical solutions with trisubstituted glycyrrhizic acid salts

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Publication number Priority date Publication date Assignee Title
EP0388125A1 (en) * 1989-03-14 1990-09-19 Beecham Group Plc Medicament
CA2030140A1 (en) * 1989-11-17 1991-05-18 Manfred Lohner Medicament preparations containing a metal salt of ibuprofen and process for preparing same
US5164398A (en) * 1991-04-01 1992-11-17 Merck & Co., Inc. Ibuprofen-antitussive combinations
WO1995007103A1 (en) * 1993-09-07 1995-03-16 The Procter & Gamble Company Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussive
EP1226831A1 (en) * 2001-01-30 2002-07-31 Leandro Baiocchi Aqueous pharmaceutical solutions with trisubstituted glycyrrhizic acid salts

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