WO2013124498A1 - Pharmaceutical composition of ibuprofen and tramadol for injection - Google Patents

Pharmaceutical composition of ibuprofen and tramadol for injection Download PDF

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Publication number
WO2013124498A1
WO2013124498A1 PCT/ES2013/000043 ES2013000043W WO2013124498A1 WO 2013124498 A1 WO2013124498 A1 WO 2013124498A1 ES 2013000043 W ES2013000043 W ES 2013000043W WO 2013124498 A1 WO2013124498 A1 WO 2013124498A1
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Prior art keywords
ibuprofen
tramadol
composition according
concentration
expressed
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PCT/ES2013/000043
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Spanish (es)
French (fr)
Inventor
Nuria Sanz Menendez
Angel Munoz Ruiz
Fernando Martinez Alzamora
Antonia Gomez Calvo
José Miguel Rizo Martínez
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Farmauder, S.A.
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Application filed by Farmauder, S.A. filed Critical Farmauder, S.A.
Publication of WO2013124498A1 publication Critical patent/WO2013124498A1/en

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for administration by injection, in particular intravenously, containing as active ingredients a combination of ibuprofen in the form of arginine salt and tramadol.
  • a pharmaceutical composition for administration by injection in particular intravenously, containing as active ingredients a combination of ibuprofen in the form of arginine salt and tramadol.
  • Tramadol is a drug with analgesic properties that acts centrally and is used in the treatment of moderate to severe pain, of chronic or acute origin. It is also used in diagnostic examination procedures that occur with pain. Tramadol was originally described in US Patent US3652589, of the Grünenthal company.
  • tramadol The mechanism of action of tramadol is usually described as an "atypical" opioid, since it is neither completely opioid nor completely non-opioid.
  • Tramadol has a mechanism of dual action because, on the one hand, it acts on the ⁇ opioid receptors to which it binds with low affinity and, on the other hand, inhibits the reuptake of norepinephrine and serotonin, thereby increasing the concentration of these neurotransmitters in localized areas of the brain, lowering the pain threshold, as described, for example, in the article Raffa et al., Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic, J Pharmacol Exp. Ther., 1992, 260 (1), 275-85.
  • tramadol was initially thought to show a low potential for abuse, subsequently, some cases of adverse effects have been described, including abuse in opiodependent patients, as detailed in the article Goeringer et al., Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers, J Anal Toxicol., 1997, 21 (7), 529-37.
  • the most common adverse effects of tramadol are dizziness and / or vertigo, nausea and / or vomiting, constipation and headache.
  • ibuprofen is a drug belonging to the group of non-steroidal anti-inflammatory drugs (commonly called NSAIDs) with analgesic, anti-pyretic and anti-inflammatory activity.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Ibuprofen was originally described in the 1960s in a family of patents from Boots Puré Drug Co Ltd (for example in British patent GB971700 or in its US equivalent US3385886), and for many years pharmaceutical specialties of ibuprofen have been marketed, essentially for oral administration.
  • ibuprofen like most NSAIDs, exerts its analgesic action by inhibiting the enzyme cyclooxygenase (COX), primarily responsible for the synthesis of prostaglandins.
  • COX cyclooxygenase
  • Cyclooxygenase-1 (COX-1) is a constitutive enzyme that protects the gastric mucosa under normal conditions, while cyclooxygenase-2 (COX-2) is an inducible enzyme that is primarily involved in inflammation.
  • Ibuprofen inhibits both COX-2 and COX-1, so that the analgesic, antipyretic and anti-inflammatory action of ibuprofen is attributed to COX-2 inhibition.
  • ibuprofen is safer than other NSAIDs, it has also been reported to cause gastric lesions and gastric bleeding. These adverse effects of ibuprofen on the gastrointestinal tract are attributed to COX-1 inhibition.
  • ibuprofen-arginine combination has been shown to cause lower gastrointestinal adverse effects than ibuprofen alone, as described in the Galician-Sandin et al. Article, Effect of ibuprofen on cyclooxygenase and nitric oxide synthase ofgastric mucosa: correlation with endoscope lesions and adverse reactions, Dig. Dis. Sci., 2004, 49 (9), 1538-44.
  • analgesic drugs In general, a strategy to minimize the side effects of analgesic drugs is to combine active ingredients with different mechanisms of action, for example opioid and non-opioid analgesics. It has been found that some of these combinations of active ingredients, in certain proportions, have a certain synergistic effect that allows the desired analgesic action to be achieved using a smaller amount of the active ingredients, thus reducing unwanted adverse effects.
  • analgesic compositions for intravenous administration are especially useful, since said route allows a faster onset of therapeutic action, as well as greater efficacy and a longer analgesic duration for the control of acute pain, particularly in the hospital environment.
  • the pharmaceutical specialty "Adolonta ® 100 mg solution for injection” is commercialized, consisting of a single dose of tramadol for administration by injection, containing 100 mg of tramadol hydrochloride in 2 ml of solution.
  • ibuprofen is a very water-soluble drug and, for this reason, the preparation of stable pharmaceutical forms of ibuprofen in aqueous solution, especially for administration for injection, traditionally presents certain difficulties.
  • Some ibuprofen salts with basic amino acids are known and, for example, in the Spanish patent ES435416 the preparation of ibuprofen salts with lysine and with arginine is described, indicating that they are moderately soluble.
  • compositions intended exclusively for oral administration containing a combination of ibuprofen and tramadol, together with arginine, and which are indicated for the treatment of pain, inflammation and / or fever .
  • An object of the present invention is an aqueous pharmaceutical composition for injection containing tramadol and ibuprofen arginate.
  • Another object of the invention is a process for the preparation of said composition.
  • Another object of the invention is a unit dosage pharmaceutical form containing said composition.
  • An object of the present invention is a pharmaceutical composition for injection characterized in that it essentially consists of tramadol or a pharmaceutically acceptable salt thereof, ibuprofen, arginine and water for injection, the molar ratio between arginine and ibuprofen being between 0.9: 1 and 1, 1: 1.
  • the authors of the present invention have developed an aqueous pharmaceutical composition for administration by injection consisting of a combination of tramadol and ibuprofen in the form of salt with arginine (ibuprofen arginate), which has advantages over the compositions described in the prior art. , since it is a composition of high stability that achieves a fast and effective analgesic action and that entails a lower risk of side effects.
  • Tramadol is the International Common Denomination (INN) by which the compound ( ⁇ ) -cis-2 - [(dimethylamino) methyl] -1- (3- methoxyphenyl) cyclohexanol is commonly known.
  • Tramadol is commercially available and can also be prepared, for example, according to the procedure described in US Patent US3652589.
  • tramadol refers broadly to any of its solvates, polymorphs, stereoisomers, mixtures of stereoisomers and racemic forms.
  • compositions of tramadol refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using organic or inorganic acids.
  • Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, salicylic acid, italic acid, etc.
  • hydrochloric acid is used.
  • tramadol is in the form of its hydrochloride salt. More preferably, it is in the form of tramadol hydrochloride in racemic form.
  • Ibuprofen is the International Common Denomination (INN) by which (RS) -2- (4-isobutylphenyl) propionic acid is commonly known.
  • ibuprofen includes ibuprofen in its racemic form ((R, S) -ibuprofen), the enantiomer (S) of ibuprofen ((S) - ibuprofen) and a mixture of the enantiomers (R) and (S) of ibuprofen, preferably enriched in form (S).
  • the ibuprofen used in the compositions of the invention is selected from (R.S) -ibuprofen and (S)-ibuprofen. More preferably, the compositions of the invention contain (R, S) - ibuprofen.
  • Ibuprofen is commercially available and can also be prepared, for example, according to the procedure described in British patent application GB-A-971700.
  • the resolution of ibuprofen in its enantiomers is described, for example, in Brushan et al., Resolution of enantiomers ofibuprofen by liquid chromatography: a review, Biomed. Chromatogr., 1998, 12 (6), 309.
  • the salt of ibuprofen and arginine is commonly known by the term ibuprofen arginate.
  • the compositions of the invention are prepared from ibuprofen and arginine separately, with ibuprofen arginate being formed in the aqueous medium.
  • the compositions are prepared from the previously formed ibuprofen arginate salt.
  • Said salt can be prepared, for example, as described in Spanish patent application ES435416.
  • Arginine is an ⁇ -amino acid, which is found in nature in its enantiomeric form L.
  • arginine is understood as any of its enantiomeric forms: L-arginine, D-arginine and mixtures thereof.
  • the arginine is in the form of L-arginine.
  • Arginine can be obtained commercially from various sources. Compositions
  • composition of the invention is prepared with water for injection that can be obtained, for example, by distillation or by reverse osmosis.
  • ibuprofen is substantially in the form of ibuprofen arginate, that is, in the form of a salt with arginine.
  • the molar ratio between arginine and ibuprofen in the composition of the invention is between 0.9: 1 and 1, 1: 1; preferably said molar ratio is 1.0: 1 and with particular preference is 0.05: 1.
  • the concentration of ibuprofen in the pharmaceutical composition of the invention is between 50 mg and 200 mg of ibuprofen per ml of solution, especially preferably 70 mg and 150 mg per ml of solution, even more preferably between 90 mg and 110 mg for each ml of solution and, most preferably, ibuprofen is in a concentration of 100 mg per ml of solution.
  • the concentration of tramadol or a pharmaceutically acceptable salt thereof in the composition of the invention is preferably between 2 mg and 50 mg for each ml of solution, especially preferably between 5 mg and 35 mg for each ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
  • the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 10 mg and 15 mg for each ml of solution, especially between 12 mg and 13 mg for each ml of solution and in particular
  • the concentration of tramadol is 12.5 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
  • the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 15 mg and 20 mg per ml of solution, especially preferably between 18.0 mg and 19.5 mg per ml. of solution and in particular the concentration of tramadol or one of its pharmaceutically acceptable salts is 18.75 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
  • the injectable composition includes:
  • ibuprofen between 80 mg / ml and 120 mg / ml, in particular between 90 mg / ml and 110 mg / ml and in particular 100 mg / ml;
  • a concentration of tramadol expressed as equivalent concentration of tramadol hydrochloride, between 10 mg / ml and 15 mg / ml, especially between 12 mg / ml and 13 mg / ml, and in particular 12.5 mg / ml .
  • the injectable composition includes: - a concentration of ibuprofen between 80 mg / ml and 120 mg / ml, especially between 90 mg / ml and 110 mg / ml, in particular 100 mg / ml ; Y
  • the injectable composition of the invention is generally dosed according to a unit dosage pharmaceutical form containing a volume of the composition suitable for administering the desired dose of the active ingredients.
  • the composition is dosed in vials or in pre-filled syringes.
  • the unit dosage dosage form includes an amount of ibuprofen between 50 mg and 1,000 mg, especially between 200 mg. and 800 mg, and an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 25 mg and 150 mg, especially between 40 mg and 85 mg.
  • the injectable composition of the invention is dosed in a unit dose containing an amount of ibuprofen between 300 mg and 500 mg, in particular 400 mg.
  • the injectable composition of the invention is dosed in a unit dose containing an amount of ibuprofen between 100 mg and 300 mg, in particular 200 mg. In another embodiment, the injectable composition of the invention is dosed in a unit dose containing an amount of ibuprofen between 700 mg and 900 mg, in particular 800 mg.
  • the injectable composition of the invention is dosed in a unit dose containing an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, comprised between 40 mg and 60 mg, in particular 50 mg.
  • the injectable composition of the invention is dosed in a unit dose containing an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg, in particular 75 mg.
  • the unit dosage dosage form contains a dose of ibuprofen selected from 200 mg, 400 mg and 800 mg and a dose of tramadol, expressed as equivalent weight of tramadol hydrochloride, selected from 50 mg to 75 mg.
  • the unit dosage dosage form comprises 400 mg of ibuprofen and a dose of tramadol, expressed as equivalent weight of tramadol hydrochloride, selected between 50 mg and 75 mg, so that the combination of 400 mg is available. of ibuprofen with 50 mg of tramadol and the combination of 400 mg of ibuprofen with 75 mg of tramadol.
  • the unit dosage dosage form contains:
  • tramadol hydrochloride an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
  • the unit dosage dosage form contains:
  • tramadol hydrochloride an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
  • the unit dosage pharmaceutical form contains:
  • tramadol hydrochloride an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
  • the unit dosage pharmaceutical form contains:
  • tramadol hydrochloride an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
  • the unit dosage pharmaceutical form contains: - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
  • the unit dosage pharmaceutical form contains:
  • tramadol hydrochloride an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
  • An object of the invention is a process for preparing a pharmaceutical composition according to the invention.
  • a suitable process for preparing the compositions of the invention includes the following steps: a) dissolve tramadol, arginine and ibuprofen in water for injection; Y
  • the water for injection is usually placed in a reactor equipped with a stirrer and the different components of the formulation, tramadol, arginine and ibuprofen, are incorporated consecutively under continuous agitation, until they are completely dissolved.
  • the pH of the solution obtained is adjusted to a value between 7.6 and 8.0 by the addition of an aqueous solution of an acid or a base.
  • an aqueous solution of an acid or a base For example, a solution of 0.1 N hydrochloric acid or a solution of 0.1 N sodium hydroxide can be used.
  • water is added for further injection until the desired concentration of the active ingredients is obtained.
  • the solution obtained can be sterilized, for example, by filtration. Subsequently, the resulting solution can be dosed according to unit dosage forms in a suitable container, for example in sterile vials or syringes. Preferably, the composition is dosed at a rate of 2 ml, 4 ml or 8 ml of solution in each dose.
  • the vials or syringes containing the composition of the invention are sterilized in an autoclave, for example by treatment at 121 ° C for approximately 20 minutes.
  • compositions of the invention have an analgesic effect and are useful for the treatment of pain, in particular chronic or acute pain of moderate to severe intensity, as well as inflammation and febrile conditions and, in general, of any disease susceptible to be treated with tramadol and / or ibuprofen.
  • composition of the invention in the treatment of pain, inflammation and / or febrile conditions or of any disease capable of being treated with tramadol and / or ibuprofen.
  • composition of the invention for the preparation of a medicament for the treatment of pain, inflammation and / or febrile conditions, or of any disease that can be treated with tramadol. and / or ibuprofen.
  • another object of the invention is the use of a dosage form of the invention for the preparation of a medicament for the treatment of pain, inflammation and / or febrile conditions, or of any disease capable of being treated with tramadol. and / or ibuprofen, which comprises administering to a mammal in need thereof, preferably to a person, a composition according to the invention.
  • compositions of the invention can be used for the treatment of different types of pain caused by different ailments, such as headaches, odontalgia, otalgia, migraine, muscle pain, joint pain, neuropathic pain, post-traumatic pain, postpartum, post pain -urgical, acute myocardial infarction pain and cancer pain They can also be used as a preoperative analgesic, as a complement to surgical anesthesia and in diagnostic examination procedures that occur with pain.
  • compositions can also be used as anti-inflammatory and, mainly due to the action of ibuprofen, as an antipyretic, so they are useful for the treatment of inflammation and / or fever caused by various medical conditions, such as rheumatoid arthritis (including juvenile rheumatoid arthritis ), osteoarthritis, ankylopoietic spondylitis, osteoarthritis and other acute or chronic rheumatic processes, bursitis, synovitis, capsulitis or other types of inflammatory injuries of traumatic or sports origin.
  • the compositions of the invention may also be useful for the treatment of other conditions that can be relieved with ibuprofen or tramadol.
  • the reference to treatment includes both the treatment of established symptoms and the prophylactic treatment. Preferably, they are used for the treatment of established symptoms.
  • the injectable pharmaceutical composition according to the present invention is administered intravenously prior dilution in appropriate solutions for infusion, well known to those skilled in the art, for example 0.9% aqueous sodium chloride solution, Ringer Lactate solution or solution 5% aqueous glucose.
  • Example 1 Injectable composition of ibuprofen / tramadol hydrochloride dose 400/50
  • a part of the water for injection was placed in a reactor at a rate of approximately 2/3 of the size of the final batch. Then, under continuous stirring, tramadol hydrochloride, arginine, and ibuprofen were added consecutively, until completely dissolved. The pH was determined and adjusted to a value of 7.8 with the solution of HCI and / or NaOH. The rest of the water for injection was added and the solution thus obtained was filtered through a 0.22 micron filter. The resulting solution was dosed in transparent glass vials, at a rate of 4 ml of solution in each vial, obtaining an injectable solution with an osmolality greater than 310 mOsm / kg.
  • Example 2 Injectable composition of ibuprofen / tramadol hydrochloride dose 400/75

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Abstract

The invention relates to a pharmaceutical composition of ibuprofen and tramadol for injection. In particular, the invention relates to an aqueous solution containing tramadol and ibuprofen arginate. The invention also relates to a method for producing the composition, to a single-dose pharmaceutical form containing same, and to the use thereof for the treatment of moderate to severe pain, inflammation and fever.

Description

COMPOSICIÓN FARMACÉUTICA DE IBUPROFENO Y TRAMADOL PARA  PHARMACEUTICAL COMPOSITION OF IBUPROFEN AND TRAMADOL FOR
INYECCIÓN  INJECTION
Campo de la técnica La presente invención se refiere a una composición farmacéutica para su administración por inyección, en particular por vía intravenosa, que contiene como principios activos una combinación de ibuprofeno en forma de sal de arginina y tramadol. Estado de la técnica anterior Field of the art The present invention relates to a pharmaceutical composition for administration by injection, in particular intravenously, containing as active ingredients a combination of ibuprofen in the form of arginine salt and tramadol. Prior art
El tramadol es un fármaco de propiedades analgésicas que actúa a nivel central y que se emplea en el tratamiento del dolor moderado a severo, de origen crónico o agudo. También se utiliza en procedimientos de exploración diagnóstica que cursan con dolor. El tramadol fue descrito originalmente en la patente norteamericana US3652589, de la empresa Grünenthal. Tramadol is a drug with analgesic properties that acts centrally and is used in the treatment of moderate to severe pain, of chronic or acute origin. It is also used in diagnostic examination procedures that occur with pain. Tramadol was originally described in US Patent US3652589, of the Grünenthal company.
El mecanismo de acción del tramadol se suele calificar como de un opioide "atípico", ya que no es ni completamente opioide ni completamente no opioide. El tramadol posee un mecanismo de acción dual pues, por un lado, actúa sobre los receptores μ opioides a los que se une con baja afinidad y, por otro lado, inhibe la recaptación de noradrenalina y serotonina, con lo que aumenta la concentración de estos neurotransmisores en zonas localizadas del cerebro, disminuyendo el umbral del dolor, según se describe, por ejemplo, en el artículo Raffa y col., Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic, J. Pharmacol. Exp. Ther., 1992, 260 (1), 275-85.  The mechanism of action of tramadol is usually described as an "atypical" opioid, since it is neither completely opioid nor completely non-opioid. Tramadol has a mechanism of dual action because, on the one hand, it acts on the μ opioid receptors to which it binds with low affinity and, on the other hand, inhibits the reuptake of norepinephrine and serotonin, thereby increasing the concentration of these neurotransmitters in localized areas of the brain, lowering the pain threshold, as described, for example, in the article Raffa et al., Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic, J Pharmacol Exp. Ther., 1992, 260 (1), 275-85.
Es bien conocido que los opioides típicos, tales como la morfina, codeína, oxicodona o hidrocodona, por ejemplo, producen unos efectos secundarios indeseables característicos, como náuseas y/o vómitos, somnolencia, depresión respiratoria, estreñimiento, confusión y sedación. Su uso a largo plazo también puede llevar a la dependencia física y a la adicción. El tramadol presenta unos efectos secundarios menos pronunciados y menos frecuentes que los opioides típicos. No obstante, aunque inicialmente se pensó que el tramadol mostraba un bajo potencial de abuso, posteriormente se han descrito algunos casos de efectos adversos, incluyendo abuso en pacientes opiode-dependientes, tal como se detalla en el artículo Goeringer y col., Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers, J. Anal. Toxicol., 1997, 21 (7), 529-37. Los efectos adversos más comunes del tramadol son mareos y/o vértigo, náuseas y/o vómitos, estreñimiento y cefaleas. It is well known that typical opioids, such as morphine, codeine, oxycodone or hydrocodone, for example, produce characteristic undesirable side effects, such as nausea and / or vomiting, drowsiness, respiratory depression, constipation, confusion and sedation. Its long-term use can also lead to physical dependence and addiction. Tramadol has less pronounced and less frequent side effects than typical opioids. However, although tramadol was initially thought to show a low potential for abuse, subsequently, some cases of adverse effects have been described, including abuse in opiodependent patients, as detailed in the article Goeringer et al., Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers, J Anal Toxicol., 1997, 21 (7), 529-37. The most common adverse effects of tramadol are dizziness and / or vertigo, nausea and / or vomiting, constipation and headache.
Por su parte, el ibuprofeno es un fármaco perteneciente al grupo de los antiinflamatorios no esteroideos (comúnmente denominados AINEs) con actividad analgésica, anti-pirética y anti-inflamatoria. El ibuprofeno fue originalmente descrito en los años 1960 en una familia de patentes de la empresa Boots Puré Drug Co Ltd (por ejemplo en la patente británica GB971700 o en su equivalente norteamericana US3385886), y desde hace años se comercializan numerosas especialidades farmacéuticas de ibuprofeno, esencialmente para su administración oral.  For its part, ibuprofen is a drug belonging to the group of non-steroidal anti-inflammatory drugs (commonly called NSAIDs) with analgesic, anti-pyretic and anti-inflammatory activity. Ibuprofen was originally described in the 1960s in a family of patents from Boots Puré Drug Co Ltd (for example in British patent GB971700 or in its US equivalent US3385886), and for many years pharmaceutical specialties of ibuprofen have been marketed, essentially for oral administration.
Se cree que el ibuprofeno, como la mayoría de AINEs, ejerce su acción analgésica mediante inhibición de la enzima ciclooxigenasa (COX), principal responsable de la síntesis de prostaglandinas. Sin embargo, existen diversas variantes de dicha enzima. La ciclooxigenasa-1 (COX-1) es una enzima constitutiva que protege la mucosa gástrica en condiciones normales, mientras que la ciclooxigenasa-2 (COX-2) es una enzima inducible que está principalmente implicada en la inflamación. El ibuprofeno inhibe tanto la COX-2 como la COX-1 , de manera que la acción analgésica, antipirética y anti-inflamatoria del ibuprofeno se atribuye a la inhibición de la COX-2.  It is believed that ibuprofen, like most NSAIDs, exerts its analgesic action by inhibiting the enzyme cyclooxygenase (COX), primarily responsible for the synthesis of prostaglandins. However, there are several variants of said enzyme. Cyclooxygenase-1 (COX-1) is a constitutive enzyme that protects the gastric mucosa under normal conditions, while cyclooxygenase-2 (COX-2) is an inducible enzyme that is primarily involved in inflammation. Ibuprofen inhibits both COX-2 and COX-1, so that the analgesic, antipyretic and anti-inflammatory action of ibuprofen is attributed to COX-2 inhibition.
Aunque el ibuprofeno es más seguro que otros AINEs, también se ha descrito que produce lesiones gástricas y sangrado gástrico. Estos efectos adversos del ibuprofeno sobre el tracto gastrointestinal se atribuyen a la inhibición de la COX-1.  Although ibuprofen is safer than other NSAIDs, it has also been reported to cause gastric lesions and gastric bleeding. These adverse effects of ibuprofen on the gastrointestinal tract are attributed to COX-1 inhibition.
Se ha demostrado que la combinación ibuprofeno-arginina causa menores efectos adversos gastrointestinales que el ibuprofeno solo, tal como se describe en el artículo Gallego-Sandín y col., Effect of ibuprofen on cyclooxygenase and nitric oxide synthase ofgastric mucosa: correlation with endoscopio lesions and adverse reactions, Dig. Dis. Sci., 2004, 49 (9), 1538-44. The ibuprofen-arginine combination has been shown to cause lower gastrointestinal adverse effects than ibuprofen alone, as described in the Galician-Sandin et al. Article, Effect of ibuprofen on cyclooxygenase and nitric oxide synthase ofgastric mucosa: correlation with endoscope lesions and adverse reactions, Dig. Dis. Sci., 2004, 49 (9), 1538-44.
En general, una estrategia de cara a minimizar los efectos secundarios de los fármacos analgésicos consiste en combinar principios activos con distintos mecanismos de acción, por ejemplo analgésicos opioides y no opioides. Se ha constatado que algunas de estas combinaciones de principios activos, en determinadas proporciones, presentan un cierto efecto sinérgico que permite conseguir la acción analgésica deseada empleando una menor cantidad de los principios activos, reduciéndose así los efectos adversos indeseados. In general, a strategy to minimize the side effects of analgesic drugs is to combine active ingredients with different mechanisms of action, for example opioid and non-opioid analgesics. It has been found that some of these combinations of active ingredients, in certain proportions, have a certain synergistic effect that allows the desired analgesic action to be achieved using a smaller amount of the active ingredients, thus reducing unwanted adverse effects.
Se ha descrito el uso combinado de varios analgésicos, entre ellos de tramadol e ibuprofeno, en odontología, como se describe en los artículos Moroz y col., Use of tramadol hydrochloríde in therapeutic operative dentistry: clinical investigation, Curr. Ther. Res., 1991 , 49 (3), 371-375 y El-Sharrawy y col., Attenuation of C-reactive protein increases añer exodontia by tramadol and ibuprofen, Anesth Prog., 2006, 53 (3), 78-82.  The combined use of various analgesics, including tramadol and ibuprofen, in dentistry has been described, as described in Moroz et al., Use of tramadol hydrochloride in therapeutic operative dentistry: clinical research, Curr. Ther. Res., 1991, 49 (3), 371-375 and El-Sharrawy et al., Attenuation of C-reactive protein increases to add exodontia by tramadol and ibuprofen, Anesth Prog., 2006, 53 (3), 78-82.
También en la solicitud de patente europea EP-A-0546676 se indica que la combinación de tramadol (o de sus derivados N-óxido u O-desmetilado) con ibuprofeno presenta un efecto analgésico sinérgico, según se concluye de un ensayo realizado en base a un modelo experimental de analgesia en ratón.  Also in European patent application EP-A-0546676 it is indicated that the combination of tramadol (or its N-oxide or O-demethylated derivatives) with ibuprofen has a synergistic analgesic effect, as concluded from a test based on an experimental model of mouse analgesia.
En determinadas circunstancias, resultan especialmente útiles las composiciones analgésicas para administración por vía intravenosa, puesto que dicha ruta permite un inicio más rápido de la acción terapéutica, así como una mayor eficacia y una duración analgésica más prolongada para el control del dolor agudo, particularmente en el ámbito hospitalario. En este sentido, se comercializa la especialidad farmacéutica "Adolonta® 100 mg solución inyectable" que consiste en una monodosis de tramadol para administración por inyección, conteniendo 100 mg de hidrocloruro de tramadol en 2 mi de solución. In certain circumstances, analgesic compositions for intravenous administration are especially useful, since said route allows a faster onset of therapeutic action, as well as greater efficacy and a longer analgesic duration for the control of acute pain, particularly in the hospital environment. In this sense, the pharmaceutical specialty "Adolonta ® 100 mg solution for injection" is commercialized, consisting of a single dose of tramadol for administration by injection, containing 100 mg of tramadol hydrochloride in 2 ml of solution.
Hasta la fecha, sin embargo, no se han encontrado descritas en la literatura formulaciones estables destinadas a su administración por inyección que contengan una combinación de tramadol e ibuprofeno. Únicamente en la patente europea EP-A- 0546676 citada anteriormente se menciona de forma genérica la posible administración por inyección de dicha combinación analgésica, si bien no se describen formulaciones específicas estables a tal efecto, sino que solamente se preparan, con finalidad experimental y para su administración inmediata en ratón, varias soluciones acuosas de tramadol e ibuprofeno en relación ponderal 1 :1 , con una concentración de 4 mg/ml para cada principio activo y que contienen además un 2% en volumen de polisorbato 80. Se da la circunstancia de que el ibuprofeno es un fármaco muy poco soluble en agua y, por este motivo, la elaboración de formas farmacéuticas estables de ibuprofeno en solución acuosa, especialmente para su administración para inyección, presenta tradicionalmente ciertas dificultades. Son conocidas algunas sales de ibuprofeno con aminoácidos básicos y, por ejemplo, en la patente española ES435416 se describe la preparación de sales de ibuprofeno con lisina y con arginina, indicándose que son moderadamente solubles. To date, however, stable formulations intended for administration by injection containing a combination of tramadol and ibuprofen have not been described in the literature. Only in the European patent EP-A-0546676 cited above, the possible administration by injection of said analgesic combination is mentioned generically, although specific stable formulations for this purpose are not described, but are only prepared, for experimental purposes and for its immediate administration in mice, several aqueous solutions of tramadol and ibuprofen in a 1: 1 weight ratio, with a concentration of 4 mg / ml for each active substance and which also contain 2% by volume of polysorbate 80. There is a circumstance that ibuprofen is a very water-soluble drug and, for this reason, the preparation of stable pharmaceutical forms of ibuprofen in aqueous solution, especially for administration for injection, traditionally presents certain difficulties. Some ibuprofen salts with basic amino acids are known and, for example, in the Spanish patent ES435416 the preparation of ibuprofen salts with lysine and with arginine is described, indicating that they are moderately soluble.
Por otro lado, aunque aparentemente la combinación de ibuprofeno con arginina o lisina en unas composiciones determinadas puede comportar efectos beneficiosos respecto a la actividad del ibuprofeno, la combinación de tramadol y L-arginina está escasamente documentada en la literatura. De hecho, su combinación de acuerdo con lo descrito en la literatura sería desaconsejable a la vista, por ejemplo, del artículo Yalcin y col., Involvement of potassium channels and nitric oxide in tramadol antinociception, Pharmacol. Biochem. Behav., 2005, 80(1), 69-75, donde se describe que la L-arginina disminuye el efecto analgésico del tramadol. On the other hand, although apparently the combination of ibuprofen with arginine or lysine in certain compositions may have beneficial effects on the activity of ibuprofen, the combination of tramadol and L-arginine is poorly documented in the literature. In fact, their combination according to what is described in the literature would be inadvisable in view, for example, of the article Yalcin et al., Involvement of potassium channels and nitric oxide in tramadol antinociception, Pharmacol. Biochem Behav., 2005, 80 (1), 69-75, where it is described that L-arginine decreases the analgesic effect of tramadol.
Únicamente en la solicitud de patente española ES-A-2356762 se describen composiciones farmacéuticas destinadas exclusivamente a la administración oral que contienen una combinación de ibuprofeno y tramadol, juntamente con arginina, y que están indicadas para el tratamiento de dolor, inflamación y/o fiebre.  Only in Spanish patent application ES-A-2356762 are described pharmaceutical compositions intended exclusively for oral administration containing a combination of ibuprofen and tramadol, together with arginine, and which are indicated for the treatment of pain, inflammation and / or fever .
Así pues, subsiste la necesidad de poder disponer de una composición analgésica para su administración por inyección que sea estable, que permita un rápido inicio de la acción terapéutica, que sea eficaz para el tratamiento del dolor de intensidad moderado a severo y que presente menores efectos secundarios.  Thus, there remains a need to have a stable analgesic composition for administration by injection, which allows a rapid onset of therapeutic action, that is effective for the treatment of moderate to severe pain and that has less effects. secondary.
Objeto de la invención Object of the invention
Un objeto de la presente invención es una composición farmacéutica acuosa para inyección que contiene tramadol e ibuprofeno arginato. An object of the present invention is an aqueous pharmaceutical composition for injection containing tramadol and ibuprofen arginate.
Es también un objeto de la invención proporcionar un procedimiento para la preparación de dicha composición. Otro objeto de la invención es una forma farmacéutica de dosificación unitaria que contiene la citada composición. También es otro objeto de la invención la utilización de la composición descrita para la preparación de un medicamento para el tratamiento del dolor de intensidad moderado a severo, la inflamación o la fiebre. It is also an object of the invention to provide a process for the preparation of said composition. Another object of the invention is a unit dosage pharmaceutical form containing said composition. It is also another object of the invention to use the composition described for the preparation of a medicament for the treatment of moderate to severe pain, inflammation or fever.
Descripción detallada de la invención Detailed description of the invention
Un objeto de la presente invención es una composición farmacéutica para inyección caracterizada porque consiste esencialmente en tramadol o una de sus sales farmacéuticamente aceptables, ibuprofeno, arginina y agua para inyección, estando comprendida la relación molar entre arginina e ibuprofeno entre 0,9:1 y 1 ,1 :1. Los autores de la presente invención han desarrollado una composición farmacéutica acuosa para su administración por inyección que consiste en una combinación de tramadol e ibuprofeno en forma de sal con arginina (ibuprofeno arginato), que presenta ventajas sobre las composiciones descritas en el estado de la técnica, puesto que se trata de una composición de elevada estabilidad que consigue una acción analgésica rápida y eficaz y que comporta un menor riesgo de efectos secundarios. An object of the present invention is a pharmaceutical composition for injection characterized in that it essentially consists of tramadol or a pharmaceutically acceptable salt thereof, ibuprofen, arginine and water for injection, the molar ratio between arginine and ibuprofen being between 0.9: 1 and 1, 1: 1. The authors of the present invention have developed an aqueous pharmaceutical composition for administration by injection consisting of a combination of tramadol and ibuprofen in the form of salt with arginine (ibuprofen arginate), which has advantages over the compositions described in the prior art. , since it is a composition of high stability that achieves a fast and effective analgesic action and that entails a lower risk of side effects.
Tramadol Tramadol
El tramadol es la Denominación Común Internacional (DCI) por la que se conoce habitualmente al compuesto (±)-cis-2-[(dimetilamino)metil]-1-(3- metoxifenil)ciclohexanol. Tramadol is the International Common Denomination (INN) by which the compound (±) -cis-2 - [(dimethylamino) methyl] -1- (3- methoxyphenyl) cyclohexanol is commonly known.
El tramadol se encuentra disponible de forma comercial y también puede prepararse, por ejemplo, según el procedimiento descrito en la patente norteamericana US3652589. Tramadol is commercially available and can also be prepared, for example, according to the procedure described in US Patent US3652589.
En el contexto de la presente invención, el término tramadol se refiere en forma amplia a cualquiera de sus solvatos, polimorfos, estereoisómeros, mezclas de estereoisómeros y formas racémicas. In the context of the present invention, the term "tramadol" refers broadly to any of its solvates, polymorphs, stereoisomers, mixtures of stereoisomers and racemic forms.
Las sales farmacéuticamente aceptables de tramadol se refieren a las sales de adición con ácidos, las cuales pueden prepararse según métodos convencionales bien conocidos por el experto en la materia, empleando ácidos orgánicos o inorgánicos farmacéuticamente aceptables y sustancialmente no tóxicos. Tales ácidos incluyen el ácido clorhídrico, ácido nítrico, ácido sulfúrico, ácido fosfórico, ácido acético, ácido propiónico, ácido maleico, ácido malónico, ácido succínico, ácido cítrico, ácido tartárico, ácido málico, ácido salicílico, ácido itálico, etc. Preferiblemente, se emplea ácido clorhídrico. Pharmaceutically acceptable salts of tramadol refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using organic or inorganic acids. Pharmaceutically acceptable and substantially non-toxic. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, salicylic acid, italic acid, etc. Preferably, hydrochloric acid is used.
En una realización preferente de la invención, el tramadol está en forma de su sal hidrocloruro. Más preferiblemente, se encuentra en forma de hidrocloruro de tramadol en forma racémica. In a preferred embodiment of the invention, tramadol is in the form of its hydrochloride salt. More preferably, it is in the form of tramadol hydrochloride in racemic form.
Ibuprofeno Ibuprofeno es la Denominación Común Internacional (DCI) por la que se conoce habitualmente al ácido (RS)-2-(4-isobutilfenil)propión¡co. Ibuprofen Ibuprofen is the International Common Denomination (INN) by which (RS) -2- (4-isobutylphenyl) propionic acid is commonly known.
Es conocido que el enantiómero activo del ibuprofeno es la forma (S), aunque se ha comprobado que los mamíferos poseen una isomerasa capaz de convertir la forma (R) en la forma activa (S). It is known that the active enantiomer of ibuprofen is form (S), although it has been proven that mammals have an isomerase capable of converting form (R) into active form (S).
En el contexto de la presente invención, el término ibuprofeno incluye ibuprofeno en su forma racémica ((R,S)-ibuprofeno), el enantiómero (S) del ibuprofeno ((S)- ibuprofeno) y una mezcla de los enantiómeros (R) y (S) del ibuprofeno, preferentemente enriquecida en la forma (S). Preferiblemente, el ibuprofeno empleado en las composiciones de la invención se selecciona de entre (R.S)-ibuprofeno y (S)- ibuprofeno. Más preferiblemente, las composiciones de la invención contienen (R,S)- ibuprofeno. In the context of the present invention, the term ibuprofen includes ibuprofen in its racemic form ((R, S) -ibuprofen), the enantiomer (S) of ibuprofen ((S) - ibuprofen) and a mixture of the enantiomers (R) and (S) of ibuprofen, preferably enriched in form (S). Preferably, the ibuprofen used in the compositions of the invention is selected from (R.S) -ibuprofen and (S)-ibuprofen. More preferably, the compositions of the invention contain (R, S) - ibuprofen.
El ibuprofeno se encuentra disponible comercialmente y también puede prepararse, por ejemplo, según el procedimiento descrito en la solicitud de patente británica GB-A-971700. La resolución del ibuprofeno en sus enantiómeros se describe, por ejemplo, en el artículo de Brushan u col., Resolution of enantiomers ofibuprofen by liquid chromatography: a review, Biomed. Chromatogr., 1998, 12 (6), 309. Ibuprofen is commercially available and can also be prepared, for example, according to the procedure described in British patent application GB-A-971700. The resolution of ibuprofen in its enantiomers is described, for example, in Brushan et al., Resolution of enantiomers ofibuprofen by liquid chromatography: a review, Biomed. Chromatogr., 1998, 12 (6), 309.
La sal de ibuprofeno y arginina se conoce habitualmente con el término ibuprofeno arginato. En general, las composiciones de la invención se preparan a partir del ibuprofeno y la arginina por separado, formándose en el medio acuoso esencialmente el ibuprofeno arginato. En una realización alternativa, pero no preferente de la invención, las composiciones se preparan a partir de la sal de ibuprofeno arginato formada previamente. Dicha sal puede prepararse, por ejemplo, según se describe en la solicitud de patente española ES435416. The salt of ibuprofen and arginine is commonly known by the term ibuprofen arginate. In general, the compositions of the invention are prepared from ibuprofen and arginine separately, with ibuprofen arginate being formed in the aqueous medium. In an alternative but not preferred embodiment of the invention, the compositions are prepared from the previously formed ibuprofen arginate salt. Said salt can be prepared, for example, as described in Spanish patent application ES435416.
Arginina Arginine
La arginina es un α-aminoácido, que se encuentra en la naturaleza en su forma enantiomérica L. En el contexto de esta invención, por arginina se entiende cualquiera de sus formas enantioméricas: L-arginina, D-arginina y sus mezclas. Preferiblemente, la arginina está en forma de L-arginina.  Arginine is an α-amino acid, which is found in nature in its enantiomeric form L. In the context of this invention, arginine is understood as any of its enantiomeric forms: L-arginine, D-arginine and mixtures thereof. Preferably, the arginine is in the form of L-arginine.
La arginina puede obtenerse de forma comercial a partir de diversas fuentes. Composiciones Arginine can be obtained commercially from various sources. Compositions
La composición de la invención se prepara con agua para inyección que se puede obtener, por ejemplo, por destilación o por osmosis inversa. The composition of the invention is prepared with water for injection that can be obtained, for example, by distillation or by reverse osmosis.
En la composición de la invención el ibuprofeno está sustancialmente en forma de ibuprofeno arginato, es decir en forma de una sal con arginina. La relación molar entre arginina e ibuprofeno en la composición de la invención está comprendida entre 0,9:1 y 1 ,1 :1 ; preferentemente dicha relación molar es 1 ,0:1 y con especial preferencia es 1 ,05:1. In the composition of the invention ibuprofen is substantially in the form of ibuprofen arginate, that is, in the form of a salt with arginine. The molar ratio between arginine and ibuprofen in the composition of the invention is between 0.9: 1 and 1, 1: 1; preferably said molar ratio is 1.0: 1 and with particular preference is 0.05: 1.
Preferiblemente la concentración de ibuprofeno en la composición farmacéutica de la invención está comprendida entre 50 mg y 200 mg de ibuprofeno por cada mi de disolución, con especial preferencia 70 mg y 150 mg por cada mi de disolución, aún con más preferencia entre 90 mg y 110 mg por cada mi de disolución y de forma totalmente preferente el ibuprofeno está en una concentración de 100 mg por mi de disolución. Preferably the concentration of ibuprofen in the pharmaceutical composition of the invention is between 50 mg and 200 mg of ibuprofen per ml of solution, especially preferably 70 mg and 150 mg per ml of solution, even more preferably between 90 mg and 110 mg for each ml of solution and, most preferably, ibuprofen is in a concentration of 100 mg per ml of solution.
La concentración de tramadol o de una de sus sales farmacéuticamente aceptables en la composición de la invención está comprendida preferiblemente entre 2 mg y 50 mg por cada mi de disolución, con especial preferencia entre 5 mg y 35 mg por cada mi de disolución, expresada como concentración equivalente de hidrocloruro de tramadol. En una realización preferente de la invención, la concentración de tramadol o de una de sus sales farmacéuticamente aceptables está comprendida entre 10 mg y 15 mg por cada mi de solución, en especial entre 12 mg y 13 mg por cada mi de solución y en particular la concentración de tramadol es de 12,5 mg por cada mi de solución, expresada como concentración equivalente de hidrocloruro de tramadol. The concentration of tramadol or a pharmaceutically acceptable salt thereof in the composition of the invention is preferably between 2 mg and 50 mg for each ml of solution, especially preferably between 5 mg and 35 mg for each ml of solution, expressed as equivalent concentration of tramadol hydrochloride. In a preferred embodiment of the invention, the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 10 mg and 15 mg for each ml of solution, especially between 12 mg and 13 mg for each ml of solution and in particular The concentration of tramadol is 12.5 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
En otra realización preferente de la invención, la concentración de tramadol o de una de sus sales farmacéuticamente aceptables está comprendida entre 15 mg y 20 mg por cada mi de solución, con especial preferencia entre 18,0 mg y 19,5 mg por cada mi de solución y en particular la concentración de tramadol o de una de sus sales farmacéuticamente aceptables es de 18,75 mg por cada mi de solución, expresada como concentración equivalente de hidrocloruro de tramadol. In another preferred embodiment of the invention, the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 15 mg and 20 mg per ml of solution, especially preferably between 18.0 mg and 19.5 mg per ml. of solution and in particular the concentration of tramadol or one of its pharmaceutically acceptable salts is 18.75 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
En una realización particularmente preferente de la invención, la composición inyectable incluye: In a particularly preferred embodiment of the invention, the injectable composition includes:
- una concentración de ibuprofeno comprendida entre 80 mg/ml y 120 mg/ml, en especial entre 90 mg/ml y 110 mg/ml y en particular de 100 mg/ml; y - a concentration of ibuprofen between 80 mg / ml and 120 mg / ml, in particular between 90 mg / ml and 110 mg / ml and in particular 100 mg / ml; Y
- una concentración de tramadol, expresada como concentración equivalente de hidrocloruro de tramadol, comprendida entre 10 mg/ml y 15 mg/ml, en especial entre 12 mg/ml y 13 mg/ml, y en particular de 12,5 mg/ml.  - a concentration of tramadol, expressed as equivalent concentration of tramadol hydrochloride, between 10 mg / ml and 15 mg / ml, especially between 12 mg / ml and 13 mg / ml, and in particular 12.5 mg / ml .
En otra realización preferente de la invención, la composición inyectable incluye: - una concentración de ibuprofeno comprendida entre 80 mg/ml y 120 mg/ml, en especial entre 90 mg/ml y 110 mg/ml, en particular de 100 mg/ml; y  In another preferred embodiment of the invention, the injectable composition includes: - a concentration of ibuprofen between 80 mg / ml and 120 mg / ml, especially between 90 mg / ml and 110 mg / ml, in particular 100 mg / ml ; Y
- una concentración de tramadol, expresada como concentración equivalente de hidrocloruro de tramadol, comprendida entre 15 mg/ml y 20 mg/ml, en especial entre 18 mg/ml y 19,5 mg/ml y en particular de 18,75 mg/ml. La composición inyectable de la invención se dosifica generalmente según una forma farmacéutica de dosificación unitaria que contiene un volumen de la composición adecuado para administrar la dosis deseada de los principios activos. Preferentemente, la composición se dosifica en viales o en jeringas precargadas.  - a concentration of tramadol, expressed as equivalent concentration of tramadol hydrochloride, between 15 mg / ml and 20 mg / ml, in particular between 18 mg / ml and 19.5 mg / ml and in particular 18.75 mg / ml. The injectable composition of the invention is generally dosed according to a unit dosage pharmaceutical form containing a volume of the composition suitable for administering the desired dose of the active ingredients. Preferably, the composition is dosed in vials or in pre-filled syringes.
Preferiblemente, la forma farmacéutica de dosificación unitaria incluye una cantidad de ibuprofeno comprendida entre 50 mg y 1.000 mg, en especial entre 200 mg y 800 mg, y una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 25 mg y 150 mg, en especial entre 40 mg y 85 mg. Preferably, the unit dosage dosage form includes an amount of ibuprofen between 50 mg and 1,000 mg, especially between 200 mg. and 800 mg, and an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 25 mg and 150 mg, especially between 40 mg and 85 mg.
En una realización particularmente preferente, la composición inyectable de la invención se dosifica en una dosis unitaria que contiene una cantidad de ibuprofeno comprendida entre 300 mg y 500 mg, en particular de 400 mg. In a particularly preferred embodiment, the injectable composition of the invention is dosed in a unit dose containing an amount of ibuprofen between 300 mg and 500 mg, in particular 400 mg.
En otra realización, la composición inyectable de la invención se dosifica en una dosis unitaria que contiene una cantidad de ibuprofeno comprendida entre 100 mg y 300 mg, en particular de 200 mg. En otra realización, la composición inyectable de la invención se dosifica en una dosis unitaria que contiene una cantidad de ibuprofeno comprendida entre 700 mg y 900 mg, en particular de 800 mg. In another embodiment, the injectable composition of the invention is dosed in a unit dose containing an amount of ibuprofen between 100 mg and 300 mg, in particular 200 mg. In another embodiment, the injectable composition of the invention is dosed in a unit dose containing an amount of ibuprofen between 700 mg and 900 mg, in particular 800 mg.
En una realización preferente, la composición inyectable de la invención se dosifica en una dosis unitaria que contiene una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 40 mg y 60 mg, en particular 50 mg. In a preferred embodiment, the injectable composition of the invention is dosed in a unit dose containing an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, comprised between 40 mg and 60 mg, in particular 50 mg.
En otra realización preferente, la composición inyectable de la invención se dosifica en una dosis unitaria que contiene una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg, en particular 75 mg. In another preferred embodiment, the injectable composition of the invention is dosed in a unit dose containing an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg, in particular 75 mg.
Preferiblemente la forma farmacéutica de dosificación unitaria contiene una dosis de ibuprofeno seleccionada de entre 200 mg, 400 mg y 800 mg y una dosis de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, seleccionada de entre 50 mg y 75 mg. Con especial preferencia, la forma farmacéutica de dosificación unitaria comprende 400 mg de ibuprofeno y una dosis de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, seleccionada de entre 50 mg y 75 mg, de modo que se dispone de la combinación de 400 mg de ibuprofeno con 50 mg de tramadol y de la combinación de 400 mg de ibuprofeno con 75 mg de tramadol. En una realización preferente de la invención, la forma farmacéutica de dosificación unitaria contiene: Preferably the unit dosage dosage form contains a dose of ibuprofen selected from 200 mg, 400 mg and 800 mg and a dose of tramadol, expressed as equivalent weight of tramadol hydrochloride, selected from 50 mg to 75 mg. With particular preference, the unit dosage dosage form comprises 400 mg of ibuprofen and a dose of tramadol, expressed as equivalent weight of tramadol hydrochloride, selected between 50 mg and 75 mg, so that the combination of 400 mg is available. of ibuprofen with 50 mg of tramadol and the combination of 400 mg of ibuprofen with 75 mg of tramadol. In a preferred embodiment of the invention, the unit dosage dosage form contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 45 mg y 55 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
- una cantidad de ibuprofeno comprendida entre 350 y 450 mg; y  - an amount of ibuprofen between 350 and 450 mg; Y
- agua para inyección hasta un volumen comprendido entre 3,5 mi y 4,5 mi.  - water for injection up to a volume between 3.5 mi and 4.5 mi.
En otra realización preferente de la invención, la forma farmacéutica de dosificación unitaria contiene: In another preferred embodiment of the invention, the unit dosage dosage form contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
- una cantidad de ibuprofeno comprendida entre 350 y 450 mg; y  - an amount of ibuprofen between 350 and 450 mg; Y
- agua para inyección hasta un volumen comprendido entre 3,5 mi y 4,5 mi.  - water for injection up to a volume between 3.5 mi and 4.5 mi.
En otra realización de la invención, la forma farmacéutica de dosificación unitaria contiene: In another embodiment of the invention, the unit dosage pharmaceutical form contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 45 mg y 55 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
- una cantidad de ibuprofeno comprendida entre 750 mg y 850; y  - an amount of ibuprofen between 750 mg and 850; Y
- agua para inyección hasta un volumen comprendido entre 7,5 mi y 8,5 mi.  - water for injection up to a volume between 7.5 mi and 8.5 mi.
En otra realización de la invención, la forma farmacéutica de dosificación unitaria contiene: In another embodiment of the invention, the unit dosage pharmaceutical form contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
- una cantidad de ibuprofeno comprendida entre 750 mg y 850 mg; y  - an amount of ibuprofen between 750 mg and 850 mg; Y
- agua para inyección hasta un volumen comprendido entre 7,5 mi y 8,5 mi.  - water for injection up to a volume between 7.5 mi and 8.5 mi.
En otra realización de la invención, la forma farmacéutica de dosificación unitaria contiene: - una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 45 mg y 55 mg; In another embodiment of the invention, the unit dosage pharmaceutical form contains: - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
- una cantidad de ibuprofeno comprendida entre 175 mg y 225; y  - an amount of ibuprofen between 175 mg and 225; Y
- agua para inyección hasta un volumen comprendido entre 1 ,8 mi y 2,2 mi.  - water for injection up to a volume between 1, 8 mi and 2.2 mi.
En otra realización de la invención, la forma farmacéutica de dosificación unitaria contiene: In another embodiment of the invention, the unit dosage pharmaceutical form contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
- una cantidad de ibuprofeno comprendida entre 175 mg y 225 mg; y  - an amount of ibuprofen between 175 mg and 225 mg; Y
- agua para inyección hasta un volumen comprendido entre 1 ,8 mi y 2,2 mi.  - water for injection up to a volume between 1, 8 mi and 2.2 mi.
Preparación de las composiciones de la invención Preparation of the compositions of the invention
Es parte objeto de la invención un procedimiento para preparar una composición farmacéutica de acuerdo con la invención. An object of the invention is a process for preparing a pharmaceutical composition according to the invention.
Un procedimiento adecuado para preparar las composiciones de la invención incluye las siguientes etapas: a) disolver tramadol, arginina e ibuprofeno en agua para inyección; y  A suitable process for preparing the compositions of the invention includes the following steps: a) dissolve tramadol, arginine and ibuprofen in water for injection; Y
b) ajusfar el pH añadiendo una solución acuosa de un ácido y/o de una base hasta un valor comprendido entre 7,6 y 8,0.  b) adjust the pH by adding an aqueous solution of an acid and / or a base to a value between 7.6 and 8.0.
Habitualmente se dispone el agua para inyección en un reactor provisto de agitador y se incorporan consecutivamente, bajo agitación continua, los diferentes componentes de la formulación, tramadol, arginina e ibuprofeno, hasta conseguir su completa disolución. The water for injection is usually placed in a reactor equipped with a stirrer and the different components of the formulation, tramadol, arginine and ibuprofen, are incorporated consecutively under continuous agitation, until they are completely dissolved.
Se ajusta el pH de la solución obtenida hasta un valor comprendido entre 7,6 y 8,0 mediante la adición de una solución acuosa de un ácido o de una base. Por ejemplo, puede emplearse una solución de ácido clorhídrico 0,1 N o una solución de hidróxido sódico 0,1 N. Finalmente, si es necesario, se añade agua para inyección adicional hasta obtener la concentración deseada de los principios activos. The pH of the solution obtained is adjusted to a value between 7.6 and 8.0 by the addition of an aqueous solution of an acid or a base. For example, a solution of 0.1 N hydrochloric acid or a solution of 0.1 N sodium hydroxide can be used. Finally, if necessary, water is added for further injection until the desired concentration of the active ingredients is obtained.
La solución obtenida se puede esterilizar, por ejemplo, por filtración. Posteriormente, la solución resultante se puede dosificar según formas farmacéuticas unitarias en un envase adecuado, por ejemplo en viales o jeringas estériles. Preferentemente, la composición se dosifica a razón de 2 mi, 4 mi u 8 mi de solución en cada dosis. The solution obtained can be sterilized, for example, by filtration. Subsequently, the resulting solution can be dosed according to unit dosage forms in a suitable container, for example in sterile vials or syringes. Preferably, the composition is dosed at a rate of 2 ml, 4 ml or 8 ml of solution in each dose.
Opcionalmente, los viales o jeringas que contienen la composición de la invención se esterilizan en un autoclave, por ejemplo por tratamiento a 121°C durante aproximadamente 20 minutos. Optionally, the vials or syringes containing the composition of the invention are sterilized in an autoclave, for example by treatment at 121 ° C for approximately 20 minutes.
Las composiciones de la invención poseen efecto analgésico y son útiles para el tratamiento del dolor, en particular del dolor crónico o agudo de intensidad de moderada a severa, así como también de la inflamación y estados febriles y, en general, de cualquier enfermedad susceptible de ser tratada con tramadol y/o ibuprofeno. The compositions of the invention have an analgesic effect and are useful for the treatment of pain, in particular chronic or acute pain of moderate to severe intensity, as well as inflammation and febrile conditions and, in general, of any disease susceptible to be treated with tramadol and / or ibuprofen.
Por ello, es también objeto de la invención la utilización de la composición de la invención en el tratamiento del dolor, inflamación y/o estados febriles o de cualquier enfermedad susceptible de ser tratada con tramadol y/o ibuprofeno. O, formulado de forma alternativa, es otro objeto de la invención la utilización de la composición de la invención para la preparación de un medicamento para el tratamiento del dolor, inflamación y/o estados febriles, o de cualquier enfermedad susceptible de ser tratada con tramadol y/o ibuprofeno. O alternativamente, es otro el objeto de la invención la utilización de una forma de dosificación de la invención para la preparación de un medicamento para el tratamiento del dolor, la inflamación y/o estados febriles, o de cualquier enfermedad susceptible de ser tratada con tramadol y/o ibuprofeno, que comprende administrar a un mamífero que lo necesite, preferentemente a una persona, una composición de acuerdo con la invención. Therefore, it is also the object of the invention to use the composition of the invention in the treatment of pain, inflammation and / or febrile conditions or of any disease capable of being treated with tramadol and / or ibuprofen. Or, alternatively formulated, it is another object of the invention to use the composition of the invention for the preparation of a medicament for the treatment of pain, inflammation and / or febrile conditions, or of any disease that can be treated with tramadol. and / or ibuprofen. Or alternatively, another object of the invention is the use of a dosage form of the invention for the preparation of a medicament for the treatment of pain, inflammation and / or febrile conditions, or of any disease capable of being treated with tramadol. and / or ibuprofen, which comprises administering to a mammal in need thereof, preferably to a person, a composition according to the invention.
Las composiciones de la invención pueden emplearse para el tratamiento de distintos tipos de dolor causados por distintas dolencias, tales como cefaleas, odontalgia, otalgia, migraña, dolor muscular, dolor articular, dolor neuropático, dolor post-traumático, post-parto, dolor post-quirúrgico, dolor de infarto agudo de miocardio y dolor oncológico. También pueden emplearse como analgésico preoperatorio, como complemento de anestesia quirúrgica y en procedimientos de exploración diagnóstica que cursen con dolor. Las composiciones además pueden emplearse como antiinflamatorio y, debido principalmente a la acción del ibuprofeno, como antipirético, por lo que son útiles para el tratamiento de la inflamación y/o la fiebre causados por distintas dolencias, tales como artritis reumatoide (incluyendo artritis reumatoide juvenil), osteoartritis, espondilitis anquilopoyética, artrosis y otros procesos reumáticos agudos o crónicos, bursitis, sinovitis, capsulitis u otros tipos de lesiones inflamatorias de origen traumático o deportivo. Las composiciones de la invención también pueden ser útiles para el tratamiento de otras dolencias que puedan aliviarse con ibuprofeno o tramadol. The compositions of the invention can be used for the treatment of different types of pain caused by different ailments, such as headaches, odontalgia, otalgia, migraine, muscle pain, joint pain, neuropathic pain, post-traumatic pain, postpartum, post pain -urgical, acute myocardial infarction pain and cancer pain They can also be used as a preoperative analgesic, as a complement to surgical anesthesia and in diagnostic examination procedures that occur with pain. The compositions can also be used as anti-inflammatory and, mainly due to the action of ibuprofen, as an antipyretic, so they are useful for the treatment of inflammation and / or fever caused by various medical conditions, such as rheumatoid arthritis (including juvenile rheumatoid arthritis ), osteoarthritis, ankylopoietic spondylitis, osteoarthritis and other acute or chronic rheumatic processes, bursitis, synovitis, capsulitis or other types of inflammatory injuries of traumatic or sports origin. The compositions of the invention may also be useful for the treatment of other conditions that can be relieved with ibuprofen or tramadol.
La referencia a tratamiento incluye aquí tanto el tratamiento de síntomas establecidos como el tratamiento profiláctico. Preferentemente, se emplean para el tratamiento de síntomas establecidos. La composición farmacéutica inyectable según la presente invención se administra por vía intravenosa previa dilución en soluciones apropiadas para perfusión, bien conocidas por el experto en la materia, por ejemplo solución acuosa de cloruro de sodio al 0,9%, solución de Ringer Lactato o solución acuosa de glucosa al 5%. The reference to treatment includes both the treatment of established symptoms and the prophylactic treatment. Preferably, they are used for the treatment of established symptoms. The injectable pharmaceutical composition according to the present invention is administered intravenously prior dilution in appropriate solutions for infusion, well known to those skilled in the art, for example 0.9% aqueous sodium chloride solution, Ringer Lactate solution or solution 5% aqueous glucose.
A continuación, se proporcionan varios ejemplos a modo ilustrativo aunque no limitativo de la invención. In the following, several examples are provided by way of illustration but not limitation of the invention.
Ejemplos Examples
Ejemplo 1 : Composición inyectable de ibuprofeno/hidrocloruro de tramadol de dosis 400/50 Example 1: Injectable composition of ibuprofen / tramadol hydrochloride dose 400/50
Se preparó una solución acuosa utilizando los componentes que se detallan en la siguiente tabla: An aqueous solution was prepared using the components detailed in the following table:
Ingrediente Cantidad (mg/ mi) Ingredient Amount (mg / mi)
Ibuprofeno 100 Tramadol HCI 12,5 Ibuprofen 100 Tramadol HCI 12.5
Arginina 89 Arginine 89
HCI 0,1 N es. hasta pH=7,8 HCI 0.1 N is. up to pH = 7.8
NaOH 0,1 N es. hasta pH=7,8 agua para inyección es. 0.1 N NaOH is. up to pH = 7.8 water for injection is.
En un reactor se dispuso una parte del agua para inyección, a razón de aproximadamente 2/3 del tamaño del lote final. A continuación, bajo continua agitación, se añadieron consecutivamente hidrocloruro de tramadol, arginina, e ibuprofeno, hasta total disolución. Se determinó el pH y se ajustó a un valor de 7,8 con la solución de HCI y/o NaOH. Se añadió el resto de agua para inyección y se filtró la solución así obtenida a través de un filtro de 0,22 mieras. La solución resultante se dosificó en viales de vidrio transparentes, a razón de 4 mi de solución en cada vial, obteniendo una solución inyectable con una osmolalidad superior a 310 mOsm/kg. A part of the water for injection was placed in a reactor at a rate of approximately 2/3 of the size of the final batch. Then, under continuous stirring, tramadol hydrochloride, arginine, and ibuprofen were added consecutively, until completely dissolved. The pH was determined and adjusted to a value of 7.8 with the solution of HCI and / or NaOH. The rest of the water for injection was added and the solution thus obtained was filtered through a 0.22 micron filter. The resulting solution was dosed in transparent glass vials, at a rate of 4 ml of solution in each vial, obtaining an injectable solution with an osmolality greater than 310 mOsm / kg.
Ejemplo 2: Composición inyectable de ibuprofeno/hidrocloruro de tramadol de dosis 400/75 Example 2: Injectable composition of ibuprofen / tramadol hydrochloride dose 400/75
Se preparó una solución acuosa utilizando los componentes que se detallan en la siguiente tabla: An aqueous solution was prepared using the components detailed in the following table:
Ingrediente Cantidad (mg/ mi) Ingredient Amount (mg / mi)
Ibuprofeno 100 Ibuprofen 100
Tramadol HCI 18,75 Tramadol HCI 18.75
Arginina 89 Arginine 89
HCI 0,1 N es. hasta pH=7,8 HCI 0.1 N is. up to pH = 7.8
NaOH 0,1N es. hasta pH=7,8 agua para inyección es. Para la preparación de esta composición, se siguió un procedimiento análogo al descrito en el Ejemplo 1. 0.1N NaOH is. up to pH = 7.8 water for injection is. For the preparation of this composition, a procedure analogous to that described in Example 1 was followed.

Claims

REIVINDICACIONES
1. Composición farmacéutica para inyección caracterizada porque consiste en tramadol o una de sus sales farmacéuticamente aceptables, ibuprofeno, arginina y agua para inyección, estando comprendida la relación molar entre arginina e ibuprofeno entre 0,9:1 y 1 ,1 :1. 1. Pharmaceutical composition for injection characterized in that it consists of tramadol or one of its pharmaceutically acceptable salts, ibuprofen, arginine and water for injection, the molar ratio between arginine and ibuprofen being between 0.9: 1 and 1, 1: 1.
2. Composición según la reivindicación 1 , caracterizada porque la relación molar entre arginina e ibuprofeno es 1 ,05:1. 2. Composition according to claim 1, characterized in that the molar ratio between arginine and ibuprofen is 1: 05: 1.
3. Composición según la reivindicación 1 , caracterizada porque el tramadol está en forma de su sal hidrocloruro. 3. Composition according to claim 1, characterized in that tramadol is in the form of its hydrochloride salt.
4. Composición según la reivindicación 1 , caracterizada porque el ibuprofeno está en forma de (R,S)-ibuprofeno. 4. Composition according to claim 1, characterized in that the ibuprofen is in the form of (R, S) -ibuprofen.
5. Composición según la reivindicación 1 , caracterizada porque la arginina está en forma de L-arginina. 5. Composition according to claim 1, characterized in that the arginine is in the form of L-arginine.
6. Composición según la reivindicación 1 o 2, caracterizada porque la concentración de ibuprofeno está comprendida entre 50 mg y 200 mg de ibuprofeno por cada mi de disolución. 6. Composition according to claim 1 or 2, characterized in that the concentration of ibuprofen is between 50 mg and 200 mg of ibuprofen per ml of solution.
7. Composición según la reivindicación 6, caracterizada porque la concentración de ibuprofeno está comprendida entre 70 mg y 150 mg de ibuprofeno por cada mi de disolución. 7. Composition according to claim 6, characterized in that the concentration of ibuprofen is between 70 mg and 150 mg of ibuprofen per ml of solution.
8. Composición según la reivindicación 7, caracterizada porque la concentración de ibuprofeno está comprendida entre 90 mg y 110 mg de ibuprofeno por cada mi de disolución. 8. Composition according to claim 7, characterized in that the concentration of ibuprofen is comprised between 90 mg and 110 mg of ibuprofen per ml of solution.
9. Composición según la reivindicación 1 o 3, caracterizada porque la concentración de tramadol o de una de sus sales farmacéuticamente aceptables está comprendida entre 2 mg y 50 mg por cada mi de disolución, expresada como concentración equivalente de hidrocloruro de tramadol. 9. Composition according to claim 1 or 3, characterized in that the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 2 mg and 50 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
10. Composición según la reivindicación 9, caracterizada porque la concentración de tramadol o de una de sus sales farmacéuticamente aceptables está comprendida entre 10 mg y 15 mg por cada mi de solución, expresada como concentración equivalente de hidrocloruro de tramadol. 10. Composition according to claim 9, characterized in that the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 10 mg and 15 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
11. Composición según la reivindicación 9, caracterizada porque la concentración de tramadol o una de sus sales farmacéuticamente aceptables está comprendida entre 15 mg y 20 mg por cada mi de solución, expresada como concentración equivalente de hidrocloruro de tramadol. Composition according to claim 9, characterized in that the concentration of tramadol or a pharmaceutically acceptable salt thereof is between 15 mg and 20 mg per ml of solution, expressed as equivalent concentration of tramadol hydrochloride.
12. Composición según cualquiera de las reivindicaciones 1 a 5, caracterizada porque incluye: 12. Composition according to any of claims 1 to 5, characterized in that it includes:
- una concentración de ibuprofeno comprendida entre 80 mg/ml y 120 mg/ml; y- a concentration of ibuprofen between 80 mg / ml and 120 mg / ml; Y
- una concentración de tramadol, expresada como concentración equivalente de hidrocloruro de tramadol, comprendida entre 10 mg/ml y 15 mg/ml. - a concentration of tramadol, expressed as equivalent concentration of tramadol hydrochloride, between 10 mg / ml and 15 mg / ml.
13. Composición según cualquiera de las reivindicaciones 1 a 5, caracterizada porque incluye: 13. Composition according to any of claims 1 to 5, characterized in that it includes:
- una concentración de ibuprofeno comprendida entre 80 mg/ml y 120 mg/ml; y - a concentration of ibuprofen between 80 mg / ml and 120 mg / ml; Y
- una concentración de tramadol, expresada como concentración equivalente de hidrocloruro de tramadol, comprendida entre 15 mg/ml y 20 mg/ml. - a concentration of tramadol, expressed as equivalent concentration of tramadol hydrochloride, between 15 mg / ml and 20 mg / ml.
14. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene una cantidad de ibuprofeno comprendida entre 50 mg y 1.000 mg, y una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 25 mg y 150 mg. 14. A unit dosage pharmaceutical form comprising a composition according to claim 1, characterized in that it contains an amount of ibuprofen between 50 mg and 1,000 mg, and an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 25 mg and 150 mg.
15. Forma farmacéutica según la reivindicación 14, caracterizada porque contiene una dosis de ibuprofeno seleccionada entre 200 mg, 400 mg y 800 mg de ibuprofeno y una dosis de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, seleccionada entre 50 mg y 75 mg. 15. Pharmaceutical form according to claim 14, characterized in that it contains a dose of ibuprofen selected from 200 mg, 400 mg and 800 mg of ibuprofen and a dose of tramadol, expressed as equivalent weight of tramadol hydrochloride, selected between 50 mg and 75 mg .
16. Forma farmacéutica según la reivindicación 15, caracterizada porque contiene 400 mg de ibuprofeno, y una dosis de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, seleccionada entre 50 mg y 75 mg. 16. Pharmaceutical form according to claim 15, characterized in that it contains 400 mg of ibuprofen, and a dose of tramadol, expressed as equivalent weight of tramadol hydrochloride, selected between 50 mg and 75 mg.
17. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene: 17. Unit dosage pharmaceutical form comprising a composition according to claim 1, characterized in that it contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 45 mg y 55 mg;  - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
- una cantidad de ibuprofeno comprendida entre 350 y 450 mg; y  - an amount of ibuprofen between 350 and 450 mg; Y
- agua para inyección hasta un volumen comprendido entre 3,5 mi y 4,5 mi.  - water for injection up to a volume between 3.5 mi and 4.5 mi.
18. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene: 18. Unit dosage pharmaceutical form comprising a composition according to claim 1, characterized in that it contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg;  - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
- una cantidad de ibuprofeno comprendida entre 350 y 450 mg; y  - an amount of ibuprofen between 350 and 450 mg; Y
- agua para inyección hasta un volumen comprendido entre 3,5 mi y 4,5 mi.  - water for injection up to a volume between 3.5 mi and 4.5 mi.
19. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene: 19. Unit dosage pharmaceutical form comprising a composition according to claim 1, characterized in that it contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 45 mg y 55 mg;  - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
- una cantidad de ibuprofeno comprendida entre 750 mg y 850; y  - an amount of ibuprofen between 750 mg and 850; Y
- agua para inyección hasta un volumen comprendido entre 7,5 mi y 8,5 mi.  - water for injection up to a volume between 7.5 mi and 8.5 mi.
20. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene: 20. A unit dosage pharmaceutical form comprising a composition according to claim 1, characterized in that it contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg;  - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
- una cantidad de ibuprofeno comprendida entre 750 mg y 850 mg; y  - an amount of ibuprofen between 750 mg and 850 mg; Y
- agua para inyección hasta un volumen comprendido entre 7,5 mi y 8,5 mi.  - water for injection up to a volume between 7.5 mi and 8.5 mi.
21. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene: 21. Pharmaceutical unit dosage form comprising a composition according to claim 1, characterized in that it contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 45 mg y 55 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 45 mg and 55 mg;
- una cantidad de ibuprofeno comprendida entre 175 mg y 225; y  - an amount of ibuprofen between 175 mg and 225; Y
- agua para inyección hasta un volumen comprendido entre 1 ,8 mi y 2,2 mi. - water for injection up to a volume between 1, 8 mi and 2.2 mi.
22. Forma farmacéutica de dosificación unitaria que comprende una composición según la reivindicación 1 , caracterizada porque contiene: 22. Pharmaceutical unit dosage form comprising a composition according to claim 1, characterized in that it contains:
- una cantidad de tramadol, expresada como peso equivalente de hidrocloruro de tramadol, comprendida entre 65 mg y 85 mg; - an amount of tramadol, expressed as equivalent weight of tramadol hydrochloride, between 65 mg and 85 mg;
- una cantidad de ibuprofeno comprendida entre 175 mg y 225 mg; y  - an amount of ibuprofen between 175 mg and 225 mg; Y
- agua para inyección hasta un volumen comprendido entre 1 ,8 mi y 2,2 mi.  - water for injection up to a volume between 1, 8 mi and 2.2 mi.
23. Procedimiento para preparar una composición según cualquiera de las reivindicaciones 1 a 13 o una forma de dosificación según las reivindicaciones 14 a 22, caracterizado porque incluye las siguientes etapas: 23. Method for preparing a composition according to any of claims 1 to 13 or a dosage form according to claims 14 to 22, characterized in that it includes the following steps:
a) disolver tramadol, arginina e ibuprofeno en agua para inyección; y  a) dissolve tramadol, arginine and ibuprofen in water for injection; Y
b) ajusfar el pH añadiendo una solución acuosa de un ácido y/o de una base hasta un valor comprendido entre 7,6 y 8,0.  b) adjust the pH by adding an aqueous solution of an acid and / or a base to a value between 7.6 and 8.0.
24. Utilización de la composición según las reivindicaciones 1 a 13 o de la forma farmacéutica según las reivindicaciones 14 a 22 para la preparación de un medicamento para el tratamiento del dolor, inflamación y de estados febriles o de cualquier enfermedad susceptible de ser tratada con tramadol y/o ibuprofeno. 24. Use of the composition according to claims 1 to 13 or of the pharmaceutical form according to claims 14 to 22 for the preparation of a medicament for the treatment of pain, inflammation and febrile conditions or of any disease capable of being treated with tramadol and / or ibuprofen.
PCT/ES2013/000043 2012-02-22 2013-02-21 Pharmaceutical composition of ibuprofen and tramadol for injection WO2013124498A1 (en)

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EP2862565A1 (en) * 2013-10-11 2015-04-22 Farmalider, S.A. Pharmaceutical composition of ibuprofen and tramadol for ophthalmological use
CN105362214A (en) * 2015-11-16 2016-03-02 沈阳双鼎制药有限公司 Dopexamine hydrochloride injection and preparation method thereof
WO2021005129A1 (en) 2019-07-09 2021-01-14 Farmalíder, S.A. Combination of ibuprofen and tramadol for relieving pain

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US5516803A (en) * 1991-10-30 1996-05-14 Mcneilab, Inc. Composition comprising a tramadol material and a non-steroidal anti-inflammatory drug
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Publication number Priority date Publication date Assignee Title
EP2862565A1 (en) * 2013-10-11 2015-04-22 Farmalider, S.A. Pharmaceutical composition of ibuprofen and tramadol for ophthalmological use
ES2540151A1 (en) * 2013-10-11 2015-07-08 Farmalider S.A. Pharmaceutical composition of ibuprofen and tramadol for ophthalmic use (Machine-translation by Google Translate, not legally binding)
RU2694369C2 (en) * 2013-10-11 2019-07-12 Фармалидер, С.А. Pharmaceutical composition of ibuprofen and tramadol for ophthalmic application
CN105362214A (en) * 2015-11-16 2016-03-02 沈阳双鼎制药有限公司 Dopexamine hydrochloride injection and preparation method thereof
WO2021005129A1 (en) 2019-07-09 2021-01-14 Farmalíder, S.A. Combination of ibuprofen and tramadol for relieving pain

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ES2423866B1 (en) 2014-06-10

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