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WO1998002182A1 - Combinations pharmaceutiques orales d'anti-inflammatoires non steroïdiens et de terpenoïdes - Google Patents

Combinations pharmaceutiques orales d'anti-inflammatoires non steroïdiens et de terpenoïdes Download PDF

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Publication number
WO1998002182A1
WO1998002182A1 PCT/EP1997/003699 EP9703699W WO9802182A1 WO 1998002182 A1 WO1998002182 A1 WO 1998002182A1 EP 9703699 W EP9703699 W EP 9703699W WO 9802182 A1 WO9802182 A1 WO 9802182A1
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Prior art keywords
nsaid
acid
terpenoid compound
pharmaceutical composition
present
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PCT/EP1997/003699
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English (en)
Inventor
Werner Tschollar
Beat Schmid
Uwe Rolf JÜRGENS
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Novartis Consumer Health S.A.
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Publication date
Application filed by Novartis Consumer Health S.A. filed Critical Novartis Consumer Health S.A.
Priority to AU34442/97A priority Critical patent/AU3444297A/en
Publication of WO1998002182A1 publication Critical patent/WO1998002182A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the invention relates to the oral treatment of painful conditions, pyretic conditions (fever) and inflammatory conditions with non-steroidal antiinflammatory drugs (NSAIDs) as well as to novel pharmaceutical compositions adapted to oral administration comprising NSAIDs.
  • NSAIDs as analgesics, anti-pyretic drugs or anti-inflammatory drugs is known in the art.
  • NSAIDs such as gastric irritation, gastric ulceration, gastric bleeding, nephrotoxicity, acute renal failure, jaundice, nausea, dyspepsia, peripheral edema, rash, pruritus, tinnitus, dizziness, headache, anxiety, aseptic meningitis or fluid retention, can only be detected to a far lesser extent than with NSAID monotherapy alone.
  • the invention relates to the use of a non-steroidal antiinflammatory drug in combination with a terpenoid compound (for the manufacture of a medicament adapted to oral administration) for the treatment of painful conditions, pyretic conditions or inflammatory conditions.
  • Painful conditions, pyretic conditions or inflammatory conditions are, for example: musculoskeletal disorders such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis; acute gouty arthritis; rheumatic fever; fever; dysmenorrhea; inflammatory bowel disease, Morbus Crohn, colitis ulcerosa; migraine (prevention or treatment); acute musculoskeletal pain; muscle strain; headache, e.g. tension-type headache, toothache, muscular pain (myalgia, strain), back pain, shoulder pain, bursitis, tendinitis or epicondylitis.
  • enfenamic acid etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate or tolfenamic acid; an (aryl or heteroaryl)-alkylcarboxylic acid or a derivative thereof, such as acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, oxametacine, pirazolac, proglumetacin, sulindac, tiar
  • droxicam isoxicam, piroxicam or tenoxicam
  • a pyrazole derivative e.g. difenamizole or epirizole
  • a pyrazolone derivative e.g. apazone, benzpiperylon, febrazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone or thiazolinobutazone
  • a non- steroidal antiinflammatory drug of another structure e.g.
  • epsilon-acetamidocaproic acid S- adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole or tenidap; or a pharmaceutically acceptable salt thereof.
  • Preferred NSAIDs are aspirin, especially aspirin, calcium acetylsalicylate or lysine acetylsalicylate; salicylic acid, acetaminophen; diclofenac, especially diclofenac, diclofenac sodium or diclofenac potassium; diflunisal, etodolac; fenoprofen, especially fenoprofen or fenoprofen calcium; flurbiprofen; ibuprofen, especially S-ibuprofen; indomethacin, ketoprofen, ketorolac; meclofenamic acid, especially meclofenamic acid or meclofenate sodium monohydrate; mefenamic acid, nabumetone; naproxen, especially naproxen or naproxen sodium; oxaprozin, phenylbutazone, piroxicam, sulindac and tolmetin, especially tolmetin or tolmet
  • NSAIDs are ibuprofen, especially S-ibuprofen, ketoprofen, diclofenac and aspirin, and pharmaceutically acceptable salts thereof.
  • S-ibuprofen, diclofenac and aspirin are preferred.
  • a pharmaceutically acceptable salt of an NSAID having an acidic group is e.g. an alkali metal or alkaline earth metal salt, e.g. the sodium, potassium, magnesium or calcium salt, an aluminium salt or a transition metal salt, e.g. the zinc or copper salt, or a corresponding salt with ammonia or organic amines.
  • Organic amines that come into consideration are, for example, the following: alkylamines, such as mono-, di- or tri-lower alkylamines, e.g.
  • alkylenediamines such as lower alkylenediamines, e.g. ethylenediamine, alkylamines substituted by phenyl, such as mono- or di-phenyl-lower alkylamines, e.g. benzylamine or 1 - or 2-phenylethylamine, hydroxy-alkylamines, such as mono-, di- or tri-hydroxy-lower alkylamines, e.g.
  • oligohydroxy-lower alkylamines e.g. tris-(hydroxymethyl)-methylamine, hydroxy-lower alkyl-di-lower alkylamines, e.g. N,N-dimethylamino- or N,N-diethylamino-ethanol, amino sugars, such as those in which the amino group is optionally substituted by at least one lower alkyl group, e.g.
  • D-glucosamine, D-galactosamine or marmosamine derived from monosaccharides in which an alcoholic hydroxy group is replaced by an amino group
  • N-methyl-D- glucosamine an N-lower alkylated amino sugar
  • cycloalkylamines such as mono- or di- cycloalkylamines, e.g. cyclohexylamine or dicyclohexylamine, basic amino acids, e.g. arginine, histidine, lysine or ornithine, or cyclic amines, such as lower alkyieneamines or lower alkenyleneamines, e.g.
  • pyrrolidine 1-ethyl-pyrrolidine, 2-hydroxyethyl- pyrrolidine, piperidine, 1-ethyl-piperidine, 2-hydroxyethyl-piperidine or pyrroline, or lower alkyieneamines or lower alkenyleneamines in which the carbon chain is interrupted by aza (-NH-), N-lower alkylaza [-N(-lower alkyl)-], oxa (-O-) and/or thia (-S-), e.g. imidazoline, 3- methylimidazoline, piperazine, 4-methyl- or 4-ethylpiperazine, morphoiine or thiomo ⁇ holine.
  • a pharmaceutically acceptable salt of an NSAID having a basic group is e.g. an acid addition salt.
  • Suitable acid components may be, for example, strong inorganic acids, typically mineral acids, e.g. sulfuric acid, phosphoric acids, e.g. orthophosphoric acid, hydrohalic acids, e.g. hydrochloric acid, or strong organic carboxylic acids, typically lower alkanecarboxylic acids which may be substituted, e.g. by halogen, such as acetic acid or trifluoroacetic acid, dicarboxylic acids which may be unsaturated, e.g.
  • a terpenoid compound is, for example, a monoterpenoid compound, a diterpenoid compound, a triterpenoid compound or a sesquiterpenoid compound.
  • a monoterpenoid compound is e.g. camphor, 3-carene, carvacrol, can/one, chrysanthemic acid; cineol, e.g. 1 ,8-cineol; gefarnate, geraniol, linalool, limonene, menthol, pulegone or thymol.
  • a diterpenoid compound is e.g. aphidicolin, forskolin, phytanic acid or phytol.
  • a triterpenoid compound is, for example, glycyrrhetinic acid or diosgenin.
  • a sesquite ⁇ enoid compound is e.g. farnesol or santonin.
  • terpenoid compound is intended also to cover any derivative and any pharmaceutically acceptable salt of a terpenoid compound.
  • a carboxylic acid is, for example, a CrC 7 -aliphatic, a cycloaliphatic, an aromatic, an aromatic-C ⁇ -C -aliphatic, a heteroaromatic or a heteroaromatic-C ⁇ -C 7 -aliphatic carboxylic acid, which carboxylic acid may be unsubstituted or substituted, for example by one or more substituents selected from hydroxy, halogen, d-C -alkoxy, carboxy, CrC 7 -alkoxycarbonyl, cyano, amino, CrC -alkylamino, di-C ⁇ -C 7 -alkylamino, C ⁇ -C 7 -alkanoylamino, nitro, C t -Cr-alkyl and halogen-CrC 7 -alkyl (e.g.trifluoromethyl).
  • substituents selected from hydroxy, halogen, d-C -alkoxy, carboxy, CrC 7 -alk
  • a carboxylic acid is a C r C 7 - alkanoic acid which is unsubstituted or substituted by hydroxy, halogen, carboxy or amino, a C 3 -C -cycloalkanoic acid; a phenyl-d-C 7 -alkanoic acid, a benzoic acid or a naphthoic acid in each of which the phenyl ring(s) may be unsubstituted or substituted by one or more substituents selected from C ⁇ -C 7 -alkyl, halogen-d-C 7 -alkyl, hydroxy, halogen, d-C 7 -alkoxy, carboxy, C C 7 -alkoxycarbonyl, cyano, ammo, d-C 7 -alkylamino, di-C ⁇ -C 7 -alkylam ⁇ no, C 1 -C 7 - alkanoylamino and nitro; or a heteroaromatic
  • Preferred terpenoid compounds are menthol, menthol esters, especially menthyl lactate, or cineol, more preferably menthol or menthyl lactate, and in one embodiment menthol, and in another embodiment menthyl lactate.
  • menthyl lactate The structural formula of menthyl lactate is as follows:
  • racemate As the compound contains 4 asymmetric carbon atoms, there are existing 16 different stereoisomers.
  • the term “menthyl lactate” is intended to cover each of these stereoisomers as well as any racemates and any other mixtures of these stereoisomers. Preferred is the racemate of the following structure
  • the oral pharmaceutical compositions of the invention have valuable pharmacological properties. Especially they are beneficial in the treatment of osteoarthritis, rheumatoid arthritis, acute musculoskeletal pain, dysmenorrhea, headache, toothache, fever, muscular pain, back pain, shoulder pain, bursitis, tendinitis or epicondylitis.
  • the beneficial effects of the combinations are especially pronounced, when the terpenoid compound(s) is (are) applied in surprisingly high doses. It is believed that the terpenoid compounds act as powerful and specifically COX 2 -inhibiting NSAIDs on their own and thus ideally complement the activity of usual NSAIDs (predominantly COX inhibiting).
  • compositions obtainable by combining an NSAID with a terpenoid compound form a further object of the present invention.
  • the invention further relates to a pharmaceutical composition adapted to oral administration comprising at least one NSAID and at least one terpenoid compound together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical compositions according to the invention comprise both the NSAID(s) and the terpenoid compound(s) in pharmacologically effective amounts.
  • the dosage of the active ingredients may depend on various factors, such as warmblooded species, sex, age, weight and individual condition of the warm-blooded animal.
  • the daily dosage which is administered to a warm-blooded animal weighing approximately 75 kg is of from 0.1 up to 100 mg/kg, especially of from 0.15 up to 60 mg/kg, more especially of from 0.25 up to 55 mg/kg, of the NSAID and of from 0.1 up to 100 mg/kg, especially of from 0.3 up to 60 mg/kg, more especially of from 0.5 up to 55 mg/kg, most especially of from 1 up to 30 mg/kg and in particular of from 1.2 up to 20 mg/kg, of the terpenoid compound ("mg/kg” means mg drug per kg body weight of the mammal - including man - to be treated).
  • These doses may be taken once daily or, if desired, also in several, optionally equal, partial doses.
  • compositions of the invention may be in single dose unit form or in non-single dose unit form. If in single dose unit form, they contain preferably of from 1% up to 90%, preferably of from 10% up to 50%, of the active ingredients (all percentages given are percentages by weight, if not indicated otherwise).
  • Single dose unit forms such as capsules, tablets or dragees contain e.g. of from 10 up to 1000 mg, especially of from 20 up to 800 mg and in particular of from 50 up to 800 mg, of the active ingredients.
  • the NSAID(s) is (are) e.g. present in an amount of from 1 up to 1200 mg, especially of from 5 up to 1000 mg and more especially of from 10 up to 800 mg.
  • the NSAID When diclofenac, or a pharmaceutically acceptable salt thereof, is applied as NSAID in an oral single dose unit composition of the invention, the NSAID is preferably present in an amount of from 10 up to 200 mg, especially of from 10 up to 100 mg and more especially of from 20 up to 75 mg.
  • the NSAID is preferably present in an amount of from 20 up to 1000 mg, especially of from 50 up to 800 mg and more especially of from 75 up to 800 mg.
  • the NSAID is preferably present in an amount of from 50 up to 1200 mg, especially of from 100 up to 1000 mg and more especially of from 250 up to 800 mg.
  • the terpenoid compound(s) is (are) e.g. present in an amount of at least 1 mg, preferably in an amount of at least 10 mg, more preferably in an amount of at least 20 mg, even more preferably in an amount of at least 30 mg, most preferably in an amount of at least 50 mg, in particular in an amount of at least 80 mg, advantageously in an amount of at least 100 mg, more advantageously in an amount of at least 150 mg; and most advantageously in an amount of at least 200 mg; or in an amount of from 1 up to 1200 mg, especially of from 10 up to 1000 mg, more especially of from 20 up to 600 mg and first and foremost of from 50 up to 500 mg.
  • compositions for oral administration in single dose unit form are, for example, drag ⁇ es, tablets or capsules. Moreover, sachets filled with the active substance in powder or granule form come into consideration. All these pharmaceutical compositions are prepared in a manner known per se, for example by means of conventional mixing, granulating or confectioning processes. For example, they can be obtained by combining the active ingredients with solid carriers, optionally granulating a resulting mixture and processing the mixture or granules, after the addition of suitable excipients, to form tablets or dragee cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes using, for example,
  • Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, e.g.
  • cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, or polyacrylates, which means homo- or co-polymers of alkyl esters, especially methyl and ethyl esters but also e.g. substituted alkyl esters such as dimethylaminoethyl esters, of acrylic acid and/or methacrylic acid (and also of free acrylic acid and/or methacrylic acid), e.g. Eudragif products such as Eudragit* S, Eudragif NE, Eudragif E or Eudragif L (e.g. Eudragit ® L30-D) of Roehm Pharma GmbH, Darmstadt (Germany). Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredients.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, or polyacrylates, which means homo- or
  • compositions in single dose unit form are e.g. hard gelatin capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the hard gelatin capsules may comprise the active ingredients in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers.
  • the active ingredients are preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.
  • compositions in non-single dose unit form are, for example, syrups, liquid suspensions or solutions. They are prepared in customary manner. Typically, they contain the active ingredients in a concentration of from 0.1 up to 50%, preferably of from 0.1 up to 40%, more preferably of from 0.5 up to 30%, most preferably of from 1 to 20%, and especially of from 1 to 10%, or in a concentration that provides a suitable single dose when administered e.g. in a measure of 1 , 5 or 10 ml.
  • the NSAID(s) is (are) typically present in a concentration from 0.1% up to 50%, preferably of from 0.1% up to 20%, more preferably of from 0.5% up to 15%, most preferably of from 0.5 up to 10%, and especially of from 1 up to 10%.
  • the terpenoid compound(s) is (are) typically present in a concentration of at least 0.5%, preferably at least 1%, more preferably at least 2%, especially in a concentration of from 0.1 up to 50%, more especially of from 0.5 up to 30%, most especially of from 1 up to 25%, advantageously of from 1 to 20%, and in particular of from 2 up to 10%.
  • compositions which are in enteric-coated form - and this especially concerns those in single dose unit form - form a preferred embodiment of the invention.
  • Enteric-coated means that the coating is resistant to gastric juice but soluble in the small intestine where the active substances are released.
  • Example 1 Soft capsules: 5000 soft gelatin capsules, each comprising 50 mg of diclofenac sodium and 50 mg of menthyl lactate, are prepared as follows.
  • composition for 5 000 capsules
  • diclofenac sodium 250 g
  • Example 2 Soft capsules: 5000 soft gelatin capsules, each comprising 50 mg of diclofenac sodium and 50 mg of menthyl lactate are prepared as follows. Composition (for 5 000 capsules) diclofenac sodium 250 g menthyl lactate 250 g
  • PEG 400 polyethylene glycol with M r from approximately 380 to approximately 420, Fluka, Switzerland
  • Tween 80 ® polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind., Inc., USA, supplied by Fluka, Switzerland
  • Example 3 Dry-fill capsules: 5000 capsules, each comprising 50 mg of diclofenac sodium and 250 mg of menthyl lactate are prepared as follows.
  • composition for 5000 capsules
  • diclofenac sodium 250 g menthyl lactate 1250 g talcum 100 g magnesium stearate 20 g mannitol 280 g
  • Preparation process The powdered substances mentioned are pressed through a sieve having a mesh size of 0.6 mm. 380 mg portions of the mixture are introduced into gelatin capsules by means of a capsule-filling machine.
  • Example 4 Hard gelatin capsules containing 25 mg diclofenac sodium of and 500 mg menthyl lactate are prepared as follows.
  • composition for 1000 capsules
  • diclofenac sodium 25 g menthyl lactate 500 g microcrystalline cellulose 200 g sodium lauryl sulfate 1 g magnesium stearate 1 g
  • Preparation process The diclofenac sodium, menthyl lactate, microcrystalline cellulose and sodium lauryl sulfate are intimately mixed and passed through a dry compactor. Then the magnesium stearate is added and the mass is pressed through a sieve having a mesh size of 1 mm. After stirring for a further 10 min., 727 mg portions of the resulting formulation are introduced into hard gelatin capsules of suitable size.
  • Example 5 Enteric-coated tablets containing 25 mg of diclofenac sodium and 250 mg of menthyl lactate are prepared as follows.
  • composition for 1000 capsules
  • diclofenac sodium 25 g menthyl lactate 250 g microcrystalline cellulose 200 g lactose 70 g magnesium stearate 1 9
  • Preparation process The diclofenac sodium, menthyl lactate, microcrystalline cellulose and lactose are intimately mixed and passed through a dry compactor. Then the magnesium stearate is added and the mass is pressed through a sieve having a mesh size of 1 mm. After stirring for a further 10 min., 546 mg portions of the resulting formulation are pressed to biconvex tablets of 12 mm diameter size.
  • the coating solution the polyethylene glycol is dissolved in water, then the talc is dispersed in this solution and the Eudragit ® L30-D is added upon stirring. This solution is applied to the tablets by the means of a suitable coating equipment.
  • Example 6 Enteric-coated tablets containing 25 mg of diclofenac sodium and 250 mg of l-menthol are prepared as follows.
  • composition for 1000 capsules
  • diclofenac sodium 25 g l-menthol 250 g microcrystalline cellulose 200 g lactose 70 g magnesium stearate 1 9

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Abstract

L'invention a pour objet des compositions pharmaceutiques pour administration par voie orale, comprenant un anti-inflammatoire non stéroïdien et un composé terpénoïde. Celle-ci sont utiles dans le traitement, entre autres, de douleurs, d'états pyrétiques (fièvre) et inflammatoires. En outre, l'invention concerne une méthode de traitement de douleurs, entre autres, d'états pyrétiques (fièvre) et inflammatoires, méthode comprenant l'administration, par voie orale, à un mammifère humain inclus, d'une quantité efficace d'un point de vue thérapeutique, d'un anti-inflammatoire non stéroïdien, de pair avec une quantité efficace d'un point de vue thérapeutique, d'un composé terpénoïde. L'invention se réfère en outre à l'utilisation d'un composé anti-inflammatoire non stéroïdien, de pair avec un composé terpénoïde (pour la fabrication d'une composition pharmaceutique adaptée à une administration par voie orale) dans le traitement de douleurs, d'états pyrétiques (fièvre) et inflammatoires.
PCT/EP1997/003699 1996-07-12 1997-07-11 Combinations pharmaceutiques orales d'anti-inflammatoires non steroïdiens et de terpenoïdes WO1998002182A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34442/97A AU3444297A (en) 1996-07-12 1997-07-11 Oral pharmaceutical combinations of nsaids with terpenoids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP96810460 1996-07-12
EP96810460.4 1996-07-12

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WO1998002182A1 true WO1998002182A1 (fr) 1998-01-22

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WO2001019346A1 (fr) * 1999-09-14 2001-03-22 Copley Pharmaceutical, Inc. Preparation de nabumetone a liberation retardee
WO2002015900A1 (fr) * 2000-08-25 2002-02-28 Kowa Company, Ltd. Solutions d'ibuprofene destinees a etre mises en gelules et preparations en gelules
EP1378503A1 (fr) * 2002-07-01 2004-01-07 Symrise GmbH & Co. KG Lactate de menthyle compacte
US7294652B2 (en) * 2002-05-13 2007-11-13 Arexis Ab Autoimmune conditions and NADPH oxidase defects
EP1942877A1 (fr) * 2005-11-02 2008-07-16 Teikoku Pharma USA, Inc. Formulations de doses orales d'ibuprofene organoleptiquement acceptables, procedes de preparation et d'utilisation de celles-ci
US20140377381A1 (en) * 2011-10-20 2014-12-25 Kraft Foods Group Brands Llc Compounds, compositions, and methods for reducing or eliminating bitter taste
US8926575B2 (en) 2008-02-14 2015-01-06 Spiracur Inc. Devices and methods for treatment of damaged tissue
WO2020013781A2 (fr) 2018-03-27 2020-01-16 Pisak Mehmet Nevzat Effet synergique de flurbiprofène et d'agent protecteur gastrique pour le traitement de la douleur et de l'inflammation
WO2020033567A1 (fr) * 2018-08-07 2020-02-13 University Of Florida Research Foundation Méthodes et compositions destinés à des analogues d'arylcycloheptane substitués
CN113491679A (zh) * 2021-03-18 2021-10-12 云南民族大学 植醇在制备抗偏头痛药物中的应用
CN114959012A (zh) * 2022-05-30 2022-08-30 北京医院 用于检测肌腱损伤的产品
US11904049B2 (en) 2017-06-08 2024-02-20 Klaria Pharma Holding Ab Pharmaceutical formulation
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation
US12285521B2 (en) 2016-11-15 2025-04-29 Klaria Pharma Holding Ab Pharmaceutical formulation

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US20140377381A1 (en) * 2011-10-20 2014-12-25 Kraft Foods Group Brands Llc Compounds, compositions, and methods for reducing or eliminating bitter taste
US12285521B2 (en) 2016-11-15 2025-04-29 Klaria Pharma Holding Ab Pharmaceutical formulation
US11904049B2 (en) 2017-06-08 2024-02-20 Klaria Pharma Holding Ab Pharmaceutical formulation
WO2020013781A2 (fr) 2018-03-27 2020-01-16 Pisak Mehmet Nevzat Effet synergique de flurbiprofène et d'agent protecteur gastrique pour le traitement de la douleur et de l'inflammation
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation
WO2020033567A1 (fr) * 2018-08-07 2020-02-13 University Of Florida Research Foundation Méthodes et compositions destinés à des analogues d'arylcycloheptane substitués
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