WO1999021585A1 - Combinaison pharmaceutique d'un inhibiteur de la cyclooxygenase-2 et de l'acetaminophene ou un opiace - Google Patents

Combinaison pharmaceutique d'un inhibiteur de la cyclooxygenase-2 et de l'acetaminophene ou un opiace Download PDF

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Publication number
WO1999021585A1
WO1999021585A1 PCT/IB1998/001789 IB9801789W WO9921585A1 WO 1999021585 A1 WO1999021585 A1 WO 1999021585A1 IB 9801789 W IB9801789 W IB 9801789W WO 9921585 A1 WO9921585 A1 WO 9921585A1
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WO
WIPO (PCT)
Prior art keywords
route
test
combination
cyclooxygenase
acetaminophen
Prior art date
Application number
PCT/IB1998/001789
Other languages
English (en)
Inventor
François CAMBORDE
Alix Cloarec
Eric Nicolai
Jean-Marie Teulon
Original Assignee
Laboratoires Upsa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Upsa filed Critical Laboratoires Upsa
Priority to AU96406/98A priority Critical patent/AU9640698A/en
Publication of WO1999021585A1 publication Critical patent/WO1999021585A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the object of the present invention is a novel pharmaceutical combination having application notably in the treatment of pain and inflammatory phenomena. 5 More specifically, the invention relates to a pharmaceutical composition which comprises, as active principle, a combination of a cyclooxygenase-2 inhibitor and a compound selected from acetaminophen and the opiates.
  • Selective cyclooxygenase-2 (COX-2) inhibitors constitute a novel class of non- steroid analgesic and anti-inflammatory agents.
  • Such compounds have been described 10 for example in the documents WO 94/15932, WO 96/03388 by GD Searle, WO
  • these compounds also possess anti-inflammatory and analgesic activities, the latter being demonstrated in various experimental inflammatory pain models.
  • hydroxyacetanilide is a well-tolerated medicament which possesses an analgesic and anti-pyretic activity and is commonly used in the symptomatic treatment of painful and febrile ailments at daily doses in the order of 500 to 3000 mg.
  • the opiate or morpholinic compounds are powerful centrally-acting analgesics indicated in the treatment of moderate to severe pain and are able to induce dependence and addiction in certain circumstances.
  • this combination enables treating pain of very varied origin in a larger number of patients.
  • the pharmaceutical combination in accordance with the present invention will be in a form suitable for an administration:
  • - via the oral route such as simple or coated tablets, capsules or granules, for example
  • - via the rectal route such as suppositories for example
  • parenteral route such as injectable preparations for example -via the ocular route, such as eye lotions or ophthalmic solutions for example;
  • the transdermal route -via the transdermal route -via the nasal route, such as aerosols and sprays for example; or -via the auricular route, such as drops for example.
  • Such a composition can be prepared, according to the methods known per se, by incorporating the active principle, consisting of the above-mentioned combination, with excipients usually used such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, wetting agents, dispersing agents or emulsifiers, silicone gels, certain polymers or co- polymers, preservatives, aromas and coloring agents.
  • excipients usually used such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, wetting agents, dispersing agents or emulsifiers, silicone gel
  • any compound having a cyclooxygenase-2 inhibiting activity can be used within the context of the present invention, preferably, diaryl methylidenetetrahydrofuran derivatives will be used such as those described in the applications FR 2747123 and FR 2747124 of the Applicant which are incorporated herein by reference.
  • a particularly preferred compound is (Z)-3-[l-(4-chlorophenyl)-l-(4- methanesulphonylphenyl)methylene]dihydrofuran-2-one known under the code name of UP 454-21.
  • the opiates which can be used within the context of the present invention may be of a different nature : powerful opiates, the top one of which is morphine, which can treat severe pain, such as morphine itself or oxycodone, or weakopiates, which can treat pain of moderate intensity, such as codeine or dextropropoxyphen.
  • compositions according to the invention will be in the form of a unit dose.
  • the weight ratio of the cyclooxygenase-2 inhibiting compound to the compound selected from acetaminophen and the opiates will be that which possesses the greater synergy between the two combined compounds, it will be between 0.01 and 10 for the majority of the examples and will be preferably from 0.1 to 3.5.
  • the daily dose which can be used of the various compounds constituting the pharmaceutical combination in accordance with the present invention will of course depend upon the state of the patient to be treated.
  • a suitable daily dose of cyclooxygenase-2 inhibitor will generally be between about 50 mg and about 800 mg.
  • compositions in accordance with the present invention are suitable in the treatment of inflammatory phenomena as well as in the treatment of pain.
  • compositions can also be used within the context of the treatment of bronchial asthma, dysmenorrhea, tendinitis, bursitis, dermatological inflammations such as psoriasis, eczema, bums and dermatitis.
  • compositions can also be used within the context of the treatment of gastrointestinal inflammations, Crohn's disease, gastritis and ulcerative colitis, in the prevention of cancer, especially adenocarcinoma of the colon, in the prevention of neurodegenerative diseases, particularly Alzheimer's disease, in the prevention of stroke and epilepsy, and in the prevention of premature labour.
  • compositions can be used within the context of the treatment of pain symptoms, especially in the treatment of myalgia, articular pain or neuralgia, dental pain, herpes zoster and migraine, in the treatment of rheumatic complaints and pain of cancerous origin, and also as complementary treatments for infectious and febrile states.
  • the invention further covers a method of therapeutic treatment of mammals, characterized in that it consists in administering to this mammal a therapeutically effective amount of a combination of a cyclooxygenase-2 inhibiting compound and a compound selected from acetaminophen and the opiates such as described previously.
  • This method especially enables treating inflammatory phenomena and pain.
  • Figure 5 graphically illustrates the antinociceptive effect of oral UP-454-21 -oxycodone combination in the hot plate test (52 °C) in mice; Dunnett's test * for p ⁇ 0.05 indicates a significant difference in comparison to the control group.
  • Figure 8 graphically illustrates the antinociceptive effect of oral UP-454-21 - paracetamol combination on carrageenin-induced hyperalgesia in rats; Dunnett's test
  • Figure 9 graphically illustrates the antinociceptive effect of oral UP-454-21 - oxycodone combination on carrageenin-induced hyperalgesia in rats; Dunnett's test *,
  • Figure 10 graphically illustrates the antinociceptive effect of oral UP-454-21 - dextropropoxyphene combination on carrageenin-induced hyperalgesia in rats;
  • Figure 11 graphically illustrates the antinociceptive effect of oral UP-454-21 - codeine combination on carrageenin-induced hyperalgesia in rats.
  • the compound used as an example of a selective cyclooxygenase-2 inhibitor is the compound known under the code name of UP 454- 21 of the following general formula:
  • the results obtained for the first four tests are expressed in percentage inhibition of the pain reaction with respect to a control group.
  • Test no. 1 phenylbenzoquinone test in the mouse
  • PBQ phenylbenzoquinone
  • Test no. 2 Heated plate test
  • the test is carried out by following the experimental protocol described by N. B. Eddy, C.F. Toucheberry and J.E. Lieberman, Synthetic analgesics. 1 -Methadone isomers and derivatives. J. Pharmacol. Exp. Ther. 1950 ; (98) : 121137.
  • the mouse disposed on a plate heated to 52'C + 0.05 shows its pain by licking its front paws, or more rarely by a jump.
  • Test no. 3 Plantar test The test is carried out in the rat by following the experimental protocol described by R. Hargreaves, F. Brown, C. Flores and J. Joris, A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988 (32) : 77-88.
  • An inflammation is induced by intraplantar injection of a 0.05% suspension of Mycobacterium butyricum. Six hours after this injection, a heat stimulus (infrared ray) is applied onto the plantar face of the hind paw of the rat.
  • a heat stimulus infrared ray
  • the nociceptive reaction of the animal manifests itself by the withdrawal or the licking of the paw.
  • the time of appearance of the pain reaction is then noted down.
  • the compounds and the combination studied are administered via the oral route one hour before the plantar test.
  • Test no. 4 Kaolin-induced arthritis test in the rat
  • An inflammation is induced by the administration of a 10% aqueous kaolin suspension into the tibio-femoral joint in the rat.
  • the compounds and the combinations studied are administered orally 30 minutes after the injection of kaolin.
  • spontaneous painful behavior (discomfort in walking) is then quoted 5 and 6 hours after the injection of kaolin.
  • the inflammation is induced in the rat by plantar administration of a 2% carrageenin solution.
  • the pain threshold expressed in grams, is then noted down.
  • the compounds and the combinations studied are administered orally one hour before the paw pressure test.
  • compositions according to the invention will now be given:
  • Example 1A Capsule (size no. 0) UP 454-21 50 mg
  • Acetaminophen 600 mg Semi-synthetic glyceride (suppocire) 1140 mg for a suppository
  • Example IE Injectable preparation
  • Example 2A Capsule (size no. 1)
  • Example 3A Capsule (size no. 1)
  • Example 3B Tablet UP 454-21 50 mg
  • Example 3C Suppository UP 454-21 100 mg
  • Example 3E Injectable preparation
  • Example 4A Capsule (size no. 1)
  • Example 4E Injectable preparation UP 454-21 0.1%

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique, caractérisée en ce qu'elle comprend, comme principe actif, une combinaison d'un inhibiteur de la cyclo-oxygénase-2 ainsi qu'un composé choisi dans le groupe constitué par l'acétaminophène et les opiacés.
PCT/IB1998/001789 1997-10-27 1998-10-19 Combinaison pharmaceutique d'un inhibiteur de la cyclooxygenase-2 et de l'acetaminophene ou un opiace WO1999021585A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU96406/98A AU9640698A (en) 1997-10-27 1998-10-19 Pharmaceutical combination of a cyclooxigenase-2 inhibitor and acetaminophen or an opiate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9713426A FR2770131A1 (fr) 1997-10-27 1997-10-27 Nouvelle association pharmaceutique a activite analgesique
FR97/13426 1997-10-27

Publications (1)

Publication Number Publication Date
WO1999021585A1 true WO1999021585A1 (fr) 1999-05-06

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PCT/IB1998/001789 WO1999021585A1 (fr) 1997-10-27 1998-10-19 Combinaison pharmaceutique d'un inhibiteur de la cyclooxygenase-2 et de l'acetaminophene ou un opiace

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Country Link
AU (1) AU9640698A (fr)
FR (1) FR2770131A1 (fr)
WO (1) WO1999021585A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000014082A1 (fr) * 1998-09-09 2000-03-16 Laboratories Upsa Derives de diarylmethylidene furane utilises comme anti-inflammatoires, analgesiques et substances a visees preventives
WO2000029022A1 (fr) * 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Combinaison d'inhibiteurs de cox-2 et d'analgesiques a action centrale
WO2003070251A1 (fr) * 2002-02-19 2003-08-28 Adcock Ingram Limited Combinaisons pharmaceutiques d'inhibiteurs de cox-2 et d'opiaces
WO2003080183A1 (fr) * 2002-03-19 2003-10-02 Euro-Celtique S.A. Compose pharmaceutique contenant un inhibiteur cox-2, l'etodolac, et des opioides
JP2004503497A (ja) * 2000-06-13 2004-02-05 ワイエス Ｃｏｘ−２インヒビターを含有する鎮痛及び抗炎症性組成物
WO2004014431A1 (fr) * 2002-08-12 2004-02-19 Ranbaxy Laboratories Limited Forme posologique parenterale d'inhibiteurs cox-2 selectifs
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
US8680081B2 (en) 2000-08-29 2014-03-25 Peter Van Patten Prophylactic treatment of migraine
WO2019140188A1 (fr) * 2018-01-11 2019-07-18 Centaurus Therapeutics Inhibiteurs de la dihydrocéramide désaturase pour le traitement d'une maladie

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR038957A1 (es) 2001-08-15 2005-02-02 Pharmacia Corp Terapia de combinacion para el tratamiento del cancer
US6864271B2 (en) * 2002-11-12 2005-03-08 The Foundation For The Lsu Health Sciences Center Synergistic combinations including N-acylated 4-hydroxyphenylamine derivatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521213A (en) * 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
WO1996019469A1 (fr) * 1994-12-21 1996-06-27 Merck Frosst Canada Inc. Diaryl-2-(5h)-furanones inhibiteurs de cox-2
US5552422A (en) * 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
WO1996031509A1 (fr) * 1995-04-04 1996-10-10 Glaxo Group Limited Derives de pyridine imidazo (1,2a)
WO1996036623A1 (fr) * 1995-05-18 1996-11-21 Merck Frosst Canada Inc. Diaryl-5-oxygene-2-(5h)-furanones utiles comme inhibiteurs de cox-2
WO1997014691A1 (fr) * 1995-10-13 1997-04-24 Merck Frosst Canada Inc. (methylsulfonyl)phenyl-2-(5h)-furanones en tant qu'inhibiteurs du cox-2

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521213A (en) * 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
WO1996019469A1 (fr) * 1994-12-21 1996-06-27 Merck Frosst Canada Inc. Diaryl-2-(5h)-furanones inhibiteurs de cox-2
US5552422A (en) * 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
WO1996031509A1 (fr) * 1995-04-04 1996-10-10 Glaxo Group Limited Derives de pyridine imidazo (1,2a)
WO1996036623A1 (fr) * 1995-05-18 1996-11-21 Merck Frosst Canada Inc. Diaryl-5-oxygene-2-(5h)-furanones utiles comme inhibiteurs de cox-2
WO1997014691A1 (fr) * 1995-10-13 1997-04-24 Merck Frosst Canada Inc. (methylsulfonyl)phenyl-2-(5h)-furanones en tant qu'inhibiteurs du cox-2

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000014082A1 (fr) * 1998-09-09 2000-03-16 Laboratories Upsa Derives de diarylmethylidene furane utilises comme anti-inflammatoires, analgesiques et substances a visees preventives
WO2000029022A1 (fr) * 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Combinaison d'inhibiteurs de cox-2 et d'analgesiques a action centrale
EP1296665A4 (fr) * 2000-06-13 2005-07-27 Wyeth Corp Compositions analgesiques et anti-inflammatoires contenant des inhibiteurs de cox-2
US7754753B2 (en) 2000-06-13 2010-07-13 Wyeth Llc Analgesic and anti-inflammatory compositions containing Cox-2-inhibitors
JP2004503497A (ja) * 2000-06-13 2004-02-05 ワイエス Ｃｏｘ−２インヒビターを含有する鎮痛及び抗炎症性組成物
US8680081B2 (en) 2000-08-29 2014-03-25 Peter Van Patten Prophylactic treatment of migraine
EP2050453A1 (fr) * 2002-02-19 2009-04-22 Adcock Ingram Limited Composes pharmaceutiques contenant du meloxicam, du tramadol et du paracetamol
AP1862A (en) * 2002-02-19 2008-07-07 Adcock Ingram Ltd Pharmaceutical combinations of COX-2 inhibitors and opiates
CN100418533C (zh) * 2002-02-19 2008-09-17 阿德科克因格拉姆有限公司 环加氧酶-2抑制剂和阿片剂的药物组合体
WO2003070251A1 (fr) * 2002-02-19 2003-08-28 Adcock Ingram Limited Combinaisons pharmaceutiques d'inhibiteurs de cox-2 et d'opiaces
WO2003080183A1 (fr) * 2002-03-19 2003-10-02 Euro-Celtique S.A. Compose pharmaceutique contenant un inhibiteur cox-2, l'etodolac, et des opioides
WO2004014431A1 (fr) * 2002-08-12 2004-02-19 Ranbaxy Laboratories Limited Forme posologique parenterale d'inhibiteurs cox-2 selectifs
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
WO2019140188A1 (fr) * 2018-01-11 2019-07-18 Centaurus Therapeutics Inhibiteurs de la dihydrocéramide désaturase pour le traitement d'une maladie
US11597715B2 (en) 2018-01-11 2023-03-07 Centaurus Therapeutics Inhibitors of dihydroceramide desaturase for treating disease

Also Published As

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FR2770131A1 (fr) 1999-04-30
AU9640698A (en) 1999-05-17

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