EP1156855A1 - Composition comprising a tramadol material and a selective cox-2 inhibitor drug - Google Patents

Composition comprising a tramadol material and a selective cox-2 inhibitor drug

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Publication number
EP1156855A1
EP1156855A1 EP00912043A EP00912043A EP1156855A1 EP 1156855 A1 EP1156855 A1 EP 1156855A1 EP 00912043 A EP00912043 A EP 00912043A EP 00912043 A EP00912043 A EP 00912043A EP 1156855 A1 EP1156855 A1 EP 1156855A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
tramadol
selective cox
inhibitor drug
pain
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00912043A
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German (de)
English (en)
French (fr)
Inventor
Ellen E. Codd
Rebecca P. Martinez
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Janssen Pharmaceuticals Inc
Original Assignee
Ortho McNeil Pharmaceutical Inc
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Filing date
Publication date
Application filed by Ortho McNeil Pharmaceutical Inc filed Critical Ortho McNeil Pharmaceutical Inc
Publication of EP1156855A1 publication Critical patent/EP1156855A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • composition Comprising a Tramadol Material and a Selective COX-2 inhibitor Drug
  • the present invention is directed to pharmaceutical compositions useful for treating or preventing pain, inflammation and certain neurological disorders and cancers. More particularly, this invention is directed to pharmaceutical compositions comprising a combination of a tramadol material and a selective cyclooxygenase-2 (COX-2) inhibitor drug.
  • COX-2 selective cyclooxygenase-2
  • United States Patent No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring.
  • the compound (1 R, 2R or 1S, 2S)-2-[(dimethylamino)methyl]- 1-(3-methoxyphenyl)cyclohexanol, commonly known as tramadol, is specifically disclosed therein.
  • a series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim. Forsch. (Drug Res.), 28(l), 114 (1978). Driessen et al., Arch.
  • tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like.
  • the Abstracts of the Vlth World Congress on Pain, April 1-6 (1990) disclose that tramadol hydrochloride is an orally active pure agonist opioid analgesic.
  • tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim. Forsch. (Drug Res.), 28(l), 183 (1978)), constipation (I. Arend et al., Arzneim. Forsch.
  • tramadol When given at a dose of 50 mg by rapid i.v. injection, tramadol may produce certain side effects unique to tramadol including hot flushes and sweating. Despite these side effects, tramadol's combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently marketed as an analgesic.
  • Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects and as a result cannot always be given repeatedly or at high doses. The side effect problems are well documented in the literature. See, for example, T. Reisine and G. Pasternak in "Goodman and Gilman's, The Pharmacological Basis of Therapeutics", 9th edition; Hardman et al.; McGraw-Hill, New York, 1996; Chapter 23; pages 521- 555 wherein it is disclosed that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone, are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
  • morphine and its congeners e.g., codeine, hydrocodone and oxycodone
  • opioids have been combined with other drugs including non-opioid analgesic agents, which lower the amount of opioid needed to produce an equivalent degree of analgesia. It has been claimed that some of these combination products also have the advantage of producing a synergistic analgesic effect.
  • A. Takemori Annals New York Acad. Sci., 281 , 262 (1976) discloses that compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (inhibitory), additive or superadditive.
  • Thera., 169(1 ), 29 (1969) disclose that the combination of morphine and methadone, another opioid analgesic, exhibits an additive effect.
  • United States Patent No. 4,571 ,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides superadditive effects when the components are within certain ratios. See also U.S. Patent Nos. 4,587,252 and 4,569,937 which disclose other ibuprofen opioid combinations.
  • Tramadol has also been combined with other drugs and such compositions have exhibited synergistic effects in treating pain.
  • U.S. Patent No. 5,516,803 discloses the combination of tramadol and a non- steroidal anti-inflammatory drug, particularly ibuprofen.
  • U.S. Patent No. 5,468,744 discloses tramadol in combination with any of oxycodone, codeine or hydrocodone and
  • U.S. Patent No. 5,336,691 discloses tramadol in combination with acetaminophen.
  • Arachidonic acid metabolites such as prostaglandin E 2 (PGE 2 ), prostaglandin G 2 (PGG 2 ), prostaglandin H 2 (PGH 2 ), prostaglandin l 2 (PGI 2 ) and thromboxane B 2 (TXB 2 ) play major roles in the inflammation process.
  • PGE 2 prostaglandin E 2
  • PEG 2 prostaglandin G 2
  • PH 2 prostaglandin H 2
  • PKI 2 prostaglandin l 2
  • TXB 2 thromboxane B 2
  • United States Patent 5,994,381 discloses a group of heteroaromatic oxazole compounds as highly effective selective COX-2 inhibitor drugs, in particular, the compound JTE-522 (5-(4-aminosulfonyl-3-fluorophenyl)-4- cyclohexyl-2-methyloxazole).
  • a pharmaceutical composition comprising an opioid analgesic together with a COX-2 inhibitor drug has been described in WO 99/13799.
  • only pharmaceutical compositions comprising a combination of morphine:nabumetone in a 1 :1000 ratio based on their respective ED 50 values and a combination of morphine:meloxicam in a 1 :10 ratio were disclosed as synergistic analgesic combinations.
  • compositions comprising combinations of the centrally acting analgesic tramadol and a selective COX-2 inhibitor drug and demonstrated that such compositions have a synergistic effect while using less of each ingredient. More particularly, pharmaceutical compositions comprising a combination of tramadol hydrochloride and the selective COX-2 inhibitor compound 5-(4- aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole have not been previously described.
  • a further object of the present invention is to produce a combination product with a tramadol material having improved properties. It is also an object of the present invention to produce a combination product with a tramadol material and a selective COX-2 inhibitor drug wherein an instant pharmaceutical composition has a synergistic effect while using less of each ingredient. It is another object of the present invention to produce a combination product with tramadol hydrochloride and the selective COX-2 inhibitor drug 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole, wherein the pharmaceutical compositions have a synergistic effect, use less of each ingredient and, thus, reduce the number and severity of side effects associated with each agent.
  • a further object of the present invention is to provide a method for treating or preventing pain, inflammation and certain neurological disorders and cancers in mammals.
  • a pharmaceutical composition comprising a combination of a tramadol material and a selective COX-2 inhibitor drug, wherein the tramadol material and the selective COX-2 inhibitor drug are present in a ratio based on a fraction of their respective 50% effective dose (ED 50 ) values, which ratio is from about 1 :1 to about 1 :300 or from about 1 :1 to about 300:1.
  • ED 50 effective dose
  • the present invention further provides a method for treating or preventing pain, inflammation and certain neurological disorders and cancers in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition for treating or preventing pain, inflammation and certain neurological disorders and cancers comprising a combination of a tramadol material and a selective COX-2 inhibitor drug, wherein the tramadol material and the selective COX-2 inhibitor drug are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1 :1 to about 1 :300 or from about 1 :1 to about 300:1.
  • a pharmaceutical composition according to this invention is useful for treating or preventing pain and inflammation including but not limited to osteoarthritis or rheumatoid arthritis and certain neurological disorders and cancers including but not limited to Alzheimer's disease, colorectal cancer or colon polyps.
  • the present invention is generally directed to pharmaceutical compositions comprising a tramadol material and a selective COX-2 inhibitor drug.
  • the tramadol material is any one of (1 R, 2R or 1 S, 2S)-2-
  • Tramadol [(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol (tramadol), its N- oxide derivative ("tramadol N-oxide”), and its O-desmethyl derivative ("O- desmethyl tramadol”) or mixtures thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts of the amines, such as the hydrochloride salt, solvates and polymorphs of the tramadol material.
  • Tramadol is commercially available from Grunenthal or may be made by the process described in United States Patent No. 3,652,589, which is herein incorporated by reference.
  • Tramadol N-oxide is prepared by treating tramadol as a free base with an oxidizing agent, e.g., hydrogen peroxide (30%), in an organic solvent, e.g., methanol or isopropanol, with, but preferably without heating.
  • an oxidizing agent e.g., hydrogen peroxide (30%)
  • organic solvent e.g., methanol or isopropanol
  • Reagents For Organic Synthesis 1 , 471 , Fieser & Fieser eds., Wiley N.Y; (1987), B. Kelentey et al., Arzneim. Forsch., 7, 594 (1957). With heating, the reaction takes about 1 hour, whereas without heating the reaction takes about 3 days.
  • the mixture is treated with an agent, e.g.
  • Pt0 2 or preferably Pt C for about a day, to destroy the excess hydrogen peroxide.
  • the mixture is filtered, followed by the evaporation of the filtrate and then the residue is recrystalized from an organic solvent mixture, e.g., methylene chloride/ethyl acetate.
  • O-desmethyl tramadol is prepared by treating tramadol as a free base under O-demethylating reaction conditions, e.g., reacting it with a strong base such as NaOH or KOH, thiophenol and diethylene giycol (DEG) with heating to reflux.
  • a strong base such as NaOH or KOH, thiophenol and diethylene giycol (DEG)
  • DEG diethylene giycol
  • Selective COX-2 inhibitor drugs are analgesic and antiinflammatory agents known to be selective COX-2 inhibitor drugs.
  • the most relevant assay for the determination of selectivity is considered to be inhibition of the action of the recombinant human COX-1 and COX-2 enzymes.
  • one may use the enzymes present in human blood JR Vane et als, Ann Rev Pharmacol Tox 38:97-120, 1998).
  • Selective COX-2 inhibitor drugs are those compounds whose action in inhibiting the COX-2 enzyme are at least 10-fold to 100-fold more potent for inhibiting the COX-2 enzyme than for inhibiting the COX-1 enzyme.
  • Examples of compounds known to be highly selective inhibitors of the COX-2 enzyme are: Celebrex® celecoxib (4-[5-(4- methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-benzenesulfonamide), Vioxx® rofecoxib (4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone), JTE-522 (5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole) and the difluoro analog to JTE-522 (5-(4-aminosulfonyl-3,5-difluorophenyl)-4- cyclohexy
  • the selective COX-2 inhibitor drug portion of the compositions may either be a single selective COX-2 inhibitor drug or a combination of one or more selective COX- 2 inhibitor drugs.
  • pharmaceutical compositions comprising a tramadol material and a selective COX-2 inhibitor drug include all of these possibilities. It is intended that pharmaceutical compositions comprising the combination of a tramadol material and a selective COX-2 inhibitor drug as the active ingredients in synergistic ratios based on a fraction of their respective ED 50 values as well as methods of preparing the instant compositions in synergistic ratios are also encompassed within the present invention.
  • compositions of the present invention a tramadol material and a selective COX-2 inhibitor drug are present in a ratio based on a fraction of their respective ED 50 values which ratio may vary from about 1 :1 to about 1 :300 or, reversibly, from about 1 :1 to about 300:1 , depending upon the desired result.
  • compositions of the invention contain a majority of a tramadol material.
  • compositions comprising a combination of a tramadol material and a selective COX-2 inhibitor drug within these ratios exhibit synergistic effects.
  • Pharmaceutical compositions according to the present invention comprise an effective amount of a tramadol material in combination with a selective COX-2 inhibitor drug for treating or preventing pain, inflammation and certain neurological disorders and cancers in a mammal in need thereof.
  • instant compositions comprise a combination of tramadol hydrochloride with 5-(4-aminosulfonyl-3-fiuorophenyl)-4-cyclohexyl-2-methyloxazole.
  • compositions comprising a tramadol material and a selective COX-2 inhibitor drug as the active ingredients in an intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral.
  • the compositions may also be administered by means of an aerosol.
  • any of the usual pharmaceutical media may be employed.
  • oral liquid preparations such as suspensions, elixirs and solution
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
  • oral solid preparations such as, for example, powders, capsules and tablets
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be sugar-coated or enteric-coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • compositions combining a tramadol material and a selective COX-2 inhibitor drug those components may be added in amounts known in the art and may be given at dosages conventional for such components.
  • the pharmaceutical compositions of the present invention will generally be in the form of a dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, wherein the preferred amount of each of the active ingredient to be contained therein is determined by the aforementioned ratios.
  • the dosage unit is calculated based on the amount of active ingredient which may be given to a 70 kg human subject in a single dose.
  • the instant pharmaceutical compositions may be given at a daily dose of from about 0.1 mg/day to about 800 mg/day of the active ingredients and, preferably from about 0.3 to 200 mg/day of the active ingredients.
  • the precise dose of the active ingredients will vary depending upon the relative amount of each active component being used, upon the particular tramadol material and selective COX-2 inhibitor drug being used and upon the aforementioned ratios.
  • a formulation demonstrating synergistic activity may contain from about 0.6 mg to about 60 mg of a tramadol material and from about 2 mg to about 20 mg of a selective COX-2 inhibitor drug such as 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl- 2-methyloxazole.
  • a selective COX-2 inhibitor drug such as 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl- 2-methyloxazole.
  • the tramadol material and a selective COX-2 inhibitor drug need not be present in the same formulation to achieve the results described herein. They may be administered individually at about the same time or in a single tablet.
  • compositions of the present invention are useful for treating or preventing pain, inflammation and certain neurological disorders and cancers in mammals by the administration of compositions comprising a combination of a tramadol material and a selective COX-2 inhibitor drug.
  • a tramadol material e.g., a tramadol material
  • a selective COX-2 inhibitor drug e.g., a selective COX-2 inhibitor drug.
  • mammalian pain include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain and neuropathic pain states, all of which would include acute pain such as caused by acute injury, trauma or surgery; chronic pain such as caused by neuropathic conditions, diabetic peripheral neuropathy, post-herpetic neuralgia, thgemina!
  • compositions are also useful for treating or preventing certain neurological disorders including, but not limited to, degeneration of nervous system cells due to Alzheimer's disease and certain cancers including, but not limited to, colorectal cancer and colon polyps.
  • compositions comprising a combination of a tramadol material and a selective cyclooxygenase-2 (COX-2) inhibitor drug can be evaluated for efficacy by use of one or more of the following tests.
  • COX-2 selective cyclooxygenase-2
  • the following experimental examples describe the invention in greater particularity and are intended to be a way of illustrating but not limiting the invention.
  • the efficacy of pharmaceutical compositions of the present invention may be determined by statistical comparison of results achieved in the presence of an instant pharmaceutical composition to that which is achieved in its absence. Alternatives may also be utilized.
  • Example 1 Preparation of Composition Doses of Tramadol and a Selective COX-2 Inhibitor Drug The preparation of different ratios of compositions comprising a combination of a tramadol material and a selective COX-2 inhibitor drug such as
  • 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole are effected by preparing solutions having concentrations or suspensions expressed in mg of active drug per 10 mL of distilled water or in mg of active drug per suspension of 10 mL of 0.5% hydroxypropyl methylcellulose in distilled water.
  • a tramadol material such as tramadol hydrochloride as the free base is added to a 10 mL suspension of 0.5% hydroxypropyl methylcellulose in distilled water.
  • the appropriate volume of the tramadol hydrochloride solution (in this case, 40 mg/10 mL) is added to the appropriate neat amount of the selective COX-2 inhibitor drug 5-(4-aminosulfonyl-3- fluorophenyl)-4-cyclohexyl-2-methyloxazole, yielding a 10mL suspension of a 1 :1 ratio based on a fraction of the respective ED 50 values of tramadol hydrochloride: 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2- methyloxazole (40 mg:40 mg).
  • the range of doses for each ratio tested are prepared separately in a similar manner. Accordingly, other ratios of pharmaceutical compositions comprising a combination of a tramadol material and a selective COX-2 inhibitor drug may also be similarly prepared at various concentrations.
  • Example 2 Mouse Abdominal Irritant Test The procedure used in detecting and comparing the analgesic activity of different classes of analgesic drugs for which there is a good correlation with human efficacy is the prevention of acetylcholine-induced abdominal constriction in mice (H. Collier, et al., Br. J. Pharmacol., 1968, 32, 295).
  • mice Male CD1 mice (weighing from 18-24 g) are utilized in determining the analgesic effects associated with the compositions of the invention.
  • mice are all dosed orally with compositions comprising a combination of tramadol hydrochloride (calculated as the base) and the selective COX-2 inhibitor drug (calculated as the base) or compositions of each agent, separately dissolved in distilled water or dissolved in a suspension of 0.5% hydroxypropyl methylcellulose in distilled water.
  • the dosing volume is 2 mL/kg.
  • mice are then injected intraperitoneally with a challenge dose of acetylcholine bromide.
  • the acetylcholine is completely dissolved in distilled water at a concentration of 5.5 mg/kg and injected at the rate of 0.20 mL/20 g.
  • an "abdominal constriction" is defined as a contraction of the abdominal musculature accompanied by arching of the back and extension of the limbs.
  • mice are observed for 10 minutes for the presence or absence of the abdominal constriction response beginning immediately after receiving the acetylcholine dose, administered at a certain time after the oral administration of tramadol hydrochloride alone, a selective COX-2 inhibitor drug alone, combined doses of tramadol hydrochloride and a selective COX-2 inhibitor drug or vehicle. Each mouse is used only once.
  • mice Male, Sprague-Dawley rats (Charles River Laboratories), weighing 80-120 g, were housed 5-10 per container in a climate-controlled, virus free environment for at least 5 days prior to testing. Food and water were available ad libitum up to test time. The animals were individually weighed and allowed to acclimate to conditions before testing.
  • Test drug was dissolved in sterile water (vehicle) and orally administered in a volume of 2 mL/kg.
  • the rat air-induced abdominal irritant test used herein was performed as described by Von Voigtlander, et al., with minor modification. Other irritant sources may be used by one skilled in the art. Thirty minutes after p.o. administration of 2 mL/kg of test drug, the animals were given i.p. injections of 10 mL of air. Each rat was placed into a plastic observation box and was observed for a maximum of 30 minutes for the occurrence of an abdominal irritant response (as defined under the mouse acetylcholine-induced abdominal irritant test). The percent of inhibition of this response was calculated as follows:
  • rofecoxib and celecoxib were evaluated in the rat abdominal irritant test one hour following oral administration of each drug. At the doses tested (rofecoxib at 30 mg/kg; celecoxib at 10, 30, 60 and 100 mg/kg) neither compound exhibited antinociceptive activity.
  • mice Male, Sprague-Dawley rats (Charles River Laboratories) are housed in a climate-controlled, virus free environment for at least 5 days prior to testing. Food and water are available ad libitum up to test time.
  • Animal Dosing Test rats are immunized by injecting an irritant (e.g., 0.1 ml of a 0.3-1.0% carrageenan solution in 0.9% saline) subcutaneously into the subplantar tissue of one of the hind paws to stimulate an acute inflammatory reaction.
  • an irritant e.g., 0.1 ml of a 0.3-1.0% carrageenan solution in 0.9% saline
  • Control rats receive a similar saline injection.
  • the rats are all dosed orally with compositions comprising a combination of tramadol hydrochloride (calculated as the base) and the selective COX-2 inhibitor drug (calculated as the base) or each agent separately, dissolved in either distilled water or dissolved in a suspension of 0.5% hydroxypropyl methylcellulose in distilled water at a fixed time following carrageenan injection.
  • the dosing volume is 2 mL/kg.
  • the hyperalgesic response of the animal is subsequently evaluated at a fixed later time.
  • Hyperalgesia is assessed by measurement of a response to a thermal or a mechanical stimulus. Measurement of thermal hyperalgesia is made with a standard laboratory hot plate apparatus, whose surface temperature is precisely determined and evenly maintained. Alternatively, hyperalgesia is evaluated with a commercially available Hargreaves apparatus which selectively elevates the temperature of an individual paw (Dirig, et al., J Neurosci Methods, 1997, 76, 183).
  • hyperalgesia is measured as a reduced latency to response compared to the latency of an untreated or vehicle treated animal, and the analgesic effect of the test compound is seen as a (partial) restoration of the latency toward normal (Dirig, et al., J Pharmcol Expt Therap, 1998, 285, 1031).
  • a response is defined as any shaking, licking, or tucking of the treated paw.
  • Hyperalgesia is measured as reduction in the force, measured in grams, needed to elicit paw withdrawal or vocalization (Randall and Selitto, Arch Int Pharmacodyn, 1957, 4, 409).
  • the analgesic effect of the test compound is seen as a (partial) restoration of the force eliciting a response toward normal.
  • the synergistic interaction between a tramadol material and a selective COX-2 inhibitor drug is determined at precise dosage ratios of tramadol hydrochloride and selective COX-2 inhibitor drugs. Multiple (typically 4-6) coded doses of each selected combination are studied for effectiveness using an experimental design which permits the complete randomization of the separate dosage forms tested.
  • ED 50mix is determined from the dose-response curve for a specific fixed-ratio of the components; ED 50add is calculated from the ED 50 values for the individual drugs. Z mix is then compared to Z add via a Student's t- test.

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EP00912043A 1999-03-01 2000-02-29 Composition comprising a tramadol material and a selective cox-2 inhibitor drug Withdrawn EP1156855A1 (en)

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HK1040945A1 (zh) 2002-06-28
WO2000051685A1 (en) 2000-09-08
CN1349423A (zh) 2002-05-15
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