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Anti-Inflammatory/Analgesic Combination of Alpha

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Anti-Inflammatory/Analgesic Combination of Alpha Patentamt JEuropàischesEuropean Patent Office ® Publication number: 0 1 09 036 Office européen des brevets g "j © EUROPEAN PATENT SPECIFICATION (45) Dateof publication of patent spécification: 02.09.87 (jjj) jnt ci 4- A 61 K 31/415, A 61 K 31/62, (22) Dateoffiling: 08.11.83 (54) Anti-inf lammatory/analgesic combination of alpha-fluoromethylhistidine and a selected non-steroidal anti-inflammatory drug (NSAID). (§) Priority: 15.11.82 US 441581 (73) Proprietor: MERCK & CO. INC. 126, East Lincoln Avenue P.O. Box 2000 Rahway New Jersey 07065 (US) (43) Date of publication of application: 23.05.84 Bulletin 84/21 @ Inventor: Goldenberg, Marvin M. 721 Shackamaxon Drive (45) Publication of the grant of the patent: Westfield New Jersey 07090 (US) 02.09.87 Bulletin 87/36 (74) Representative: Abitz, Walter, Dr.-lng. et al (84) Designated Contracting States: Abitz, Morf, Gritschneder, Freiherr von CH DE FR GB IT LI NL Wittgenstein Postfach 86 01 09 D-8000 Munchen 86 (DE) (§) References cited: EP-A-0 046290 US-A-4325 961 CÛ (£> o o> o Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall CL be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been LU paid. (Art. 99( 1 ) European patent convention). Courier Press, Leamington Spa, England. BACKGROUND OF THE INVENTION This invention relates to novel pharmaceutical combinations comprising a-fluoromethylhistidine (FMH) and a non-steroidal anti-inflammatory/analgesic drug (NSAID) particularly indomethacin, diflunisal and naproxen. Unexpectedly, these novel combinations exhibit synergistic improvements over either of the separate component alone in the treatment of inflammation and pain. They are superior in terms of both more rapid onset of action and higher efficacy. Non-narcotic analgesics, also known as non-steroidal anti-inflammatory drugs (NSAID), are widely administered orally in the treatment of mild to moderate pain. Within this class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, anti-inflammatory agents and antipyretic agents. Aspirin, acetaminophen and phenacetin have long been among the most commonly used members of this group; more recently, however, a large number of alternative non- narcotic agents offering a variety of advantages over the earlier drugs have been developed. Tolerance or addiction to these drugs is not generally a problem with their continuous use in the treatment of pain, acute or chronic inflammatory diseases, (notably, rheumatoid arthritis and osteoarthritis, dysmenorrhea); However, these new drugs generally have a higher potential for adverse side-effects. Furthermore, their effectiveness usually reaches a plateau at the upper limits of their effective dose ranges above which administration of additional drug does not increase the analgesic or anti-inflammatory effect. Among the newer compounds in the non-narcotic analgesic/non-steroidal anti-inflammatory group are compounds such as indomethacin (INDOCIN)®, diflunisal (DOLOBID)®, zomepirac sodium (ZOMAX)®, ibuprofen (MOTRIN)®, naproxen (NAPROSYN)®, fenoprofen (NALFON)®, flurbiprofen and sulindac (CLINORIL)®. See Physician's Desk Reference, 35th edition, 1981, and The Merck Index, 9th edition, Merck & Co., Rahway, New Jersey (1976), for information on specific nonsteroidal anti-inflammatory agents. @-Fluoromethylhistidine is a known compound being described in U.S. Patent 4,325,961 issued to J. Kollonitsch etal. on April 20,1982. The compound inhibits mammalian histidine decarboxylase in vivo and thereby decreases considerably histamine levels in the body for a prolonged period. Normally, in the classical carrageenan foot edema assay using the Sprague-Dawley male rat, (Winter et al, Proc. Soc. Exp. Bio/., 111, 544 1962), a-fluoromethylhistidine is ineffective in blocking inflammation induced by carrageenan although pretreatment of the rats with a-fluoromethylhistidine one and a half days prior to carrageenan significantly inhibited the hindpaw edema. However, when a-fluoromethylhistidine is used in combination with a NSAID such as indomethacin, greater anti-inflammatory effect was achieved that either agent acting alone. Such an unexpected potentiating effect was observed even at lower dose levels of both components. Accordingly, it is the object of the present invention to provide a synergistic combination of a-fluoro- methylhistidine and a NSAID for use in eliciting anti-inflammatory responses more effectively and rapidly than any of the components alone. Another object of the invention is to provide pharmaceutical compositions for the administration of these synergistic combinations. DETAILED DESCRIPTION OF THE INVENTION This invention relates to synergistic combinations which elicit unexpectedly higher analgesic and/or anti-inflammatory responses at lower dose levels than possible from the individual component used alone. The invention therefore provides a pharmaceutical composition for treatment of pain and inflammation comprising a therapeutically effective amount of a nonsteroidal anti-inflammatory drug (NSAID), as hereinafter defined, or a pharmaceutically acceptable non-toxic salt thereof and a-fluoromethylhistidine and, if desired a pharmaceutically acceptable carrier. The components of the composition are (A) five to 200 parts by weight of a-fluoromethylhistidine preferably 10 to 100 parts by weight and even more preferably 10 to 30 parts by weight of the structural formula: or (R)(+)-, (S)(-)-, or racemic (±)-form thereof; and (B) one part by weight of a non-steroidal anti- inflammatory drug (NSAID) selected from compounds which can be categorized into three groups: (1) the propionic acid derivatives; (2) the acetic acid derivatives; and (3) the biphenylcarboxylic acid derivatives; or a pharmaceutically acceptable salt thereof. The propionic acid derivatives which may be used are ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, microprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid or pharmaceutically acceptable salts thereof, for example, sodium salts. Structural formulae for representative group members are set forth below: The acetic acid derivatives which may be used are indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac and fenclozic acid or pharmaceutically acceptable salts thereof, for example, sodium salts. Structural formulas for representative group members are set forth below: The biphenylcarboxylic acid derivatives which can be used are diflunisal and flufenisal or pharmaceutically acceptable salts thereof, for example, sodium salts. When the selected NSAID, for example, indomethacin, is combined with a-fluoromethylhistidine according to the present invention, the following unexpected results are obtained from the classical carrageenan foot edema assay in the Sprague-Dawley male rat following the procedures described in Winter et al, Proc. Soc. Exp. Biol., 111, 544 (1962): Protocol: Following subplantar administration of 1 mg of carrageenan in the rat hindpaw, local intense swelling, commencing the first hour, occurs over a 3-hour period. Drugs in aqueous vehicle were administered to the animals prior to the administration of carrageenan and hindpaw swelling was measured by mercury volume displacement, 1, and 3 hours later. The response of drug-treated animals was compared to that of control groups receiving only aqueous vehicle. Statistically significant differences from control groups were determined using Student's "t" test. Analysis of Results: 1) Indomethacin alone A single dose of perorally-administered indomethacin, at 3 mg/kg, significantly diminished hindpaw swelling at 1, 2 and 3 hours post carrageenan. 2) @-Fluoromethylhistidine alone Unlike indomethacin, one acute dose of a-FMH (50 or 100 mg/kg i.p.) was ineffective in blocking inflammation induced by carrageenan. However, pretreatment of the rat with a-FMH, 112 days prior to carrageenan; caused inhibition of hindpaw swelling (Table 1). That is, 3 doses of a-FMH, twice on day-1 (4 hours apart) and once on day-0, at 50 or 100 mg/kg i.p., significantly inhibited edema induced by carrageenan administered on day-0, by 71% at 2 hours and 46% at 3 hours at both dose levels. 3) Combination of a-fluoromethylhistidine (a-FMH) and a NSAID Using the above-mentioned 3-dose protocol, loser dose levels of a-FMH (10 or 30 mg/kg i.p.) were combined with single doses of either indomethacin, diflunisal, or naproxen. As shown in Table 2, a greater anti-inflammatory effect was noted at 2 and 3 hours post carrageenan when 0.3 mg/kg of indomethacin was combined with 30 mg/kg of a-FMH. At 2 hours, the combination therapy resulted in 46% inhibition of edema, while indomethacin alone or a-FMH alone resulted in only 1.8% and 13.8% inhibition, respectively. At 3 hours the combination resulted in 33.3% diminution of swelling, while indomethacin alone or a-FMH alone resulted in 8.6% and 12.4% inhibition, respectively. A more striking effect was achieved when 1 mg/kg of indomethacin was combined with 10 or 30 mg/kg of a- FMH. At 2 hours, the combination resulted in 70.6% and 61.2% inhibition, respectively, while indomethacin alone
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