Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-09
2003-05-13
Seidel, Marianne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S643000
Reexamination Certificate
active
06562865
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a pharmaceutical composition useful in the treatment of pain. More particularly, this invention is directed to a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug.
BACKGROUND OF THE INVENTION
Throughout this disclosure, various publications are cited and are herein incorporated by reference to describe more fully the state of the art to which this invention pertains.
U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1R,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.), 1978, 28(I), 114. Tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like (Driessen, et al.,
Arch. Pharmacol.,
1990, 341, R104). The Abstracts of the VI
th
World Congress on Pain, Apr. 1-6 (1990), disclose that tramadol hydrochloride is an orally active pure agonist opioid analgesic. However, clinical experience indicates that tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al.,
Arzneim. Forsch.,
(Drug Res.), 1978, 28(I), 183), constipation (I. Arend et al.,
Arzneim. Forsch.,
(Drug Res.), 1978, 28(I), 199), tolerance (L. Flohe et al.,
Arzneim. Forsch.,
(Drug Res.), 1978, 28(I), 213) and abuse liability (T. Yanagita,
Arzneim. Forsch.,
(Drug Res.), 1978, 28(I), 158). 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 ‘atypical’ 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.
To reduce the side effect problems of opioids, 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 requiring less of each ingredient while producing a synergistic analgesic effect. Compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (inhibitory), additive or superadditive (A. Takemori,
Annals New York Acad. Sci.,
1976, 281, 262). A combination of morphine and methadone, another opioid analgesic, exhibits an additive effect (R. Taber, et al.,
J. Pharm. Expt. Thera.,
1969,169(1), 29). U.S. Pat. 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. Pat. Nos. 4,587,252 and 4,569,937 which disclose other ibuprofen opioid combinations. Superadditive analgesia with a 1:125 mixture of butorphanol:acetaminophen (an opioid analgesic combined with a non-opioid analgesic) has been reported, whereas a 1:10 mixture did not show any statistically significant superadditive analgesia (A. Pircio, et al.,
Arch. Int. Pharmacodyn.,
1978, 235,116).
As an analgesic, tramadol has been combined with both opioid and non-opioid analgesic drugs. Such compositions have exhibited synergistic effects in treating pain while using less of each ingredient to produce an equivalent degree of analgesia. Specifically, U.S. Pat. No. 5,516,803 discloses the composition of tramadol and a NSAID, particularly ibuprofen. U.S. Pat. No. 5,468,744 discloses tramadol plus any of oxycodone, codeine or hydrocodone and U.S. Pat. No. 5,336,691 discloses tramadol in combination with acetaminophen.
As a class, anticonvulsant drugs are not known to be useful in the treatment of pain. However, certain anticonvulsant drugs have been found useful in the treatment of neuropathic pain. U.S. Pat. No. 4,513,006 discloses a class of anticonvulsant drugs including the 2,3,4,5-bis-O-(1-methylethylidene)-&bgr;-D-fructopyranose sulfamates known as topiramate. U.S. Pat. No. 5,760,007, which is herein incorporated by reference, further discloses topiramate as useful for the treatment of neuropathic pain.
In addition, anticonvulsant drugs have been combined with non-toxic blockers for the N-methyl-d-aspartate (NMDA) receptor. Such compositions have been described as useful in the treatment of neuropathic pain. For example, WO 98/07447 broadly discloses the combination of a neuropathic pain alleviating amount of an anticonvulsant drug, including gabapentin, lamotrigine, valproic acid, topiramate, famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan or L-5-hydroxytrytophan and an anticonvulsant potentiating amount of a non-toxic blocker for the NMDA receptor. This reference, however, does not teach the synergistic composition of the present invention.
Anticonvulsant drugs combined with NSAIDS or narcotic analgesics have also been described as useful in the treatment of pain. WO 99/12537 discloses a composition of the anticonvulsant compounds gabapentin or pregabalin in combination with the NSAID naproxen or with narcotic analgesics. Combinations of anticonvulsants and other drugs with opioid analgesics have been suggested (Donnadieu, S., et al., Pain Relief,
Presse Medicale,
1998, 27/39, 2062-2069). These references, however, also do not teach the synergistic composition of the present invention.
Heretofore, no reference has disclosed a pharmaceutical composition comprising a combination of the centrally acting analgesic tramadol and an anticonvulsant drug demonstrating that such a composition has a synergistic effect while using less of each ingredient for treating conditions of pain and neurological or psychiatric disorders in mammals.
Therefore, it is an object of the present invention 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 an anticonvulsant drug wherein the combination 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 an anticonvulsant drug selected from, but not limited to, topiramate, gabapentin, lamotrigine or RWJ-333369; wherein the combination has a synergistic effect while using less of each ingredient. A further object of the present invention is to provide a method for treating conditions of pain and neurological or psychiatric disorders in mammals.
SUMMARY OF THE INVENTION
Briefly, according to the present invention, there is provided a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug, wherein the tramadol m
Codd Ellen E.
Martinez Rebecca P.
Rogers Kathryn E.
Kim Vickie
Ortho-McNeil Pharmaceutical , Inc.
Seidel Marianne C.
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