METHODS AND COMPOSITIONS TO INHIBIT TOLERANCE TO OPIOIDS
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`Docket No: 2448-8P
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`[0001] The present invention relates to methods, and compositions, for inhibiting the tolerance to
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`FIELD OF THE INVENTION
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`opioids upon opioid therapy.
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`BACKGROUNDOF THE INVENTION
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`[0002] Opioidsare a class of drugs that include the illegal drug heroin and analgesics available
`legally by prescription, such as oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine and
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`morphine. Opioids are powerful pain relievers, but their use is hindered by toleranceto the
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`analgesic effects, physical dependenceresulting in withdrawal syndrome, and the possibility
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`of addiction.
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`[0003] Tolerance is the need for progressively higher doses of an opioid in order to maintain
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`the sametherapeutic effect, e.g., same reduction in pain. Tolerance typically develops upon
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`sustained opioid therapy. While opioid rotation is currently used to minimize tolerance, this
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`approach requires close monitoring due to variable cross-tolerance and side effect profiles
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`among different patients (Fine, P., J Pain Palliat Care Pharmacother 18:75-79. (2004)). In
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`its most severe form, opioid tolerance can manifest as opioid-induced hyperalgesia; thatis,
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`the opioid no longer reduces pain but instead increases or induces pain (Fine, 2004). Opioid-
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`induced hyperalgesia is extremely difficult to treat.
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`[0004] Dueto the potential dire consequencesof opioid use, there is an urgent need to minimize
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`the dosage required by patients to maintain a desired pharmacologicaleffect.
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`

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`SUMMARYOF THE INVENTION
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`[0005] In one embodiment, the present invention includes methodsof inhibiting tolerance to an
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`opioid in a human subject in need thereof. The methods comprise administering an effective
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`amountof a pharmaceutical composition to the subject during opioid therapy. The
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`pharmaceutical composition comprises a) a non-steroidal anti-inflammatory drug (NSAID); and
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`b) a co-agent selected from the group consisting of: fexofenadine, ketotifen, desloratadine,
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`cetirizine, salts thereof and combinationsthereof.
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`[0006] In one embodiment, the NSAIDis aspirin, ibuprofen, naproxen, diclofenac, diflunisal,
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`etodolac, indomethacin, ketoprofen, ketorolac, meloxicam, nabumetone, oxaprozin, piroxicam,
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`salsalate, sulindac, and tolmetin.
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`[0007] In one embodiment, the NSAID is ibuprofen and the co-agent is fexofenadine. In one
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`embodiment, the amount of ibuprofen is about 150mg to about 900mg, and the amountof
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`fexofenadine is about 60mg to about 180mg. In one embodiment, the ibuprofen and the
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`fexofenadine are combinedinto one unit dose. In one embodiment, the ibuprofen and the
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`fexofenadineare in the form of a tablet, lozenge or chewing gum.
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`[0008] In one embodiment, the present invention is a pharmaceutical composition comprising a)
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`an NSAID, and/orasalt thereof; and b) a co-agent selected from the group consisting of:
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`fexofenadine, ketotifen, desloratadine, cetirizine salts thereof and combinations thereof. In one
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`embodiment, the pharmaceutical composition includes ibuprofen and fexofenadine. In one
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`embodiment, the amount of ibuprofen is about 150mg to about 900mg, and the amountof
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`fexofenadine is about 25mg to about 200mg.
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`DETAILED DESCRIPTION OF THE INVENTION
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`[0009]
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`In one embodiment, the present invention is directed to methodsof inhibiting the
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`tolerance to opioids in human subjects. The methodsinclude the administration of particular
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`pharmaceutical compositions.
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`

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`[0010] Throughoutthis specification, quantities are defined by ranges, and by lower and upper
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`boundaries of ranges. Each lower boundary can be combined with each upper boundary to
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`define a range. The lower and upper boundaries should each be taken as a separate element.
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`[0011]
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`Opioids are substances that act by binding to opioid receptors, which receptors are
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`found principally in the central and peripheral nervous system and the gastrointestinal tract.
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`These receptors mediate both the psychoactive and the somatic effects of opioids. Medically
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`opioids are primarily used for pain relief, including anesthesia. Other medical uses include
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`suppression of diarrhea and suppressing cough.
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`[0012] Opioids include opiates, which are alkaloid compoundsnaturally found in the opium
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`poppyplant(i.e., Papaver somniferum). The psychoactive compounds foundin the opium plant
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`include opium, heroin, morphine, codeine and thebaine. Examples of synthetic, or semi-
`synthetic, opioids include hydrocodone(e.g., Vicodin®, Lorcet®, Lortab®, Percocet®,
`Percodan®); oxycodone(e.g., OxyContin®); fentanyl(e.g., Duragesic®); methadone
`(Dolophine*); pethidine(e.g., Demerol®); and hydromorphone(e.g., Dilaudid®).
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`[0013]
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`Opioid therapyis the treatment of a humansubject with opioids, typically a prolonged
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`treatment with opioids, typically to achieve analgesic effects.
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`[0014]
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`In one embodiment, the methodsof the present invention comprise the administration
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`of a pharmaceutical composition to a human subject, in need thereof, in an amount whichis
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`effective to inhibit the tolerance to opioids by the subject. A human subject in need thereofis a
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`subject whois to receive, or is receiving, opioid therapy. Administration includes administration
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`by a physician or by self-administration.
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`[0015]
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`Tolerance to an opioid drug is defined as the failure of a steady dose of the opioid to
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`sustain the desired pharmacological effect over time. That is, there is a need to increase the
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`opioid dosage to maintain the initial pharmacologicaleffect, e.g., the original analgesic effect of
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`the opioid. Tolerance to opioids can develop in subjects during opioid therapy.
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`

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`[0016]
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`When administered the pharmaceutical composition of the present invention, the
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`tolerance for a given opioid in a subjectis inhibited, 1.e., tolerance does not develop or tolerance
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`is minimized. That is, the same doseoriginally given to the subject for a certain therapeutic
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`effect (e.g., analgesic effect) will remain sufficient, or substantially sufficient, throughout the
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`opioid therapy.
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`[0017]
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`The pharmaceutical composition is administered to the human subject, in need
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`thereof, during opioid therapy, alternatively, slightly before opioid therapy. For example,
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`administration is begun at most about 48 hours before the first dose of an opioid or at the time of
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`the first dose of an opioid, and is substantially continued for the duration of the opioid therapy.
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`Alternatively, administration can be begun at any point during opioid therapy.
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`[0018]
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`In the present specification, the term “inhibit” includes “reduce” and/or “prevent”
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`and/or “shorten duration.” That is, the methods of the present invention are considered to be
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`effective if they cause one or more of: a reduction/prevention of tolerance to an opioid and/or
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`shortening of the duration of any tolerance to an opioid. For example, tolerance is inhibited if
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`the same amountof an opioid renders the same, or substantially the same, or greater effect (e.g.,
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`analgesic effect) during an opioid therapy. Thatis, the initial prescribed dose of an opioid is not
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`required to be increased to achieve the sametherapeutic effect.
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`[0019]
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`Inhibition of tolerance can be assessed by comparing the magnitude and/or duration
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`of tolerance in a subject at two different occasions, that is, i) when administered the
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`pharmaceutical composition during an opioid therapy; and ii) when not administered the
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`pharmaceutical composition during an opioid therapy. An assessment is made as to whether the
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`same pharmaceutical effect is achieved with substantially the same dose of an opioid throughout
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`an opioid therapy at the different occasions. Inhibition of tolerance can also be assessed by
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`comparing the magnitude and/or duration of tolerance in different subjects being treated with the
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`same opioid, some of whom are administered the pharmaceutical composition during a therapy
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`and some whomare not administered the pharmaceutical composition during a therapy. An
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`assessment is made as to whether the same pharmaceutical effect is achieved with substantially
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`the same doseof an opioid throughout an opioid therapy between the different subjects.
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`

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`[0020]
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`Typically, tolerance is inhibited by at least about 10%, at least about 20%, at least
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`about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at
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`least about 80%, at least about 90%, or about 100%.
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`[0021] The pharmaceutical composition comprises a) at least one non-steroidal anti-
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`inflammatory drug (“NSAID”), and b) a co-agent.
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`[0022]
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`The NSAID of the present invention includes any NSAID andsalts thereof.
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`Examples of suitable NSAIDs include, but are not limited to, aspirin (1.e., acetylsalicylic acid);
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`ibuprofen (1.e., isobutylphenylpropanoic acid); naproxen (e., 6-methoxy-a-methyl-2-
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`naphthaleneacetic acid); diclofenac(i.e., 2-[(2,6-dichlorophenyD-amino|benzene acetic acid);
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`diflunisal (1.e., 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid); etodolac (1.e., (RS)-2-(1,8-
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`diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl)acetic acid); indomethacin (i.e., 2-{ 1-[(4-
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`chlorophenyl)-carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl} acetic acid); ketoprofen(i.e., 3-
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`benzoyl-o-methyl-benzeneacetic acid); ketorolac (1.e., 2-amino-2-(hydroxymethyl)-1,3-
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`propanediol); meloxicam (i.e., 4-hydroxy-2-methyl-N-(5-methy1-2-thiazolyl)-2H-1,2-
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`benzothiazine-3-carboxamide-1,1-dioxide); nabumetone(i.e., 4-(6-methoxy-2-naphthyl)-2-
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`butanone); oxaprozin (i.e., 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid); piroxicam (1e., 4-
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`hydroxy-2-methyl-N-2-pyridinyl- 2H-1,2-benzothiazine-3-carboxamide 1 ,1-dioxide); salsalate
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`(i.e., 2-(2-hydroxybenzoyl)-oxybenzoic acid); sulindac (.e., {(1Z)-5-fluoro-2-methyl-1-[4-
`
`(methylsulfinyl)-benzylidene]-1H-indene-3-yl}acetic acid); and tolmetin (i.e., [1-methyl-5-(4-
`
`methylbenzoyl)-14-pyrrol-2-ylJacetic acid).
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`[0023]
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`Suitable co-agents include desloratadine(i.e., 8-chloro-6, 1 1-dihydro-11-(4-
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`piperdinylidene)- 5H-benzo[5,6]cyclohepta[1,2-b]pyridine); fexofenadine(1.e., (+)-4-[1 hydroxy-
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`4-[4-(hydroxydiphenylmethyl)- 1-piperidinyl]-butyl]-a, o-dimethyl benzeneacetic acid);
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`ketotifen; cetirizine; and salts of such co-agents.
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`[OO24}
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`The NSAIDs and co-agents inchide all pharmaceutically acceptable versions of the
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`NSAIDs and co-agents, including, for example, stereoisomers and/or any mixtures thereof, all
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`pharmaceutically acceptable zwitterions and/or any mixtures thereof, all pharmaceutically
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`

`

`acceptable polymorphic forms and/or any mixtures thereof, and all pharmaceutically acceptable
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`complexes (including solvates) and/or any mixtures thereof,
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`[0025]
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`Salts include all salts of NSAIDs and of co-agents which are pharmaceutically
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`acceptable (L.e., non-toxic at therapeutically effective doses}. And, salts include their racemates,
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`enantiomers, or any mixtures thereof,
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`[0026]
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`Particularly suitable salts of the NSAIDs comprise alkali-metal salts (e.g., sodium
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`and/or potassiamsalts), alkaline earth metal salts (e.g., magnesiuns and/or calciumsalts),
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`aluminumsalts, arnamoniumsalts, salts of suitable organic bases (¢.g., salts of alkylamines and/or
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`-methyl-D-glutamine), salts of amino acids (¢.g., salts of arginine and/or lysine). The NSAID
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`salis also include ail enantiomeric salts formed with pharmaceutically acceptable chiral acids
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`and/or bases and/or any mixtures of enantiomers of such salts (e.g., (+) tartrates, (-) tartrates
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`and/or any mixtures thereof mcluding racemic mixtures). For example, a typical salt of an
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`NSAID is naproxen sodium.
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`[0027 }
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`Exarnples of suitable salts of the co-agents include ketotifen fumarate, fexofenadine
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`hydrochloride and cetirizine hydrochloride.
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`[0028]
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`The actual preferred amounts of a pharmaceutical composition in a specified case will
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`vary according to the particular composition formulated, the mode of application, the particular
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`sites of application, and the subject being treated (e.g., age, gender, size, tolerance to drug,etc.).
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`[0029]
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`Examplesof typical daily amounts of NSAIDs to be administered in the methodsof
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`the present invention follows. The daily amounts can be administered in one dose, or in multiple
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`doses, typically, two doses.
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`[0030]
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`Naproxen from about 110mg to about 1500mg: Examples of other lower boundaries
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`of this range include about 150mg, about 220mg, about 275mg, about 320mg and about 420mg.
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`Examples of other upper boundaries of this range include about 580mg, about 680mg, about
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`780mg, about 880mg and about 950mg.
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`[0031]
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`Ibuprofen from about 100mg to about 3200mg: Examplesof other lower
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`boundaries of this range include about 200mg, about 400mg, about 600mg, about 700mg, about
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`

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`950mg and about 1000mg. Examples of other upper boundariesof this range include about
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`1200mg, about 1500mg, about 2000mg, about 2500mg and about 3000mg.
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`[0032]
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`Aspirin from about 250mg to about 4000mg: Examples of other lower boundaries of
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`this range include about 325mg, about 450mg, about 550mg, about 700mg, about 1000mg, about
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`1500mg, and about 1800mg. Examples of other upper boundaries of this range include about
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`2000mg, about 2500mg, about 3000mg, about 3500mg, and about 3800mg.
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`[0033]
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`Examplesof typical daily amounts of the co-agent to be administered in the methods
`
`of the present invention follows. The daily amounts can be administered in one dose,or in
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`multiple doses, typically, two doses.
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`[0034]
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`Fexofenadine from about 25mg to about 200mg: Examples of other lower boundaries
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`of this range include about 60mg, about 70mg, about 80mg and about 90mg. Examples of other
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`upper boundaries of this range include about 100mg, about 120mg, about 150mg and about
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`180mg. Ketotifen from about 0.5mg to about 3mg: Examples of other lower boundariesof this
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`range include about Img, about 1.5mg and about 1.8mg. Examples of other upper boundaries of
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`this range include about 2mg, about 2.5mg and about 2.8mg. Desloratidine from about 2mg to
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`about 40mg: Examples of other lower boundaries of this range include about 5mg, about 6mg
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`and about 7mg. Examples of other upper boundaries of this range include about 8mg, about 9mg
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`and about 10mg. Cetirizine from about 2mg to about 10mg: Examples of other lower
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`boundaries of this range include about 5mg, about 6mg and about 7mg. Examples of other upper
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`boundaries of this range include about 8mg, about 9mg and about 10mg.
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`[0035]
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`In one embodimentof the invention, a pharmaceutical composition comprises about
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`800mg ibuprofen and about 60mg fexofenadine. The pharmaceutical composition can be
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`administered every twelve hours beginning before the last dose of an opioid is taken, preferably
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`by delayed release administration.
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`[0036]
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`The pharmaceutical composition can be administered by methods knownin theart.
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`For example, the pharmaceutical composition can be administered systemically. For the
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`purposesofthis specification, “systemic administration” means administration to a human by a
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`method that causes the compositions to be absorbed into the bloodstream.
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`

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`[0037]
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`In one embodiment, the pharmaceutical compositions are administered orally by any
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`method knownin the art. For example, the compositions can be administered in the form of
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`tablets, including, e.g., orally-dissolvable tablets, chewable tablets; capsules; lozenges; pills (e.g.,
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`pastilles, dragees); troches; elixirs; suspensions; syrups; wafers; chewing gum;strips; films(e.g.,
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`orally-dissolving thin films); soluble powders; effervescent compositions; andthe like.
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`[0038]
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`The NSAID (and/orsalt thereof) and the co-agent can be supplied in combination as
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`one unit dose, or can be supplied individually, e.g., supplied in a package with a unit dose of
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`NSAID and a unit dose ofthe co-agent.
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`[0039]
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`Additionally, the pharmaceutical compositions can be administered enterally or
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`parenterally, e.g., intravenously; intramuscularly; subcutaneously, as injectable solutions or
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`suspensions; intraperitoneally; sublingually; or rectally (e.g., by suppositories). Administration
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`can also be intranasally, in the form of, for example, an intranasal spray; or transdermally, in the
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`form of, for example, a patch.
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`[0040]
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`The pharmaceutical composition compoundsof the invention can be formulated per
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`se in pharmaceutical preparations, optionally, with a suitable pharmaceutical carrier (vehicle) or
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`excipient, as understood bypractitioners in the art. These preparations can be made according to
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`conventional chemical methods.
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`[0041]
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`In the case of tablets for oral use, carriers commonly used include lactose and corn
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`starch, and lubricating agents such as magnesium stearate are commonly added. For oral
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`administration in capsule form, useful carriers include lactose and corn starch. Further examples
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`of carriers and excipients include milk, sugar, certain types of clay, gelatin, stearic acid orsalts
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`thereof, calcium stearate, talc, vegetable fats or oils, gums and glycols.
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`[0042]
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`When aqueous suspensionsare used for oral administration, emulsifying and/or
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`suspending agents are commonly added. In addition, sweetening and/or flavoring agents may be
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`added to the oral compositions.
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`[0043]
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`For intramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions
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`of the pharmaceutically compositions can be employed, and the pH of the solutions can be
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`

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`suitably adjusted and buffered. For intravenous use, the total concentration of the solute(s) can
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`be controlled in order to render the preparation isotonic.
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`[0044]
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`A preferred embodimentof the invention is an orally dissolving tablet comprising an
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`NSAID and a coagent with or without a taste masking ingredient, diluents, etc. Such tablet can
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`be administered without water onto the tongue leading to immediate dissolution and is absorbed
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`gastrointestinally or buccally. Orally dissolving tablets can be formulated by a numberof
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`techniques including compression and lyophilization, as would be knownto a skilled artisan.
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`[0045]
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`Another preferred embodiment of the invention is a lozenge or troche comprising an
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`NSAID and a coagent with or without a taste masking ingredient, diluents, etc. Such
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`lozenge/troche can be administered without water, and can slowly dissolve in the mouth, or can
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`be swallowed or chewed. Such lozenges/troches can be formulated by compression, as would be
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`knownto a skilled artisan.
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`[0046]
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`The pharmaceutical compositions of the present invention can further comprise one
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`or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, buffers,
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`coloring agents, flavoring agents, and the like. In some embodiments, orally administered
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`pharmaceutical compositions can contain breathe neutralizers, e.g., peppermint or menthol
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`scents.
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`[0047]
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`The pharmaceutical composition may be administered by controlled release.
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`Controlled release administration is a method of drug delivery to achieve a certain level of the
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`drug overa particular period of time. The level typically is measured by plasma concentration.
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`Methods for controlled release of drugs are well knownintheart.
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`[0048]
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`The pharmaceutical compositions can be formulated for controlled release. For
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`example, in one embodiment, the composition can be a capsule containing beadlets, wherein
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`someof the beadlets dissolve instantaneously and someof the beadlets dissolve at delayed times
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`dueto different types of beadlet coatings.
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`[0049]
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`In one embodiment, the pharmaceutical composition comprises an active ingredient,
`
`wherein the active ingredient consists of: a) NSAID, and b) a co-agent selected from the group
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`

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`consisting of: fexofenadine, ketotifen, desloratadine, cetirizine, salts thereof and combinations
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`thereof.
`
`[0050]
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`In one embodiment, the pharmaceutical composition consists of: a) NSAID, and/or
`
`salt thereof, b) a co-agent selected from the group consisting of: fexofenadine, ketotifen,
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`desloratadine, cetirizine, salts thereof, and combinations thereof; and c) at least one carrier and/or
`
`excipient.
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`[0051]
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`In one embodiment, the pharmaceutical composition consists essentially of the active
`
`ingredients of: a) NSAID and/orsalt thereof, and b) a co-agent selected from the group
`
`consisting of: fexofenadine, ketotifen, desloratadine, cetirizine, salts thereof and combinations
`
`thereof. That is, any other ingredients that may materially affect the basic and novel
`
`characteristics of the active ingredients of the invention are specifically excluded from the
`
`composition. Any ingredient which can potentially cause an undesirable effect/side effect,
`
`including, for example, an allergic response, may materially affect the basic and novel
`
`characteristics of the active ingredients of the invention.
`
`[0052]
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`The following are some examples of components which may materially affect the
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`basic and novel characteristics of the active ingredients of the pharmaceutical compositions and
`
`may be excluded from certain embodiments of the present invention: cyclooxygenase-2-
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`selective inhibitors (i.e., COX-2-selective inhibitors) or prodrugs thereof; sedating antihistamines
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`(e.g., phenyltoloxamine(e.g., phenyltoloxaminecitrate), doxylamine (e.g., doxylamine
`succinate)); antiemetic antihistamines(e.g., dimenhydrinate (Dramamine®), clizines(e.g.,
`cyclizine, meclizine), diphenhydramine (Benadryl®), promethazine (Pentazine®, Phenergan®,
`Promacot®), and hydroxyzine (Vistaril®)); decongestants; flunixin meglumine(i.e., banamine);
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`5-HT3 receptor antagonists; cough suppressants (e.g., guaifenesin, dextromethorphan); and
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`corticosteroids.
`
`[0053]
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`The aforementioned ingredients may materially change the characteristics of the
`
`present pharmaceutical composition due to unwanted effects and/or potential allergic responses.
`
`[0054]
`
`Examples of unwanted potential effects of COX-2-selective inhibitors, or prodrugs
`
`thereof, include an increased risk in the incidence of myocardial infarctions. COX-2-selective
`
`10
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`

`

`inhibitors are compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1,
`
`and also include pharmaceutically acceptable salts of such compounds, and prodrugs of such
`
`compounds. A COX-2 selective inhibitor is any inhibitor for which the ratio of COX-1 ICsp to
`
`COX-2 ICso is greater than 1. Examples of unwanted potential effects of sedating
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`antihistamines, decongestants, and diphenhydramineincludesleepiness, fatigue, dizziness,
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`headache, dry mouth, difficulty urinating or an enlarged prostate and allergic reactions.
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`Examples of unwanted potential effects of flunixin meglumineinclude ataxia, incoordination,
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`hyperventilation, hysteria and muscle weakness. Examples of unwanted potential effects of 5-
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`HT3 receptor antagonists include constipation, diarrhea, headache, dizziness and arrhythmias.
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`Examples of unwanted potential effects of guaifenesin include diarrhea, dizziness, headache,
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`hives, nausea or vomiting, skin rash and stomach pain. Examples of unwanted potential effects
`
`of dextromethorphan include confusion, constipation, dizziness, drowsiness, headache, nausea or
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`vomiting and stomach pain. Examples of unwanted potential effects of corticosteroids include
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`fluid retention, edema, weight gain, high blood pressure, headache and muscle weakness.
`
`[0055]
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`In one embodiment, the pharmaceutical composition is combined with an opioid
`
`during opioid therapy(i.e., instead of the opioid being given separately). That is, an NSAID, a
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`co-agent and an opioid are formulated into a single pharmaceutical preparation, optionally, with
`
`a suitable pharmaceutical carrier (vehicle) or excipient, as understood bypractitioners in theart.
`
`These preparations can be made according to conventional chemical methods, as described
`
`above.
`
`[0056]
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`In one embodiment, the pharmaceutical composition is administered during
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`methadonedetoxification therapy. Such therapy can either be donerelatively rapidly in less than
`
`a month or gradually over as long as six months.
`
`[0057]
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`Opioid therapy can last for about two to eight weeks, or indefinitely. During such
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`period, the pharmaceutical composition can be administered on a substantially daily basis. Daily
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`NSAID use has been associated with adverse gastrointestinal effects (e.g., upset stomach,
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`ulcers). However, when the NSAIDs of the present invention are taken in combination with the
`
`co-agents, adverse gastrointestinal effects are surprisingly slight or absent. Thus, it has
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`unexpectedly been found that the components of the compositions of the present invention have
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`11
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`

`

`a synergistic effect when inhibiting the adverse symptomsassociated with the withdrawal from
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`opioids.
`
`[0058]
`
`Thus, while there have been described what are presently believed to be the preferred
`
`embodiments of the present invention, other and further embodiments, modifications, and
`
`improvements will be knownto those skilled in the art, and it is intended to includeall such
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`further embodiments, modifications, and improvements as come within the true scope of the
`
`claims as set forth below.
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`12
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`

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`SOME EMBODIMENTS:
`
`1.
`
`A method of inhibiting tolerance to an opioid by a human subject in need thereof,
`
`comprising:
`
`administering an effective amountof a pharmaceutical composition to the subject during
`
`opioid therapy, wherein the pharmaceutical composition comprises:
`
`a) a non-steroidal anti-inflammatory drug (NSAID); and
`
`b) a co-agent selected from the group consisting of: fexofenadine, ketotifen,
`
`desloratadine, cetirizine, salts thereof and combinations thereof;
`
`wherein tolerance to an opioid is inhibited in the human subject.
`
`2.
`
`The method wherein the NSAIDis selected from the group consisting of: aspirin,
`
`ibuprofen, naproxen, diclofenac, diflunisal, etodolac, indomethacin, ketoprofen, ketorolac,
`
`meloxicam, nabumetone, oxaprozin, piroxicam,salsalate, sulindac, and tolmetin.
`
`3.
`
`4,
`
`The method wherein the NSAID is ibuprofen and the co-agentis fexofenadine.
`
`The method wherein the amountof ibuprofen is about 150mg to about 900mg, and the
`
`amountof fexofenadine is about 60mg to about 180mg.
`
`5.
`
`6.
`
`The method wherein the ibuprofen and the fexofenadine is combined in one unit dose.
`
`The method wherein the ibuprofen and the fexofenadineis in the form ofa tablet, lozenge
`
`or chewing gum.
`
`7.
`
`A pharmaceutical composition comprising a) an NSAID, and/ora salt thereof; and b) a
`
`co-agent selected from the group consisting of: fexofenadine, ketotifen, desloratadine, cetirizine
`
`salts thereof and combinations thereof.
`
`8.
`
`The pharmaceutical composition wherein the composition is in the form of an orally-
`
`dissolving tablet or lozenge.
`
`13
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`

`9.
`
`The pharmaceutical composition wherein the NSAIDis selected from the group
`
`consisting of: aspirin, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, indomethacin,
`
`ketoprofen, ketorolac, meloxicam, nabumetone, oxaprozin, piroxicam,salsalate, sulindac, and
`
`tolmetin.
`
`10.
`
`The pharmaceutical composition wherein the NSAID is ibuprofen and the co-agentis
`
`fexofenadine.
`
`17.
`
`The pharmaceutical composition wherein the amountof ibuprofen is about 150mg to
`
`about 900mg, and the amount of fexofenadine is about 25mg to about 200mg.
`
`14
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`