Methods and compositions for treating migraine and conditions associated with pain

Abstract

The present invention relates to pharmaceutical compositions of an non-steroidal anti-inflammatory drug (NSAIDs) such as, aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen, or any pharmaceutically acceptable salts, solvates, or prodrugs thereof, and the medical use of these compositions. The compositions, which can be formulated for topical administration, can provide extended release of the NSAIDs. The compositions of the invention are useful, for example, in the prophylactic treatment or treatment and/or reduction of pain, in the prophylactic treatment or treatment of headaches such as migraine headaches and symptoms of migraine headaches, and in the treatment of temporomandibular disorders (TMD).

What is claimed is: 
     
         1 . A method of treating or reducing the likelihood of a migraine in a subject in need thereof, said method comprising topically administering to said subject a sustained release composition comprising from about 0.5% (w/w) to about 5% (w/w) of a therapeutic agent and a dermatologically acceptable excipient, wherein said composition is in an amount effective to treat or reduce the likelihood of a migraine in said subject and wherein administration of said composition to said subject results in a peak plasma concentration of said therapeutic agent at three hours that is at most about 450 ng/mL. 
     
     
         2 . A method for prophylactic reduction of a migraine or symptom of a migraine in a subject in need thereof, said method comprising topically administering to said subject a sustained release composition comprising form about 0.5% (w/w) to about 5% (w/w) of a therapeutic agent and a dermatologically acceptable excipient, wherein said composition is in an amount effective to prophylactically reducing a migraine or a symptom of a migraine and wherein administration of said composition to said subject results in peak plasma concentration of said therapeutic agent at three hours that is at most about 450 ng/mL. 
     
     
         3 . The method of  claim 2 , wherein said composition is administered at a time prior to when said subject expects to experience a migraine-triggering stimulus. 
     
     
         4 . The method of  claim 3 , wherein said time prior to is at least 3 hours or at least one day. 
     
     
         5 . The method of  claim 3 , wherein said migraine-triggering stimulus is selected from the group consisting of: stress, change in routine, sleep, environmental stimuli, hormonal spikes, glare, food, lack of food, additives, alcohol, mild dehydration, drugs, exercise, oral contraceptives, teeth grinding, or physical conditions. 
     
     
         6 . The method of  claim 2 , wherein said subject has a history of a migraine or is predisposed to having a migraine. 
     
     
         7 . The method of  claim 6 , wherein said subject has been or is involved in pre-monitoring symptoms of a migraine. 
     
     
         8 . The method of  claim 1  or  2 , wherein said peak plasma concentration of said therapeutic agent when administered topically is lower than the peak plasma concentration of said therapeutic agent when administered orally. 
     
     
         9 . The method of  claim 1  or  2 , wherein administration of said composition to said subject provides for gradual release of said therapeutic agent over 2-24 hours. 
     
     
         10 . The method of  claim 9 , wherein administration of said composition results in a plasma concentration of said therapeutic agent that is maintained between about 50 ng/mL and about 150 ng/mL for up to 24 hours. 
     
     
         11 . The method of  claim 1  or  2 , wherein the half-life of said therapeutic agent is between about 7 to about 13 hours. 
     
     
         12 . The method of  claim 1 , wherein said method further ameliorates a symptom of migraine. 
     
     
         13 . The method of  claim 2  or  12 , wherein said symptom of a migraine is selected from the group consisting of: severe headache, nausea, muscle tenderness, abdominal pain, visual aura, sensory hyper excitability, blurred vision, nasal congestion, diarrhea, polyuria, pallor, sweating, localized edema of the scalp or face, scalp tenderness, prominence of a vein or artery in the temple, stiffness or tenderness of the neck, impairment of concentration or mood, vertigo, lightheadedness, fatigue, depression, and euphoria. 
     
     
         14 . The method of  claim 1  or  2 , wherein said composition further reduces the frequency or duration of said migraine. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein said therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 15 , wherein said NSAID or a pharmaceutically acceptable salt thereof is selected from the group consisting of: aspirin, choline and magnesium salicylates and salts thereof, celecoxib, diclofenac and salts thereof, diflunisal, etodolac, fenoprofen and salts thereof, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate and salts, thereof, mefenamic acid, meloxicam, nabumetone, naproxen and salts thereof, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, tolmetin and salts thereof, and valdecoxib. 
     
     
         17 . The method of  claim 16 , wherein said NSAID or a pharmaceutically acceptable salt thereof is ketoprofen. 
     
     
         18 . The method of  claim 17 , wherein said composition comprises from about 20 mg to about 200 mg of ketoprofen in unit dosage form. 
     
     
         19 . The method of  claim 17 , wherein said composition comprises a total maximum dosage of about 135 mg of ketoprofen. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein said composition is formulated as a gel, cream, lotion, ointment, foam, powder, solution, spray, emulsion, or suspension for topical administration. 
     
     
         21 . The method of  claim 20 , wherein said composition if formulated as a gel for topical administration. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein said composition is administered one or more times a day. 
     
     
         23 . The method of any one of  claims 1 - 22 , wherein said composition is administered for one day or at least two to twenty days. 
     
     
         24 . The method of any one of  claims 1 - 23 , wherein said composition is administered for more than twenty days. 
     
     
         25 . The method of any one of  claims 1 - 24 , wherein said composition is administered with a second agent. 
     
     
         26 . The method of  claim 25 , wherein said second agent is selected from the group consisting of: a corticosteroid, acetaminophen, an opioid, a muscle relaxant, an anti-anxiety drug, an anti-depressant, an anti-convulsant drug, an antipsychotic, an antiepileptic drug, and a selective serotonin reuptake inhibitor (SSRI). 
     
     
         27 . A method of treating a temporomandibular disorder (TMD) in a subject in need thereof, said method comprising topically administering to said subject a sustained release composition comprising from about 0.5% (w/w) to about 5% (w/w) of a therapeutic agent and a dermatologically acceptable excipient, wherein said composition is in an amount effective to treat said temporomandibular disorder (TMD) in said subject and wherein administration of said composition to said subject results in a peak plasma concentration of said therapeutic agent at three hours that is at most about 450 ng/mL 
     
     
         28 . The method of  claim 27 , wherein said peak plasma concentration of said therapeutic agent when administered topically is lower than the peak plasma concentration of said therapeutic agent when administered orally. 
     
     
         29 . The method of  claim 27 , wherein administration of said composition to said subject provides for gradual release of said therapeutic agent over 2-24 hours. 
     
     
         30 . The method of  claim 29 , wherein administration of said composition results in a plasma concentration of said therapeutic agent that is maintained between about 50 ng/mL and about 150 ng/mL for up to 24 hours. 
     
     
         31 . The method of  claim 27 , wherein the half-life of said therapeutic agent is from about 7 to about 13 hours. 
     
     
         32 . The method of  claim 27 , further comprising monitoring whether the subject experiences amelioration of a symptom of TMD. 
     
     
         33 . The method of  claim 32 , wherein said symptom of TMD is selected from the group consisting of: a toothache, headache, neck ache, dizziness, earache, upper shoulder pain, tenderness in the face, pain in the temporomandibular joint or its surrounding tissues, functional limitations of the mandible, clicking in the temporomandibular joint during motion, and swelling of the face. 
     
     
         34 . The method of  claim 27 , wherein said therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 34 , wherein said NSAID or a pharmaceutically acceptable salt thereof is selected from the group consisting of: aspirin, choline and magnesium salicylates and salts thereof, celecoxib, diclofenac and salts thereof, diflunisal, etodolac, fenoprofen and salts thereof, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate and salts thereof, mefenamic acid, meloxicam, nabumetone, naproxen and salts thereof, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, tolmetin and salts thereof, and valdecoxib. 
     
     
         36 . The method of  claim 34 , wherein said NSAID or a pharmaceutically acceptable salt thereof is ketoprofen. 
     
     
         37 . The method of  claim 36 , wherein said composition comprises from about 20 mg to about 200 mg of ketoprofen in unit dosage form. 
     
     
         38 . The method of  claim 36 , wherein said composition comprises a total maximum dosage of about 135 mg of ketoprofen. 
     
     
         39 . The method of  claim 27 , wherein said composition is formulated as a gel, cream, lotion, ointment, foam, powder, solution, spray, emulsion, or suspension for topical administration. 
     
     
         40 . The method of  claim 39 , wherein said composition if formulated as a gel for topical administration. 
     
     
         41 . The method of  claim 27 , wherein said composition is administered one or more times a day. 
     
     
         42 . The method of  claim 27 , wherein said composition is administered for one day or at least two to twenty days. 
     
     
         43 . The method of  claim 27 , wherein said composition is administered for more than twenty days. 
     
     
         44 . The method of  claim 27 , wherein said composition is administered with a second agent. 
     
     
         45 . The method of  claim 44 , wherein said second agent is selected from the group consisting of: a corticosteroid, acetaminophen, an opioid, a muscle relaxant, an anti-anxiety drug, an anti-depressant, an anti-convulsant drug, an antipsychotic, an antiepileptic drug, and a selective serotonin reuptake inhibitor (SSRI).