US20170266106A1 - Methods and compositions for treating migraine and conditions associated with pain - Google Patents

Methods and compositions for treating migraine and conditions associated with pain Download PDF

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US20170266106A1
US20170266106A1 US15/532,425 US201515532425A US2017266106A1 US 20170266106 A1 US20170266106 A1 US 20170266106A1 US 201515532425 A US201515532425 A US 201515532425A US 2017266106 A1 US2017266106 A1 US 2017266106A1
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migraine
ketoprofen
pain
therapeutic agent
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Crist J. Frangakis
William Bauer
Wolfgang Liedtke
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Achelios Therapeutics Inc
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Achelios Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
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    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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

Definitions

  • the invention relates to methods and compositions for treating conditions associated with pain and particularly for treating headaches, including migraine headaches.
  • Three categories of pain are generally recognized: nociceptive pain, which is caused by stimulation of peripheral nerve fibers; inflammatory pain, which is associated with tissue damage and the infiltration of immune cells; and pathological pain, which is a disease state caused by damage to the nervous system or by its abnormal function (e.g., dysfunctional pain in condition such as fibromyalgia, irritable bowel syndrome, and tension type headache).
  • Migraine is a common disorder characterized by intermittent attacks of moderate-to-severe head pain associated with nausea, photophobia, and phonophobia.
  • An aura i.e., vision changes
  • Migraine is a common and disabling brain disorder with a strong inherited component. Because subjects experiencing a migraine have severe and disabling attacks, usually of headache with other symptoms of sensory disturbance (e.g., light and sound sensitivity), medical treatment is often required.
  • NSAIDs that are being used increasingly to treat acute migraine, include, for example, TreximaTM (a combination drug consisting of a single tablet containing sumatriptan succinate and naproxen sodium), Advil® Migraine (ibuprofen), CambiaTM (diclofenac potassium), Aleve® (naproxen), and Orudis®/Oruvail® (ketoprofen). All of these agents have a common property in that they inhibit prostaglandin synthesis thereby reducing the consequences of the inflammatory reaction, whether it be from different origin or mechanism.
  • TreximaTM a combination drug consisting of a single tablet containing sumatriptan succinate and naproxen sodium
  • Advil® Migraine ibuprofen
  • CambiaTM diclofenac potassium
  • Aleve® naproxen
  • Orudis®/Oruvail® ketoprofen
  • the headache phase of migraine may develop as a result of an abnormal interaction and perhaps an abnormal release of vaso-active neurotransmitters from terminals of the trigeminal nerve with large intracranial and extra cranial blood vessels. These blood vessels, which dilate during the headache phase of migraine, are thought to receive axonal projections from all three divisions of the trigeminal nerve.
  • NSAIDs potentiate and inhibit sympathetic neural transmission. NSAIDs also promote the contraction and relaxation of vascular smooth muscles, enhance vascular permeability, and mediate the actions of other vasoactive substances.
  • NSAIDs can be classified based on their chemical structure or mechanism of action. Common NSAID classification groups include: salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, selective COX-2 inhibitors, and sulphonamides. NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among the compounds relate to dosing regimens, route of administration, and tolerability profile.
  • NSAIDs Although subjects often prefer the convenience of oral therapy of the above-mentioned NSAIDs, these medications can have numerous side effects, for example, nausea, vomiting, and gastrointestinal and renal effects that can sometimes limit the effectiveness of this route of administration. Accordingly, there exists a need in the medical field to develop safe and effective formulations of NSAIDs that minimize systemic side effects and gastrointestinal irritation to treat conditions associated with pain, migraine, and temporomandibular disorders.
  • the present invention features a method of treating or reducing the likelihood of a migraine in a subject in need thereof, the method including topically administering to the subject a sustained release composition including from about 0.5% (w/w) to about 5% (w/w) of a therapeutic agent and a dermatologically acceptable excipient, wherein the composition is in an amount effective to treat or reduce the likelihood of a migraine in the subject and wherein administration of the composition to the subject results in a peak plasma concentration of the therapeutic agent at three hours that is at most about 450 ng/mL.
  • the present invention features a method for prophylactic reduction of a migraine or symptom of a migraine in a subject in need thereof, the method including topically administering to the subject a sustained release composition including form about 0.5% (w/w) to about 5% (w/w) of a therapeutic agent and a dermatologically acceptable excipient, wherein the composition is in an amount effective to prophylactically reducing a migraine or a symptom of a migraine and wherein administration of the composition to the subject results in peak plasma concentration of the therapeutic agent at three hours that is at most about 450 ng/mL.
  • the composition is administered at a time prior to when the subject expects to experience a migraine-triggering stimulus, wherein the time prior to is at least 3 hours or at least one day.
  • the 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.
  • the subject has a history of a migraine or is predisposed to having a migraine.
  • the subject has been or is involved in pre-monitoring symptoms of a migraine.
  • the method further ameliorates a symptom of migraine, wherein the 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.
  • the composition further reduces the frequency or duration of the migraine.
  • the present invention features a method of treating a temporomandibular disorder (TMD) in a subject in need thereof, the method including topically administering to the subject a sustained release composition including from about 0.5% (w/w) to about 5% (w/w) of a therapeutic agent and a dermatologically acceptable excipient, wherein the composition is in an amount effective to treat the temporomandibular disorder (TMD) in the subject and wherein administration of the composition to the subject results in a peak plasma concentration of the therapeutic agent at three hours that is at most about 450 ng/mL.
  • TMD temporomandibular disorder
  • the method further including monitoring whether the subject experiences amelioration of a symptom of TMD, wherein the 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.
  • the 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.
  • the peak plasma concentration of the therapeutic agent when administered topically is lower than the peak plasma concentration of the therapeutic agent when administered orally.
  • administration of the composition to the subject provides for gradual release of the therapeutic agent over 2-24 hours.
  • administration of the composition results in a plasma concentration of the therapeutic agent that is maintained between about 50 ng/mL and about 150 ng/mL for up to 24 hours.
  • the half-life of the therapeutic agent is between about 7 to about 13 hours (e.g., about 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, or 13).
  • the therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof.
  • NSAID non-steroidal anti-inflammatory drug
  • the 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.
  • the NSAID or a pharmaceutically acceptable salt thereof is ketoprofen.
  • the composition includes from about 20 mg to about 200 mg of ketoprofen in unit dosage form (e.g., about 21 mg, 22 mg, 22.5 mg, 23 mg, 24 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, etc).
  • the composition includes a total maximum dosage of about 135 mg of ketoprofen.
  • the composition is formulated as a gel, cream, lotion, ointment, foam, powder, solution, spray, emulsion, or suspension for topical administration. In preferred embodiments, the composition is formulated as a gel for topical administration.
  • the composition is administered one or more times a day. In other embodiments, the composition is administered for one day or at least two to twenty days. In yet other embodiments, the composition is administered for more than twenty days.
  • the composition is administered with a second agent, wherein the 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).
  • administering refers to a method of giving a dosage of a composition to a subject.
  • the preferred method of administration may depend on a variety of factors, e.g., the components of the composition and the nature and severity of the disease, disorder, or condition.
  • administered together means that two or more therapeutic agents (e.g., any of the NSAIDs described herein) are formulated together in a single composition or two or more therapeutic agents (e.g., any of the NSAIDs described herein) are administered in combination to the subject.
  • an amount effective refers to an amount of at least one therapeutic agent that prevents a condition associated with pain, migraine, and temporomandibular disorders, diminishes the frequency or intensity of pain, migraine, and temporomandibular disorders, or relieves one or more symptoms caused by pain associated with migraine, migraine, and temporomandibular disorders.
  • an effective amount refers to an amount of at least one therapeutic agent that prevents, treats, or palliates a disease, a disorder, or a condition as described herein.
  • chronic pain is meant pain that lasts longer than three to six months or pain that extends beyond the expected period of healing.
  • Chronic pain may originate with an initial trauma/injury or infection, or may be an ongoing cause of pain, headaches, joint pain, backaches, sinus pain, muscle pain, nerve pain, and pain affecting specific parts of the body, such as shoulders, pelvis, and neck.
  • Chronic pain may also be associated with chronic migraine that relates to having more than 15 migraine headaches a month.
  • Chronic pain may also be associated with lower back pain, arthritis, headache, multiple sclerosis, fibromyalgia, shingles, nerve damage, or cancer.
  • compositions or components thereof are suitable for use in contact with dermal tissue without undue toxicity, incompatibility, instability, allergic response, and the like.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, maltose, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc,
  • extended release or “sustained release” interchangeably refer to a drug formulation that provides for gradual release of a drug over an extended period of time, e.g., 2-24 hours or more (e.g., 2-4 hours, 2-8 hours, 2-10 hours, 2-15 hours, 2-20 hours, 4-8 hours, 4-10 hours, 4-20 hours, 8-10 hours, 8-15 hours, 10-15 hours, 15-20 hours, 20-25 hours), compared to an immediate release formulation of the same drug or therapeutic agent.
  • a peak plasma concentration range that is between, for example from about 50 ng/mL to about 150 ng/mL (e.g., about 50 ng/mL to about 75 ng/mL, about 50 ng/mL to about 100 ng/mL, about 50 ng/mL to about 125 ng/mL, about 80 ng/mL to about 100 ng/mL, about 90 ng/mL to about 100 ng/mL, about 105 ng/mL to about 115 ng/mL, about 105 ng/mL to about 120 ng/mL, about 110 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL).
  • about 50 ng/mL to about 150 ng/mL e.g., about 50 ng/mL to about 75 ng/mL
  • headache is meant any type of headache, including, but not limited to, a migraine headache, a tension headache, or a cluster headache.
  • migraine is meant a subset of headaches characterized by unusually severe, unilateral, throbbing head pain that often includes additional symptoms described herein.
  • Migraine is meant to include, for example, migraine without aura (e.g., common migraine), migraine with aura (e.g., classical migraine), migraine with typical aura, migraine with prolonged aura, migraine without headache, hemiplegic migraine (e.g., familial hemiplegic migraine), basilar migraine (e.g., basilar artery migraine), carotidynia, abdominal migraine (e.g., periodic syndrome), hormonal migraine (e.g., pregnancy-induced migraine), exertion migraine, migraine with acute onset aura, ophthalmoplegic migraine, status migrainous, transformed migraine, retinal migraine, nocturnal migraine, childhood periodic syndromes that may be precursors to or associated with migraine, benign paroxysmal vertigo of childhood, alternating hemiplegia of childhood, and migrainous infarction.
  • migraine without aura e.g., common
  • migraines include, e.g., severe headache, nausea, muscle tenderness, abdominal pain, visual aura, sensory hyperexcitability (e.g., photophobia, phonophobia, or osmophobia), tinnitus, vomiting, dizziness, pale or clammy skin, 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.
  • sensory hyperexcitability e.g., photophobia, phonophobia, or osmophobia
  • tinnitus e.g., vomiting, dizziness, pale or clammy skin
  • blurred vision nasal congestion, diarrhea, polyuria, pallor, sweating, localized edema of the scalp or face, scalp tenderness, prominence of a vein or artery
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use , (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic or inorganic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • predisposition or is diagnosed is meant a population of subjects (e.g. mammals, including humans and non-humans) that has been pre-selected as having a condition associated with pain, a mood disorder and/or an imbalance in psychological state, or a disorder of brain development.
  • the conditions associated with pain include but are not limited to: musculo-skeletal pain (after trauma, infections), pain associated with traumatic injury, spinal cord injury, tumors, compression, inflammation, dental pain, episiotomy pain, deep and visceral pain (e.g., heart pain, bladder pain, or pelvic organ pain), muscle pain, eye pain, orofacial pain (e.g., odontalgia, trigeminal neuralgia, glossopharyngeal neuralgia), abdominal pain, gynecological pain (e.g., dysmenorrhea and labor pain), pain associated with nerve and root damage due to trauma, compression, inflammation, toxic chemicals, hereditary conditions, central nervous system pain, such as pain due to spinal cord or brain stem damage, cerebrovascular accidents, tumors, infections, demyelinating diseases including multiple sclerosis, low back pain, sciatica, and post-operative pain.
  • musculo-skeletal pain after trauma, infections
  • pain associated with traumatic injury spinal cord injury, tumors,
  • prevention is meant that a prophylactic treatment is given to a subject who has or will have a disease, a disorder, a condition, or one or more symptoms associated with a disease, a disorder, or a condition.
  • reduction or reducing of a disease, a disorder, or a condition is meant that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or the time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • subject is meant a mammal, including, but not limited to, a human or non-human mammal.
  • treatment is meant an approach for obtaining beneficial or desired results, such as clinical results.
  • beneficial or desired results can include, but are not limited to, alleviation, amelioration, or prevention of a disease, a disorder, a condition, or one or more symptoms associated with a disease, a disorder, or a condition; diminishment of extent of disease, disorder, or condition; stabilization (i.e., not worsening) of a disease, disorder, or condition; delay or slowing the progress of a disease, disorder, or condition; and amelioration or palliation of a disease, disorder, or condition.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • therapeutic agent any agent that produces a healing, curative, stabilizing, or ameliorative effect.
  • a or “an” means “at least one” or “one or more” unless otherwise indicated.
  • the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
  • reference to a composition containing “a therapeutic agent” includes a mixture of two or more therapeutic agents.
  • FIGS. 1A-1B are linear-linear ( FIG. 1A ) and log-linear ( FIG. 1B ) plots depicting the mean plasma ketoprofen concentration vs. time following administration of an oral ketoprofen formulation and the topical ketoprofen formulation, ELS-M10.
  • FIGS. 2A-2B are linear-linear ( FIG. 2A ) and log-linear ( FIG. 2B ) plots depicting the median plasma ketoprofen concentration vs. time following administration of an oral ketoprofen formulation and the topical ketoprofen formulation, ELS-M10.
  • FIG. 3 is a plot of individual ketoprofen AUC(0-24) (area under plasma concentration vs. time curve from time 0 (i.e., time of dosing) to 24 hours post dose, calculated by linear trapezoidal method) across treatments.
  • FIG. 4 is a plot of individual ketoprofen AUC(0-12) (area under plasma concentration vs. time curve from time 0 (i.e., time of dosing) to 12 hours post dose, calculated by linear trapezoidal method) across treatments.
  • FIG. 5 is a plot of individual ketoprofen AUC(0-inf) (area under plasma concentration vs. time curve extrapolated to infinity, calculated as the sum of AUC(0t)Clast/ ⁇ z where Clast is the plasma concentration at Tlast) across treatments.
  • FIG. 6 is a plot of individual ketoprofen Cmax (first observed maximum plasma concentration in ng/mL) across treatments.
  • FIG. 7 is a plot of individual ketoprofen AUC(t half ) (area under plasma concentration vs. time curve for apparent plasma elimination half-life calculated as 1n2/ ⁇ z ) across treatments.
  • FIG. 8 is a plot of the plasma ketoprofen concentration vs. time curves for all subjects. Circles represent subjects with full exposure. Squares represent subjects with ⁇ hour exposure.
  • FIG. 9 is a graph showing topical application of ELS-M10 in an inflammation model of the temporomandibular joint. Bite force is measured at 24 hours post complete Freund's adjuvants (CFA) injection and 1 and 3 hours post treatment with ELS-M10.
  • CFA complete Freund's adjuvants
  • FIGS. 10A-10C are graphs showing the effects of topical application of ELS-M10 in a formalin irritant pain model to the mouse whisker pad.
  • FIGS. 10A and 10B are graphs showing rubbing of the mouse whisker pad (measure of pain behavior) over time of formalin injection.
  • FIG. 10C is a graph showing the effects of ELS-M10 on pain behavior as measured by rubbing of the whisker pad.
  • FIG. 11 is a graph showing weight bearing difference between paws (%) of rats upon topical application of ELS-M10 and oral administration of ketoprofen 1, 4, 8, and 12 hours post treatment.
  • FIGS. 12A-12B are graphs showing the pain free response in human patients upon after initial topical application of ELS-M11.
  • FIG. 13 is a graph showing the percentage of patients that were pain-free after a period of time (up to 48 hours) following bilateral administration of either placebo or ELS-M11 along the trigeminal nerve region.
  • compositions including a gel dosage form of an NSAID for topical application for the acute treatment of migraine attacks in subjects with a history of migraine with or without aura.
  • an NSAID e.g., ketoprofen
  • the compositions of the invention exhibit relatively high NSAID drug penetration and bioavailability with non-significant skin irritation, sensitivity, and damage.
  • the compositions of the invention provide a non-oral route of dosing that is particularly useful in patients who experience nausea (a common symptom associated with migraine).
  • the compositions of the invention provide topical delivery as a clinically-desirable method of drug administration for migraine sufferers. Topical administration offers effective delivery of an NSAID for patients affected by migraine-related gastric stasis, nausea, or vomiting, any of which can limit or delay absorption of oral medication, and for subjects with an aversion to swallowing tablets.
  • compositions as described herein comprising an NSAID when administered topically, can act via a peripheral mechanism, thus providing an opportunity to target peripheral receptors and neural pathways without systemic pain relief.
  • the compositions of the invention are best suited for treating conditions associated with pain that affect localized superficial musculoskeletal soft tissues in areas that are accessible through topical delivery, such as the head, neck, shoulder, elbow, knee, hip, foot, or ankle. Accordingly, the present invention features a method for treatment and/or prevention of conditions associated with pain, migraine, and temporomandibular disorders by topically administering the compositions described herein.
  • compositions that include an NSAID (e.g., aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen, and/or salts thereof, enantiomers and racemic mixtures thereof) for both prophylactic and therapeutic treatments for alleviating conditions associated with pain (e.g., migraine).
  • an NSAID e.g., aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen, and/or salts thereof, enantiomers and racemic mixtures thereof
  • compositions of an NSAID e.g., aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen
  • an NSAID e.g., aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen
  • Inflammatory pain is a form of pain that is caused by tissue injury or inflammation (e.g., in postoperative pain or rheumatoid arthritis). Following a peripheral nerve injury, symptoms are typically experienced in a chronic fashion, distal to the site of injury and are characterized by hyperesthesia (enhanced sensitivity to a natural stimulus), hyperalgesia (abnormal sensitivity to a noxious stimulus), allodynia (widespread tenderness associated with hypersensitivity to normally innocuous tactile stimuli), and/or spontaneous burning or shooting lancinating pain.
  • symptoms are apparent, at least initially, at the site of injury or inflamed tissues and typically accompany arthritis-associated pain, musculo-skeletal pain, and postoperative pain. The different types of pain may coexist or pain may be transformed from inflammatory to neuropathic during the natural course of the disease, as in post-herpetic neuralgia.
  • Functional pain refers to conditions in which there is no obvious peripheral pathology or lesion to the nervous system. This particular form of pain is generated by abnormal function of the nervous system and conditions characterized by such pain include fibromyalgia, tension-type headache, and irritable bowel syndrome.
  • compositions and methods described herein may be useful for the treatment, reduction, or prevention of various forms of pain, namely inflammatory pain, nociceptive pain, and functional pain, whether acute or chronic.
  • exemplary conditions that may be associated with pain include, for example, soft tissue, joint, bone inflammation and/or damage (e.g., acute trauma, osteoarthritis, or rheumatoid arthritis), myofascial pain syndromes (fibromylagia), headaches (including cluster headache, migraine, and tension type headache), myocardial infarction, angina, ischemic cardiovascular disease, post-stroke pain, sickle cell anemia, peripheral vascular occlusive disease, cancer, inflammatory conditions of the skin or joints, diabetic neuropathy, and acute tissue damage from surgery or traumatic injury (e.g., burns, lacerations, or fractures).
  • soft tissue, joint, bone inflammation and/or damage e.g., acute trauma, osteoarthritis, or rheumatoid arthritis
  • myofascial pain syndromes
  • the present invention may also be useful for the treatment or reduction of musculo-skeletal pain (after trauma, infections, and exercise), pain caused by spinal cord injury, tumors, compression, inflammation, dental pain, episiotomy pain, deep and visceral pain (e.g., heart pain, bladder pain, or pelvic organ pain), muscle pain, eye pain, orofacial pain (e.g., odontalgia, trigeminal neuralgia, glossopharyngeal neuralgia), abdominal pain, gynecological pain (e.g., dysmenorrhea and labor pain), pain associated with nerve and root damage due to trauma, compression, inflammation, toxic chemicals, hereditary conditions, central nervous system pain, such as pain due to spinal cord or brain stem damage, cerebrovascular accidents, tumors, infections, demyelinating diseases including multiple sclerosis, low back pain, sciatica, and post-operative pain.
  • the invention provides a method for treating headaches, including symptoms associated with headaches.
  • the method involves topical administration of at least one therapeutic agent to the orbital foramen region of the patient.
  • the orbital foramen region in mammals includes the notch of the eyebrow (or supraorbital foramen), which is an area where drugs in liquid formulation, as an ointment, as a gel, or as a cream formulation can penetrate into the regional arterial space and affect cerebral blood flow.
  • the orbital foramen region also includes areas surrounding the supraorbital foramen, such as the base of the auriculo-temporal branch of the trigeminal nerve or the auriculo-temporal branch of the greater occipital nerve.
  • compositions may also be administered to the postauricular area, such as the area back of the ear; the forehead; or the either side of the head, such as on the left or right side of the scalp just above the ears, in the form of a liquid, ointment, gel, lotion, or patch.
  • a liquid, ointment, gel, lotion, or patch in the form of a liquid, ointment, gel, lotion, or patch.
  • the methods and compositions of the invention can be used to treat a headache either by preventing the recurrence of a headache or by treating one or more symptoms associated with an established headache.
  • the invention can be used to treat any type of headache, including a migraine headache, a tension headache, or a cluster headache. Symptoms and diagnosis of headaches can be readily determined by any parameters well known in the art, for example, as described in “The International Classification of Headache Disorders” (2d ed., ed. International Headache Society).
  • Exemplary symptoms of a migraine headache include: moderate to severe headache intensity; a unilateral headache; a headache with a pulsating or throbbing quality; a headache that worsens with physical activity; a headache that interferes with regular activities; nausea; vomiting; sensitivity to light, sound, or smell; depression; sleep disruption; ptosis; experiencing an aura, such as changes to vision; or paresthesia of the hand, arm, leg, or face.
  • the signs and symptoms of migraine vary among patients. Therefore, what a patient experiences before, during, and after an attack cannot be precisely defined.
  • the four common phases of a migraine attack are listed below. However, the phases experienced and the symptoms experienced during those phases can vary from one migraine attack to another in the same migraineur (or migraine sufferer). These phases include: the prodrome phase, which occurs hours or days before the headache; the aura phase, which immediately precedes the headache; the pain phase, also known as headache phase; and the postdromal phase.
  • Symptoms within the prodromal phase include altered mood, irritability, depression or euphoria, fatigue, yawning, excessive sleepiness, craving for certain food (e.g., chocolate), stiff muscles (e.g., in the neck), constipation or diarrhea, increased urination, and other visceral symptoms. These symptoms usually precede the headache phase of the migraine attack by several hours or days, and experience teaches the patient or observant family how to detect that a migraine attack is near.
  • the aura phase comprises focal neurological phenomena that precede or accompany the attack. This phase typically appears gradually over 5 to 20 minutes and generally last fewer than 60 minutes. Symptoms of migraine aura can be visual, sensory, or motor in nature. Neurological symptoms during the visual aura phase include disturbance of vision (e.g., photopsia or scintillating scotoma, which is called “fortification spectra” or “teichopsia”); blurred or shimmering or cloudy vision; tunnel vision; and hemianopsia. Symptoms during the somatosensory aura phases include digitolingual or cheiro-oral paresthesias in the hand, in the arm, on the nose-mouth area on the same side; or on the face, lips and tongue. Other symptoms of the aura phase can include auditory or olfactory hallucinations, temporary dysphasia, vertigo, tingling or numbness of the face and extremities, and hypersensitivity to touch.
  • Symptoms of migraine aura can be visual, sensory, or motor in nature.
  • the pain phase usually begins within 60 minutes of the end of the aura phase, but can be delayed up to several hours, and it can be missing entirely.
  • the typical migraine headache is unilateral, throbbing, and moderate to severe and can be aggravated by physical activity. Not all these features are necessary.
  • the pain may be bilateral at the onset or start on one side and become generalized, and usually it alternates sides from one attack to the next. The onset is usually gradual.
  • the pain peaks and then subsides and usually lasts 4 to 72 hours in adults and 1 to 48 hours in children.
  • the frequency of attacks is extremely variable, from a few in a lifetime to several times a week, where the average migraineur experiences one to three headaches a month.
  • the head pain varies greatly in intensity.
  • migraine The pain of migraine is invariably accompanied by other features. Nausea occurs in about 18-40% of patients, and vomiting occurs in about one third of patients. Many patients experience sensory hyperexcitability manifested by photophobia, phonophobia, and osmophobia, where these patients typically seek a dark and quiet room. Typical symptoms include: blurred vision, nasal stuffiness, diarrhea, polyuria, pallor, sweating, localized edema of the scalp or face, scalp tenderness, prominence of a vein or artery in the temple, stiffness and tenderness of the neck, or impairment of concentration and mood are common. The extremities tend to feel cold and moist. Vertigo may be experienced; a variation of the typical migraine, called vestibular migraine, has also been described. Lightheadedness, rather than true vertigo, and a feeling of faintness may occur.
  • the patient may feel tired or “hung-over” and have head pain, cognitive difficulties, gastrointestinal symptoms, mood changes, and weakness. Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise. Often, some of the minor headache phase symptoms may continue, such as loss of appetite, photophobia, and lightheadedness. For some patients, a 5- to 6-hour nap may reduce the pain, but slight headaches may still occur when the patient stands or sits quickly. These symptoms may go away after a good night's rest, although there is no guarantee. Some people may suffer and recover differently than others.
  • Tension type headaches include those that are episodic or chronic. Both types of tension type headaches exhibit similar symptoms, where chronic TTH typically evolves from an episodic TTH. A chronic TTH typically lasts >15 days per month, where an episodic TTH typically lasts ⁇ 15 days per month. Exemplary symptoms of chronic and episodic TTH include: headaches lasting from 30 minutes to 7 days; a nonpulsating feeling, such as pressing or tightening; mild or moderate intensity; bilateral location; lack of aggravation from routine physical activity; lack of nausea or vomiting; photophobia; or phonophobia.
  • a cluster headache is characterized as a trigeminal autonomic cephalgia.
  • Exemplary symptoms include: severe or very severe unilateral orbital, supraorbital and/or temporal pain; ipsilateral conjunctival injection and/or lacrimation; ipsilateral nasal congestion and/or rhinorrhoea; ipsilateral eyelid edema; ipsilateral forehead and facial sweating; ipsilateral miosis and/or ptosis; or a sense of restlessness or agitation.
  • TMD Temporomandibular Disorders
  • compositions of the invention are also useful for treating temporomandibular disorders (TMD).
  • TMD occur as a result of problems with the jaw, jaw joint, and surrounding facial muscles that control chewing and moving the jaw.
  • the temporomandibular joint (TMJ) is the hinge joint that connects the lower jaw (mandible) to the temporal bone of the skull, which is immediately in front of the ear on each side of the head.
  • the joints are flexible, allowing the jaw to move smoothly up and down and side to side and enabling you to talk, chew, and yawn. Muscles attached to and surrounding the jaw joint control the position and movement of the jaw.
  • compositions of the invention can be applied to the sternocleidomastoid muscle at the temporomandibular joint, it is within the scope of the invention that the composition will also be useful in treating TMD.
  • the compositions of the invention when topically administered can alleviate one or more symptoms associated with TMD. People with TMD can experience severe pain and discomfort that can be temporary or last for many years. More women than men experience TMD, and TMD is seen most commonly in people between the ages of 20 and 40.
  • the common symptoms of TMD include, but are not limited to:
  • compositions described herein can be tested for efficacy in any standard animal model of pain.
  • Various models test the sensitivity of normal animals to intense or noxious stimuli (physiological or nociceptive pain). These tests include responses to thermal, mechanical, or chemical stimuli.
  • Thermal stimuli usually involve the application of hot stimuli (typically varying between 42-55° C.) including, for example: radiant heat to the tail (the tail flick test), radiant heat to the plantar surface of the hind paw (the Hargreaves test), the hotplate test, and immersion of the hind paw or tail into hot water. Immersion in cold water, acetone evaporation, or cold plate tests may also be used to test cold pain responsiveness.
  • Tests involving mechanical stimuli typically measure the threshold for eliciting a withdrawal reflex of the hind paw to graded strength monofilament von Frey hairs or to a sustained pressure stimulus to a paw (e.g., the Ugo Basile analgesiometer).
  • the duration of a response to a standard pinprick may also be measured.
  • a chemical irritant e.g., capsaicin, mustard oil, bradykinin, ATP, formalin, acetic acid
  • peripheral sensitization i.e., changes in the threshold and responsiveness of high threshold nociceptors
  • sensitizing chemicals e.g., prostaglandins, bradykinin, histamine, serotonin, capsaicin, or mustard oil.
  • Central sensitization i.e., changes in the excitability of neurons in the central nervous system induced by activity in peripheral pain fibers
  • noxious stimuli e.g., heat
  • chemical stimuli e.g., injection or application of chemical irritants
  • electrical activation of sensory fibers e.g., electrical activation of sensory fibers.
  • outcome measures may be assessed, for example, according to behavior, electrophysiology, neurochemistry, or imaging techniques to detect changes in neural activity.
  • an improvement in pain reduction can also be assessed by determining the pharmacological and non-pharmacological characteristics of pain such as pain intensity (as measured on a standardized pain scale), pattern (e.g., constant, intermittent), location, radiation, frequency, timing, and duration, impact on quality of life (sleep, function, appetite, and mood).
  • Suitable therapeutic agents or combinations thereof for use in the compositions and methods of the invention generally include those that will act locally to decrease painful vasodilatation of superficial cerebral arteries.
  • a therapeutic agent or combination thereof that provides an antihistaminic effect may do so in any number of ways, such as by H-1 receptor antagonism or by the release of histamine contained in mast cells that reside in the vicinity of the superficial cerebral arteries.
  • Suitable therapeutic agents or combinations thereof also include, but are not limited to, those that inhibit the reuptake of norepinephrine from the nerve endings that surround the vasodilated cerebral artery; exhibit anti-cholinergic activity; provide local anesthetic activity; or have specific ion channel blocking activity, such as blocking sodium uptake and/or decrease the afferent activity of the nervous system or act functionally as non-steroidal anti-inflammatory drugs (by incorporation all drugs referred to as NSAIDS).
  • NSAIDS non-steroidal anti-inflammatory drugs
  • compositions of the invention typically utilize a therapeutic agent, either alone or in combination.
  • exemplary classes of therapeutic agents that may be used in the methods and/or compositions of the invention include an alpha adrenoceptor agonist; an anesthetic; an anticonvulsant; an anticholinergic compound; an antihistamine, including a tricyclic with antihistaminic activity; an anti-inflammatory compound, such as a cyclooxygenase (COX) inhibitor or a non-steroidal anti-inflammatory drug (NSAID); a beta receptor antagonist; an ion channel blocking compound (e.g., an analgesic), such as a sodium channel (e.g., Nav1.1, Nav1.2, Nav1.5, Nav1.6, or Nav.1.7) blocker or a calcium channel (L-, N-, P/Q-, T-, or R-calcium channel, or TRPV1-6 channels) blocker; a N-methyl d-aspartate (NMDA) receptor antagonist; a nore
  • Preferred therapeutic agents to be formulated alone or in combination include: sumatriptan, ibuprofen, ketoprofen, diclofenac, dextromethorphan, gabapentin, amitriptyline, diphenhydramine, and doxepin.
  • alpha adrenoceptor agonists include phenylephrine, pseudoephedrine, and oxymetazoline.
  • anesthetics include physostigmine, neostigmine, and procaine.
  • anticonvulsants include gabapentin, topiramate, hydantoin, benzodiazepines, zonisamide, valproic acid, ethosuximide, carbamazepine, primidone, lamotrigine, felbamate, levetiracetam, and tiagabine.
  • anticholinergic compounds include ipratropium bromide, oxitropium bromide, or tiotropium.
  • antihistamines examples include carbinoxamine, clemastine, dimenhydrinate, pyrilamine, tripelennamine, chlorpheniramine, brompheniramine, hydroxyzine, cyclizine, acrivastine, cetririzine, azelastine, loratadine, fexofenadine, doxepin, diphenhydramine, and all tricyclics that have antihistaminic activity, such as amitriptyline, imipramine, promethazine, chlorpromazine, and nortriptyline.
  • Examples of anti-inflammatory compounds include aspirin, diclofenac, and COX inhibitors.
  • Exemplary COX inhibitors include a non-selective COX inhibitor, such as an inhibitor for COX-1 and COX-2 or an inhibitor for COX and lipoxygenase (LOX); a selective COX-1 inhibitor; a selective COX-2 inhibitor (e.g., valdecoxib, rofecoxib, celecoxib, or any of the compounds described in U.S. Pat. No. 6,440,963, herein incorporated by reference); and/or a selective COX-3 inhibitor (e.g., paracetamol, phenacetin, antipyrine, or dipyrone).
  • Examples of COX inhibitors include ibuprofen, including a racemic mixture or an enantiomer thereof; ketoprofen, including a racemic mixture or an enantiomer thereof; and/or naproxen.
  • beta receptor antagonists examples include propranolol, nadolol, timolol, pindolol, labetalol, metroprolol, atenalol, esmolol, and acebutolol.
  • ion channel blocking compounds include flunarizine, verapamil, nifedipine, and nimodipine.
  • NMDA receptor antagonists include dextromethorphan, ketamine, memantine, riluzole, and phencyclidine.
  • norepinephrine reuptake inhibitor examples include reboxetine, duloxetine, and amitriptyline.
  • opioids include morphine, codeine, meperidine, and oxycodone.
  • triptans include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan.
  • the therapeutic agents used in the composition should have appropriate properties for topical administration.
  • suitable therapeutic agents for topical formulations include those that will act locally and upon absorption will be diluted into the large blood volume of the vascular space; or produce no adverse events.
  • Suitable therapeutic agents and combinations are best administered in a non-greasy ointment or in a cream base.
  • Combinations of two or more therapeutic agents can be administered to a subject to treat a migraine headache.
  • exemplary combinations include a combination of an anti-inflammatory compound and an ion channel blocking compound, such as a COX-2 inhibitor and a calcium channel blocking compound; a combination of a COX inhibitor and an antihistamine; a combination of a general anti-inflammatory compound and an NMDA receptor antagonist; a combination of a triptan and a general anti-inflammatory compound; a combination of a triptan and an antihistamine; and a combination of a general anti-inflammatory compound and an opioid.
  • an anti-inflammatory compound and an ion channel blocking compound such as a COX-2 inhibitor and a calcium channel blocking compound
  • a combination of a COX inhibitor and an antihistamine such as a COX-2 inhibitor and a calcium channel blocking compound
  • a combination of a COX inhibitor and an antihistamine such as a COX-2 inhibitor and a calcium channel blocking compound
  • muscle relaxants such as anticonvulsants; opioids; analgesics, such as narcotic analgesics, opioids, NSAIDs, or COX inhibitors; NSAIDs; serotonergic agonists, such as a serotonin agonist or a serotonin partial agonist; COX-2 inhibitors; nitrates; beta blockers or beta receptor antagonist; anticonvulsants, such as hydantoin, benzodiazepines, or topiramate; alpha agonists or alpha adrenoceptor agonists; antihistamines; and local anesthetics.
  • muscle relaxants such as anticonvulsants
  • opioids such as narcotic analgesics, opioids, NSAIDs, or COX inhibitors
  • NSAIDs such as narcotic analgesics, opioids, NSAIDs, or COX inhibitors
  • serotonergic agonists such as a serotonin agonist or
  • compositions and methods of the invention can also be used in conjunction with other remedies known in the art that are used to treat pain including, corticosteroids, acetaminophen, opioids, muscle relaxants, anti-anxiety drugs, anti-depressants, anti-convulsant drugs, antipsychotics, mood stabilizers, lithium, and serotonin reuptake inhibitors (SSRIs).
  • SSRIs serotonin reuptake inhibitors
  • the compositions and methods of the invention can also be used in conjunction with other forms of treatment including but not limited to: cognitive-behavioral therapies, music therapies, art therapies, group therapies, psychotherapies, physical exercise, pet therapies, communication therapies, educational therapies, and family therapies. The choice of specific treatment may vary and will depend upon the severity of the pain, the subject's general health, and the judgment of the attending clinician.
  • compositions can also be formulated in combination with one or more additional active ingredients, which can include a pharmaceutical agent such NSAIDs (e.g., Aspirin (Anacin, Ascriptin, Bayer, Bufferin, Ecotrin, Excedrin), Choline and magnesium salicylates (CMT, Tricosal, Trilisate), Choline salicylate (Arthropan), Celecoxib (Celebrex), Diclofenac potassium (Cataflam), Diclofenac sodium (Voltaren, Voltaren XR), Diclofenac sodium with misoprostol (Arthrotec), Diflunisal (Dolobid), Etodolac (Lodine, Lodine XL), Fenoprofen calcium (Nalfon), Flurbiprofen (Ansaid), Ibuprofen (Advil, Motrin, Motrin IB, Nuprin), Indomethacin (Indocin, Indocin SR), Ketoprofen (A
  • any of the foregoing compounds may be formulated with an NSAID (e.g., aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen) or administered along with an NSAID (e.g., aspirin, diclofenac, ibuprofen, ketoprofen, or naproxen) to a patient suffering from pain (e.g., pain associated with a migraine headache).
  • the two compounds are desirably administered within 24 hours of each other (e.g., within 12 hours, 8 hours, 4, hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or substantially simultaneously).
  • compositions of the invention may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example, as described in “Remington: The Science and Practice of Pharmacy” (20th ed., ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins).
  • concentration of at least one therapeutic agent in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
  • a composition containing a therapeutic agent (e.g., ketoprofen) and a dermatologically acceptable excipient may be administered topically (e.g., to the trigeminal nerve area) in accordance with methods of the invention in an amount sufficient to provide 0.1 mg to 1000 mg (e.g., from 20 mg to 200 mg or, preferably, from 20 mg to 135 mg) of the therapeutic agent.
  • the composition may contain from about 0.5% to about 5% by weight of the therapeutic agent.
  • the therapeutic agents may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry.
  • acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like.
  • Metal complexes include zinc, iron, and the like.
  • the composition can be prepared in any useful method.
  • at least one therapeutic agent is dissolved in ethanol and added to a mixture of polyethylene glycols (PEGs).
  • the composition further includes a skin penetrating enhancer of a dimethyl alanine amide of medium chain fatty acids with carbon units varying between C-12 and C-16.
  • therapeutic agents alone or combinations thereof may be prepared in an ointment form or a cream form. In these forms, unit dispensing would be preferred, where the unit dosage of the therapeutic agent and vehicle would be in the range of 0.1 mg to 1000 mg and most preferred between 20 mg and 200 mg.
  • the dosages can contain from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.2 mg to about 20 mg, from about 0.3 mg to about 15 mg, from about 0.4 mg to about 10 mg, from about 0.5 mg to about 1 mg; from about 0.5 mg to about 100 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 30 mg, from about 0.5 mg to about 20 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 5 mg; from about 1 mg from to about 50 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg; from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg; from about 10 mg to about 100 mg, from about 20 mg to about 200 mg, from about 30 mg to about 150 mg, from about 40 mg to about 100
  • the dosage can represent a total maximum dose (e.g., a total maximum dose of 20 mg, a total maximum dose of 50 mg, a total maximum dose of 100 mg, or preferably a total maximum dose of 135 mg).
  • the dosage can represent a unit dose (e.g., a unit dose of 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5 mg, or preferably the unit dose is about 22.5 mg).
  • the unit dose can be applied or administered to achieve a total maximum daily dose.
  • a unit dose of 22.5 mg is administered to each side of the face to treat or prevent a head (e.g., a migraine headache) at least one time a day (one time, two times, three times, four times, or five times) for a total maximum dose of 45 mg, 90 mg, 135 mg, or 180 mg.
  • a head e.g., a migraine headache
  • a total maximum dose 45 mg, 90 mg, 135 mg, or 180 mg.
  • the therapeutic agent in this composition by weight would be in the range of 0.5% to 30% (w/w). The most preferred range would be between 0.5% and 5% (w/w).
  • the composition comprises between 0.5%-2%, 0.5%-3%, 0.5%-4%, 0.5%-5%, 0.5%-8%, 0.5%-10%, 1%-2%, 2.5%-5%, 8%-12%, 10%-20%, or 20-30% (w/w) of at least one therapeutic agent.
  • the therapeutic agent is present in the composition in an amount of at least 0.5%, at least 1%, at least 2%, at least 2.5%, at least 3%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, or at least 25% (w/w), and may be, for example, ketoprofen or ibuprofen.
  • Administration may be one or multiple times daily (e.g., two times, three times, up to four times a day), weekly (or at some other multiple day interval) or on an intermittent schedule, with that cycle repeated a given number of times (e.g., 2-10 cycles) or indefinitely.
  • the compositions can be administered for at least two days (e.g., 2 days, 3, days, 4 days, 5 days, one week, or two weeks).
  • the compositions may be administered as symptoms occur or until the symptoms subside.
  • the compositions can also be administered chronically (e.g., more than twenty days, e.g., 21 days, 30 days, 60 days, 3 months, 6 months, 9 months, one year, two years, or three years).
  • the composition comprises between 1% to 30% (w/w) of at least one therapeutic agent (e.g., ketoprofen; gabapentin; dextromethorphan; a multi-mechanistic tricyclic molecule with activities including neurotransmitter uptake inhibition, antihistaminic or anticholinergic activity, such as imipramine, amitriptyline, and nortriptyline; or combinations thereof).
  • at least one therapeutic agent e.g., ketoprofen; gabapentin; dextromethorphan; a multi-mechanistic tricyclic molecule with activities including neurotransmitter uptake inhibition, antihistaminic or anticholinergic activity, such as imipramine, amitriptyline, and nortriptyline; or combinations thereof.
  • compositions can be formulated using any dermatologically acceptable carrier.
  • exemplary carriers include a solid carrier, such as alumina, clay, microcrystalline cellulose, silica, or talc; and/or a liquid carrier, such as an alcohol, a glycol, or a water-alcohol/glycol blend.
  • the therapeutic agents may also be administered in liposomal formulations that allow therapeutic agents to enter the skin. Such liposomal formulations are described in U.S. Pat. Nos.
  • Suitable vehicles of the invention may also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oil.
  • the composition can further include a skin penetrating enhancer, such as those described in “Percutaneous Penetration enhancers”, (eds. Smith E W and Maibach H I. CRC Press 1995).
  • skin penetrating enhancers include alkyl (N,N-disubstituted amino alkanoate) esters, such as dodecyl 2-(N,N dimethylamino) propionate (DDAIP), which is described in U.S. Pat. Nos.
  • a water-dispersible acid polymer such as a polyacrylic acid polymer, a carbomer (e.g., CarbopolTM or Carbopol 940PTM, available from B. F. Goodrich Company (Akron, Ohio)), copolymers of polyacrylic acid (e.g., PemulenTM from B. F. Goodrich Company or PolycarbophilTM from A. H.
  • a polysaccharide gum such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum, and galactomannan gum (e.g., guar gum, carob gum, and locust bean gum), as well as other gums known in the art (see for instance, Industrial Gums: Polysaccharides & Their Derivatives, Whistler R. L., BeMiller J. N. (eds.), 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980)); or combinations thereof.
  • a polysaccharide gum such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum
  • Suitable polymeric skin penetrating enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Additionally, known transdermal penetrating enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptane-2-one (AzoneTM, a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives and so on.
  • DMSO dimethyl sulfoxide
  • DMA dimethyl acetamide
  • 2-pyrrolidone 2-pyrrolidone
  • biodegradable absorption enhancers which are alkyl N,N-2-(disubstituted amino) alkanoates as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No.
  • 5,082,866 which are both incorporated herein by reference, including: tetradecyl (N,N-dimethylamino) acetate, dodecyl (N,N-dimethylamino) acetate, decyl (N,N-dimethylamino) acetate, octyl (N,N-dimethylamino) acetate, and dodecyl (N,N-diethylamino) acetate.
  • Particularly preferred skin penetrating enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide of a medium chain fatty acid; dodecyl 2-(N,N-dimethylamino) propionate or salts thereof, such as its organic (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acid addition salts) and inorganic salts (e.g., acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfamic, picric, and lactic acid addition salts), as described in U.S.
  • organic e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acid addition salts
  • the skin penetrating enhancer in this composition by weight would be in the range of 0.5% to 10 (w/w). The most preferred range would be between 1.0% and 5% (w/w). In another embodiment, the skin penetrating enhancer comprises between 0.5%-1%, 1%-2%, 2%-3%, 3%-4%, or 4%-5%, (w/w) of the composition.
  • compositions can be provided in any useful form.
  • the compositions of the invention may be formulated as solutions, emulsions (including microemulsions), suspensions, creams, foams, lotions, gels, powders, or other typical solid, semi-solid, or liquid compositions (e.g., topical sprays) used for application to the skin or other tissues where the compositions may be used.
  • the preferred compositions may also be applied as a patch, preferably to the postauricular area or on the neck just behind the ear.
  • compositions may contain other ingredients typically used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, a fatty acid salt or ester, a fatty alcohol, a modified cellulose, a modified mineral material, Krisgel 100TM or a synthetic polymer), antimicrobials, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyestuffs, viscosity-controlling agents, preservatives, humectants, emollients (e.g., natural or synthetic oils, hydrocarbon oils, waxes, or silicones), hydration agents, chelating agents, demulcents, solubilizing excipients, adjuvants, dispersants, skin penetrating enhancers, plasticizing agents, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and optionally including
  • compositions can also include other like ingredients to provide additional benefits and improve the feel and/or appearance of the topical formulation.
  • Specific classes of additives commonly use in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine, such as phospholipon G), Krisgel 100TM, distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetrating enhancer), menthol crystals, lavender oil, butylated hydroxytoluene, ethyl diglycol reagent, and 95% percent (190 proof) ethanol.
  • the therapeutic agent when administered topically results in a peak plasma concentration that is lower than the peak plasma concentration of the same therapeutic agent when orally administered at about the same dosage (e.g., at about 130-150 mg of the therapeutic agent).
  • the therapeutic agent when administered topically results in a peak plasma concentration at between two to three hours that is at most about 1100 ng/mL (e.g., 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 420 ng/mL, 440 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, or 1050 ng/mL, and up to 1100 ng/mL
  • the peak plasma concentration at three hours is about 440 ng/mL.
  • the peak plasma concentrations of the topically administered therapeutic agent described herein are lower than the peak plasma concentrations of the same therapeutic agent when orally administered.
  • the peak plasma concentration of an orally administered therapeutic agent e.g., ketoprofen
  • the therapeutic agent is administered in an amount such that the plasma concentration of the therapeutic agent (e.g., an NSAID, e.g., ketoprofen) ranges from about 50 ng/mL to about 150 ng/mL (e.g., about 50 ng/mL to about 75 ng/mL, about 50 ng/mL to about 100 ng/mL, about 50 ng/mL to about 125 ng/mL, about 80 ng/mL to about 100 ng/mL, about 90 ng/mL to about 100 ng/mL, about 105 ng/mL to about 115 ng/mL, about 105 ng/mL to about 120 ng/mL, about 110 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL).
  • the plasma concentration of the therapeutic agent
  • the plasma concentration of the therapeutic agent is desirably maintained.
  • the composition is formulated such that the therapeutic agent is released over an extended period of time, e.g., 2-24 hours or more (e.g., 2-4 hours, 2-8 hours, 2-10 hours, 2-15 hours, 2-20 hours, 4-8 hours, 4-10 hours, 4-20 hours, 8-10 hours, 8-15 hours, 10-15 hours, 15-20 hours, 20-25 hours), wherein the plasma concentrations may be maintained for up to 24 hours (e.g., up to 2 hours, up to 4 hours, up to 8 hours, up to 10 hours, up to 14 hours, up to 16 hours, up to 20 hours, up to 22 hours).
  • up to 24 hours e.g., up to 2 hours, up to 4 hours, up to 8 hours, up to 10 hours, up to 14 hours, up to 16 hours, up to 20 hours, up to 22 hours.
  • compositions of the invention are formulated as described in U.S. Publication No. 2014-0088195 and International Publication No. WO 2014-052313, each of which is hereby incorporated by reference.
  • compositions in liquid form can be applied from absorbent pads; used to impregnate bandages and other dressings, directly onto the orbital foramen or surrounding areas of the subject (e.g., the mandibular junction and areas in close proximity to the trigeminal nerves).
  • the composition in solid form, including semi-solid form can be applied from a tube; or be applied directly onto the orbital foramen or surrounding areas of the subject.
  • the composition in liquid form or solid form can be applied by using an applicator to spread the composition onto the orbital foramen region.
  • the composition may also be applied to the skin under occlusive dressing in a dermal delivery system (e.g., a transdermal patch).
  • the compositions can also be formulated as a topical spray for direct application onto the area to be treated.
  • Administration of therapeutic agents in controlled release formulations may be useful where the therapeutic agent has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; (ii) a narrow slow absorption rate by or through the epithelium and/or dermis; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain a therapeutic level.
  • a narrow therapeutic index e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • a narrow slow absorption rate by or through the epithelium and/or dermis e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • a narrow slow absorption rate by or through the epithelium and/or dermis e.g., the difference between the plasma concentration leading to harmful side effects or
  • controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings. Examples include oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • Ketoprofen was obtained from Boehinger-Ingelheim for preclinical work and obtained from COSMA S.p.A. for clinical work.
  • An isocratic reversed-phase HPLC system was used to determine the stability and photostability of the ketoprofen formulations.
  • the HPLC instrument was Agilent 1100. NovaPak® 4.6 ⁇ 300 mm C18 column from Waters was used.
  • the mobile phase consisted of a mixture of formic acid buffer (0.025M) adjusted to pH 2.3 with hydrochloric acid and acetonitrile (50:50). The flow rate was 1.0 ml/min. Detection was accomplished at 220 nm and 254 nm. The volume of injection was set to 25 ⁇ l.
  • ketoprofen and oxybenzone were approximately 5 min. and 13 min., respectively.
  • concentration ranges for the calibration curves of ketoprofen and oxybenzone were 7-210 ⁇ g/ml and 120-480 ⁇ g/ml, respectively.
  • the run time for the samples was 20 min.
  • the ELS-M10 formulation includes oxybenzone, a sunblocker. This formulation was used in permeation studies and toxicology studies (repeat dose dermal toxicity, photoallergy, and eye irritation). ELS-M10 is to be stored at 5° C. and is stable for 1 month.
  • the ELS-M11 formulation described below and disclosed in International Publication No. WO/2014/052313 includes all of the components of the ELS-M10 formulation without the benzyl alcohol, which eliminates the irritation involved in topical application of the formulation. ELS-M11 was used in phase 2 clinical studies (see, Example 7) and registered under the trademark TOPOFENTM (Trademark Application No. 86/447,026).
  • ketoprofen containing 10%, 5%, and 0.5% by weight ketoprofen.
  • Carbopol ® 980 NF 0.5 0.5 0.5 0.5 Carbopol ® Ultrez 10, NF 1.25 1.25 1.25 PEG-40 Hydrogenated Castor Oil, NF 0.5 0.5 0.5 Vitamin E USP 0.05 0.05 0.05 Ethyl Alcohol USP, anhydrous 10 10 10 Propylene glycol, USP 10 10 10 Isopropanol, USP 9 10 10 Isopropyl Myristate, USP 3 3 3 3 3 Benzyl Alcohol, NF 1 1 1 1 Oxybenzone, USP 5 5 5 5 Butylated Hydroxytoluene, NF 1 1 1 1 Triethanolamine 1.5 1.5 1.5 pH 5 5 5 5
  • composition represented in Table 2 exhibited improved permeation after 4 hours and 22 hours.
  • the 10% cream had higher ketoprofen permeation at all time points.
  • the primary objective of the Phase I study was to evaluate the relative bioavailability of ketoprofen following topical administration of a single dose (135 mg) of a gel formulation of ketoprofen (ELS-M10) compared to oral administration of a generic dose (150 mg) of ketoprofen.
  • the secondary objectives included evaluating additional plasma ketoprofen pharmacokinetic (PK) parameter estimates following topical administration of a single dose of ELS-M10 compared to oral administration of a single dose of ketoprofen and evaluating the safety and tolerability of single doses of ELS-M10 in healthy volunteers.
  • PK pharmacokinetic
  • Example 3 Phase 1 Study Design and Study Population
  • the Phase 1 study was a single center, randomized, crossover, open-label study to evaluate the pharmacokinetics, safety, and tolerability of single maximal doses of ELS-M10 and oral ketoprofen in a total of 20 healthy males or nonpregnant, nonlactating, healthy females between 18 and 50 years of age (inclusive) with a body mass index (BMI) in the range of 19 to 28 (inclusive).
  • BMI body mass index
  • the study design is depicted graphically in Table 9 below. Subjects considered to have completed the study were those who had completed all study assessments. All subjects who completed the study assessments returned one week after treatment to complete additional safety and clinical laboratory assessments.
  • Plasma Concentration Population included all subjects in the Safety Population who had valid plasma ketoprofen concentration data. Five subjects experiencing burning and erythema at the ELS-M10 gel application site were removed from summary analyses.
  • the Pharmacokinetic Parameter Population included all subjects in the Plasma Concentration Population who had adequate plasma ketoprofen concentration data for the calculation of pharmacokinetic parameters in any of the treatment and dosing periods. Five subjects experiencing burning and erythema at the gel application site were removed from summary analyses.
  • a total of 20 subjects (11 males and 9 females) were enrolled in the study.
  • the ages of the enrolled subjects ranged from 18-50 (median: 37.3) years, and BMIs ranged from 19.0-31.0 (mean: 25.7) kg/m 2 .
  • ELS-M10 a topical gel containing 5% ketoprofen
  • Site personnel applied 2.7 mL of ELS-M10 gel before a standardized breakfast.
  • ketoprofen was supplied as the commercially-available, 75 mg capsules manufactured by Teva Pharmaceuticals USA. Subjects took two 75 mg ketoprofen capsules (total dose 150 mg) before a standardized breakfast.
  • Subjects were required to report to the clinical site at 7 am in a fasted state on the mornings of Visit 2 and Visit 3, and remained at the site until at least 24 hours post-dosing. On arrival, subjects completed all pre-dose assessments, including vital signs assessment and PK sampling, and received their scheduled treatment. Subjects had breakfast after dosing and prior to the 0.5 hour post-dose PK sample. Subjects remained in the clinic until after collection of the 24-hour post-dose PK sample. Standard meals (breakfast, lunch, snack, and dinner) were provided during confinement at the clinical center. Aside from the inclusion and exclusion criteria, subjects agreed to abide by each of the following restrictions for the specified time:
  • the primary assessment is the PK profile of each dosage form of ketoprofen.
  • Plasma PK samples were obtained from all study subjects according to the schedule listed in Table 10.
  • a vital signs assessment (heart rate and BP) was performed on all study subjects prior to the PK blood draw.
  • the plasma concentration population included all subjects who received a dose of study drug and had valid ketoprofen concentration data.
  • the pharmacokinetic parameter population included all subjects in the plasma concentration population who had adequate plasma ketoprofen concentration data for the calculation of PK parameters during any of the time periods.
  • Plasma concentration data of ketoprofen is listed by subject, period, treatment, nominal sampling time, and actual sampling time, along with calculated elapsed time and summarized by treatment and nominal time. Standard summary statistics were calculated for concentrations at each time point, applying methods described in the Statistical Analysis Plan (SAP). Mean and median plasma ketoprofen concentration vs. time data were plotted on a linear scale using nominal time overlaying the two treatments in one plot. Figures of linear and semi-logarithmic plots were generated for individual subject plasma concentration vs. time data overlay the two treatments using the actual sampling times.
  • ketoprofen were derived from individual plasma concentration vs. time data by noncompartmental methods using WinNonlin Professional Edition version 5.2.1 or above (Pharsight Corporation, Mountain View, Calif., USA). Actual times were used to estimate the individual plasma pharmacokinetic parameters. The following pharmacokinetic parameters were calculated as described in Table 11:
  • time curve using at least three time points t 1/2 (hr) apparent plasma elimination half-life calculated (if data permit) as 1n2/ ⁇ z AUC 0-inf (hr * ng/mL) area under the plasma concentration vs. time curve extrapolated to infinity, where data permit, calculated as the sum of AUC(0 t ) C last / ⁇ z , where C last is the plasma concentration at T last % AUC extrap the percentage of AUC 0-inf obtained by extrapolation beyond the last time point with measurable plasma concentration, calculated as 100% ⁇ [AUC 0-inf ⁇ AUC 0-t ]/AUC 0-inf
  • CV % is closer to 100%, then a CI half width of 0.6 can be produced with 95% probability. If the exposure of ELS-M10 is less than 60% of that of oral ketoprofen, then the upper limit of the 90% CI may still be less than 1.25 with respect to the ratio of the two treatments.
  • Plasma concentration data of Ketoprofen, along with dosing date/time, sampling date/time, and the calculated actual sampling time for individual subjects are presented in Table 13.
  • Study subjects were sampled at the planned times with sample time deviations ranging from ⁇ 2 min to +5 min.
  • Subject 9 exceeded the planned sample time by 12 minutes at the 3-hr mark and 16 minutes at the 6-hr mark.
  • Five subjects during the ELS-M10 treatment had a premature treatment withdrawal by removing the gel at time less than an hour due to skin irritation. These subjects were not included in the summaries (unless otherwise specified).
  • Mean and median plasma ketoprofen concentration vs. time profiles following administration are depicted in FIGS. 1A and 1B and FIGS. 2A and 2B , respectively, as linear-linear and log-linear plots.
  • Table 14 The summary statistics of PK parameter estimates by treatment are presented in Table 14. Note that this table does not include data for the five subjects who were removed early from the study. Additionally, one subject had R 2 values too low for reliable calculation of half-life and AUC(inf). Individual plots of the PK parameters (spaghetti plots) are seen in FIGS. 3-7 .
  • Ketoprofen plasma concentrations (ng/mL) Hour Treatment N Mean Median STD Min Max 0.0 ELS-M10 15 0.2 0.0 0.431 0 1 Oral Ketoprofen 20 0.5 0.0 0.876 0 3 0.5 ELS-M10 15 38.7 20.9 42.605 2 153 Oral Ketoprofen 20 8071.3 6545.0 6442.8 152 19700 1.0 ELS-M10 15 213.8 154.0 207.60 14 718 Oral Ketoprofen 20 8102.4 8180.0 3902.1 377 13800 2.0 ELS-M10 15 433.9 366.0 281.83 125 1050 Oral Ketoprofen 20 634.0 6350.0 1729.1 2720 9370 3.0 ELS-M10 15 442.1 391.0 233.67 197 930 Oral Ketoprofen 20 4414.6 3960.0 2360.3 322 9310 5.0 ELS-M10 15 321.6 285.0 132.03 179 666 Oral Ketoprofen 20 2177.
  • the ELS-M10 ketoprofen treatment concentrations were >20.9 ng/mL in plasma at the first sampling time (0.5 hour post dose), while the oral ketoprofen treatment had most subjects with concentration levels >6545 ng/mL at the first sampling time point. All subjects reached maximum concentrations by five hours with median times of three hours for ELS-M10 and one hour for oral ketoprofen. All treatments had ketoprofen concentration levels ⁇ 110 ng/mL by 24 hours.
  • ELS-M10 ketoprofen Maximum concentrations were higher for all subjects when treated with oral ketoprofen versus being topically treated with ELS-M10 ketoprofen.
  • Maximum mean exposure of ELS-M10 ketoprofen was estimated as 4% of oral ketoprofen (ratio 90% CI of 0.03 to 0.11) with geometric means of 417 ng/mL versus 9690 ng/mL.
  • the overall range of the maximum concentration of ELS-M10 ketoprofen was 197 ng/mL to 1050 ng/mL.
  • the overall range of the maximum concentration for oral ketoprofen ranged from 5440 ng/mL to 19700 ng/mL.
  • Ketoprofen half-life for ELS-M10 was substantially longer than for oral ketoprofen (mean(std) of 10.22(3.60) hours versus 3.17(0.57) hours).
  • ELS-M10 mean ketoprofen twelve hour exposure (AUC(0-12)) and ELS-M10 mean ketoprofen exposure over the sampling time AUC(0-24), were estimated as 13% (ratio 90% CI of 0.11 to 0.15) and 10% (ratio 90% CI of 0.08 to 0.12), respectively, of the oral ketoprofen.
  • FIG. 3 showed all patients overlaid with the treatment withdrawals color coded separate from the treatment completers.
  • Table 16 shows summaries of the ELS-M10 ketoprofen pharmacokinetic parameters of these five patients along with the 15 fully exposed subjects.
  • Tmax was seen an hour earlier for the five early treatment withdrawal subjects (median values of 2 hours versus 3 hours) versus the 15 ELS-M10 treatment completers. Although median maximum concentration levels for these five subjects was similar to the treatment completers (median(range) of 414(137,649) of ELS-M10 ketoprofen versus 391(197,1050) oral ketoprofen). Median total exposure as estimated by AUC(0-inf) was less in the early treatment withdrawal patients versus treatment completers by approximately 10% (median(rang) of 4347.1(1775,4990) of ELS-M10 ketoprofen versus 4687.4(2638,8201) oral ketoprofen).
  • ELS-M10 demonstrated promising pharmacokinetic properties. All subjects showed measurable levels of systemic ketoprofen concentrations where maximum ketoprofen concentrations were much lower for the topically applied ELS-M10 gel in treated subjects versus the maximum ketoprofen concentrations in subjects receiving oral ketoprofen. In addition, exposure parameters (AUC(0-inf), AUC(0-12) and AUC(0-24)), demonstrated lower systemic exposure for the ELS-M10 treated subjects versus the oral ketoprofen treated subjects even though the half-life for ELS-M10 ketoprofen was shown to be substantially longer than that of the oral ketoprofen.
  • ELS-M10 and ELS-placebo were applied to the temporomandibular joints (TMJ) of mice that were sensitized by microinjections of complete Freund's adjuvants (CFA) into the temporomandibular joints bilaterally.
  • CFA complete Freund's adjuvants
  • topical ELS-M10 is effective in this inflammatory model of TMJ pain. Further, without wishing to be bound by theory, it is believed that expression of cyclooxygenase (COX) in trigeminal ganglion sensory neurons is key to this effect, which relies on efficient transdermal targeting of trigeminal peripheral projections to the TMJ by ELS-M10 topical application.
  • COX cyclooxygenase
  • ELS-M10 topical application was assessed on the formalin irritant-pain model to the mouse whisker pad.
  • the pain behavior is bi-phasic, as it is for the paw and pain behavior is increased with injection of equal volume/concentration of formalin into the paw, reflecting the higher sensitivity of the trigeminal system ( FIGS. 10A-10B ).
  • FIG. 10C topical application of ELS-M10 attenuates pain behavior in the acute, peripheral irritation phase and robustly attenuates pain behavior in the second, neuropathic phase. This finding indicates that ELS-M10 is effective against irritant induced trigeminal pain and acts sufficiently rapid to prevent the late phase of pain behavior.
  • the data are consistent with the effect of systemic ketoprofen on formalin pain behavior in the paw.
  • the weight bearing test is measured at baseline and day 1 (1, 4, 8, 12, and 24 hours post treatment) of treatment with topical ELS-M10 and oral ketoprofen.
  • topical application of ELS-M10 decreased the percentage difference between the paws by half at 4 hours post treatment and comparable to the decrease seen in oral administration of ketoprofen.
  • This study indicates that ELS-M10 is as effective as oral administration of ketoprofen in reducing spontaneous pain within a short time period (i.e., within 1 hour) after application.
  • Example 7 Topical Administration of ELS-Ketoprofen Formulation for Prophylactic Use
  • ELS-M10 and ELS-M11 make them desirable for use in prophylactic treatment of a migraine or symptom(s) of a migraine.
  • FIGS. 12A and 12B the pain free response in human patients after application of ELS-M11 is sustained for 24 hours after the initial application of the composition.
  • Prophylactic treatment is intended to reduce the frequency and intensity of migraine attacks.
  • the prophylactic methods described herein do not necessarily result in complete freedom from symptoms associated with migraine attacks, but may provide for fewer symptoms or symptoms of reduced intensity. For many patients, it is the non-headache symptoms of migraine that are most disabling, and for which the patient is most desirous of relief.
  • the prophylactic methods of the present invention are directed to the entire range of symptoms experienced by a patient during a migraine attack (e.g., throbbing pain on one side, aura, nausea, vomiting, sensitivity to bright lights, sensitivity to sounds, sensitivity to smells, blurry vision, neck pain, nasal stiffness, frequent urination, pallor, or sweating), and not merely at the prevention of headaches associated with a migraine attack.
  • Prophylactic treatment is generally proposed for patients who suffer from two or more migraine attacks per month.
  • Prophylactic treatment should also be considered for patients who experience less frequent migraine attacks that are more potent or even disabling.
  • a third category of patients that may benefit from prophylactic treatment includes those who do not respond well to abortive treatments.
  • compositions of the invention can also be useful for targeted prophylactic treatment of a migraine condition.
  • the targeted prophylactic approach is relevant for persons with frequent, recurring migraine symptoms who anticipate critical activities during which it is very important to prevent or minimize their migraine-related symptoms.
  • the targeted prophylactic approach may be especially relevant for persons who expect to experience a stimulus that is known to trigger migraine symptoms or is associated with an increased chance of experiencing migraine symptoms.
  • such stimuli include stress, change in routine, sleep, environmental stimuli (e.g., high altitude, weather changes, high humidity, loud noises), hormonal spikes (such as during regular or irregular menstrual cycles), glare (such as when starting at a computer screen, driving, skiing, flying, or boating on a clear day), food (e.g., a craving for sweet foods prior to experiencing migraines), lack of food, additives, alcohol, mild dehydration, drugs (e.g., taking drugs, e.g., cocaine and withdrawal from drugs), exercise, oral contraceptives, teeth grinding, or physical conditions (e.g., head injury, muscle tension, coughing).
  • environmental stimuli e.g., high altitude, weather changes, high humidity, loud noises
  • hormonal spikes such as during regular or irregular menstrual cycles
  • glare such as when starting at a computer screen, driving, skiing, flying, or boating on a clear day
  • food e.g., a craving for sweet foods prior to experiencing migraines
  • the method for targeted prophylactic treatment includes determining a time window or selected time period in which a patient desires to be free from migraine or a symptom of migraine; and administering to the patient, at a time prior to the determined time window, a therapeutically effective amount of a therapeutic agent (e.g., any described herein, e.g., an NSAID, e.g., ELS-M10), either alone or in combination with a second agent (e.g., 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)), to prevent or reduce migraine symptoms during the time window.
  • a therapeutic agent e.g., any described herein, e.g., an NSAID, e.g., ELS-M10
  • a second agent
  • the therapeutic agent can further be administered (e.g., any described herein, e.g., an NSAID, e.g., ELS-M10) alone or in combination with non pharmacological treatments (e.g., relaxation techniques, bio-feedback, cognitive behavioural therapy, and/or acupuncture) for the prophylactic treatment of a migraine or symptom associated with a migraine.
  • non pharmacological treatments e.g., relaxation techniques, bio-feedback, cognitive behavioural therapy, and/or acupuncture
  • the time window would include the period of time over which the patient anticipates participating in the critical activities during which the patient desires to be as free from migraine symptoms as is possible, or the period over which a patient expects to experience a migraine-triggering stimulus.
  • the time window or selected time period could also include a period (lasting hours or several days) after a known or probable migraine-inducing stimulus, such as the consumption of red wine, disruption of sleep, or a skipped meal.
  • a patient with an established history of migraine brought on by occasional consumption of red wine can apply ELS-M10 on the same day as such consumption before migraine attack symptoms are evident.
  • the patient will be free of, or experience substantially reduced, migraine symptoms for a time period during which symptoms would normally be experienced or expected in the absence of application of ELS-M10.
  • a patient with an established history of recurrent migraine can be treated with once a day application of ELS-M10.
  • the patient will be free of migraine symptoms during the first week of use and notice a reduced intensity of the symptoms of subsequent migraine attacks as well as a reduced frequency of migraine attacks during the treatment period of three to four weeks.
  • a patient with an established history of migraine brought on by glare associated with an ophthalmic operating room microscope can apply ELS-M10 the night before or the week before (depending on the severity of the migraine when it occurs) the scheduled ophthalmic operation.
  • the patient will be free of migraine symptoms before, during and after the scheduled operation after targeted prophylactic treatment with ELS-M10 alone or in combination with a second agent.
  • the patient may also experience migraine symptoms at a greatly reduced intensity as compared to a full-fledged migraine, so that he was able to function effectively during the scheduled operations.
  • a patient with a well-established history of recurrent migraine attacks learns to recognize his/her prodromal symptoms of altered mood, irritability, fatigue, and craving for sweets which typically occur 3 to 24 hours prior to the fully developed phase of his migraine. He/she learns over time that these prodromal symptoms eventually lead to a migraine attack in most cases. His/her migraine attacks typically include unusual sensitivity to light and sound, difficulty concentrating, headache, and less commonly, nausea. As soon as he/she recognizes the prodromal symptoms, he/she applies a one-time dose of ELS-M10. He/she notes that he/she is either free of, or has greatly reduced, migraine attack symptoms subsequent to applying ELS-M10. Continued daily dosing extends that period of benefit for several days (or longer) subsequent to the initial symptoms.
  • a middle-aged female patient with a well-established history of recurrent migraine attacks heralded by an aura of dysphasia applies ELS-M10 at the onset of the dysphasic symptoms. She notes a reduction in the intensity and length of the migraine attack symptoms which usually, but not always, follow the aura. Because she has lately suffered more than four migraine attacks per month, on the advice of her physician she continues daily dosing of ELS-M10 over time. She then notes a substantial decrease in the frequency and intensity of the migraine attacks while continuing to apply ELS-M10.
  • the treatment may be termed “acutely targeted” if the goal is to eliminate or substantially reduce the migraine symptoms during the particular time or activity for the patient.
  • the patient will learn to recognize early or premonitory migraine symptoms, or will be aware of a pattern or frequency of migraine attacks, and will be able to self-administer the treatment at an appropriate time.

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WO2016089893A1 (en) 2016-06-09
US11026882B2 (en) 2021-06-08
US20220125712A1 (en) 2022-04-28
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