EP3920909A1 - Compositions pharmaceutiques comprenant du méloxicam - Google Patents

Compositions pharmaceutiques comprenant du méloxicam

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Publication number
EP3920909A1
EP3920909A1 EP20752178.2A EP20752178A EP3920909A1 EP 3920909 A1 EP3920909 A1 EP 3920909A1 EP 20752178 A EP20752178 A EP 20752178A EP 3920909 A1 EP3920909 A1 EP 3920909A1
Authority
EP
European Patent Office
Prior art keywords
meloxicam
dosage form
rizatriptan
migraine
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20752178.2A
Other languages
German (de)
English (en)
Other versions
EP3920909A4 (fr
Inventor
Herriot TABUTEAU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axsome Therapeutics Inc
Original Assignee
Axsome Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Axsome Therapeutics Inc filed Critical Axsome Therapeutics Inc
Publication of EP3920909A1 publication Critical patent/EP3920909A1/fr
Publication of EP3920909A4 publication Critical patent/EP3920909A4/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/41—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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/54—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
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • NSAID nonsteroidal anti-inflammatory
  • the meloxicam mechanism of action may be related to prostaglandin synthetase (cyclo-oxygenase, COX) inhibition which is involved in the initial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin.
  • prostaglandin synthetase cyclo-oxygenase, COX
  • Cyclodextrins also known as cycloamyloses
  • cycloamyloses are generally cyclic polysaccharides which form a bucket-like shape. Cyclodextrins help to increase bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the inside which helps to facilitate the transport of molecules.
  • cyclodextrins include six, seven, and eight glucose units (a, b, and y-cyclodextrin, respectively).
  • synthetic cyclodextrins containing more or less glucose units are possible.
  • cyclodextrins can form complexes (i.e., an inclusion complex) with drugs by incorporating the drug into the center/hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around a drug in a micelle-type structure. This ability of cyclodextrins may allow them to act as carriers to increase the bioavailability of less soluble drugs.
  • Some embodiments include a method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a com bination of: 1) a complex of meloxicam with a sulfobutyl ether b-cyclodextrin (SBEbCD), 2) a bicarbonate, and 3) a rizatriptan.
  • SBEbCD sulfobutyl ether b-cyclodextrin
  • Some embodiments include an inclusion complex of meloxicam in a cyclodextrin.
  • Some embodiments include a dosage form comprising: 1) an inclusion complex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or a bicarbonate.
  • Some embodiments include a method of administering meloxicam intravenously, comprising intravenously administering a dosage form described herein to a patient in need of treatment.
  • Disclosed herein are formulations and methods for delivering meloxicam with cyclodextrin to a subject by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means. [0011] Disclosed also are methods for treating pain and pain associated with conditions by delivering a dosage form with meloxicam, cyclodextrin, and bicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means to a subject.
  • a combination of rizatriptan and meloxicam (referred to herein for convenience as a "subject combination”) may be used to treat a variety of pain conditions.
  • Rizatriptan has the structure as shown below.
  • Some embodiments include a subject combination comprising: 1) an inclusion complex of meloxicam and a cyclodextrin, 2) rizatriptan, and 3) a bicarbonate for treating migraine in a human being.
  • the migraine may be treatment-resistant migraine.
  • the human being may have a history of inadequate response to prior treatments.
  • Some embodiments include a subject combination comprising rizatriptan and meloxicam that has rapid, sustained, substantial and statistically significant efficacy as compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of inadequate response to prior acute treatments.
  • Some embodiments include a subject combination comprising rizatriptan and meloxicam that requires significantly less use of rescue medication as compared to rizatriptan, meloxicam, or placebo.
  • Figure 1 is a depiction of the results described in Example 2 and contained in Table 6.
  • Figure 2 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 3 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 4 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 5 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 6 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 7 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 8 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 9 is another depiction of the results described in Example 2 and contained in Table 6.
  • Figure 10 is another depiction of the results described in Example 2 and contained in Table 6.
  • FIG. 11 is a plot of meloxicam plasma concentration at various time points over the first 24 hours for an embodiment of a dosage form described herein and a commercially available meloxicam dosage form.
  • FIG. 12 is a plot of meloxicam plasma concentration at various time points over the first 24 hours for a dosage form of Meloxicam/Rizatriptan described in Example 6 and a commercially available meloxicam dosage form.
  • FIG. 13 is a plot of rizatriptan plasma concentration at various time points over the first 12 hours for a dosage form of Meloxicam/Rizatriptan described in Example 6 and a commercially available meloxicam dosage form.
  • Fig. 14 shows plots of the percentages of subjects reporting pain relief at various time points over the first 4 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11 .
  • Fig. 15 shows the percentages of subjects achieving pain freedom at 2 hours, 4 hours, 12 hours, and 16 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
  • Fig. 16B shows the percentages of subjects achieving sustained pain relief from 2 hours to 24 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
  • Fig. 17A shows the percentages of subjects achieving sustained pain freedom from 2 hours to 48 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
  • Fig. 17B shows the percentages of subjects achieving sustained pain relief from 2 hours to 48 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
  • Fig. 18 shows the percentages of subjects who took rescue medication through hour 24 post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
  • a dosage form may be given enterally including, but not limited to, oral, sublingual, or rectal delivery, or parenterally including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous delivery.
  • Some methods include administration of a product that combines an NSAID that is formulated with: a) a cyclodextrin and/or b) a buffering agent.
  • the method involves treating a patient with a pharmaceutical formulation comprising meloxicam and a cyclodextrin and/or a carbonate/bicarbonate.
  • Method embodiments may also include treating a patient to increase the bioavailability of meloxicam in the patient or increase the rate at which the meloxicam becomes bioavailable.
  • any reference to a compound herein, such as meloxicam or rizatriptan, by structure, name, or any other means includes pharmaceutically acceptable salts, alternate solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species, such as precursors, prodrugs, or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • the combination of meloxicam and rizatriptan is administered so that the human being receives the meloxicam and rizatriptan within a short period of time with respect to one another.
  • the meloxicam and rizatriptan may be administered within about 2 hours, within about 1 hour, within about 30 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, within about 5 minutes, or within about 1 minute of one another.
  • the meloxicam and rizatriptan are administered simultaneously, which for the purpose of this disclosure includes administration within about 5 minutes.
  • the meloxicam and rizatriptan are administered in a single dosage form.
  • treating broadly includes any kind of treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
  • the dosage form or the subject combination may be used to treat, or provide relief of, any type of pain including, but not limited to, migraine and other types of headache, inflam matory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, systemic pain, cancer-related pain, acute pain, pain due to injury, pain due to illness (e.g., fever), post-operative pain, etc.
  • pain relief may be palliative, or pain relief may be provided independent of improvement of the disease or condition or the underlying cause of the disease or condition.
  • the pain affects a muscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths, bursae, or joint.
  • the human being who is being treated for migraine pain suffers from allodynia with their migraine attacks.
  • Allodynia which is pain from normally non painful stimuli (such as brushing hair, wearing glasses, taking a shower, etc.). Patients having allodynia are believed to be less likely to respond well to triptan medications.
  • Administering a subject combination to a human being suffering from migraine may quickly result in a reduction in a migraine symptom, such as pain, nausea, vomiting, photophobia, or phonophobia, such as at or within about 5 minutes (intended as a shorthand for "at about 5 minutes, or within about 5 minutes"), at or within about 10 minutes, at or within about 30 minutes, at or within about 1 hour, at or within about 90 minutes, at or within about 2 hours, at or within about 2.5 hours, or at or within about 3 hours.
  • a migraine symptom such as pain, nausea, vomiting, photophobia, or phonophobia
  • a human being experiences a reduction of, or complete relief from, pain, such as headache pain or migraine pain, nausea, vomiting, photophobia, and/or phonophobia, at or within about 1 hour, at or within about 90 minutes, at or within about 2 hours, at or within about 2.5 hours, or at or within about 3 hours.
  • the relief experienced is greater than would be experienced by receiving the same amount of rizatriptan without meloxicam. In some embodiments, the relief experienced, is greater than would be experienced by receiving the same amount of meloxicam without rizatriptan.
  • meloxicam is a potent, COX-2 preferential NSAID which is limited by slow absorption.
  • Rizatriptan is a potent 5-HT1 B/D agonist believed to have efficacy in migraine.
  • Observation of relief or reduction in a symptom at a specific period of time is useful because it allows the effectiveness of the treatment to be evaluated at a specific or consistent time point, which facilitates comparison between patients.
  • Observation of relief or reduction in a symptom within a specific period of time is useful because it is desirable for relief or reduction of a symptom to occur as early as possible, and specifying that relief occur within a specified time sets a guideline in which it is desirable that relief occur.
  • administration of the subject combination may achieve a reduction in migraine pain, nausea, vomiting, photophobia, or phonophobia that lasts at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8-24 hours, about 24 hours, or more than 24 hours.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g.
  • a single dosage form such as a single oral dosage form
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from nausea than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from nausea than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from vomiting than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from vomiting than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from photophobia than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from photophobia than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g.
  • a single dosage form such as a single oral dosage form
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from phonophobia than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.
  • the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty- four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from phonophobia than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.
  • the human being receiving the subject combination has indicated that he or she was “never” pain-free within two hours of treatment for most attacks. In some embodiments, the human being receiving the subject combination has indicated that he or she was "rarely” pain-free within two hours of treatment for most attacks. In some embodiments, the human being receiving the subject combination has indicated that he or she was pain-free within two hours of treatment for most attacks "less than half the time.”
  • the human being receiving the subject combination has indicated that one dose of medication "never” relieved the respondent's headache and kept it away for at least 24 hours. In some embodiments, the human being receiving the subject combination has indicated that one dose of medication "rarely” relieved the respondent's headache and kept it away for at least 24 hours. In some embodiments, the human being receiving the subject combination has indicated that one dose of medication relieved the respondent's headache and kept it away for at least 24 hours "less than half the time.”
  • the human being receiving the subject combination has migraine, and may have a history of inadequate response to prior migraine treatments.
  • the human being having migraine does not have cluster headaches or other types of migraines.
  • the human being having migraine does not have chronic daily headache.
  • the human being having migraine does not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 non-migraine headache days per month.
  • the human being having migraine does not have a history of significant cardiovascular disease.
  • the human being having migraine does not have uncontrolled hypertension.
  • the dosage form may also be administered to relieve arthritis pain.
  • the dosage form may be administered to relieve other signs and/or symptoms of arthritis.
  • arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (pauciarticular and polyarticular course), osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid), arthropathies, non- articular rheumatism, peri-articular disorders, axial spondyloarthritis, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and neuropathic arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.
  • the arthritis pain may be chronic or acute.
  • the dosage form may be administered to relief the signs and/or symptoms of an arthritis including but
  • the dosage form may also be administered to relieve neuropathic pain, including diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, sciatica, pudendal neuralgia, and central pain.
  • neuropathic pain including diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, sciatica, pudendal neuralgia, and central pain.
  • Other causes of neuropathic pain may include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio-therapy or chemo therapy associated neuropathy.
  • the neuropathic pain treated may be chronic or acute.
  • the dosage form may be administered to relieve inflammatory pain including inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndrome.
  • the inflammatory pain may be chronic or acute.
  • Arthritis refers to inflammatory joint diseases that can be associated with pain.
  • arthritis pain include but are not limited to pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non- rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.
  • the inflammatory joint disease treated may be chronic or acute.
  • the meloxicam may be administered to relieve musculoskeletal pain.
  • musculoskeletal pain may include, but are not limited to, back pain, low back pain (e.g., lumbosacral pain), neck pain, infection, cramps, tendonitis, epidondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to injury, Tunnel syndromes, pain associated with bone fractures, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip.
  • the musculoskeletal pain may be chronic or acute.
  • administration of the dosage form or the subject combination may achieve a reduction in pain that lasts at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8 to about 24 hours, or about 24 hours.
  • administration of the subject combination may achieve a reduction in pain that is observed at about 10 minutes, at about 30 minutes, at about one hour, at about two hours, at about three hours, at about four hours, at about five hours, at about six hours, at or within about 5 minutes, at or within about 10 minutes, at or within about 15 minutes, at or within about 20 minutes, at or within about 25 minutes, at or within about 30 minutes, at or within about 35 minutes, at or within about 40 minutes, at or within about 45 minutes, at or within about 50 minutes, or at or within about 60 minutes, at two hours or less, at three hours or less, or other time period bound by these ranges, after administration of the subject combination.
  • a human being that is treated for a disease or condition with the dosage forms described herein may be of any age.
  • the person may have an age of about 10 years to about 90 years, about 20 years to about 80 years, about 30 years to about 75 years, about 40 years to about 70 years, about 1 year to about 16 years, about 80 years to about 95 years, about 18 years or more, about 20 years or more, about 25 years or more, about 30 years or more, about 40 years or more, about 45 years or more, about 50 years or more, about 55 years or more, about 60 years or more, about 65 years or more, or any other age in a range bounded by, or between, these values.
  • a human being who is treated for migraine with a dosage forms described herein such as a dosage form comprising meloxicam, rizatriptan, SBEbCD, and a bicarbonate such as sodium bicarbonate, may be white, black or African American, or Asian.
  • a human being that is treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has suffered from the pain or condition associated with the pain for at least 1 day, at least one week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or any duration in a range bounded by, or between, these values.
  • a human being that is treated for migraine with a dosage form comprising meloxicam and rizatriptan has been diagnosed of migraine with or without aura as defined by the ICHD-3 criteria for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years, or longer, or at least 1 year, or any duration in a range bounded by, or between, these values.
  • a human being has an average 2 to 8, 2-3, 3-4, 4-5, 5-6, 6- 7, or 7-8 moderate to severe migraines per month.
  • a cyclodextrin used in a dosage form with meloxicam could include a cyclodextrin, a cyclodextrin derivative, and/or a salt thereof.
  • An inclusion complex of meloxicam and cyclodextrin may be more water-soluble relative to the non-complexed meloxicam.
  • the cyclodextrin may be a naturally-occurring cyclodextrin (e.g., a, b, or y-cyclodextrins) or a synthetic cyclodextrin.
  • a-cyclodextrins, derivatives, or salts thereof may be used.
  • b-cyclodextrins may include, but are not limited to, hydroxypropyl-b-cyclodextrin, 6- monodeoxy-6-monoamino-b-cyclodextrin, glucosyl-b-cyclodextrin, maltosyl-b-cyclodextrin, 6-0-a-D-glucosyl-b-cyclodextrin, 6-0-a-maltosyl-b-cyclodextrin, 6-azido-6-deoxy-b- cyclodextrin, (2,3-di-0-acetyl-6-0-sulfo)-b-cyclodextrin, methyl-b-cyclodextrin, dimethyl-b- cyclodextrin (DIV ⁇ CD), trimethyl-b-cyclodextrin (TMbCD), (2,3-
  • a b-cyclodextrin may be a sulfoalkyl ether cyclodextrin, derivative, or salt thereof.
  • sulfoalkyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-b-cyclodextrin (e.g., SBEbCD, betadex, CAPTISOL ® ).
  • a SBEbCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.
  • y-cyclodextrins, derivatives, or salts thereof may be used y-cyclodextrins may include carboxymethyl-g-cyclodextrin, (2,3,6-tri-0-acetyl)-g-cyclodextrin, (2,3,6-tri-0-methyl)-g-cyclodextrin, (2,6-di-0-pentyl)-g-cyclodextrin, 6-(dimethyl-tert- butylsilyl)-6-deoxy-g-cydodextrin, 6-bromo-6-deoxy-g-cyclodextrin, 6-iodo-6-deoxy-g- cyclodextrin, (6-0-t-butyldimethylsilyl)-g-cyclodextrin, succinyl-g-cyclodextrin, hydroxy propyl-g-cyclodextrin (2-hydroxypropyl)-g-c
  • the dosage form may include a bicarbonate, such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or a combination thereof.
  • a bicarbonate may help to increase bioavailability of the meloxicam.
  • the dosage form may include a carbonate, derivatives, or salts thereof.
  • carbonates may include aluminum carbonate, ammonium carbonate, barium carbonate, calcium carbonate, cobalt(ll) carbonate, lanthanum carbonate, lithium carbonate, magnesium carbonate, manganese(ll) carbonate, potassium carbonate, sodium carbonate, or combinations thereof.
  • enhanced bioavailability of the dosage form may be achieved in treating one of these conditions by administering a dosage form comprising a salt form of the meloxicam, by creating an inclusion complex with meloxicam and cyclodextrin, and/or by including a bicarbonate. This may allow a reduced molar amount of the meloxicam to be used as compared to other meloxicam dosage forms.
  • use of a cyclodextrin, a carbonate, or a bicarbonate may improve the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any amount in a range bounded by, or between, these values as compared to administration of meloxicam alone.
  • the dosage form may contain, or a subject may receive, on a molar basis, less of the meloxicam than would otherwise be administered.
  • a dosage form may contain, or a mammal may receive, at least about 10 mole% less, at least about 20 mole% less, at least about 30 mole% less, at least about 40 mole% less, at least about 50 mole% less, at least about 60 mole% less, at least about 70 mole% less, at least about 80 mole% less, at least about 85 mole% less, and/or up to about 90 mole% less, 95 mole% less, or any amount in a range bounded by, or between, these values as would otherwise be administered of meloxicam.
  • use of other NSAIDs, opioids, or other pain medications may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, up to about 100%, as compared to the use of other NSAIDs, opioids or other pain medications without administration of meloxicam with cyclodextrin, carbonate, and/or bicarbonate.
  • a dosage form may contain meloxicam in an amount from about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 5-20 mg; about 5-10 mg; about 5-15 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; about 40-50 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30 mg; or any amount in a range bounded by, or between, any of these values.
  • These doses may be a safe dose for repeated administration, such as once hourly dosing to once daily dosing, twice daily dosing, dosing one to 12 times daily, doing 3, 4, 5, or 6 times daily, etc.
  • the meloxicam may be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times a day, once a day, or less frequently, such as once a week, once every two weeks, once a month, etc.
  • meloxicam forms a complex with the substituted-b- cyclodextrin or other another cyclodextrin which may be formulated into a solid dosage form.
  • a dosage form may be suitable for oral administration.
  • a meloxicam-cyclodextrin inclusion complex may also be dissolved in water or another solvent to form a parenteral formulation.
  • physical mixtures of meloxicam and the substituted-b-cyclodextrin or other cyclodextrins may also be used in oral or parenteral dosage forms.
  • Formation of an inclusion complex of meloxicam and a cyclodextrin may help to improve the properties of a dosage form.
  • the meloxicam and the cyclodextrin may have a molar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7- 0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or any ratio in a range bounded by any of these values.
  • a molar ratio of 0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin
  • a cyclodextrin e.g., SBEbCD
  • a weight ratio to the meloxicam within the range from about 1-1000 (e.g. 1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about 1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in a range bounded by, or between, any of these values.
  • a cyclodextrin e.g., SBEbCD
  • a weight ratio to the meloxicam within the range from about 0.001-1 (e.g. 0.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about 0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weight ratio in a range bounded by, or between, any of these values.
  • Each type of cyclodextrin employed may have a different ratio.
  • the cyclodextrin may be present in an amount from about 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about 40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount in a range bounded by, or between, any of these values.
  • Some dosage forms contain a carbonate in amount from about 1-1000 mg; about
  • the weekly dose of meloxicam (e.g., an oral dose) is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about 30-70 mg; about 40- 60 mg; about 50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100-150 mg; about 30-100 mg; or any amount in a range bounded by, or between, any of these values.
  • the weekly dose may be given as a single dose, given once during the week, or may be given in 2, 3, 4, 5, 6, or 7 individual doses during the week.
  • the monthly dose of meloxicam (e.g., an oral dose), or a dose administered over a period of a month, is about 5000 mg or less; about 4000 mg or less; about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700 mg or less; about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg; about 50-200 mg; about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg; about 360- 400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; or any monthly dose in a range bounded
  • the dosage form may be administered weekly for about one, two, three, four, or more consecutive weeks, every other week or bi-weekly, or once every three weeks. This regimen may be repeated once weekly, twice in a month, three times in a month, once monthly, once every two months, once every three months, or as directed by a medical professional.
  • the pharmaceutical composition results in increased bioavailability (e.g., reduced T max , increased C max , increased AUC, etc.) of the meloxicam from the dosage form as compared to a dosage form containing meloxicam but not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).
  • the bioavailability of meloxicam will increase with multiple dosing.
  • the bioavailability of meloxicam in the dosage form may increase after about 1-10 days of dosing; about 2-6 days of dosing; about 3-5 days of dosing; about 4-6 days of dosing; about 5-8 days of dosing; about 5 days of dosing; about 6 days of dosing; about 7 days of dosing; about 8 days of dosing; about 10 days of dosing; about 15 days of dosing; or time in any range bounded by, or between, any of these values; as compared to the bioavailability of meloxicam in a dosage form not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).
  • a buffering agent such as a bicarbonate
  • the AUC refers to the AUC calculated to the last measured concentration (AUC 0-t ), such as, over a period of 6 hours (AUC 0-6 ), over a period of
  • Example 3 the AUC 0-24 of meloxicam in human beings for an oral dosage form containing sodium bicarbonate and sulfobutylether b-cyclodextrin (SBEbCD) was about 27 mg ⁇ hr/mL. This dosage form contained 15 mg of meloxicam.
  • the AUC for a short period after oral administration may be of particular interest.
  • some dosage forms may result in an AUCo- 6 of at least about 6 mg ⁇ hr/mL; at least about 7 mg ⁇ hr/mL; at least about 8 mg ⁇ hr/mL; at least about 9 mg ⁇ hr/mL; about 6-10 mg ⁇ hr/mL; about 7-11 mg ⁇ hr/mL; about 8-12 mg ⁇ hr/mL; about 9-
  • a method described herein may reduce the T max of meloxicam.
  • the method may include treating a patient to achieve the T max of meloxicam in the patient within about 10 minutes; about 20 minutes; about 30 minutes; about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes; about 180 minutes; about 1-10 hr; about 2-9 hr; about 3-7 hr; about 4-6 hr; about 1-5 hr; about 2-7 hr; about 3-8 hr; about 4-9 hr; about 1-4 hr; about 2-5 hr; about 3-6 hr; about 4-7 hr; about 5-8 hr; about 6-9 hr; about 7-10 hr; after administration or any T max in a range bounded by, or between, any of these values.
  • meloxicam is administered at a dose that results in a meloxicam plasma level (such as a C avg , or average plasma level) of about 0.01-0.5 mg/mL; about 0.5-0.7 mg/mL; about 0.6-0.8 mg/mL; about 0.7-0.9 mg/mL; about 0.8-1 mg/mL; about 0.9-1.1 mg/mL; about 1-1.2 mg/mL; about 1.1-1.3 mg/mL; about 1.2-1.4 mg/mL; about 1.3-1.5 mg/mL; about 1.4-1.6 mg/mL; about 1.5-1.7 mg/mL; about 1.6-1.8 mg/mL; about 1.7-1.9 mg/mL; about 1.8-2 mg/mL; about 1.9-2.1 mg/mL; about 2-2.2 mg/mL; about 2.1-2.3 mg/mL; about 2.2- 2.4 mg/mL; about 2.3-2.5 mg/mL; about 2.4-2.6 mg/mL; about 2.5-
  • the method may achieve a T max of rizatriptan in the patient within about 50 minutes; within about 60 minutes; within about 70 minutes; within about 80 minutes; or within about 90 minutes; at about 40-60 minutes, at about 40-45 minutes, at about 45-50 minutes, at about 50-55 minutes, or about 55-60 minutes after administration, or any T max in a range bounded by any of these values.
  • the daily dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15- 50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg or any other amount in a range bounded by, or between, any of these values.
  • These doses may be safe for repeated administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, etc.
  • a pharmaceutical composition may be in the form of a tablet or capsule that has: (a) the acid inhibitor; and/or (b) a buffering agent; and (c) the non-steroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in a patient upon administration of one or more of said unit dosage forms.
  • the components of the pharmaceutical composition may be in an immediate or extended release form individually or in total.
  • the unit dosage form is suitable for oral administration to a patient.
  • the unit dosage form is a tablet.
  • the unit dosage form is a multilayer tablet comprising a single core and one or more layers outside of the core.
  • Some dosage forms may comprise a first layer comprising meloxicam, an SBEbCD, and a bicarbonate; and a second layer comprising a second therapeutically active agent and a bicarbonate.
  • the first layer may contain, for example, any amount of meloxicam in one of the ranges recited above.
  • all of the meloxicam in the dosage form may be present in the first layer.
  • the second layer may contain all of the second therapeutically active agent, such that any amount in the ranges recited above with respect to the second therapeutically active agent may apply to the second layer.
  • the pharmaceutical composition may have an effective amount of meloxicam, a cyclodextrin, and a carbonate or bicarbonate to increase bioavailability of meloxicam.
  • the pharmaceutical composition may have an effective amount of meloxicam, sulfobutylether-b-cyclodextrin (SBEbCD), and sodium bicarbonate to increase bioavailability of meloxicam or reduce the T max of meloxicam.
  • An embodiment of the present disclosure is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient for treat a disease, a condition, or disorder, such as migraine, comprising:
  • the pharmaceutical composition results in faster release or dissolution of the meloxicam from the dosage form as compared to a dosage form containing meloxicam but not containing the acid inhibitor, or not containing the buffering agent.
  • a dosage form comprising a combination of rizatriptan and meloxicam may be used to treat migraine.
  • the subject combination may be used for the acute treatment of migraine.
  • the subject combination may provide substantially greater and more sustained migraine pain relief compared to rizatriptan, meloxicam, or placebo.
  • the subject combination may provide rapid relief of migraine pain.
  • the subject combination may significantly reduce the use of rescue medication compared to rizatriptan, meloxicam and placebo.
  • the migraine patients being treated with a combination of rizatriptan and meloxicam described herein may have a history of inadequate response to prior acute treatments.
  • the migraine patients being treated with a combination of rizatriptan and meloxicam described herein may have allodynia.
  • the migraine patients being treated with a combination of rizatriptan and meloxicam described herein may have severe pain intensity.
  • the migraine patients being treated with a combination of rizatriptan and meloxicam described herein may have obesity.
  • the migraine patients being treated with a combination of rizatriptan and meloxicam described herein may have morning migraine.
  • the migraine patients being treated with a combination of rizatriptan and meloxicam described herein may have a total mean score of the Migraine Treatment Optimization Questionnaire (mTOQ-4) of less than 7, such as 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7.
  • mTOQ-4 Migraine Treatment Optimization Questionnaire
  • rizatriptan and meloxicam described herein may provide relief of migraine pain that is numerically greater than rizatriptan at less than 15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes, about 30-45 minutes, about 45-60 minutes, about 1-1.5 hours, about 1.5-2 hours, about 2- 2.5 hours, about 2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours, about 5- 6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-24 hours, about 24- 48 hours, or longer, post dose.
  • the percentage of migraine patients reporting pain relief with the treatment of a combination of rizatriptan and meloxicam described herein may be 1- 100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60- 70%, 70-80%, 80-90%, 90-95%, or 95-100%.
  • the percentage of migraine patients achieving pain freedom increases over time after receiving a dose of a combination of rizatriptan and meloxicam described herein.
  • the percentage of migraine patients achieving pain freedom may be about 15-25%, about 15-20%, about 20%, about 20-25%.
  • the percentage of migraine patients achieving pain freedom may be about 30-50%, about 30-40%, about 40%, about 40-45%, about 45-47%, about 47-50%.
  • the percentage of migraine patients achieving pain freedom may be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 56-57%, about 60-65%, about 65-70%.
  • migraine patients receiving the combination of rizatriptan and meloxicam described herein may maintain it through 48 hours post dose.
  • the increase of the number of migraine patients (or improvement) achieving sustained pain freedom from 2-48 hours post dose of the subject combination may be about 60-90%, about 60-70%, about 70-75%, about 75-80%, about 80-90%, or about 75% as compared to administering rizatriptan.
  • Embodiment 3 The dosage form of embodiment 2 comprising the inclusion complex, wherein the cyclodextrin comprises substituted b-cyclodextrin.
  • Embodiment 15 The method of embodiment 14, wherein the T max of meloxicam is achieved in the patient at a time in a range of about 10 minutes to about 180 minutes after administration.
  • Embodiment 16 The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, having an oral bioavailability of meloxicam that is higher than a dosage form not having a carbonate, a bicarbonate, or a cyclodextrin.
  • Embodiment 17 The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
  • Embodiment 22 The method of embodiment 21, wherein the dosage form is administered to treat pain.
  • Embodiment 23 The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain.
  • Embodiment 35 The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34, wherein about 50 mg to about 200 mg of SBEbCD is present in the dosage form.
  • Embodiment 36 The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the bicarbonate is present in an amount of about 400 mg to about 1000 mg.
  • Embodiment 57 The method of embodiment 56, wherein the oral dosage form contains about 20 mg of meloxicam.
  • Embodiment 74 A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether b-cyclodextrin (SBEbCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free of migraine pain two hours after the dosage form is orally administered to the human migraine patient.
  • SBEbCD sulfobutyl ether b-cyclodextrin
  • Embodiment 78 A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether b-cyclodextrin (SBEbCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free of photophobia two hours after the dosage form is orally administered to the human migraine patient.
  • SBEbCD sulfobutyl ether b-cyclodextrin
  • a female migraine sufferer visits her physician in the hope of having relief from her migraine pain.
  • Her doctor gives her 10 mg rizatriptan (Maxalt ® ), which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms.
  • her doctor gives her 20 mg of meloxicam in a tablet also containing SBEbCD and 500 mg of sodium bicarbonate, which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms.
  • her doctor gives her a tablet described in Example 4 above. She reports that at 2 hours and 24 hours after taking the tablet, she has about 60-100% improvement in pain, nausea, allodynia, photophobia, and/or phonophobia over what she experienced after taking meloxicam or rizatriptan alone.
  • Migraine is characterized by recurrent attacks of pulsating, often severe and disabling head pain associated with nausea, and sensitivity to light and or sound. It is estimated that migraine accounts for $78 billion in direct (e.g. doctor visits, medications) and indirect (e.g. missed work, lost productivity) costs each year in the United States [Gooch CL, Pracht E, Borenstein AR, The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol.
  • Eligible patients must have an age of 18 to 65 years, an established diagnosis (at least 1 year) of migraine with or without aura as defined by ICHD-3 criteria, an average of 2 to 8 moderate to severe migraines per month, had a history of inadequate response to prior acute migraine treatments, assessed by a score of 7 using the Migraine Treatment Optimization Questionnaire (mTOQ-4) (the average score was 3.6), corresponding to poor response to prior acute treatments.
  • mTOQ-4 the Migraine Treatment Optimization Questionnaire

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Abstract

La présente invention concerne des compositions comprenant un anti-inflammatoire non stéroïdien (AINS), tel que le méloxicam et/ou le rizatriptan, en association avec une cyclodextrine et/ou un carbonate ou un bicarbonate. Ces compositions peuvent être administrées par voie orale, par exemple, pour améliorer la biodisponibilité ou la pharmacocinétique de l'AINS dans le traitement de la douleur, par exemple la migraine, l'arthrite, et d'autres états pathologiques. L'invention concerne également des procédés de traitement de la douleur, tels que la migraine, comprenant l'administration de méloxicam et de rizatriptan à un être humain souffrant de douleur, par exemple de migraine. Pour la migraine, ces procédés peuvent être particulièrement utiles lorsque le méloxicam et le rizatriptan sont administrés pendant que l'être humain souffre d'une attaque aiguë de douleur migraineuse ou de migraine avec aura. Selon certains modes de réalisation, la combinaison de méloxicam et de rizatriptan peut être administrée de manière à obtenir un Tmax de méloxicam de 3 heures ou moins.
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CA3128940C (fr) 2023-11-07
CL2021002070A1 (es) 2022-04-01
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WO2020163620A1 (fr) 2020-08-13
CA3128940A1 (fr) 2020-08-13
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BR112021015467A2 (pt) 2021-10-05
JP2024026732A (ja) 2024-02-28
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JP2022519670A (ja) 2022-03-24
AU2023202545A1 (en) 2023-05-18
SG11202107926XA (en) 2021-08-30
MA54904A (fr) 2021-12-15
CO2021010380A2 (es) 2021-09-30
IL285389A (en) 2021-09-30
CA3213549A1 (fr) 2020-08-13
EP3920909A4 (fr) 2022-11-30

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