JP2023520574A - Pharmaceutical composition containing meloxicam - Google Patents

Abstract

Disclosed herein are compositions comprising an NSAID such as meloxicam and/or rizatriptan in combination with cyclodextrin and/or carbonate or bicarbonate. These compositions can be administered orally, for example, to improve the bioavailability or pharmacokinetics of NSAIDs for the treatment of pain such as migraine, arthritis, and other conditions. Also described herein are methods of treating pain, such as migraine, comprising administering meloxicam and rizatriptan to a human suffering from pain, such as migraine. For migraine, these methods may be particularly useful when administering meloxicam and rizatriptan while the human is suffering from an acute migraine attack or migraine aura. In some embodiments, the combination of meloxicam and rizatriptan may be administered such that the Tmax of meloxicam is 3 hours or less. [Selection figure] None

Description

(Cross reference to related applications)
This application is filed April 6, 2020, U.S. Provisional Patent Application No. 63/006,023; No. 16/842,063 filed May 7, 2020 and U.S. Patent Application No. 16/867,929 filed May 6, 2020, all of which , the entire contents of which are expressly incorporated by reference.

Meloxicam, which has the structure below, is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activity. Meloxicam's mechanism of action may be related to prostaglandin synthetase (cyclooxygenase, COX) inhibition, which is involved in the early stages of the arachidonic acid cascade, reducing the formation of prostaglandins, thromboxanes and prostacilins.

Meloxicam and some other NSAIDs are poorly soluble in water, thereby reducing their bioavailability and potentially delaying the onset of pain relief resulting from their use. One means of increasing the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cycloamyloses) are cyclic polysaccharides that generally form a bucket-like shape. Cyclodextrins help increase the bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the inside which helps facilitate transport of the molecule. Naturally occurring cyclodextrins contain 6, 7 and 8 glucose units (α, β and γ-cyclodextrins respectively). However, synthetic cyclodextrins containing more or less glucose units are possible. In aqueous solution, cyclodextrins can form complexes with drugs (ie, inclusion complexes) by incorporating the drug into the central/hydrophobic portion of the cyclodextrin ring. Cyclodextrin compounds are also known to aggregate around drugs in a micellar structure. This ability of cyclodextrins may allow them to act as carriers and increase the bioavailability of less soluble drugs.

Some embodiments treat migraine comprising selecting a human migraine patient with a history of inadequate response to previous migraine therapy and administering a dosage form to the migraine patient. Including methods of treatment, dosage forms include combinations of 1) meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan.

Some embodiments include inclusion complexes of meloxicam in cyclodextrins.

Some embodiments include dosage forms that include 1) an inclusion complex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or bicarbonate.

Some embodiments include a method of orally administering meloxicam comprising orally administering a dosage form described herein to a patient in need of treatment.

Some embodiments include a method of administering meloxicam intravenously, comprising administering a dosage form described herein intravenously to a patient in need thereof.

Disclosed herein are formulations and methods of use of inclusion complexes of cyclodextrin and meloxicam formulated with bicarbonate.

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.

Treat pain and pain by delivering a dosage form comprising meloxicam, cyclodextrin and bicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal or other parenteral means to a subject Methods of treating related conditions are also disclosed.

A combination of rizatriptan and meloxicam (also referred to herein as a "thematic combination" for convenience) may be used to treat a variety of pain conditions.

Rizatriptan has the structure shown below.

Some embodiments include a combination for treating migraine in humans comprising 1) an inclusion complex of meloxicam and a cyclodextrin, 2) rizatriptan, and 3) bicarbonate. The migraine may be treatment-resistant migraine. The human may have a history of poor response to previous therapy.

Some embodiments provide rapid, sustained, and substantial improvement compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of poor response to prior therapy. and which have statistically significant efficacy, including the subject combinations comprising rizatriptan and meloxicam.

Some embodiments include a subject combination comprising zatriptan and meloxicam with significantly less rescue medication use compared to placebo, rizatriptan, or meloxicam.

FIG. 6 is a diagram of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. FIG. 6 is another illustration of the results described in Example 2 and contained in Table 6. FIG. 1 is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for one embodiment of a dosage form described herein and a commercially available meloxicam dosage form. 1 is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for the meloxicam/rizatriptan dosage form described in Example 6 and the commercially available meloxicam dosage form. 2 is a plot of rizatriptan plasma concentrations at various time points over the first 12 hours for the meloxicam/rizatriptan dosage form described in Example 6 and the commercially available meloxicam dosage form. FIG. 4 shows a plot of the percentage of subjects reporting pain relief at various time points over the first 4 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Percentage of subjects reporting pain relief compared to placebo at 1.0 and 1.5 hours for meloxicam, rizatriptan, and meloxicam/rizatriptan. 2 shows the percentage of subjects free from pain at 2, 4, 12, and 16 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. FIG. 10 shows the percentage of subjects with sustained pain relief 2-24 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 3 shows the percentage of subjects with sustained pain relief 2-24 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. FIG. 10 shows the percentage of subjects with sustained pain relief 2-48 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 3 shows the percentage of subjects with sustained pain relief 2-48 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Percentage of subjects with sustained pain relief from 2 to 48 hours is shown for meloxicam/rizatriptan dosage forms, rizatriptan, and meloxicam/rizatriptan. Percentage of subjects with sustained pain relief from 2 to 48 hours for meloxicam/rizatriptan dosage forms, rizatriptan, and meloxicam/rizatriptan. Figure 3 shows the percentage of subjects taking rescue medication up to 24 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 12 shows the percentage of subjects who were free from pain and resolved their most bothersome symptoms for subjects who took meloxicam/rizatriptan and placebo in Example 12. Figure 12 shows the percentage of subjects who were free from pain and had resolution of bothersome symptoms for subjects who took meloxicam/rizatriptan and placebo in Example 12. 12 shows the percentage of subjects free from pain for subjects taking meloxicam/rizatriptan and placebo in Example 12. FIG. Figure 12 shows the percentage of subjects free from the most bothersome symptoms for subjects taking meloxicam/rizatriptan and placebo in Example 12. Figure 12 shows the percentage of subjects who were pain free over 2-24 hours and 2-48 hours for subjects taking meloxicam/rizatriptan and placebo in Example 12. Figure 12 shows the percentage of subjects who were pain free over 2-24 hours and 2-48 hours for subjects taking meloxicam/rizatriptan and placebo in Example 12. Figure 12 shows the percentage of subjects free from pain progression over 2-24 hours for subjects taking meloxicam/rizatriptan and placebo in Example 12. FIG. 10 shows the percentage of subjects who took rescue medication for subjects who took meloxicam/rizatriptan and placebo in Example 12. FIG. 24 shows the percentage of subjects without impairment at 24 hours for subjects taking meloxicam/rizatriptan and placebo in Example 12. FIG. Figure 12 shows the percentage of subjects with "very much improved" or "well improved" Patient Global Impression of Change (PGI-C) at 2 hours for subjects taking meloxicam/rizatriptan and placebo in Example 12. .

Provided herein are dosage forms comprising an NSAID (eg, meloxicam) and a cyclodextrin (optionally in an inclusion complex) and/or bicarbonate salt, and methods of treatment using the dosage forms.

The dosage form may be administered orally, enterally, including but not limited to, sublingual or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal or subcutaneous delivery. good too.

Some methods involve administering a product that combines an NSAID formulated with a) a cyclodextrin and/or b) a buffer. In some embodiments, the method comprises treating the patient with a pharmaceutical formulation comprising meloxicam and cyclodextrin and/or carbonate/bicarbonate. Embodiments of the method can also include treating a patient to increase the bioavailability of meloxicam in the patient or to increase the rate at which meloxicam becomes bioavailable.

The combination of meloxicam, cyclodextrin (such as SBEβCD), and bicarbonate (such as sodium bicarbonate) substantially increases the solubility and absorption of meloxicam after oral administration, whereas mammals, such as humans, after oral administration. plasma concentration half-life remains prolonged.

The combination of meloxicam, cyclodextrin (such as SBEβCD), and bicarbonate (such as sodium bicarbonate) substantially increases the bioavailability of meloxicam in mammals such as humans after oral administration.

Unless otherwise stated, references to compounds herein, such as meloxicam or rizatriptan, by structure, name, or by any other means, may include alternative solid forms such as pharmaceutically acceptable salts, polymorphs, etc. forms, solvates, hydrates, optical isomers, tautomers, deuterium-modified forms, or precursors, prodrugs, or rapidly under conditions of use as described herein. Any chemical species is included, including any other chemical species that can be rapidly converted to the compounds described herein.

The subject combinations are administered by enteral delivery, including but not limited to oral, sublingual, or rectal delivery, or by parenteral delivery, including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous delivery. may In some embodiments, both meloxicam and rizatriptan are administered orally. In some embodiments, meloxicam is administered intravenously and rizatriptan is administered orally. In some embodiments, meloxicam is administered intramuscularly and rizatriptan is administered orally.

Typically, the combination of meloxicam and rizatriptan is administered such that the human receives meloxicam and rizatriptan within a short period of time of each other. For example, meloxicam and rizatriptan 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 each other may be administered to In some embodiments, meloxicam and rizatriptan are administered simultaneously, including within about 5 minutes for the purposes of this disclosure. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form.

The term "treat" or "treatment" means any kind of therapeutic activity, including diagnosis, cure, alleviation or prevention of disease in humans or other animals, or non-therapeutic activity, but in humans or other animals. Broadly includes any activity that affects the structure or any function of the body.

The dosage form or subject combination may be used to treat migraine and other types of headache, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, generalized pain, cancer-related pain, acute pain , injury pain, disease pain (e.g., fever), postoperative pain, etc., to treat or provide relief from any type of pain. In some cases, pain relief may be temporary, or pain relief may be provided independent of amelioration of the disease or condition, or the underlying causes of the disease or condition. For example, the underlying disease may not improve or may continue to progress, but an individual suffering from the disease may experience pain relief. In some embodiments, the pain affects muscles, nerves, cartilage, bones, ligaments, tendons, tendon sheaths, eardrums, or joints.

Migraine is a disabling neurological disorder characterized by periodic attacks of pulsatile head pain, accompanied by nausea and sensitivity to light and sound. The pain is moderate to severe, but is often severe, immobilizing, and requires bed rest. The headache may affect half of the head, is pulsating, and may last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, hypersensitivity to light (photophobia), sound (phonophobia), or smell. Migraines may be accompanied by visual impairment. Migraines can be exacerbated by physical activity. A migraine may have an aura, which may be a brief visual disturbance that signals an impending headache. Some migraine sufferers have no aura.

In some embodiments, the human being treated for migraine suffers from allodynia associated with migraine attacks, such as cutaneous allodynia. Allodynia, such as cutaneous allodynia, is pain caused by stimuli that are not normally painful (such as combing hair, dressing, or taking a shower). Patients with allodynia, such as cutaneous allodynia, are believed to respond poorly to triptan drugs.

Current therapies are suboptimal, with over 70% of patients complaining of current acute treatments. The most common reasons for patient complaints are slow onset of pain relief, inconsistent pain relief, and recurrence of pain within the day. Suboptimal acute treatment is associated with a significantly increased risk of new episodes of chronic migraine, which can be prevented by improving the outcome of acute treatment.

Administering a subject combination to a human suffering from migraine, such as an acute attack or aura of migraine, causes migraine symptoms, such as pain, nausea, vomiting, photophobia, or phonophobia, for about 5 minutes or within (intended as an abbreviation for “within 5 minutes” or “within 5 minutes”), within about 10 minutes or less, within about 30 minutes or less, within about 1 hour or less, within about 90 minutes or less , about 2 hours or less, about 2.5 hours or less, or about 3 hours or less. In some embodiments, the human has a headache or within about 1 hour or less, about 90 minutes or less, about 2 hours or less, about 2.5 hours or less, or about 3 hours or less. Experience a reduction or complete alleviation of pain such as migraines, nausea, vomiting, photophobia, and/or phonophobia. In some embodiments, the relief experienced is greater than that experienced by receiving the same dose of rizatriptan without meloxicam. In some embodiments, the relief experienced is greater than experienced by administration of the same dose of meloxicam without rizatriptan.

The subject combinations are administered at the onset of early signs of migraine pain or soon after early signs of migraine headache, e.g., within about 1 minute, within about 5 minutes, within about 10 minutes, within about 15 minutes, about 20 minutes may be administered within, within about 30 minutes, or within about 1 hour. At this early stage, the pain may still be mild, or may be before the pain progresses to moderate or severe. In some methods, the subject combinations may be administered when migraine pain reaches moderate or moderate severity.

In some embodiments, the combination of meloxicam and rizatriptan is administered to a patient with, or selected to have, an impairment. In some embodiments, treatment allows a human migraine sufferer to return to normal activity within 24 hours of receiving treatment.

The combination of meloxicam and rizatriptan may have two distinct mechanisms of function as an acute treatment for migraine. Meloxicam is a potent, COX-2 preferential NSAID, limited by slow absorption. Rizatriptan is a potent 5-HT1 _B/D agonist that is believed to be effective in migraine.

Findings of symptom relief or reduction at a specific time point, such as "2 hours," is useful because it allows the efficacy of treatment to be assessed at a specific or consistent time point, facilitating comparisons between patients. be. It is desirable that relief or alleviation of symptoms occur as soon as possible, and to clarify that relief is to occur within a certain time period is to set a guideline that relief is desirable, so “2 hours Findings of symptom relief or reduction within a specified time period, such as "within", are useful.

For some methods, administration of the subject combinations causes pain, nausea, vomiting, photophobia, or phonophobia for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about The relief may continue for about 6 hours, at least about 8 hours, at least about 8-24 hours, at least about 24 hours, or 24 hours or more.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan They experience greater pain relief than they do two hours after administering the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan They experience greater pain relief than they do 24 hours after administering the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam at 2 hours after administration of the same dose of rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam experience greater pain relief than that experienced 24 hours after administration of the same dose of rizatriptan at .

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of nausea is experienced than is experienced 2 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of nausea is experienced than is experienced 24 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam at 2 hours after administration of the same dose of rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam experience greater nausea relief than that experienced 24 hours after administration of the same dose of rizatriptan at .

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of vomiting is experienced than is experienced 2 hours after administration of the same dose of meloxicam without administration.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of vomiting is experienced than is experienced 24 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam at 2 hours after administration of the same dose of rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam at 24 hours after administration of the same dose of rizatriptan. In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of photophobia is experienced than that experienced 2 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of photophobia is experienced than that experienced 24 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam at 2 hours after administration of the same dose of rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam at 24 hours after administration of the same dose of rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of phonophobia is experienced than that experienced 2 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan A greater relief of phonophobia is experienced than that experienced 24 hours after administration of the same dose of meloxicam without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam experience greater relief of phonophobia than that experienced 2 hours after administration of the same dose of rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is free of meloxicam experience greater relief of phonophobia than that experienced 24 hours after administration of the same dose of rizatriptan at .

In some embodiments, a human being administered a subject combination has a history of incomplete response to prior migraine therapy. For example, for most attacks, people were asked if they were pain free within 2 hours of treatment and were given the options "never", "rarely", "less than half", or "more than half". , the person has an incomplete response to treatment if the person answers "never", "rarely", or "less than half". Similarly, asked if headaches were relieved most of the time after a single dose and were headache-free for at least 24 hours, the options were 'never', 'rarely', 'less than half', or 'more than half'. is given and the person answers "none", "rarely", or "less than half", the person has an incomplete response to the treatment.

In some embodiments, humans administered the subject combinations demonstrate "never" pain relief within 2 hours of treatment for most attacks. In some embodiments, humans administered the subject combinations show that for most attacks, pain was "rarely" gone within 2 hours of treatment. In some embodiments, humans administered the subject combinations demonstrate that “less than half” of most attacks are pain free within 2 hours of treatment.

In some embodiments, humans administered the subject combinations demonstrate that one administration relieved the respondent's headache and "never" freed them from occurring for at least 24 hours. . In some embodiments, humans administered the subject combinations demonstrate that one administration relieved the respondent's headache and "rarely" had no headaches for at least 24 hours. . In some embodiments, humans administered a subject combination indicated that one administration relieved the respondent's headache and that "less than half" were headache free for at least 24 hours. ing.

In some embodiments, humans administered a subject combination have a total mean score of less than 7, less than 6, less than 5, less than 4, less than 3 on the Migraine Treatment Optimization Questionnaire (mTOQ-4) Inadequate response to prior migraine therapy as assessed by <2, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7 have a history of In some embodiments, the human has used a triptan prior to being administered the subject combination, such as a combination comprising meloxicam and rizatriptan.

In some embodiments, the human being administered a subject combination, such as a combination comprising meloxicam and rizatriptan, has migraine headaches and a history of inadequate response to prior migraine therapy. There may be. In some embodiments, the human with migraine does not have cluster headaches or other types of migraines. In some embodiments, the human with migraine does not have chronic daily headache. In some embodiments, the human with migraine has no more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 migraine-free days per month . In some embodiments, the human with migraine has no history of significant cardiovascular disease. In some embodiments, the human with migraine does not have uncontrolled hypertension.

In some embodiments, the dosage form may be administered to relieve arthritic pain. In some embodiments, dosage forms may be administered to alleviate other signs and/or symptoms of arthritis. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (small and polyarticular), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid), arthritis , non-rheumatoid arthritis, periarticular disorders, axonal spondyloarthritis, transient osteoarthritis of the hip, vertebral contusion fractures, osteoporosis, and neuropathic arthropathies including Charcot's foot, spinal joints including ankylosing spondylitis disease as well as SAPHO syndrome. In other embodiments, arthritis pain can be chronic or acute. In some embodiments, dosage forms may be administered to alleviate signs and/or symptoms of arthritis, including but not limited to osteoarthritis.

In some methods, administration of the dosage form provides pain relief lasting at least about 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least about 8 hours, from about 8 hours to about 24 hours, or about 24 hours. can be achieved. In other embodiments, administration of the dosage form is about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours after administration of the dosage form, less than 15 minutes, less than 20 minutes, 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 60 minutes, or any of these Observed pain relief over other periods bounded by the range can be achieved.

In some embodiments, the dosage form is used to relieve neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monocuspid neuralgia, phantom limb pain, sciatica, pudendal neuralgia and central pain. can be administered. Other causes of neuropathic pain include, but are not limited to, cancer-related pain, lumbar root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy and radiotherapy or chemotherapy. May include neuropathies associated with therapeutic treatment. Neuropathic pain to be treated can be chronic or acute.

In some methods, the dosage form can be administered to relieve inflammatory pain, including inflammatory musculoskeletal pain, injury pain, arthritis pain, and complex regional pain syndromes. In other embodiments, inflammatory pain can be chronic or acute.

Arthritis refers to inflammatory joint disease that can be associated with pain. Examples of arthritic pain include, but are not limited to, osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthritis, non-rheumatoid arthritis, arthritis Included are pain associated with peripheral disorders, neuropathic arthropathies including Charcot's foot, axonal spondyloarthropathies including ankylosing spondylitis, and SAPHO syndrome. The inflammatory joint disease treated can be chronic or acute.

In some methods, meloxicam can be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain include, but are not limited to, low back pain, lower back pain (e.g., lumbosacral pain), neck pain, infections, spasms, tendonitis, thyroiditis, carpal tunnel syndrome, joint pain, fibrosing Myalgia, pain from injury, carpal tunnel syndrome, pain associated with fractures, sprains, fibrodysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis and transient osteoporosis of the hip may be included. In other embodiments, musculoskeletal pain can be chronic or acute.

In some methods, administration of the dosage form or the subject combination takes at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8 to about Pain reduction lasting 24 hours, or about 24 hours, can be achieved. In another embodiment, administration of the subject combinations results in about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 5 minutes or less, about 10 minutes or less, about 15 minutes or less, about 20 minutes or less, about 25 minutes or less, about 30 minutes or less , about 35 minutes or less, about 40 minutes or less, about 45 minutes or less, about 50 minutes or less, or about 60 minutes or less, 2 hours or less, 3 hours or less, in these ranges A reduction in pain seen in other periods bounded by

A human being treated for a disease or condition with the dosage forms described herein can be of any age. For example, about 10 to about 90 years old, about 20 to about 80 years old, about 30 to about 75 years old, about 40 to about 70 years old, about 1 to about 16 years old, about 80 to about 95 years old, About 18 years old or older, about 20 years old or older, about 25 years old or older, about 30 years old or older, about 40 years old or older, about 45 years old or older, about 50 years old or older, about 55 years old or older, about 60 years old or older, about 65 years old or older, or any other age within a range bounded by or between these values.

In some embodiments, a human being treated for migraine with a dosage form described herein comprising, for example, meloxicam, rizatriptan, SBEβCD, and a bicarbonate such as sodium bicarbonate is 18 years old to 65 years old, about 18-20 years old, about 20-25 years old, about 25-30 years old, about 30-40 years old, about 40-45 years old, about 40-50 years old, about 50-60 years old, about 60-65 years old years, or any other age bounded by or within the range between these values.

In some embodiments, a human being treated for migraine with a dosage form described herein, such as a dosage form comprising meloxicam, rizatriptan, SBEβCD, and a bicarbonate such as sodium bicarbonate , Caucasian, Black or African American, or Asian.

In some embodiments, a human being treated for a disease or condition with a dosage form comprising meloxicam or another NSAID is treated for at least one day, at least one week, at least two weeks, at least one month, at least six weeks, at least Has been suffering from pain or a condition associated with pain for 2 months, at least 3 months, at least 6 months, or at least 1 year, or any time period bounded by or within these values.

In some embodiments, the human being treated for migraine with a dosage form comprising meloxicam and rizatriptan is treated for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2 Diagnosis of migraine with or without aura, as defined by ICHD-3 criteria, for ~3 years, or longer, or any period bounded by or within these values is recieving.

In some embodiments, the human has an average of 2-8, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8 moderate to severe of migraines occur.

Cyclodextrins used in dosage forms containing meloxicam can include cyclodextrins, cyclodextrin derivatives and/or salts thereof. Inclusion complexes of meloxicam and cyclodextrin may be more water soluble than uncomplexed meloxicam. Cyclodextrins can be natural cyclodextrins (eg, α, β or γ-cyclodextrins) or synthetic cyclodextrins. In some embodiments, α-cyclodextrin, derivatives or salts thereof may be used. α-Cyclodextrins include, but are not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin , (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O -tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

In some embodiments, β-cyclodextrin, derivatives or salts thereof may be used. β-Cyclodextrin includes, but is not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6- O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl- 6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl- 6-O-sulfo)-β-cyclodextrin, (2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3 ,6-tri-O-methyl)-β-cyclodextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, (2,3,6-tri-O-benzoyl)-β- Cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β -cyclodextrin, 6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6 -di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-O-t-butyldimethylsilyl- 2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,6-di-O-)ethyl-β-cyclodextrin, (2- carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl (6- O-tert-butyldimethyl)-2,3-di-O-acetyl)-β-cyclodextrin, succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomly methylated It may contain β-cyclodextrin, branched-β-cyclodextrin, or combinations thereof.

In other embodiments, the β-cyclodextrin can be a sulfoalkyl ether cyclodextrin, derivative or salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives can include, without limitation, sulfobutyl ether-β-cyclodextrin (eg, SBEβCD, Betadex, CAPTISOL®). In some embodiments, the SBEβCD has about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule. obtain.

In some embodiments, γ-cyclodextrin, its derivatives or salts may be used. γ-Cyclodextrin is carboxymethyl-γ-cyclodextrin, (2,3,6-tri-O-acetyl)-γ-cyclodextrin, (2,3,6-tri-O-methyl)-γ-cyclodextrin Dextrin, (2,6-di-O-pentyl)-γ-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin, 6-bromo-6-deoxy-γ-cyclodextrin , 6-iodo-6-deoxy-γ-cyclodextrin, (6-Ot-butyldimethylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin (2-hydroxypropyl )-γ-cyclodextrin, acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin or combinations thereof.

In some embodiments, dosage forms may include bicarbonates such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or combinations thereof. Bicarbonate may help increase the bioavailability of meloxicam.

In other embodiments, the dosage form may contain a carbonate, derivative or salt thereof. Examples of carbonates include aluminum carbonate, ammonium carbonate, barium carbonate, calcium carbonate, cobalt(II) carbonate, lanthanum carbonate, lithium carbonate, magnesium carbonate, manganese(II) carbonate, potassium carbonate, sodium carbonate, or combinations thereof. obtain.

In some embodiments, the enhanced bioavailability of the dosage form is achieved by generating an inclusion complex of meloxicam and cyclodextrin by administering a dosage form comprising a salt form of meloxicam. and/or bicarbonate, in treating one of these conditions. This allows the molar amount of meloxicam to be used to be reduced compared to other meloxicam dosage forms.

Unless otherwise indicated, compounds herein by structure, name or by any other means, such as meloxicam or cyclodextrin, are pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers isomers, tautomers, deuterium modified forms or any other chemical species that can be rapidly converted to the compounds described herein under the conditions under which the compounds described herein are used. including morphology.

In some embodiments, the use of cyclodextrins, carbonates or bicarbonates reduces 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 bounded by these values compared to administration of meloxicam alone , or any amount within the range therebetween.

Due to the improved bioavailability, dosage forms can contain or be administered to a subject meloxicam on a lower molar basis than meloxicam that would otherwise be administered. For example, the dosage form is at least about 10 mol % less, at least about 20 mol % less, at least about 30 mol % less, at least about 40 mol % less, at least about 40 mol % less, than meloxicam that would otherwise be administered. about 50 mol % less, at least about 60 mol % less, at least about 70 mol % less, at least about 80 mol % less, at least about 85 mol % less, and/or up to about 90 mol % less, 95 mol % less, or Any amount of meloxicam within the range bounded by or between these values can be contained or administered to the mammal.

In other embodiments, the use of other NSAIDs, opioids, or other analgesics is 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%, cyclodextrin , compared to the use of other NSAIDs, opioids or other analgesics without administering meloxicam with carbonate and/or bicarbonate.

In some embodiments, the dosage form is 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 these Any amount of meloxicam within a range bounded by or between the values of These doses are for repeated dosing, such as 1 to 1 dose per hour, 2 doses per day, 1 to 12 doses per day, 3, 4, 5 or 6 times per day. can be a safe dose of In some embodiments, meloxicam is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times daily, about 3 to about 10 times daily, It can be safely administered once a day or less frequently, eg, once a week, once every two weeks, once a month, and the like.

In some dosage forms, meloxicam is complexed with substituted beta cyclodextrins or other cyclodextrins that can be formulated into solid dosage forms. Such dosage forms may be suitable for oral administration. The meloxicam-cyclodextrin inclusion complex may also be dissolved in water or another solvent to form a parenteral formulation. However, physical mixtures of meloxicam with substituted β-cyclodextrins or other cyclodextrins can also be used in oral or parenteral dosage forms.

Inclusion complex formation between meloxicam and cyclodextrin can help improve the properties of the dosage form. For some inclusion complexes, meloxicam and cyclodextrin (eg, SBEβCD) are 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 to 1.9, about 1.8 to 2, about 0.8 to 1.2, about 1, or any molar ratio within a range bounded by or between these values can have

In some dosage forms, the cyclodextrin (e.g., SBEβCD) is about 1-1000 (e.g., 1 g cyclodextrin per g meloxicam weight ratio), about 1-20, about 1-10, about 1-1000 15, about 2 to 4, about 3 to 5, about 4 to 6, about 5 to 7, about 6 to 8, about 7 to 9, about 8 to 10, or within a range bounded by these values can be used in any weight ratio to meloxicam. In some dosage forms, the cyclodextrin (eg, SBEβCD) is added from about 0.001 to 1 (eg, at a weight ratio of 0.1 g of cyclodextrin per g of meloxicam), from about 0.01 to 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, A weight ratio to meloxicam of about 0.7 to 1, about 0.8 to 1, or any range bounded by or between these values may be used. Each type of cyclodextrin used may have different ratios.

In some dosage forms, the cyclodextrin is about 1-200 mg, about 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 within a range bounded by or between these values.

In some methods, inclusion complexes of meloxicam and cyclodextrins (eg, substituted β-cyclodextrins) are delivered orally (eg, via tablets, capsules, elixirs, etc.). Other possible routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal or other parenteral means. Meloxicam may be delivered alone or uncomplexed with a cyclodextrin.

Some dosage forms are about 1-2000 mg, about 1-1000 mg, about 100-1000 mg, about 200-800 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500- 1000 mg, about 100-500 mg, about 100-300 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 250-750 mg, about 100-200 mg, about 200-300 mg, about 300- 400 mg, about 400-500 mg, about 410-510 mg, about 420-520 mg, about 430-530 mg, about 440-540 mg, about 450-550 mg, about 460-560 mg, about 470-570 mg, about 480-580 mg, about 490- 590 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any range bounded by or therebetween. amount of bicarbonate (eg, sodium bicarbonate).

Some dosage forms are about 1-1000 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 200- 800 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 250-750 mg, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 500- 600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any amount bounded by or between these values. .

In some embodiments, the daily dose of meloxicam (eg, oral dose, parenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or by values thereof Any quantity within a range bounded by or in between.

In some embodiments, the weekly dose (eg, oral dose) of meloxicam 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 within the range bounded by or between these values. Weekly doses may be given as a single dose given once a week, or may be given in separate doses 2, 3, 4, 5, 6 or 7 times a week.

In some embodiments, the monthly dose (e.g., oral dose) of meloxicam, or dose administered over a period of one 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 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 bounded by or between these values is any amount within the range of . The monthly dose can be given as a single dose or as two or more separate doses administered during the month. In some embodiments, the monthly dose is administered in two or three biweekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28-31 daily doses, or 56-62 daily doses or more. In some embodiments, the monthly dose is administered in 5-15 separate doses per month. Monthly doses may be administered for only one month, or may be administered repeatedly for two or more months.

In other embodiments, the dosage form can be administered every week for about 1, 2, 3, 4 or more consecutive weeks, every other week, ie every other week, or once every three weeks. This regimen can be repeated weekly, twice a month, three times a month, once a month, once every two months, once every three months, or as directed by a healthcare practitioner.

In certain embodiments, the pharmaceutical composition has improved meloxicam from the dosage form compared to a dosage form containing meloxicam but not containing cyclodextrins, acid inhibitors or buffering agents (e.g., bicarbonate). Resulting in bioavailability (eg, decreased T _max , increased C _max , increased AUC, etc.). In some embodiments, meloxicam bioavailability increases with multiple administrations. For example, the bioavailability of meloxicam in a dosage form is compared to the bioavailability of meloxicam in dosage forms that do not contain cyclodextrins, acid inhibitors or buffers (e.g., bicarbonate). about 1-10 days after administration, about 2-6 days after administration, about 3-5 days after administration, about 4-6 days after administration, about 5-8 days after administration, about 5 days after administration, about 6 days after administration days, about 7 days of administration, about 8 days of administration, about 10 days of administration, about 15 days of administration, or after any period within the range bounded by or between these values.

Some dosage forms may provide a desired range of area under the plasma concentration curve (AUC) of meloxicam. For example, doses of meloxicam are about 1-150 μg-hr/mL, about 10-30 μg-hr/mL, about 20-40 μg-hr/mL, about 30-50 μg-hr/mL, about 40-60 μg-hr/mL. mL, about 50-70 μg-hr/mL, about 60-80 μg-hr/mL, about 70-90 μg-hr/mL, about 80-100 μg-hr/mL, about 10-100 μg-hr/mL, about 50- 150 μg hr/mL, about 25-125 μg hr/mL, about 75-150 μg hr/mL, about 20-50 μg hr/mL, about 40-70 μg hr/mL, about 60-90 μg hr/mL , about 80-110 μg-hr/mL, about 100-130 μg-hr/mL, about 120-150 μg-hr/mL, or any AUC bounded by or between these values can result in

Unless otherwise indicated, AUC is AUC over a 6-hour period (AUC _0-6 ), AUC over a 12-hour period (AUC _0-12 ), AUC over a 24-hour period (AUC _0-24 ), etc. refers to the AUC calculated relative to the last measured concentration of (AUC _0-t ), or the AUC extrapolated to infinity (AUC _0-inf ).

In Example 3 below, for oral dosage forms containing sodium bicarbonate and sulfobutyl ether β-cyclodextrin (SBEβCD), the AUC _0-24 of meloxicam in humans was approximately 27 μg·hr/mL. This dosage form contained 15 mg of meloxicam.

Even at 15 mg IV and IM, the AUC _0-24 of meloxicam in humans was approximately 27 μg·hr/mL. The AUC of meloxicam is believed to be approximately proportional to dose. Thus, for this oral dosage form, or for an IV or intramuscular dosage form, for example, administration of about 17 mg to about 30 mg of meloxicam would result in an AUC _0-24 of meloxicam of about 30-50 μg·hr/mL. .

For acute pain symptoms such as migraine or other types of headache, AUCs in the short-term post-administration are of particular interest, such as AUCs measured over 6 hours (AUC _0-6 ). For example, some dosage forms contain at least about 6 μg-hr/mL, at least about 7 μg-hr/mL, at least about 8 μg-hr/mL, at least about 9 μg-hr/mL, about 6-10 μg-hr/mL, AUC of meloxicam of about 7-11 μg-hr/mL, about 8-12 μg-hr/mL, about 9-13 μg-hr/mL, or any AUC bounded by or between these values can bring

In some embodiments, the dosage form is about 10-2500 ng/mL, about 100-2250 ng/mL, about 500-2000 ng/mL, about 1000-2500 ng/mL, about 1000-2000 ng/mL, about 100-900 ng /mL, about 750-1500 ng/mL, about 1250-2000 ng/mL, about 1500-2300 ng/mL, about 800-1200 ng/mL, about 1900-2400 ng/mL, about 50-500 ng/mL, about 400-950 ng/mL mL, about 900-1500 ng/mL, about 1100-2200 ng/mL, about 1300-1600 ng/mL, about 1200-1500 ng/mL, about 1400-2100 ng/mL, about 1500-1900 ng/mL, about 1600-2100 ng/mL , about 1700-2000 ng/mL, about 1800-2000 ng/mL, about 1900-2500 ng/mL, about 150-1700 ng/mL, about 1600-1800 ng/mL, about 1700-1900 ng/mL, about 1800-2000 ng/mL, C _max of meloxicam of about 1900-2100 ng/mL, about 2000-2200 ng/mL, about 2100-2300 ng/mL, about 2200-2400 ng/mL, about 2300-2500 ng/mL, about 2500-3000 ng/mL, or any of these Any C _max within the range bounded by or between the values may result.

For example, the methods described herein can lower the T _max of meloxicam. In some embodiments, the method comprises 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 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, about 7- This may involve treating the patient to achieve the T _max of meloxicam within 10 hours or after its administration, or any T _max bounded by or within these values.

In some embodiments, an oral dosage form may have a shorter meloxicam T _max than that achieved by administration of meloxicam by intramuscular injection. In some embodiments, the oral dosage form is at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8 times lower than that observed with intramuscular injection. , about 9, about 10, about 12, about 15, about 20 times, or about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100 times faster, or bounded by or between these values can have a shorter T _max of meloxicam or increase the plasma concentration of meloxicam by any factor of speed within the range of .

The oral dosage form of Example 3 below provides a T _max of meloxicam in approximately 30 minutes. The T _max of intravenous meloxicam has been reported to be approximately 30 minutes for infusion and approximately 3 minutes for bolus. The T _max of intramuscular meloxicam has been reported to be approximately 60-84 minutes.

In some embodiments, the dosage form comprising meloxicam has about 0.01-0.5 μg/mL, about 0.5-0.7 μg/mL, about 0.6-0.8 μg/mL, about 0.01-0.5 μg/mL, about 0.6-0.8 μg/mL, 7-0.9 μg/mL, about 0.8-1 μg/mL, about 0.9-1.1 μg/mL, about 1-1.2 μg/mL, about 1.1-1.3 μg/mL, about 1 .2-1.4 μg/mL, about 1.3-1.5 μg/mL, about 1.4-1.6 μg/mL, about 1.5-1.7 μg/mL, about 1.6-1.8 μg /mL, about 1.7-1.9 μg/mL, about 1.8-2 μg/mL, about 1.9-2.1 μg/mL, about 2-2.2 μg/mL, about 2.1-2. 3 μg/mL, about 2.2-2.4 μg/mL, about 2.3-2.5 μg/mL, about 2.4-2.6 μg/mL, about 2.5-2.7 μg/mL, about 2 .6-2.8 μg/mL, about 2.7-2.9 μg/mL, about 2.8-3 μg/mL, about 2.9-3.1 μg/mL, about 3-3.2 μg/mL, about 3.1-3.3 μg/mL, about 3.2-3.4 μg/mL, about 3.3-3.5 μg/mL, about 3.4-3.6 μg/mL, about 3.5-3. 7 μg/mL, about 3.6-3.8 μg/mL, about 3.7-3.9 μg/mL, about 3.8-4 μg/mL, or any range bounded by or between these values Any plasma concentration, meloxicam plasma concentration at 12 hours may result.

In some embodiments, meloxicam is about 0.01-0.5 μg/mL, about 0.5-0.7 μg/mL, about 0.6-0.8 μg/mL, about 0.7-0. 9 μg/mL, about 0.8-1 μg/mL, about 0.9-1.1 μg/mL, about 1-1.2 μg/mL, about 1.1-1.3 μg/mL, about 1.2-1 .4 μg/mL, about 1.3-1.5 μg/mL, about 1.4-1.6 μg/mL, about 1.5-1.7 μg/mL, about 1.6-1.8 μg/mL, about 1.7-1.9 μg/mL, about 1.8-2 μg/mL, about 1.9-2.1 μg/mL, about 2-2.2 μg/mL, about 2.1-2.3 μg/mL, about 2.2-2.4 μg/mL, about 2.3-2.5 μg/mL, about 2.4-2.6 μg/mL, about 2.5-2.7 μg/mL, about 2.6-2 .8 μg/mL, about 2.7-2.9 μg/mL, about 2.8-3 μg/mL, about 2.9-3.1 μg/mL, about 3-3.2 μg/mL, about 3.1- 3.3 μg/mL, about 3.2-3.4 μg/mL, about 3.3-3.5 μg/mL, about 3.4-3.6 μg/mL, about 3.5-3.7 μg/mL, about 3.6-3.8 μg/mL, about 3.7-3.9 μg/mL, about 3.8-4 μg/mL, about 0.1-20 μg/mL, about 0.5-15 μg/mL, about 0.5-10 μg/mL, about 5-15 μg/mL, about 10-20 μg/mL, about 7.5-15 μg/mL, about 2-10 μg/mL, about 1-8 μg/mL, about 1-6 μg/mL mL, about 1-2 μg/mL, about 0.5-3.5 μg/mL, about 0.5-7 μg/mL, about 12-20 μg/mL, about 8-12 μg/mL, about 1-4 μg/mL, about 4-7 μg/mL, about 7-11 μg/mL, about 11-15 μg/mL, about 15-19 μg/mL, about 16-20 μg/mL, or a range bounded by or between these values Any meloxicam plasma level (eg, C _avg or mean plasma level) is administered at a dose.

Administration of the dosage forms described herein can decrease the time to reach therapeutic plasma concentrations of meloxicam. The therapeutic plasma concentration is C _avg at 15 mg Mobic® meloxicam. In some embodiments, the time to reach therapeutic plasma concentration (T _thera ) of meloxicam is about 10-30 minutes, about 10-15 minutes, about 15-20 minutes, about 20-25 minutes, about 25-30 minutes, about 10-20 minutes, about 20-30 minutes, about 16-18 minutes, or about 17 minutes.

The methods described herein can reduce the T _max of rizatriptan. For example, the method can be administered within about 50 minutes, within about 60 minutes, within about 70 minutes, within about 80 minutes, within about 90 minutes, within about 40-60 minutes, about 40-45 minutes, about 45-50 minutes, A T _max of rizatriptan in a patient of about 50-55 minutes, or about 55-60 minutes, or any T _max bounded by these values, can be achieved.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is Greater relief from allodynia, such as cutaneous allodynia, is experienced than is experienced 2 hours after administration of the same dose of meloxicam without the triptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is Greater relief from allodynia, such as cutaneous allodynia, is experienced than is experienced 24 hours after administration of the same dose of meloxicam without triptans.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human is administered meloxicam A greater relief from allodynia, such as cutaneous allodynia, is experienced than is experienced 2 hours after administration of the same dose of rizatriptan without.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (eg, in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human is administered meloxicam A greater relief from allodynia, such as cutaneous allodynia, is experienced than is experienced 24 hours after administration of the same dose of rizatriptan without.

One embodiment reduces the risk of gastrointestinal side effects and improves the bioavailability of NSAIDs for pain relief and in people taking NSAIDs during other conditions, especially chronic treatments. The method. In one embodiment, the method relates to administration of a) an agent that actively raises gastric pH and b) a product that combines an NSAID formulated with a cyclodextrin. In another embodiment, the method relates to administration of a product that combines a) an agent that actively raises gastric pH, b) an NSAID formulated with a cyclodextrin, and c) a buffering agent. Either short or long acting acid inhibitors can be effectively used in the dosage form. This method has the added advantage of protecting the patient from other sources of gastrointestinal ulcers whose efficacy may be enhanced by the disruption of gastroprotective prostaglandins resulting from NSAID therapy.

Aqueous parenteral forms of meloxicam formulations have a pH of about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or any other pH within the range bounded by or between these values. Oral forms of meloxicam formulations have a Buffers may be included to adjust the pH of the gastric fluid at any other pH within the bounds or range therebetween. Examples of buffers suitable for use herein include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, and the like.

In some embodiments, dosage forms may be formulated for oral administration, for example, with an inert diluent or an edible carrier, or may be enclosed in hard or soft shell gelatin capsules, or may be compressed into tablets. , or may be included directly in the diet. For oral therapeutic administration, the active compound is incorporated with excipients to form ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches. It can be used in the form of

Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; corn starch; starch, disintegrating agents such as alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose, lactose or saccharin, or flavoring agents such as peppermint, oil of wintergreen or cherry flavoring. may When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may also be present as coatings, for example tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. It may be desirable for substances in dosage forms or pharmaceutical compositions to be pharmaceutically pure and substantially non-toxic in the amounts employed.

Some compositions or dosage forms may be liquid or may contain a solid phase dispersed in a liquid.

The dosage form may contain a second therapeutically active agent such as an antacid or an analgesic.

In some embodiments, the dosage form, when administered in one or more unit dosage forms, reduces the patient's gastric pH to at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and It can further include an acid inhibitor present in an effective amount to raise it to at least 5 higher. The term "acid inhibitor" refers to agents that inhibit gastric acid secretion and increase gastric pH. Certain H2 blockers, also called H2 antagonists or histamine H2 blockers or antagonists, include, without limitation, cimetidine, ranitidine, ebrotidine, pavtidine, lafutidine, loxtidine, famotidine or combinations thereof.

Other drugs that can be effectively used as acid inhibitors are proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments, the daily dose of 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 range bounded by or between these values. quantity.

Examples of specific proton pump inhibitors are esomeprazole present in unit dosage form in amounts between 5 mg and 50 mg, omeprazole present in unit dosage forms in amounts between 5 mg and 50 mg, 5 mg and 150 mg. and lansoprazole present in unit dosage form in an amount between (preferably between 5 mg and 30 mg) and pantoprazole present in unit dosage form in an amount between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about It is present in the dosage form in an amount of 80-100 mg. Recently, a newer class of acid inhibitors has been developed that compete with potassium for the acid pump. This class of compounds, termed "reversible proton pump inhibitors" or "acid pump antagonists," may be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO 96/05177 and WO 96/05199). Other compounds in this group are H-335/25 (AstraZeneca, Dialogue File 128, Accession No. 020806), Sch-28080 (Schering-Plough, Dialogue File 128, Accession No. 009663), Sch-32651 (Schering-Plough, Dialogue File 128, Accession No. 006883) and SK&F-96067 (CAS Registry No. 115607-61-9).

A second therapeutically active agent may include a second non-steroidal anti-inflammatory agent, an opioid, a steroid, an analgesic such as a triptan. In some embodiments, the dosage form or treatment also further comprises administering an amount of a second non-steroidal anti-inflammatory drug effective to reduce or eliminate pain or inflammation. NSAIDs include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (for purposes of this disclosure (considered as an NSAID in the United States), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac , tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof. For the purposes of this disclosure, references to acid inhibitors, NSAIDs or analgesics are understood to include all common forms of these compounds, particularly the pharmaceutically acceptable salts thereof. The amount of therapeutically effective NSAID in the presence of acid inhibitors or in the presence of buffering agents is actually lower than that found elsewhere due to potential positive kinetic interactions and NSAID absorption. can also be lower in the current embodiment.

In other embodiments, the dosage form or treatment can further comprise administering an amount of an opioid effective to reduce or eliminate pain or inflammation. Opioids include, but are not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprozin, vezitramide, buprenorphine, butorphanol, carfentanil, desmethylprozin, dextromoramide, dezocine, diacetylmorphine, dihydroco Deinone, dihydroethorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lephetamine, levacetylmethadol, levomethorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine , nalmefene, naloxone, naltrexone, nicomorphine, omefentanil, oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenatazocine, pyritramide, prozine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof obtain.

Useful triptans can include sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, arbitriptan, zolmitriptan, and the like. In some embodiments, triptans include rizatriptan. In some embodiments, the dosage form is about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg , about 9-14 mg, about 10-15 mg, about 15-20 mg, or about 20-30 mg, or any amount within the ranges bounded by these values.

In some embodiments, dosage forms comprising the subject combinations are about 1-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, or about 40-50 mg, about 10-10 mg, 40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 1-10 mg, about 5-20 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5- 10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-11 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about 12-17 mg, about 13-18 mg, about 14- 19 mg, about 15-20 mg, about 5-15 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or any range bounded by or therebetween. of rizatriptan.

For acute migraine, the amount of meloxicam and/or rizatriptan in a single dose or the AUC of meloxicam and/or rizatriptan in relation to a single dose is of particular interest. For example, a single dose may be followed by long-term relief of symptoms such that repeat doses may not be required in the short term. Daily, weekly, or monthly dosages for chronic, persistent, or even persistent symptoms, including frequent migraine episodes, may be of particular interest.

For the amounts of rizatriptan described herein, the salt form of rizatriptan may be present in the amounts described above or in molar equivalents of those amounts for rizatriptan free base. For example, given that the molecular weight of rizatriptan free base is 269.3 g/mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. A molar equivalent of 10 mg of rizatriptan free base is therefore an amount of 37.1 mmol of the salt form. For example, for benzoate (mw=391.2 g/mol), the molar equivalent of 10 mg of free base (or 37.1 mmol) is 14.5 mg. These doses may be 1, 2, 3, or 4 times daily, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 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 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. may be safe with repeated doses of

The pharmaceutical composition comprises (a) an acid inhibitor, and/or (b) a buffering agent, (c) 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. It may be in tablet or capsule form with a non-steroidal anti-inflammatory drug (NSAID) present. The components of the pharmaceutical composition, individually or as a whole, may be in immediate release or sustained release form.

The term "unit dosage form" as used herein refers to a single entity for drug administration. For example, a single tablet or capsule combining both the acid inhibitor and the NSAID would be the unit dosage form. A “unit dosage form” (or “unit dosage form”) is also known as a “fixed dosage form” (or “fixed dosage form”) or a “fixed dosage combination” (or “fixed dosage combination”). and are interchangeable in other literature. In one embodiment, the unit dosage form is a multi-layer tablet.

In other embodiments, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In yet another embodiment, the unit dosage form is a multi-layer tablet comprising a single core and one or more layers outside the core.

Some dosage forms may include a first layer comprising meloxicam, SBEβCD, and bicarbonate, and a second layer comprising a second therapeutically active agent and bicarbonate.

The first layer can include meloxicam, for example, in any amount of one of the ranges set forth above. For example, all meloxicam in the dosage form can be in the first layer. The second layer can include all of the second therapeutically active agent, such that any amount in the range described above for the second therapeutically active agent can be applied to the second layer.

In some embodiments, the first layer comprises about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg, or ranges bounded by these values. any amount of bicarbonate, such as sodium bicarbonate.

In some embodiments, the second layer is about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg, or ranges bounded by these values. any amount of bicarbonate, such as sodium bicarbonate.

In some embodiments, the pharmaceutical composition can have effective amounts of meloxicam, cyclodextrin, and carbonate or bicarbonate to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition comprises an effective amount of meloxicam, sulfobutyl ether-β- _cyclodextrin (SBEβCD), and sodium bicarbonate.

Some oral dosage forms may have enteric coatings or film coatings. In some embodiments, dosage forms may include tablets or capsules having enteric coatings. In some embodiments, dosage forms may include tablets or capsules having film coatings.

One embodiment of the present disclosure is a pharmaceutical composition in unit dosage form suitable for administration to a patient comprising:
(a) esomeprazole, which may or may not be surrounded by an enteric coating;
(b) sodium or potassium bicarbonate and/or sodium or potassium carbonate, and (c) cyclodextrin, which may or may not be formulated and may or may not be surrounded by an enteric coating. It relates to a pharmaceutical composition containing meloxicam.

One embodiment of the present disclosure is a pharmaceutical composition, in unit dosage form suitable for administration to a patient, for treating a disease, condition, or disorder, such as migraine, comprising:
(1) an inclusion complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD);
(2) bicarbonates such as sodium or potassium bicarbonate, and
(3) It relates to a pharmaceutical composition containing a triptan such as rizatriptan.

In certain embodiments, the pharmaceutical composition contains meloxicam but provides faster release or dissolution of meloxicam from the dosage form compared to a dosage form that does not contain an acid inhibitor or does not contain a buffer. .

A dosage form containing the combination of rizatriptan and meloxicam (the "subject combination") can be used to treat migraine. The subject combinations may be used for acute treatment of migraine. The subject combination may provide greater and more durable migraine relief compared to rizatriptan, meloxicam, or placebo. Thematic combinations can provide rapid relief of migraine pain. The subject combination may significantly reduce rescue medication use compared to rizatriptan, meloxicam, or placebo. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have a history of inadequate response to previous acute therapy. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have allodynia, such as cutaneous allodynia. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have severe pain. A migraine patient treated with the combination of rizatriptan and meloxicam described herein may be obese. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have morning migraines. Migraine patients treated with the combination of rizatriptan and meloxicam described herein have a total mean score of less than 7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4), e.g. It may be 3, 3-4, 4-5, 5-6, or 6-7. Migraine patients treated with the combination of rizatriptan and meloxicam described herein have allodynia, such as cutaneous allodynia, have severe pain, are obese, have morning migraines, May have a total mean score of less than 7 on mTOQ-4 and a history of inadequate response to previous acute therapy. Dosage forms containing the combination of rizatriptan and meloxicam described herein are safe and well tolerated by the patients treated.

Dosage forms comprising the combination of rizatriptan and meloxicam described herein may be administered for less than 15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, less than 1 hour, 0.5-0.75 hours after administration. , or 0.75 to 1 hour, can provide rapid relief of migraine pain. The combination of rizatriptan and meloxicam described herein can be administered for less than 15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes, about 30-30 minutes after administration. 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 and may provide numerically greater migraine pain relief than rizatriptan. Percentage of migraine patients reporting pain relief with rizatriptan and meloxicam combination treatment described herein is 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 It can be ~95%, or 95-100%.

Migraine patients administered a dosage form comprising a combination of rizatriptan and meloxicam (the "subject combination") described herein will be administered less than 2 hours, about 2 hours, about 2-3 hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about 20-24 hours, about 24- Pain relief can be achieved in 30 hours, about 30-36 hours, about 36-40 hours, about 40-44 hours, about 44-48 hours, or even longer.

The rate at which migraine sufferers achieve relief from pain increases over time after administration of the combination of rizatriptan and meloxicam described herein. For example, 2 hours after administration, the percentage of migraine patients who achieve relief from pain can be about 15-25%, about 15-20%, about 20%, about 20-25%. Four hours after dosing, the percentage of migraine patients who achieve relief from pain is about 30-50%, about 30-40%, about 40%, about 40-45%, about 45-47%, about 47 It can be ~50%. 12 hours after administration, the percentage of migraine patients who achieve pain relief is about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 56-57%, It can be about 60-65%, about 65-70%. 16 hours after dosing, the percentage of migraine patients who achieve relief from pain is about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 58-59%, It can be about 60-65%, about 65-70%. The combination of rizatriptan and meloxicam described herein may provide significant improvement relative to rizatriptan in pain relief in migraine sufferers. About 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8% of migraine patients administered a combination of rizatriptan and meloxicam as described herein , 8-9%, or 9-10% or more at 2-16 hours after dosing, about 10-25%, 10-15%, 14-15%, 15-16% more than patients receiving rizatriptan , 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25% improvement in pain relief may be achieved. For example, 4 hours after dosing, 40% of migraine patients receiving the subject combination achieved pain relief and 33% of migraine patients receiving rizatriptan achieved pain relief. Then the subject combination improvement is about 21% [((40-33)/33) x 100%]. The improvement of treatment with the subject combination over meloxicam in migraine patients achieving relief from pain may be greater than the improvement over rizatriptan. For example, in migraine patients achieving relief from pain, improvements to meloxicam with the subject combinations were about 25-75%, 25-30%, 27-28%, 2-16 hours after dosing, It can be 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75%.

at least 50%, at least 60%, at least 70%, at least 80%, about 70-80% of migraine patients receiving a combination of rizatriptan and meloxicam as described herein (the "subject combination"); About 80-90%, about 90-95%, about 80% are pain free 2 hours after administration and can be maintained up to 24 hours after administration. The number (or degree of improvement) of migraine patients achieving sustained pain relief 2-24 hours after administration of the subject combinations was about 35-55%, compared to administration of rizatriptan, It can be increased by 40%, about 40-45%, about 45-50%, or about 50-55%. The number (or degree of improvement) of migraine patients achieving sustained pain relief 2-24 hours after administration of the subject combinations was about 100-165%, about 100-110 compared to administration of meloxicam. %, about 110-120%, about 120-130%, about 130-140%, about 140-150%, about 150-160%, or about 160-165%.

The number (or degree of improvement) of migraine patients achieving sustained pain relief 2-24 hours after administration of the subject combinations was about 15-30%, about 15-20 compared to administration of rizatriptan. %, about 20-25%, about 25-30%, about 20-22%, or about 21%. The number (or degree of improvement) of migraine patients achieving sustained pain relief 2-24 hours after administration of the subject combination is about 20-35%, about 20-25% compared to administration of meloxicam , about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-30%, or about 27%.

at least 50%, at least 60%, at least 70%, at least 80%, about 70-80% of migraine patients receiving a combination of rizatriptan and meloxicam as described herein (the "subject combination"); About 80-90%, about 90-95%, or about 77% may be free from pain 2 hours after administration and maintain it up to 48 hours after administration. The number of migraine patients achieving sustained pain relief 2-48 hours after administration of the subject combinations (or degree of improvement) was about 60-90%, compared to administration of rizatriptan, It can be increased by 70%, about 70-75%, about 75-80%, about 80-90%, or about 75%. The number (or degree of improvement) of migraine patients achieving sustained pain relief 2-48 hours after administration of the subject combinations was about 70-110%, about 70-80 compared to administration of meloxicam. %, about 80-90%, about 90-100%, about 100-110%, or about 90%.

The number of migraine patients achieving sustained pain relief 2-48 hours after administration of the subject combination (or degree of improvement) was about 20-35% compared to administration of rizatriptan, about 20-25 %, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-20%, or about 27%. The number (or degree of improvement) of migraine patients achieving sustained pain relief 2-48 hours after administration of the subject combination is about 15-30%, about 15-20% compared to administration of meloxicam , about 20-25%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%, about 24-25%, or about 23% .

At least 50%; at least 60%; at least 70%; %, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or about 77% may not require rescue medication. The number of migraine patients taking rescue medication up to 24 hours after administration of the subject combination was about 35-60%, about 35-40%, about 40-45%, about 45% compared to those receiving placebo. It can be reduced by -50%, about 50-55%, about 55-60%, about 47-48%, or about 47%. The number of migraine patients taking rescue medication up to 24 hours after administration of the subject combination is about 25-45%, about 25-30%, about 30-35%, about 35% compared to administration of meloxicam It can be reduced by ˜40%, about 40-45%, about 34-36%, or about 35%. The number of migraine patients taking rescue medications up to 24 hours after administration of the subject combinations is about 25-40%, about 25-30%, about 30-35%, about It can be reduced by 35-40%, about 33-35%, or about 34%. In some embodiments, the migraine sufferer has not taken rescue medication in 24 hours after being administered the subject combination.

The following embodiments are contemplated.

Embodiment 1.
Inclusion complex of meloxicam in cyclodextrin.

Embodiment 2.
1) the inclusion complex of embodiment 1; or 2) a dosage form comprising meloxicam and a carbonate or bicarbonate.

Embodiment 3.
The dosage form of embodiment 2 comprising an inclusion complex, wherein the cyclodextrin comprises a substituted β-cyclodextrin.

Embodiment 4.
The dosage form of embodiment 3, wherein the substituted β-cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPβCD).

Embodiment 5.
5. The dosage form of embodiment 4, wherein the cyclodextrin is SBEβCD.

Embodiment 6.
The dosage form of embodiment 5, wherein SBEβCD has from about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 7.
The dosage form of embodiment 6, wherein meloxicam and SBEβCD have a molar ratio of about 0.8 to about 1.2.

Embodiment 8.
7. The dosage form of embodiment 6, wherein meloxicam and SBEβCD have a molar ratio of about one.

Embodiment 9.
The dosage form of embodiment 2, 3, 4, 5, 6, 7 or 8 comprising bicarbonate.

Embodiment 10.
10. The dosage form of embodiment 9, wherein the bicarbonate comprises sodium bicarbonate.

Embodiment 11.
The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9 or 10, which is an oral dosage form.

Embodiment 12.
The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10 or 11, wherein from about 50 mg to about 200 mg of SBEβCD is present in the dosage form.

Embodiment 13.
The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the carbonate or bicarbonate is present in an amount ranging from about 400 mg to about 600 mg.

Embodiment 14.
Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, wherein the T _max of meloxicam is decreased compared to dosage forms without carbonate, bicarbonate or cyclodextrin, 12, or 13 dosage forms.

Embodiment 15.
15. The method of embodiment 14, wherein the T _max of meloxicam is achieved in the patient at a time point ranging from about 10 minutes to about 180 minutes after administration.

Embodiment 16.
Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, having higher oral bioavailability of meloxicam than dosage forms without carbonate, bicarbonate or cyclodextrin, 12, 13, 14, or 15 dosage forms.

Embodiment 17.
The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, further comprising an acid inhibitor.

Embodiment 18.
18. The dosage form of embodiment 17, wherein the acid inhibitor is a proton pump inhibitor.

Embodiment 19.
19. The dosage form of embodiment 18, wherein the proton pump inhibitor is esomeprazole.

Embodiment 20.
The dosage form of embodiment 19, wherein from about 30 mg to about 50 mg of esomeprazole is present in the dosage form.

Embodiment 21.
A patient in need of treatment with the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or A method of orally administering meloxicam comprising orally administering to.

Embodiment 22.
22. The method of embodiment 21, wherein the dosage form is administered to treat pain.

Embodiment 23.
22. The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain.

Embodiment 24.
22. The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

Embodiment 25.
administering meloxicam intravenously, comprising intravenously administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, or 15 to a patient in need thereof; Method of administration.

Embodiment 26.
22. The method of embodiment 21, wherein the dosage form is administered to treat migraine.

Embodiment 27.
A dosage form comprising 1) an inclusion complex of meloxicam in cyclodextrin, 2) a bicarbonate salt, and 3) a triptan.

Embodiment 28.
28. The dosage form of embodiment 27, wherein the triptan is rizatriptan.

Embodiment 29.
28. The dosage form of embodiment 27, wherein the bicarbonate comprises sodium bicarbonate.

Embodiment 30.
28. The dosage form of embodiment 27, wherein the cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD).

Embodiment 31.
31. The dosage form of embodiment 30, wherein SBEβCD has from about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 32.
The dosage form of embodiment 30, wherein the molar ratio of meloxicam to SBEβCD is from about 0.8 to about 1.2.

Embodiment 33.
33. The dosage form of embodiment 32, wherein the molar ratio of meloxicam to SBEβCD is about one.

Embodiment 34.
The dosage form of embodiment 27, 28, 29, 30, 31, 32, or 33, which is an oral dosage form.

Embodiment 35.
The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34, wherein from about 50 mg to about 200 mg of SBEβCD 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 from about 400 mg to about 1000 mg.

Embodiment 37.
A method of treating migraine comprising administering to a human suffering from migraine a dosage form comprising meloxicam, at least 400 mg of bicarbonate, and rizatriptan, wherein the T _max of rizatriptan in the dosage form is is shorter than that of a reference dosage form that a) contains the same amount of rizatriptan, b) does not contain meloxicam, and c) does not contain bicarbonate.

Embodiment 38.
treating migraine comprising administering meloxicam and about 8 mg to about 13 mg of rizatriptan based on the weight of rizatriptan in free base form to a human suffering from an acute attack of migraine or migraine aura The method wherein meloxicam and rizatriptan are administered within 30 minutes of each other, and administration of meloxicam to a human is achieved with a T _max of meloxicam of 110 minutes or less and an AUC of meloxicam of about 30 μg/mL to about 50 μg/mL. A method that yields _0-24 .

Embodiment 39.
1) about 0.028 mmol to 0.085 mmol of meloxicam in free acid or salt form, 2) about 0.019 mmol to 0.056 mmol of rizatriptan in free base or salt form, 3) about 100 mg to about 175 mg of sulfobutyl ether β. - a pharmaceutical dosage form comprising cyclodextrin (SBEβCD), and 4) about 400 mg to about 600 mg of sodium bicarbonate.

Embodiment 40.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan.

Embodiment 41.
41. The method of embodiment 40, wherein the human migraine sufferer experiences migraine relief as a result of oral administration of the dosage form to the migraine sufferer.

Embodiment 42.
42. The method of embodiment 40 or 41, wherein the human migraine patient is free of migraine pain 2 hours after the dosage form is orally administered to the human migraine patient.

Embodiment 43.
The method of embodiment 40, 41, or 42, wherein the migraine sufferer experiences relief of nausea as a result of oral administration of the dosage form to the migraine sufferer.

Embodiment 44.
The method of embodiment 40, 41, 42 or 43, wherein the human migraine patient is nauseated 2 hours after the dosage form is orally administered to the human migraine patient.

Embodiment 45.
The method of embodiment 40, 41, 42, 43, or 44, wherein the migraine sufferer experiences a reduction in photophobia as a result of oral administration of the dosage form to the migraine sufferer.

Embodiment 46.
The method of embodiment 40, 41, 42, 43, 44, or 45, wherein 2 hours after the dosage form is orally administered to the human migraine patient, the human migraine patient remains photophobic.

Embodiment 47.
The method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein the migraine sufferer experiences a reduction in phonophobia as a result of oral administration of the dosage form to the migraine sufferer.

Embodiment 48.
The method of embodiment 40, 41, 42, 43, 44, 45, 46, or 47, wherein the human migraine patient is free of phonophobia 2 hours after the dosage form is orally administered to the human migraine patient. .

Embodiment 49.
The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, or 48, wherein the dosage form comprises 400 mg to 600 mg of bicarbonate.

Embodiment 50.
The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, wherein the dosage form comprises about 5 mg to about 50 mg of meloxicam.

Embodiment 51.
The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein the dosage form comprises from about 50 mg to about 200 mg of SBEβCD.

Embodiment 52.
The dosage form is a solid oral dosage form in which the T _max of meloxicam in humans is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. 52. The method of form 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51.

Embodiment 53.
embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, wherein from about 1 mg to about 50 mg of rizatriptan based on the weight of the free base form of rizatriptan is present in the oral dosage form; 50, 51, or 52 methods.

Embodiment 54.
54. The method of embodiment 53, wherein rizatriptan is present in salt form in an amount of about 10 mg molar equivalents of rizatriptan in free base form.

Embodiment 55.
55. The method of embodiment 53 or 54, wherein rizatriptan is present as rizatriptan benzoate.

Embodiment 56.
The oral dosage form of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 comprises about 10 mg to about 30 mg of meloxicam. Method.

Embodiment 57.
57. The method of embodiment 56, wherein the oral dosage form comprises about 20 mg of meloxicam.

Embodiment 58.
57. The method of embodiment 56, wherein the oral dosage form comprises about 15 mg of meloxicam.

Embodiment 59.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin , 52, 53, 54, 55, 56, 57, or 58.

Embodiment 60.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, wherein the oral dosage form comprises from about 50 mg to about 150 mg of SBEβCD. , 57, 58, or 59.

Embodiment 61.
61. The method of embodiment 60, wherein the oral dosage form comprises about 100 mg of SBEβCD.

Embodiment 62.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, wherein the molar ratio of SBEβCD to meloxicam is from about 0.5 to about 2 , 56, 57, 58, 59, 60 or 61.

Embodiment 63.
63. The method of embodiment 62, wherein the molar ratio of SBEβCD to meloxicam is from about 0.8 to about 1.2.

Embodiment 64.
63. The method of embodiment 62, wherein the molar ratio of SBEβCD to meloxicam is about one.

Embodiment 65.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, wherein the oral dosage form comprises about 10 mg to about 40 mg meloxicam and about 5 mg to about 50 mg rizatriptan. , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64.

Embodiment 66.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, wherein the oral dosage form comprises SBEβCD in a weight ratio of SBEβCD to rizatriptan ranging from about 1 to about 100. , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65.

Embodiment 67.
67. The method of embodiment 66, wherein the oral dosage form comprises SBEβCD in a weight ratio of about 10 to rizatriptan.

Embodiment 68.
bicarbonate includes sodium bicarbonate, embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67.

Embodiment 69.
69. The method of embodiment 68, wherein the oral dosage form comprises 500 mg sodium bicarbonate.

Embodiment 70.
The oral dosage form has been shown to have a median T _max of meloxicam of less than about 90 minutes in fasting human subjects, embodiments 40, 41, 42, 43, 44, 45, 46, 47 , 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69.

Embodiment 71.
71. The method of embodiment 70, wherein the oral dosage form has been shown to have a median T _max of meloxicam of less than about 2 hours in fasting human subjects.

Embodiment 72.
Oral dosage forms have been shown to have faster times to reach therapeutic plasma concentrations in humans compared to reference dosage forms, embodiments 52, 53, 54, 55, 56, 57, 58, 59 , 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71.

Embodiment 73.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein human migraine sufferers are given the dosage form of migraine sufferers experience relief of migraine pain as a result of oral administration.

Embodiment 74.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the dosage form is for human migraine patients. The method wherein the human migraine patient is free of migraine pain 2 hours after administration.

Embodiment 75.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein migraine sufferers may A method wherein a migraine patient experiences a reduction in nausea as a result of oral administration.

Embodiment 76.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the dosage form is for human migraine patients. A method wherein the human migraine patient is nausea-free 2 hours after administration.

Embodiment 77.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein migraine sufferers may A method wherein a migraine patient experiences a decrease in photophobia as a result of oral administration.

Embodiment 78.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the dosage form is for human migraine patients. A method wherein the human migraine patient remains photophobic 2 hours after administration.

Embodiment 79.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein migraine sufferers may A method of experiencing a reduction in phonophobia as a result of oral administration to a migraine patient.

Embodiment 80.
A method of treating migraine comprising selecting a human migraine patient with a history of incomplete response to prior migraine therapy and orally administering a dosage form to the migraine patient , the dosage form comprises a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the dosage form is for human migraine patients. A method wherein the human migraine patient is free of phonophobia 2 hours after administration.

Embodiment 81.
A segment related to rizatriptan therapy, including orally administering a combination of 1) meloxicam and sulfobutyl ether β-cyclodextrin, 2) bicarbonate, and 3) rizatriptan to a human in need of palliative treatment. A method of improving headache pain relief more rapidly, wherein one hour after the combination is administered, a human is more likely to experience a reduction than one hour after the same amount of rizatriptan is administered alone. The method also experienced a greater reduction in migraine pain.

Embodiment 82.
A method of relieving migraine pain comprising orally administering to a human in need of relief a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan. wherein the combination is administered orally when a human is suffering from acute migraine headache moderate to severe migraine pain, and two hours after the combination is administered, the human receives the same dose of rizatriptan alone A method that experiences a reduction in the most bothersome symptoms in the human that is greater than the reduction that the human would experience two hours after administration.

Embodiment 83.
A method of relieving migraine pain comprising orally administering to a human in need of relief a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan. wherein the combination is orally administered when a human is suffering from acute migraine headache moderate to severe migraine pain and the human is suffering from migraine with cutaneous allodynia and the combination is orally administered A method, wherein after 2 hours the human experiences a reduction in migraine pain that is greater than the reduction that the human would experience 2 hours after administration of the same amount of meloxicam alone.

Embodiment 84.
A method of relieving migraine pain comprising orally administering to a human in need of relief a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan. wherein the combination is orally administered when a human is suffering from severe migraine pain of acute migraine, and two hours after the combination is orally administered, the human is administered the same amount of meloxicam alone wherein a reduction in migraine pain is experienced that is greater than the reduction the human would experience after only 2 hours.

Embodiment 85.
A method of relieving migraine pain comprising orally administering to a human in need of relief a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan. wherein the combination is orally administered when the human is suffering from acute migraine headache moderate to severe migraine pain, the human is obese, and 2 hours after the combination is orally administered, the human is A method wherein a reduction in migraine pain is experienced that is greater than that the human would experience two hours after administration of the same amount of meloxicam alone.

Embodiment 86.
A method of relieving migraine pain comprising orally administering to a human in need of relief a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan. wherein the combination is orally administered when a human is suffering from acute migraine headache moderate to severe migraine pain, the human has a morning migraine, 2 hours after the combination is orally administered, A method, wherein the human experiences a reduction in migraine pain that is greater than the reduction that the human would experience two hours after administration of the same amount of meloxicam alone.

Embodiment 87.
A method of relieving migraine pain comprising orally administering to a human in need of relief a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan. wherein the combination is administered orally when a human is suffering from acute migraine headache moderate to severe migraine pain, and the human is administered an international Having been diagnosed as having migraine with aura or migraine without aura as defined by the Classification of Headache Disorders, Third Edition (ICHD-3), 2 hours after the combination was orally administered, humans received an equivalent dose of A method wherein a reduction in migraine pain is experienced that is greater than that the human would experience two hours after being administered meloxicam alone.

Embodiment 88.
1. A method of treating migraine comprising orally administering to a human migraine patient a dosage form comprising: a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD); 2) bicarbonate; and 3) the human migraine patient is suffering from migraine headache with cutaneous allodynia when the dosage form is administered, and 2 hours after the dosage form is orally administered to the human migraine patient, A human migraine patient is free from cutaneous allodynia, a method.

Embodiment 89.
The method of embodiment 81, 82, 83, 84, 85, 86, 87, or 88, wherein the migraine pain is accompanied by vision impairment.

Embodiment 90.
90. The method of embodiment 89, wherein the human has no visual impairment 2 hours after the combination is administered.

(Example 1)
The effect of varying amounts of potassium carbonate ( _{K2CO3 )} and sodium bicarbonate ( _NaHCO3 ) on the pH of acidic media was tested. The acidic medium was chosen to simulate gastric conditions. K ₂ CO ₃ or NaHCO ₃ was added to 50 mL of 0.01 N HCl solution (pH 2). After addition _{of K2CO3} or _NaHCO3 , the pH of the solution was measured. Deionized water (240 mL) was then added to the mixture and the pH was measured again. The results are shown in Tables 1-4.

(Example 2)
A combination of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD) (a cyclodextrin containing about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin) with K ₂ CO ₃ or NaHCO ₃ Tablets containing were manufactured and tested for dissolution. Tablets containing meloxicam alone (MOBIC®) were purchased and also tested for dissolution. The tested tablets are listed in Table 5. Meloxicam in the form of a meloxicam/SBEβCD inclusion complex was used in tablets containing meloxicam and SBEβCD. Inclusion complexes were formed by mixing meloxicam and SBEβCD in pH-adjusted aqueous solutions. A buffer was used to adjust the pH of the solution. The resulting soluble meloxicam/SBEβCD inclusion complex was then spray dried. This spray-dried dispersion was used to manufacture tablets containing SBEβCD.

Dissolution testing in acidic media (selected to simulate gastric conditions) was performed by placing the tablets in a 0.01N HCl solution at a stirring speed of 75 RPM and a vessel temperature of approximately 37°C. The results are shown in Table 6 and Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90 and 120 minutes) are presented as percent (%) dissolved meloxicam.

Meloxicam dissolution was greater in tablets containing meloxicam and various combinations of SBEβCD, K ₂ CO ₃ , or NaHCO ₃ compared to tablets containing meloxicam alone. For example, after 120 minutes, dissolution of meloxicam tablets containing NaHCO ₃ was 95% compared to 2% for tablets containing meloxicam alone.

Dissolution of meloxicam increased with increasing amounts of K ₂ CO ₃ in the absence of SBEβCD. However, in the presence of SBEβCD, increasing the amount of K ₂ CO ₃ did not appear to increase meloxicam dissolution. At the highest dose of potassium carbonate tested, the dissolution of meloxicam in the presence of SBEβCD was reduced by approximately 50% compared to the dissolution of meloxicam in the absence of SBEβCD at 120 minutes.

Dissolution of meloxicam in NaHCO ₃ was significantly greater than that observed with the highest dose of K ₂ CO ₃ at 15 min (50% vs 30%) and 120 min (92% vs 23%). Dissolution of meloxicam in the presence of SBEβCD was also significantly greater with _NaHCO3 compared to the highest dose of _{K2CO3 at} 15 min (85% vs 26%) and 120 min (86% vs 12%) . NaHCO ₃ in the presence of SBEβCD increased dissolution of meloxicam more at 15 min compared to potassium carbonate, which decreased dissolution.

(Example 3)
A bilayer tablet was prepared containing 1) an inclusion complex of SBEβCD with meloxicam prepared as described below and 2) sodium bicarbonate (SBEβCD-meloxicam/bicarbonate). The first layer contained 15 mg meloxicam and 100 mg SBEβCD inclusion complex and 100 mg sodium bicarbonate. The second layer contained 40 mg esomeprazole and 400 mg sodium bicarbonate.

A total of 20 human subjects were either treated with SBEβCD-meloxicam/bicarbonate tablets as described above or treated with Mobic® tablets (meloxicam 15 mg) (once daily for 6 days, fasting conditions). were randomly assigned in a 1:1 ratio.

Plasma samples were collected on the first day of dosing for analysis of meloxicam concentrations at multiple time points. The concentration of meloxicam was determined using LC-MS/MS. Pharmacokinetic parameters were calculated. The results are shown in FIG.

The median T _max for meloxicam, the study's primary endpoint, was nine times faster for SBEβCD-meloxicam/bicarbonate tablets compared to Mobic® (0.5 hours vs. 4.5 hours, respectively). time, p<0.0001).

SBEβCD-meloxicam/bicarbonate tablets also had a higher mean maximum plasma concentration (C _max ) (p=0.0018) and a faster time to therapeutic plasma concentration ( p<0.0001), and a faster time to half-maximal plasma concentration (p<0.0001).

For tablets containing meloxicam and cyclodextrin, meloxicam in the form of a meloxicam/SBEβCD inclusion complex was used. This inclusion complex was formed by mixing meloxicam and SBEβCD in a pH adjusted aqueous solution. The pH of this solution was adjusted using a buffer. The resulting soluble meloxicam/SBEβCD inclusion complex was then spray dried. This spray-dried dispersion was used to make tablets containing SBEβCD.

(Example 4)
Single layer tablets were prepared containing 1) an inclusion complex of SBEβCD with meloxicam, 2) rizatriptan, and 3) sodium bicarbonate (SBEβCD-meloxicam/rizatriptan/bicarbonate). The monolayer tablet contained 20 mg meloxicam, 10 mg rizatriptan, and 500 mg sodium bicarbonate. The inclusion complex is similar to that of Example 3.

A solubility test of the tablets in an acidic medium (selected to mimic gastric conditions) was performed by placing the tablets in a 0.01N HCl solution with a stirring speed of 75 RPM and a vessel temperature of approximately 37°C. The results are shown in Table 7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent meloxicam dissolved and percent rizatriptan dissolved.

As shown in Table 7, the dissolution results of the tablets of Example 4 were very similar to the dissolution results of Example 3. Therefore, the inventors believe that the pharmacokinetic properties (bioavailability, T _max of meloxicam, etc.) of the tablets of Example 4 are similar to those described in Example 3 and FIG. This prediction turned out to be correct, as shown in the examples below.

(Example 5)
The monolayer tablets of Example 4 were administered to 6 subjects. On the first day of dosing, plasma samples were collected for concentration analysis of rizatriptan at multiple time points. The concentrations of rizatriptan and meloxicam were determined using LC-MS/MS. Pharmacokinetic parameters were calculated. Results for meloxicam were comparable to those reported for the bilayer formulation of Example 3. The median T _max for rizatriptan was 0.75 hours and the mean C _max for rizatriptan was 20.710 ng/mL. In contrast, the reported T _max of the marketed rizatriptan dosage form, Maxalt®, is 1.0-1.5 hours.

(Example 6)
A phase 1, randomized, single-dose, parallel group clinical trial was conducted to compare 2) Maxalt® (10 mg rizatriptan) in healthy human volunteers after oral administration under fasting conditions, 1 ) The PK, safety and tolerability of the combination of meloxicam (20 mg), rizatriptan (10 mg), SBEβCD, and sodium bicarbonate (meloxicam/rizatriptan) was evaluated. A total of 20 healthy adult male or female volunteers were randomized 1:1 to receive single-dose meloxicam/rizatriptan or Maxalt® (10 mg rizatriptan) groups.

Blood samples for PK analysis were taken pre-dose and at multiple time points post-dose. The pre-specified primary endpoint is T _thera , defined as the Cavg of meloxicam after administration of the maximum tolerated dose (15 mg) of standard meloxicam, the time to reach therapeutic plasma concentration of meloxicam, which is approximately 1000 ng/mL. PK results for the rizatriptan component of meloxicam/rizatriptan were compared to those for Maxalt®(/rizatriptan).

The PK results for the meloxicam (20 mg) component of meloxicam/rizatriptan were compared to the PK results for Mobic® (15 mg meloxicam) in Example 3.

(Results of Phase 1)
Meloxicam was rapidly absorbed after oral administration of meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan), with a median time to therapeutic plasma concentration (T _thera ) of 17 minutes, the primary endpoint (Fig. 12 and Table 8). The median T _max is 1 hour compared to 4.5 hours for standard meloxicam 15 mg (Mobic®). The very short T _max suggests the potential for rapid onset of action of meloxicam/rizatriptan in the treatment of migraine. The mean plasma elimination half-life (T _1/2 ) for meloxicam was 18.2 hours after administration of meloxicam/rizatriptan compared to 21.5 hours for standard meloxicam. The long elimination half-life suggests the potential to enhance and prolong the effect of meloxicam/rizatriptan and reduce recurrence of migraine pain.

Rizatriptan was rapidly absorbed after oral administration of meloxicam/rizatriptan with a T _max of 0.88 hours compared to 0.88 hours for the same dose of standard rizatriptan (Maxalt®). 64 hours (38 minutes) (Figure 13 and Table 9). Systemic exposure, measured using _Cmax and AUC, was numerically greater for rizatriptan after meloxicam/rizatriptan versus standard rizatriptan.

Meloxicam/rizatriptan was well tolerated, with no relevant differences in safety profile between the two treatment arms. There were no serious adverse events in this study.

(Example 7)
A phase 3, randomized, double-blind, multicenter, positive-controlled and placebo-controlled trial was conducted in patients with a history of incomplete response to previous acute therapy for moderate and severe We evaluated the efficacy and safety of meloxicam/rizatriptan in the acute migraine treatment of migraine. Eligible patients were meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, SBEβCD, and sodium bicarbonate, as described in Example 4 above) group, rizatriptan (10 mg) (rizatriptan group), meloxicam (20 mg), SBEβCD , and sodium bicarbonate (meloxicam group), or placebo group, randomly assigned 2:2:2:1 for treatment. Co-primary endpoints were relief from headache pain 2 hours after dosing and relief from the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) for meloxicam/rizatriptan compared to placebo. is.

Superiority of meloxicam/rizatriptan group over rizatriptan group and meloxicam group (component contribution) was based on sustained relief from headache pain from 2 hours to 24 hours after dosing (key secondary endpoint) will be established

Eligible patients must have a history of inadequate response to previous acute migraine therapy as assessed using the Migraine Treatment Optimization Questionnaire (mTOQ-4). mTOQ-4 was previously evaluated based on four criteria: pain relief in 2 hours, efficacy for at least 24 hours with a single dose, ability to plan daily activities, and interference with daily living. A validated questionnaire assessing efficacy response to acute treatment.

Meloxicam/rizatriptan showed significant improvement over the placebo group, superior to the rizatriptan and meloxicam groups, due to rapid absorption and the two different mechanisms of action of meloxicam/rizatriptan described herein. will show

(Example 8)
A female migraine sufferer visited her primary care physician in hopes of relief from her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®) which she will take during her next acute migraine headache. It relieves pain, nausea, allodynia such as cutaneous allodynia, photophobia, and phonophobia to some extent, but not completely. At the next visit, her doctor prescribed 20 mg meloxicam, which she would take during her next acute migraine headache, in tablets also containing SBEβCD and 500 mg sodium bicarbonate. It relieves pain, nausea, allodynia such as cutaneous allodynia, photophobia, and phonophobia a little, but not completely. At her next visit, her doctor will prescribe her the tablets of Example 4 above. At 2 and 24 hours after ingestion of the tablets, she reported that pain, nausea, allodynia such as cutaneous allodynia, photophobia, and/or phonophobia were less than the slight relief she experienced after ingestion of meloxicam or rizatriptan alone. reported an improvement of about 10-30%.

(Example 9)
A male migraine sufferer visited his primary care physician in hopes of relief from his migraines. His doctor prescribed 10 mg rizatriptan (Maxalt®) which he will take during his next acute migraine headache. It relieves pain, nausea, allodynia such as cutaneous allodynia, photophobia, and phonophobia to some extent, but not completely. At his next visit, his doctor prescribed 20 mg meloxicam, in a tablet that also contained SBEβCD and 500 mg sodium bicarbonate, which he would take during his next acute migraine headache. It relieves pain, nausea, allodynia such as cutaneous allodynia, photophobia, and phonophobia a little, but not completely. At his next visit, his doctor will prescribe him the tablets of Example 4 above. At 2 and 24 hours after ingestion of the tablets, he reported pain, nausea, allodynia such as cutaneous allodynia, photophobia, and/or phonophobia to the slight relief he experienced after ingestion of meloxicam or rizatriptan alone. reported an improvement of about 30-60%.

(Example 10)
A female migraine sufferer visited her primary care physician in hopes of relief from her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®) which she will take during her next acute migraine headache. It relieves pain, nausea, allodynia such as cutaneous allodynia, photophobia, and phonophobia a little, but not completely. At the next visit, her doctor prescribed 20 mg meloxicam, which she would take during her next acute migraine headache, in tablets also containing SBEβCD and 500 mg sodium bicarbonate. It relieves pain, nausea, allodynia such as cutaneous allodynia, photophobia, and phonophobia a little, but not completely. At her next visit, her doctor will prescribe her the tablets of Example 4 above. At 2 and 24 hours after taking the tablets, she reported pain, nausea, allodynia such as cutaneous allodynia, photophobia, and/or phonophobia compared to the improvement she experienced after taking meloxicam or rizatriptan alone. , reported an improvement of about 60-100%.

(Example 11)
Migraine headaches affect 37 million Americans, according to the Centers for Disease Control, and are the number one cause of disability among neurological disorders in the United States, according to the Migraine Foundation of America. Migraines are characterized by throbbing attacks, severe and often disabling vertigo-related pain, and sensitivity to light and/or sound. In the United States, direct (e.g., reception, medication) and indirect (e.g., absenteeism, lost productivity) costs from migraine are estimated at $78 billion annually [Gooch CL, Pracht E, Borenstein AR, The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol. 2017 Apr;81(4):479-484]. A published survey of migraine sufferers found that more than 70% were not fully satisfied with their current treatment, nearly 80% were willing to try new treatments, experienced faster and more consistent results, and reduced symptoms. (1) Smelt AF, Louter MA, Kies DA, Blom JW, Terwindt GM, van der Heijden GJ, De Gucht V, Ferrari MD, Assendelft WJ, What do Patients consider to be the most important outcomes for effective studies on migraine treatments? Results of a Delphi study. PLoS One. 2014 Jun 16;9(6):e98933,6, and (2) Lipton RB, Stewart WF, Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999;39(suppl2):S20-S26].

The World Health Organization has classified severe migraine attacks as one of the most disabling illnesses, rivaling dementia, quadriplegia and active psychosis [(1) Menken et al., Arch Neurol. 2000;57:418-420, and (2) Shapiro and Goadsby. Cephalalgia. 2007;27:991-4]. Debilitating pain and constant fear of the next migraine attack impair family life, social life, and work [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. Humans with migraine are twice as depressed and anxious as healthy individuals [Antonaci et al., J Headache Pain. 2011; 12:115-125]. Widespread misperceptions about the severity of migraine contribute to its under-awareness and under-treatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of patients are not fully satisfied with their current treatments. Therefore, new treatments that offer improved efficacy for this serious neurological disease are urgently needed.

A Phase 3, Randomized, Double-Blind, Multicenter, Placebo-Controlled and Positive-Controlled Trial Determining the Efficacy of Meloxicam and Rizatriptan Combination (Meloxicam/rizatriptan) in the Acute Treatment of Moderate and Severe Migraines and safety were evaluated. Eligible patients are 18-65 years old, have a confirmed diagnosis of migraine with or without aura according to ICHD-3 criteria (at least 1 year), and moderate to severe, averaging 2-8 days per month of migraine headaches, a history of incomplete response to previous acute migraine therapy, and a migraine treatment optimization questionnaire (mTOQ-4) corresponding to poor response to previous acute therapy (mean The score must have been evaluated with a score of 7 using 3.6). Exclusion criteria included cluster migraine or other types of migraine, chronic daily headache (≥15 non-migraine days per month), history of significant cardiovascular disease, and uncontrolled Includes hypertension. In addition to a history of inadequate response, enrolled patients had cutaneous allodynia (75.4%), severe migraine pain (41.2%), obesity (43.7%), morning migraine ( 36.6%) showed a high proportion of features strongly associated with poor outcome. A total of 1,594 patients received monolayer tablets of Example 4 (20 mg meloxicam/10 mg rizatriptan plus SBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg) and SBEβCD (MoSEIC meloxicam), or Patients were randomized in a 2:2:2:1 ratio to placebo to treat single migraine attacks of moderate or severe intensity. The two co-primary endpoints of the study were the proportion of patients free of headache pain 2 hours after dosing and the most bothersome migraine-related symptom (nausea) 2 hours after dosing for meloxicam/rizatriptan compared to placebo. , photophobia, or phonophobia). The superiority of meloxicam/rizatriptan over the rizatriptan and meloxicam groups (component contribution) was to be established based on sustained relief from headache pain 2-24 hours after dosing (important secondary evaluation items). The study was conducted under the FDA's Special Protocol Assessment (SPA). The active comparator in this study, rizatriptan, is the fastest acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT (1B/1D) agonists) in cute migraine treatment: a meta-analysis of 53 trials. Lancet. 20 01 Nov 17;358(9294):1668 -75)

Meloxicam/rizatriptan provided rapid relief of migraine pain, and at all time points measured from 15 minutes onwards, a greater proportion of patients achieved pain relief with meloxicam/rizatriptan than with rizatriptan. Numerically larger and statistically significant only at 60 minutes (p=0.04) (Figure 14). The proportion of patients experiencing pain relief 1.5 hours after dosing was 52.5% with rizatriptan and 48.3% with placebo (P=0.019 vs. meloxicam/rizatriptan respectively, P=004). 60.5% for meloxicam/rizatriptan compared to 20% (Figure 14). FIG. 14A shows the percentage of subjects reporting pain relief compared to placebo at 1.0 and 1.5 hours for meloxicam, rizatriptan, and meloxicam/rizatriptan.

Meloxicam/rizatriptan was associated with a higher proportion of pain-free patients (19.9% vs. 6.7%, p<0.001, FIG. 15) and the most bothersome compared to placebo 2 hours after dosing Two pre-determined co-primary endpoints were met by demonstrating high statistical significance with a high proportion of symptom-free patients (36.9% vs. 24.4%, p=0.002).

The superiority of meloxicam/rizatriptan over rizatriptan (activity comparator) and MoSEIC® meloxicam (contribution of ingredients) was that the achievement of sustained pain relief 2-24 hours after dosing , MoSEIC® meloxicam, and placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively, vs. meloxicam/rizatriptan, respectively, p=0.038, p=0. 0.001, and p<0.001, FIG. 16A), indicating a pre-specified significant sub-primary item indicating the contribution of the components. and established as specified in the SPA. Approximately 80% of patients treated with meloxicam/rizatriptan who achieved pain relief at 2 hours maintained pain relief through 24 hours. These results demonstrated a significant improvement in pain relief and superiority of meloxicam/rizatriptan over rizatriptan in the treatment of migraine.

Meloxicam/rizatriptan provided substantially greater and more durable relief of migraine pain compared to placebo and rizatriptan, which was associated with meloxicam/rizatriptan compared to placebo and rizatriptan. It can be interpreted as resulting in a significant reduction in drug use. The proportion of patients who experienced sustained pain relief 2-24 hours after dosing was 33.5% for placebo and 43.9% for rizatriptan (P<0.001 vs. meloxicam/rizatriptan respectively, P = 0.006)) compared to 53.3% for meloxicam/rizatriptan (Figure 16B).

Sustained pain relief from 2 hours to 48 hours was also associated with placebo (31.3%) and rizatriptan (36.5%) patients (P<0.001 vs. meloxicam/rizatriptan, respectively, P=0.003). ), a statistically significantly higher proportion of meloxicam/rizatriptan patients (46.5%) experienced (FIG. 17B). FIG. 17D shows the percentage of subjects with sustained pain relief from 2 to 48 hours for meloxicam/rizatriptan dosage forms, rizatriptan, and meloxicam/rizatriptan. Persistent pain relief from 2 hours to 48 hours was also observed in placebo (5.3%) and rizatriptan (8.8%) and MoSEIC® meloxicam (8.1%) patients (vs. A statistically significantly higher proportion of meloxicam/rizatriptan patients (15.4%) experienced (Fig. 17A). FIG. 17C shows the percentage of subjects with sustained pain relief from 2 to 48 hours for meloxicam/rizatriptan dosage forms, rizatriptan, and meloxicam/rizatriptan. Approximately 77% of patients treated with meloxicam/rizatriptan who achieved pain relief at 2 hours maintained pain relief through 48 hours.

meloxicam/rizatriptan compared to 43% of patients receiving placebo and 34.7% of patients receiving rizatriptan (p<0.001 for each arm vs. meloxicam/rizatriptan) 23.0% of patients treated used rescue medication (Fig. 18). Approximately 77% of patients receiving meloxicam/rizatriptan did not require rescue medication. These results demonstrated the superiority of meloxicam/rizatriptan over the active comparator rizatriptan in the treatment of migraine.

Meloxicam/rizatriptan was associated with several other side effects, including Patient Global Impression of Change (PGI-C) (p=0.022) and return to normal functioning at 24 hours (p=0.027). was statistically significantly superior to rizatriptan in clinical endpoints.

Some of the p-values of meloxicam/rizatriptan vs. rizatriptan for various endpoints are listed in Table 10 below showing the statistically significant superiority of meloxicam/rizatriptan over rizatriptan in migraine treatment. .

The study's active comparator, rizatriptan, is the fastest acting oral triptan and is believed to be one of the most effective medications currently available for the acute treatment of migraine; The study observed a therapeutic effect of meloxicam/rizatriptan that provided greater and more durable migraine pain relief than rizatriptan given that it was in patients with difficult-to-treat migraines. that is very important. Many patients experience suboptimal responses to current acute migraine treatments that put them at increased risk of headache-related disability and progression to chronic migraine, a factor associated with increased healthcare costs. . The results of this study suggest that meloxicam/rizatriptan may provide an important treatment option for people with difficult-to-treat migraines.

Meloxicam/rizatriptan was safe and well tolerated in the patients studied in this trial. The most commonly reported adverse events with meloxicam/rizatriptan were nausea, dizziness, and somnolence, none of which occurred at a rate greater than placebo or >3%. . There was one serious adverse event in the meloxicam/rizatriptan group that was judged by the investigator to be unrelated to study drug.

The results of this study demonstrated that meloxicam/rizatriptan reduced migraine pain more rapidly and compared to the potent active comparator rizatriptan in a rigorously designed trial in patients with difficult-to-treat migraine. It has been shown to provide migraine sufferers with unique benefits of potent and sustained relief. These results may have important implications for patient care, based on the poor response to current treatments and the high rate of patient dissatisfaction.

Meloxicam/rizatriptan is intended to incorporate multiple mechanisms of action to address various migraine processes and enhance efficacy. Meloxicam/rizatriptan is believed to act by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and inhibiting neuroinflammation, pain signaling, and central sensitization. The results of this study validate this approach and show that meloxicam/rizatriptan can provide benefits significantly greater than those of currently available treatments, even in patients with difficult-to-treat migraines. . Meloxicam/rizatriptan can be effectively used for the acute treatment of migraine in adults with or without aura.

(Example 12)
A Phase 3, randomized, double-blind, multicenter, placebo-controlled trial evaluating the early treatment of migraine with meloxicam/rizatriptan was conducted. Meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, as described in Example 4 above, 20 mg A total of 302 patients were randomized in a 1:1 ratio to treat a single migraine attack with a single dose of meloxicam/10 mg rizatriptan, SBEβCD, and sodium bicarbonate) or placebo.

This clinical trial differs from the clinical trial of Example 11. The clinical trial of Example 11 was limited to patients whose migraine pain was of moderate or severe intensity, who had a history of incomplete response to previous acute treatments, and who were awaiting treatment for attacks. was registered. The clinical trial of Example 11 enrolled all volunteers and patients received meloxicam/ This is in contrast to this clinical trial in which patients were instructed to administer rizatriptan.

Patients are adult subjects with a confirmed diagnosis of migraine with or without aura.

Co-primary endpoints were relief from headache pain and relief from the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) at 2 hours post-dose for meloxicam/rizatriptan compared to placebo. .

Secondary co-primaries included relief from persistent pain, relief from progression of migraine pain, change in functional impairment, and rescue medication use.

Inclusion criteria included 18-65 years old with a confirmed diagnosis of migraine with or without aura according to ICHD-3 criteria (at least 1 year) with an average of 2-8 migraines per month. Includes male or female. Exclusion criteria included cluster headache, tension headache, or other type of migraine, chronic daily headache (15 or more non-migraine-type headache days per month), significant cardiovascular Includes history of disease and uncontrolled hypertension.

In a phase 3 trial of meloxicam/rizatriptan in the early treatment of migraine, meloxicam/rizatriptan substantially and significantly eliminated migraine pain and substantially and significantly prevented the progression of migraine pain intensity bottom. In this study, meloxicam/rizatriptan met the co-primary endpoints of relief from migraine pain and relief from most bothersome symptoms compared to placebo.

Meloxicam/rizatriptan showed relief from pain (32.6% vs. 16.3%, p=0.002) and relief from the most bothersome symptoms (43.9% vs. 26.7%) at 2 hours after dosing. %, p=0.003) showed statistically significant improvements compared to placebo in both co-primary endpoints (Figures 19A and 19B). The most bothersome symptoms are nausea, photophobia, or phonophobia.

Meloxicam/rizatriptan was numerically significantly more significant than placebo for relief from migraine pain (Figure 20) and relief from the most bothersome symptoms (Figure 21) as early as 30 minutes and 90 minutes (p=0. 003) and at all times thereafter achieved statistical significance for relief from migraine pain (Figure 20). At 12 hours, 64% of patients receiving meloxicam/rizatriptan were pain free compared to 42% of patients receiving placebo. At 24 hours, 69% of patients receiving meloxicam/rizatriptan were pain free compared to 47% of patients receiving placebo.

Meloxicam/rizatriptan relieved migraine pain in a statistically significant greater proportion of patients compared to placebo, 2-24 hours after dosing (22.7% vs. 12.6%, p= 0.030), and sustained pain relief 2-48 hours (20.5% vs. 9.6%, p=0.013) after dosing (Figures 22A and 22B).

Meloxicam/rizatriptan prevented the progression of migraine pain intensity to greater than mild from 2 to 24 hours in 73.5% of patients compared to 47.4% of patients who took placebo (p <0.001) (Fig. 23). A single dose of meloxicam/rizatriptan prevented the progression of mild to onset migraine pain.

The effect on pain progression resulted in a significant reduction in rescue medication use, with 42.2% of patients taking placebo compared with only 15.3% of patients taking meloxicam/rizatriptan. , required rescue medication through 24 hours after dosing (p<0.001) (FIG. 24).

Meloxicam/rizatriptan substantially and significantly reduced functional impairment, indicating overall disease improvement. At 24 hours, the ability to perform usual activities reached 73.5% of patients taking meloxicam/rizatriptan compared to 47.4% in patients taking placebo (p< 0.001) (Fig. 25).

On the Patient Global Impression of Change (PGI-C) scale of change, at 2 hours, 52.4% of patients taking meloxicam/rizatriptan compared with 27.7% of patients taking placebo had Very significant or greatly improved (p<0.001) (Figure 26).

Meloxicam/rizatriptan was generally safe and well tolerated in trials. The most commonly reported adverse events with meloxicam/rizatriptan were somnolence, dizziness, and paresthesia, all occurring at a rate of less than 5% (Table 11). There were no serious adverse events in this study.

Dr. Stewart Tepper, Professor of Neurology at Geisel College of Medicine, Dartmouth, said, "This study shows that treatment with meloxicam/rizatriptan provides a high rate of relief from migraine pain and reduces the progression of migraine pain. An innovative design was employed to assess that early treatment with meloxicam/rizatriptan prevented the progression of migraine pain in the majority of patients, and a similarly high proportion of patients were able to restore normal function. is amazing,” he said. “The multiple mechanisms of meloxicam/rizatriptan correspond to disturbances in many of the physiological processes involved in migraine attacks. Together with the data, this synergistic, multi-mechanism approach, and rapid absorption of meloxicam/rizatriptan, provides clinical evidence that may have important benefits for a wide range of patients. , meloxicam/rizatriptan represents an important new treatment for this disabling condition as we continue to search for options that are more effective than currently available treatments. obtain."

This Phase 3 trial confirmed the superiority and sustained efficacy of meloxicam/rizatriptan. Prevention of Migraine Pain Progression and Substantial Increase in Migraine Pain Free Rate Expands and Strengthens Differentiated Profile for Acute Treatment of Migraine with Early Treatment with Meloxicam/rizatriptan indicates that With this Phase 3 trial, and the Phase 3 trial described in Example 11 in patients with a history of inadequate response to previous acute therapy, meloxicam/rizatriptan is now double positive Evaluated in controlled trials. These trials demonstrate the efficacy of meloxicam/rizatriptan against potent active and placebo comparators across a range of migraine attack settings, regardless of migraine treatment timing, disease severity, or baseline pain intensity. showed efficacy.

Cedric O'Gorman, M.D., senior vice president of clinical development and medical affairs at Axum, said, "Migraine headaches are the most disruptive to daily living, depriving patients of activity and severely impairing home life, social activities, and ability to work. "It's one of those disabling disorders. Published research highlights that patients remain dissatisfied with the efficacy of currently available treatments." "The results of this study show for the first time that meloxicam/rizatriptan can halt the progression of migraine pain before it reaches moderate or severe intensity. These data demonstrate that meloxicam/rizatriptan , has mounting clinical evidence supporting its potential to be an effective multi-mechanism treatment for migraine, superior to the current standard of care, providing rapid, robust, and sustained symptom relief. and allow the patient to return to normal daily activities."

Unless otherwise stated, figures expressing amounts, amounts, percentages and other characteristics of ingredients used in the specification and claims are in all cases to the exact values indicated and are "about ” should be understood to indicate both modified values. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At least, without intending to limit its application as equivalents to the claims, each numerical parameter is at least construed in light of the reported number of significant digits by applying the usual rounding measures. should.

The terms “a,” “an,” “the,” and similar references used in the context of describing embodiments (especially in the context of the claims below) are used unless otherwise stated or clear by context. should be construed to cover both singular and plural forms unless contradicted by the . Any and all examples, or use of exemplary language (e.g., "such as") provided herein, is intended to better clarify the embodiments and may be used to clarify the scope of the claims. It does not impose any restrictions. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the claim.

Groupings of alternative elements or embodiments disclosed herein should not be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of the group will be included in or deleted from the group for reasons of convenience and/or expedite implementation. When such inclusion or deletion occurs, the specification is deemed to contain the modified group and fulfills all descriptions of the Markush group when used in the appended claims.

Several embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors do not intend to practice the claimed embodiments other than as specifically described herein. is intended. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, combinations of the above-described elements in all possible variations are contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Accordingly, alternative configurations of the present invention may be utilized in accordance with the teachings herein, by way of example and not limitation. Therefore, the claims are not limited to the precise embodiments shown and described.

(Appendix)
(Appendix 1)
A method of treating migraine comprising selecting a human migraine patient with functional impairment and orally administering to said migraine patient a dosage form comprising: 1) meloxicam and sulfobutyl ether A method comprising a combination of a complex of β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan.

(Appendix 2)
In accordance with the use of a combination of meloxicam and rizatriptan in the manufacture of a medicament for treating migraine, said medicament comprising: 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) a dosage form comprising rizatriptan, wherein said medicament is for administration to human migraine patients with functional impairment.

(Appendix 3)
3. The method or use of Clause 1 or 2, wherein said human migraine sufferer experiences migraine relief as a result of oral administration of said dosage form to said migraine sufferer.

(Appendix 4)
4. The method or use of Clause 1, 2, or 3, wherein said migraine sufferer has nausea, photophobia, or phonophobia associated with migraine.

(Appendix 5)
5. The method or use of Claim 4, wherein said migraine sufferer experiences reduced nausea as a result of oral administration of said dosage form to said migraine sufferer.

(Appendix 6)
5. The method or use of Clause 4, wherein said migraine sufferer experiences decreased photophobia as a result of oral administration of said dosage form to said migraine sufferer.

(Appendix 7)
5. The method or use of Claim 4, wherein said migraine sufferer experiences a reduction in phonophobia as a result of oral administration of said dosage form to said migraine sufferer.

(Appendix 8)
The method or use of Clause 1, 2, 3, 4, 5, 6, or 7, wherein said dosage form comprises 400 mg to 600 mg of bicarbonate.

(Appendix 9)
9. The method or use of Clause 1, 2, 3, 4, 5, 6, 7, or 8, wherein said dosage form comprises about 5 mg to about 50 mg of meloxicam.

(Appendix 10)
10. The method or use of Clause 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein said dosage form comprises from about 50 mg to about 200 mg of SBEβCD.

(Appendix 11)
said dosage form is a solid oral dosage form in which the T _max of meloxicam in humans is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. 11. The method or use of Clause 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

(Appendix 12)
Appendices 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein from about 1 mg to about 50 mg of rizatriptan based on the weight of the free base form of rizatriptan is present in said oral dosage form; or the method or use of 11.

(Appendix 13)
13. The method or use of Clause 12, wherein rizatriptan is present in salt form in an amount of about 10 mg molar equivalents of rizatriptan in free base form.

(Appendix 14)
14. The method or use of Clause 12 or 13, wherein rizatriptan is present as rizatriptan benzoate.

(Appendix 15)
15. The method of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, or use.

(Appendix 16)
16. The method or use of Clause 15, wherein said oral dosage form comprises about 20 mg of meloxicam.

(Appendix 17)
SBEβCD has from about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin, Supplements 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 17. The method or use of 13, 14, 15 or 16.

(Appendix 18)
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 18. A method or use according to 17.

(Appendix 19)
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, wherein said oral dosage form comprises about 400 mg to about 600 mg sodium bicarbonate , 17, or 18.

(Appendix 20)
Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, wherein said human migraine sufferer is able to return to normal activity within 24 hours after receiving treatment; 20. The method or use of 13, 14, 15, 16, 17, 18, or 19.

Claims (20)

A method of treating migraine comprising selecting a human migraine patient with functional impairment and orally administering to said migraine patient a dosage form comprising: 1) meloxicam and sulfobutyl ether A method comprising a combination of a complex of β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan. In accordance with the use of a combination of meloxicam and rizatriptan in the manufacture of a medicament for treating migraine, said medicament comprising: 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) a dosage form comprising rizatriptan, wherein said medicament is for administration to human migraine patients with functional impairment. 3. The method or use of claim 1 or 2, wherein said human migraine sufferer experiences migraine relief as a result of oral administration of said dosage form to said migraine sufferer. 4. The method or use of claim 1, 2 or 3, wherein the migraine sufferer has nausea, photophobia, or phonophobia associated with migraine. 5. The method or use of claim 4, wherein the migraine sufferer experiences reduced nausea as a result of oral administration of the dosage form to the migraine sufferer. 5. The method or use of claim 4, wherein the migraine sufferer experiences decreased photophobia as a result of oral administration of the dosage form to the migraine sufferer. 5. The method or use of claim 4, wherein the migraine sufferer experiences a reduction in phonophobia as a result of oral administration of the dosage form to the migraine sufferer. 8. The method or use of claim 1, 2, 3, 4, 5, 6, or 7, wherein said dosage form comprises 400 mg to 600 mg of bicarbonate. 9. The method or use of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein said dosage form comprises about 5 mg to about 50 mg of meloxicam. 10. The method or use of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein said dosage form comprises from about 50 mg to about 200 mg of SBEβCD. said dosage form is a solid oral dosage form in which the T _max of meloxicam in humans is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. 11. A method or use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 wherein from about 1 mg to about 50 mg of rizatriptan based on the weight of rizatriptan in free base form is present in said oral dosage form. , or the method or use of 11. 13. The method or use of claim 12, wherein rizatriptan is present in salt form in an amount of about 10 mg molar equivalents of rizatriptan in free base form. 14. A method or use according to claim 12 or 13, wherein rizatriptan is present as rizatriptan benzoate. 15. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein said oral dosage form comprises about 10 mg to about 30 mg of meloxicam. Or use. 16. The method or use of claim 15, wherein said oral dosage form comprises about 20 mg of meloxicam. Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, wherein the SBEβCD has from about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin. , 13, 14, 15, or 16. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, wherein said oral dosage form comprises from about 50 mg to about 150 mg of SBEβCD, or the method or use of 17. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, wherein said oral dosage form comprises from about 400 mg to about 600 mg sodium bicarbonate, 19. The method or use of 16, 17 or 18. Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, wherein said human migraine sufferer is able to return to normal activity within 24 hours after receiving treatment. , 13, 14, 15, 16, 17, 18, or 19.

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