Pharmaceutical composition containing meloxicam

Abstract

Disclosed herein is a method for treating migraines in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who, in at least the past month, 1) have had two to eight migraines per month, and 2a) are not at all or very comfortable enough, according to the patient, to be able to plan their daily activities with their migraine medication, 2b) are not at all or very comfortable enough, according to the patient, to be able to carry out their daily activities without difficulty after taking their migraine medication, 2c) have an mTOQ-4 score of 0, and / or 2d) have a history of depression, and administering to the patient, during a migraine attack, a combination of meloxicam or a pharmaceutically acceptable salt thereof and rizatriptan or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] (Related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 579,833, filed on 31 August 2023, which is incorporated herein by reference in its entirety. [Overview of the project] [Means for solving the problem]

[0002] Some embodiments include a method for treating migraines in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who, in at least the past four weeks, 1) has had two to eight migraines per month, and 2) is not at all or very comfortable enough to plan daily activities with his / her migraine medication; and, after the patient has been selected, administering to the patient, during a migraine attack, a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof.

[0003] Some embodiments include a method for treating migraines in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who, in at least the past four weeks, 1) has had two to eight migraines per month, and 2) according to the patient, does not feel at all or very well in control of his migraines after taking migraine medication, to the extent that he feels he is not interfering with his daily activities; and, after the patient has been selected, administering to the patient, during a migraine attack, a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof.

[0004] Some embodiments include a method for treating migraines in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting patients who have had an inadequate response to migraine treatments, having 1) 2 to 8 migraines per month and 2) an mTOQ-4 score of 0 in the past four weeks, and, after patient selection, administering to the patients, during a migraine attack, a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof.

[0005] Some implementations include methods for treating migraines in patients with a history of inadequate response to previous migraine treatments, the methods comprising: selecting patients who 1) have had two to eight migraines per month for at least the past four weeks, and 2) have a history of depression; and, after the patients have been selected, administering to the patients, during a migraine attack, a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments include a method for treating migraines, the method comprising orally administering to a person requiring a combination of about 15 to 30 mg of meloxicam or a pharmaceutically acceptable salt thereof and rizatriptan or a pharmaceutically acceptable salt thereof, the person having a history of depression and suffering from migraine pain or aura. [Brief explanation of the drawing]

[0007] [Figure 1] Figure 1 shows a plot of the percentage of subjects who reported pain relief at various time points during the first four hours after administration of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo, as described in Example 1. [Figure 1A] Figure 1A shows the percentage of subjects who reported pain relief at 1.0 and 1.5 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan, excluding the placebo group. [Figure 2] Figure 2 shows the percentage of subjects who achieved pain freedom at 2, 4, 12, and 16 hours after administration for the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1. [Figure 3A] Figure 3A shows the percentage of subjects who achieved sustained pain relief from 2 to 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1. [Figure 3B] Figure 3B shows the percentage of subjects who achieved sustained pain relief from 2 to 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1. [Figure 4A] Figure 4A shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1. [Figure 4B] Figure 4B shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours after administration for the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1. [Figure 4C] Figure 4C shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan, excluding the placebo group. [Figure 4D] Figure 4D shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan, excluding the placebo group. [Figure 5] Figure 5 shows the percentage of subjects who took rescue medication within 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1. [Figure 6] Figure 6 shows the proportion of patients in Example 1 who answered "not at all" or "hardly ever" to each question of mTOQ-4. [Figure 7A] Figures 7A and 7B show the percentage of subjects who achieved pain freedom and resolution of the most bothersome symptom among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 7B] See the description of Figure 7A. [Figure 8] Figure 8 shows the percentage of subjects who achieved pain freedom over time among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 9] Figure 9 shows the percentage of subjects relieved from the most bothersome symptom over time among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 10A] Figures 10A and 10B show the percentage of subjects who achieved pain freedom from 2 hours to 24 hours and from 2 hours to 48 hours among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 10B] See the description of Figure 10A. [Figure 11] Figure 11 shows the percentage of subjects who achieved pain freedom from 2 hours to 24 hours among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 12] Figure 12 shows the percentage of subjects who took rescue medication among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 13] Figure 13 shows the percentage of subjects with no functional impairment after 24 hours among subjects administered meloxicam / rizatriptan and subjects administered placebo in Example 3. [Figure 14] Figure 14 shows the percentage of subjects in Example 3 who, 2 hours after administration, had a Patient Global Impression of Change (PGI-C) of "very much improved" or "much improved", among subjects administered meloxicam / rizatriptan and subjects administered placebo. [Figure 15] Figure 15 shows the 24-hour sustained pain-free rate compared to placebo for patients with a high BMI, allodynia, morning-type migraine, and a history of depression. MODE FOR CARRYING OUT THE INVENTION

[0008] DETAILED DESCRIPTION OF THE INVENTION Meloxicam, which has the following structure, is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic effects. The mechanism of action of meloxicam may be associated with the inhibition of prostaglandin synthase (cyclooxygenase, COX), which is involved in the initial step of the arachidonic acid cascade, and as a result, the production of prostaglandins, thromboxane and prostacyclin is suppressed.

[0009]

Chemical Formula

[0010] Because meloxicam and other nonsteroidal anti-inflammatory drugs (NSAIDs) have low water solubility, their bioavailability may be reduced, potentially delaying the onset of pain relief with their use. One way to improve the solubility and bioavailability of meloxicam is to use cyclodextrins. Cyclodextrins (also known as cycloamylose) are cyclic polysaccharides, generally shaped like buckets. Because cyclodextrins are hydrophobic on the inside and hydrophilic on the outside, they help facilitate the transport of molecules such as hydrophobic molecules, thereby increasing the bioavailability of other molecules. Naturally occurring cyclodextrins contain 6, 7, and 8 glucose units (α, β, and γ-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are also possible. Although cyclodextrin compounds are also known to aggregate around drugs in micelle-like structures, in aqueous solution, cyclodextrins can form complexes (inclusion complexes) with drugs by incorporating the drug into the central / hydrophobic portion of the cyclodextrin ring. This ability of cyclodextrins can sometimes allow them to act as drug carriers, increasing the bioavailability of poorly soluble drugs.

[0011] The combination of rizatriptan and meloxicam (referred to herein for convenience as the "subject combination") may be used to treat a variety of pain symptoms.

[0012] Rizatriptan has the following structure.

[0013] [ka]

[0014] Some embodiments include combinations of the subject for treating human migraines, comprising 1) an inclusion complex of meloxicam and cyclodextrin, 2) rizatriptan, and 3) a bicarbonate. The migraine may be treatment-resistant. The person may have a history of inadequate response to previous treatments. In some embodiments, the cyclodextrin is SBEβCD.

[0015] The dosage form may be enteral administration, including but not limited to oral, sublingual, or rectal administration, or parenteral administration, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous administration.

[0016] Unless otherwise noted, any reference herein to compounds such as meloxicam or lyzatriptan, by structure, name, or other means, includes pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, precursors, prodrugs, or any other chemical species that may be rapidly converted to the compounds described herein under the conditions under which the compounds are used as described herein.

[0017] The subject may be administered by enteral administration, including but not limited to oral, sublingual, or rectal administration, or by parenteral administration, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous administration. In some embodiments, both meloxicam and rizatriptan are administered orally.

[0018] Typically, the combination of meloxicam and rizatriptan is administered so that a human receives meloxicam and rizatriptan in a short period of time from one another. For example, meloxicam and rizatriptan may be administered within approximately 2 hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute from one another. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which for the purposes of this disclosure includes administration within approximately 5 minutes. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form, such as a solid dosage form (e.g., an oral solid dosage form for direct oral administration).

[0019] The terms “treatment” or “procedure” broadly include any therapeutic activity of any kind, including the diagnosis, treatment, alleviation, or prevention of disease in humans or other animals, or any activity that affects the structure or function of the body in humans or other animals.

[0020] Migraine is a debilitating neurological disorder characterized by recurrent episodes of throbbing headaches accompanied by nausea and sensitivity to light and sound. The pain can be mild, moderate, or severe, but is often severe and debilitating, requiring bed rest. The headache occurs on one side of the head, may be throbbing, and may last from 2 hours to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or smell. Migraine pain may be accompanied by visual disturbances. Migraine pain may be worsened by physical activity. Migraines may be preceded by an aura, which is a short-term visual disturbance that signals that a headache is about to occur. Some migraine sufferers do not experience an aura.

[0021] In some embodiments, individuals being treated for migraines may experience allodynia, such as cutaneous allodynia, associated with migraine attacks. Allodynia, like cutaneous allodynia, is pain caused by stimuli that are normally not painful (such as combing hair, putting on glasses, or showering). Patients with allodynia, like cutaneous allodynia, are thought to be less responsive to triptan medications.

[0022] Current treatments are not optimal, with over 70% of sufferers reporting dissatisfaction with existing acute-phase treatments. The most frequently reported reasons for patient dissatisfaction are delayed onset of pain relief, inconsistent pain relief, and pain recurrence on the same day. Inadequate acute-phase treatment is associated with a significant increased risk of developing new chronic migraines, which can sometimes be prevented by improving the outcomes of acute-phase treatment.

[0023] When the combination of the subject is administered to a person suffering from migraine, such as an acute attack of migraine pain or aura, a reduction in migraine symptoms, such as pain, nausea, vomiting, photophobia, or phonophobia, occurs rapidly, such as within approximately 5 minutes (intended as an abbreviation for "approximately 5 minutes later or within approximately 5 minutes"), 10 minutes, 30 minutes, 1 hour, 90 minutes, 2 hours, 2.5 hours, or 3 hours. In some embodiments, the person experiences a reduction or complete relief of headache pain or migraine-like pain, nausea, vomiting, photophobia, and / or phonophobia within approximately 1 hour, 90 minutes, 2 hours, 2.5 hours, or 3 hours. In some embodiments, the relief experienced is greater than that experienced by taking the same amount of rizatriptan without meloxicam.

[0024] The subject combination may be administered at the earliest sign of migraine pain, or shortly thereafter (e.g., within approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, or 1 hour). In this early stage, the pain may still be mild or may not progress to moderate or severe intensity. In some cases, the subject combination may be administered when the intensity of migraine pain has reached moderate or severe.

[0025] In some embodiments, the combination of meloxicam and rizatriptan is administered to human migraine patients who have or are selected to have impaired function. In some embodiments, as a result of the treatment, human migraine patients can return to normal activities within 24 hours after treatment.

[0026] The combination of meloxicam and rizatriptan may have two different mechanisms of action in the acute treatment of migraines. Meloxicam is a potent COX-2 preferential NSAID, but it has the limitation of slow absorption. Rizatriptan is a potent 5-HT1 B / D It is an agonist and is thought to be effective for migraines.

[0027] Observing symptom reduction or decrease within a specific timeframe, such as "at 2 hours," is useful because it allows for evaluation of treatment effectiveness at a specific or consistent point in time, facilitating comparisons between patients. Observing symptom reduction or decrease within a specific timeframe, such as "within about 2 hours," is useful because it is desirable for symptom reduction or decrease to occur as early as possible, and specifying that reduction should occur within a specific time frame sets a guideline for when reduction is desirable.

[0028] In some cases, administration of the subject combination may achieve relief of migraine pain, nausea, vomiting, photophobia, or phonophobia lasting for 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 24 hours, about 24 hours, or more than 24 hours.

[0029] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form, such as a single oral dosage form including a single solid oral dosage form for direct oral administration), and two hours after administration of meloxicam and rizatriptan, the person experiences greater pain relief than the person would have experienced two hours after taking the same amount of meloxicam without rizatriptan.

[0030] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences greater pain relief than a person would have experienced 24 hours after taking the same amount of meloxicam without rizatriptan.

[0031] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater pain relief than a person would have experienced two hours after taking the same amount of rizatriptan without meloxicam.

[0032] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences greater pain relief than a person would have experienced 24 hours after taking the same amount of rizatriptan without meloxicam.

[0033] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in nausea than a person would have experienced two hours after taking the same amount of meloxicam without rizatriptan.

[0034] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in nausea than a person would have experienced 24 hours after taking the same amount of meloxicam without rizatriptan.

[0035] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in nausea than they would have experienced two hours after taking the same amount of rizatriptan without meloxicam.

[0036] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, humans experience a greater reduction in nausea than they would have experienced 24 hours after taking the same amount of rizatriptan without meloxicam.

[0037] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in vomiting than a person would have experienced two hours after taking the same amount of meloxicam without rizatriptan.

[0038] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in vomiting than a person would have experienced 24 hours after taking the same amount of meloxicam without rizatriptan.

[0039] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in vomiting than a person would have experienced two hours after taking the same amount of rizatriptan without meloxicam.

[0040] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in vomiting than a person would have experienced 24 hours after taking the same amount of rizatriptan without meloxicam. In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in photophobia than a person would have experienced 2 hours after taking the same amount of meloxicam without rizatriptan.

[0041] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in photophobia than a person would have experienced 24 hours after taking the same amount of meloxicam without rizatriptan.

[0042] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in photophobia than a person would have experienced two hours after taking the same amount of rizatriptan without meloxicam.

[0043] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in photophobia than a person would have experienced 24 hours after taking the same amount of rizatriptan without meloxicam.

[0044] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in phonophobia than a person would have experienced two hours after taking the same amount of meloxicam without rizatriptan.

[0045] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in phonophobia than a person would have experienced 24 hours after taking the same amount of meloxicam without rizatriptan.

[0046] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in phonophobia than a person would have experienced two hours after taking the same amount of rizatriptan without meloxicam.

[0047] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences a greater reduction in phonophobia than a person would have experienced 24 hours after taking the same amount of rizatriptan without meloxicam.

[0048] In some embodiments, the human being has a history of triptan use prior to ingesting a combination of the subject, such as a combination containing meloxicam and rizatriptan.

[0049] In some embodiments, individuals ingesting the subject combination have a score of 0 or 1 on the Migraine Treatment Optimization Questionnaire (mTOQ-4).

[0050] In some embodiments, individuals ingesting the subject combination showed that, prior to ingesting the subject combination, pain was “never” or “almost never” resolved within two hours after treatment for most seizures.

[0051] In some embodiments, individuals who ingested the subject combination indicated that, prior to ingesting the subject combination, they had “never” or “very rarely” experienced a reduction in their headaches for at least 24 hours and that the headaches “kept it away” after a single dose.

[0052] In some embodiments, individuals taking the subject combination were shown to be “never” or “very rarely” comfortable enough to plan their daily activities with their migraine medication before taking the subject combination.

[0053] In some embodiments, individuals taking the subject combination reported "never" or "very little" feeling that their migraines were controlled well enough to allow them to perform their daily activities without difficulty, either before taking the subject combination or after taking migraine medication.

[0054] In some embodiments, individuals ingesting the subject combination have a history of depression prior to ingesting the subject combination.

[0055] In some embodiments, individuals taking a combination of the subject, such as a combination containing meloxicam and rizatriptan, may have migraines and a history of inadequate response to previous migraine treatments. In some embodiments, individuals with migraines do not have cluster headaches or other types of migraines. In some embodiments, individuals with migraines do not have chronic daily headaches. In some embodiments, individuals with migraines do not have more than 15, 15 to 20, 20 to 25, 25 to 28, 28 to 30, or 30 to 31 non-migraine headache days per month. In some embodiments, individuals with migraines have no history of significant cardiovascular disease. In some embodiments, individuals with migraines do not have uncontrolled hypertension.

[0056] In some embodiments, administration of this dosage form may achieve pain reduction lasting at least approximately 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least approximately 8 hours, 8 to 24 hours, or approximately 24 hours. In other embodiments, administration of this dosage form may achieve pain reduction observed at approximately 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, less than 15 minutes, less than 20 minutes, 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, approximately 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, or 60 minutes, or at other times within a range limited to any of these values.

[0057] In some cases, administration of this dosage form or combination of the subject may achieve pain reduction lasting 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 24 hours, or about 24 hours. In other embodiments, administration of the combination of the subject may achieve pain reduction at about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or within about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, or about 60 minutes, within 2 hours, within 3 hours, or other periods bordered by these ranges.

[0058] A person receiving treatment for a disease or symptom with the dosage forms described herein may be of any age. For example, the person's age may be approximately 10 to 90 years, approximately 20 to 80 years, approximately 30 to 75 years, approximately 40 to 70 years, approximately 1 to 16 years, approximately 80 to 95 years, approximately 16 years or older, approximately 18 years or older, approximately 20 years or older, approximately 25 years or older, approximately 30 years or older, approximately 40 years or older, approximately 45 years or older, approximately 50 years or older, approximately 55 years or older, approximately 60 years or older, approximately 65 years or older, or any other age within or between these values.

[0059] In some embodiments, a person receiving treatment for migraines with the dosage forms described herein, including, for example, meloxicam, rizatriptan, SBEβCD, and a bicarbonate such as sodium bicarbonate, may be between 18 and 65 years of age, about 18 and 20 years of age, about 20 and 25 years of age, about 25 and 30 years of age, about 30 and 40 years of age, about 40 and 45 years of age, about 40 and 50 years of age, about 50 and 60 years of age, about 60 and 65 years of age, or other ages limited to or between these values.

[0060] In some embodiments, a person receiving treatment for migraines with a dosage form described herein, such as meloxicam, rizatriptan, sulfobutyl ether-β-cyclodextrin (SBEβCD), and a bicarbonate such as sodium bicarbonate, may be Black or African American, White, or Asian. In some embodiments, the person is Black or African American. In some embodiments, the person is White. In some embodiments, the person is Asian.

[0061] In some embodiments, a person being treated for a disease or symptom with a dosage form containing meloxicam or another NSAID suffers from pain or a pain-related symptom for at least one day, at least one week, at least two weeks, at least one month, at least six months, at least two months, at least three months, at least six months, or at least one year, or any period within or between these values.

[0062] In some embodiments, a person being treated for migraine with a dosage form comprising meloxicam and rizatriptan has been diagnosed with migraine with aura or migraine without aura, as defined by the ICHD-3 criteria, for a period of at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1 to 2 years, 2 to 3 years, or longer, or at least 1 year, or within a range limited by these values, or any period between these values.

[0063] In some embodiments, a person has or has had moderate to severe migraines on average 2 to 8 times, 2 to 3 times, 3 to 4 times, 4 to 5 times, 5 to 6 times, 6 to 7 times, or 7 to 8 times per month, such as at least in the past month.

[0064] The cyclodextrin used in the dosage form with meloxicam may include cyclodextrin, cyclodextrin derivatives, and / or salts thereof. Inclusion complexes of meloxicam and cyclodextrin may have higher water solubility than uncomplexed meloxicam. The cyclodextrin may be a natural cyclodextrin (e.g., α, β, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, derivatives, or salts thereof may be used. α-cyclodextrins may 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-tert-butyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0065] In some embodiments, β-cyclodextrin, derivatives, or salts thereof may be used. β-cyclodextrins include 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, and (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-Ot-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 β-cyclodextrin This may include, but is not limited to, methylated-β-cyclodextrin, branched-β-cyclodextrin, or combinations thereof.

[0066] In other embodiments, the β-cyclodextrin may be a sulfoalkyl ether cyclodextrin, a derivative thereof, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-β-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In some embodiments, SBEβCD may have about 4 to 8, about 5 to 8, about 4 to 7, about 6 to 7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0067] In some embodiments, γ-cyclodextrin, derivatives, or salts thereof may be used. γ-cyclodextrin may include carboxymethyl-γ-cyclodextrin, (2,3,6-tri-O-acetyl)-γ-cyclodextrin, (2,3,6-tri-O-methyl)-γ-cyclodextrin, (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.

[0068] In some embodiments, this dosage form may contain a bicarbonate such as sodium bicarbonate, potassium bicarbonate, or a combination thereof. Bicarbonates may help increase the solubility and bioavailability of meloxicam or rizatriptan.

[0069] Unless otherwise noted, references to compounds described herein, such as meloxicam or cyclodextrin, by structure, name, or any other means include pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species that may be rapidly converted to compounds described herein under the conditions under which the compound is used as described herein.

[0070] In some embodiments, the dosage form may contain meloxicam in amounts of approximately 15 mg to 25 mg, approximately 18 mg to 22 mg, or approximately 20 mg. These doses may be safe doses for repeated administration, such as once an hour or once a day, twice a day, once to 12 times a day, or three, four, five, or six times a day. In some embodiments, meloxicam may be safely administered twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen times a day, or approximately three to approximately ten times a day, or less frequently, such as once a week, once every two weeks, or once a month.

[0071] For any amount of meloxicam described herein, the salt form of meloxicam may be present in the amounts described above, or in amounts molar equivalent to these amounts for meloxicam free acid. For example, considering that the molecular weight of meloxicam free acid is 351.4 g / mol, 20 mg of meloxicam in free acid form is 56.9 mmol. Therefore, the molar equivalent of 20 mg of meloxicam free acid is the mass of 56.9 mmol of meloxicam in salt form. For example, the weight of meloxicam sodium salt (molecular weight 373.4 g / mol) in the same molar equivalent as 20 mg (or 56.9 mmol) of meloxicam free acid is 21.25 mg. These doses may be safe for repeated administration, such as once, twice, three or four times a day, or for repeated administration at intervals of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days, 4 weeks, 4-6 weeks, about 1 or 2 months, about 6 weeks, about 2 or 3 months, about 3 or 4 months, about 4 or 5 months, about 5 or 6 months, about 6 or 7 months, about 7 or 8 months, about 8 or 9 months, about 9 or 10 months, about 10 or 11 months, about 11 or 12 months or longer.

[0072] For some dosage forms, meloxicam may be formulated into solid dosage forms by complexing with substituted-β-cyclodextrins or other cyclodextrins. Such dosage forms may be suitable for oral administration. Meloxicam-cyclodextrin inclusion complexes may also be dissolved in water or another solvent to form parenteral formulations. However, physical mixtures of meloxicam and substituted-β-cyclodextrins or other cyclodextrins may also be used for oral or parenteral dosage forms.

[0073] The formation of inclusion complexes between meloxicam and cyclodextrin may be beneficial for improving the properties of this dosage form. In some inclusion complexes, the molar ratio of meloxicam to cyclodextrin (e.g., SBEβCD) may be approximately 0.5 to 2 (a molar ratio of 0.5 is 0.5 moles of meloxicam per mole of cyclodextrin), approximately 0.5 to 0.7, approximately 0.6 to 0.8, approximately 0.7 to 0.9, approximately 0.8 to 1, approximately 0.9 to 1.1, approximately 1 to 1.2, approximately 1.1 to 1.3, approximately 1.2 to 1.4, approximately 1.3 to 1.5, approximately 1.4 to 1.6, approximately 1.5 to 1.7, approximately 1.6 to 1.8, approximately 1.7 to 1.9, approximately 1.8 to 2, approximately 0.8 to 1.2, approximately 1, or any of the ranges limited by any of these values.

[0074] For some dosage forms, cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of approximately 1 to 1000 (e.g., 1 g of cyclodextrin per 1 g of meloxicam); approximately 1 to 20; approximately 1 to 10; approximately 1 to 15; approximately 2 to 4, approximately 3 to 5, approximately 4 to 6, approximately 5 to 7, approximately 6 to 8, approximately 7 to 9, approximately 8 to 10, or a range limited to any of these values, or any weight ratio to meloxicam between these values. For some dosage forms, cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of approximately 0.001 to 1 (e.g., 0.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); approximately 0.01 to 1; approximately 0.05 to 1; approximately 0.1 to 1; approximately 0.2 to 1; approximately 0.3 to 1, approximately 0.4 to 1, approximately 0.5 to 1, approximately 0.6 to 1, approximately 0.7 to 1, approximately 0.8 to 1, or any of these limited ranges or any of these values. Each type of cyclodextrin used may have a different ratio.

[0075] For some dosage forms, cyclodextrin may be present in amounts of approximately 1 mg to 200 mg; 25 mg to 175 mg; approximately 50 mg to 150 mg; approximately 25 mg to 100 mg; approximately 75 mg to 150 mg; approximately 100 mg to 175 mg; approximately 20 mg to 80 mg; approximately 25 mg to 50 mg; approximately 60 mg to 100 mg; approximately 80 mg to 100 mg; approximately 80 mg to 120 mg; approximately 100 mg to 120 mg; approximately 100 mg to 140 mg; approximately 120 mg to 160 mg; approximately 140 mg to 180 mg; approximately 30 mg to 90 mg; approximately 40 mg to 80 mg; approximately 50 mg to 70 mg; approximately 55 mg to 65 mg; approximately 60 mg to 62 mg, or amounts limited to these values ​​or between these values.

[0076] In some cases, meloxicam inclusion complexes with cyclodextrins such as substituted β-cyclodextrins are delivered orally (e.g., by tablets, capsules, elixirs, etc.). Other possible routes of administration include intravenous, intramuscular, nasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal, or other parenteral means. Meloxicam may also be delivered alone or without forming complexes with cyclodextrins.

[0077] Several dosage forms contain a carbonate (e.g., sodium bicarbonate) in approximately 1 mg to 2000 mg; approximately 1 mg to 1000 mg; approximately 100 mg to 1000 mg; approximately 200 mg to 800 mg; approximately 1 mg to 500 mg; approximately 1 mg to 200 mg; approximately 1 mg to 100 mg; approximately 50 mg to 750 mg; approximately 500 mg to 1000 mg; approximately 100 mg to 500 mg; approximately 100 mg to 300 mg; approximately 500 mg to 1000 mg; approximately 300 mg to 700 mg; approximately 400 mg to 600 mg; approximately 50 mg to 250 mg; approximately 250 mg to 750 mg; approximately 100 mg to 200 mg; approximately 200 mg to 300 mg; approximately 3 00 mg to 400 mg; approximately 400 mg to 500 mg; approximately 410 mg to 510 mg; approximately 420 mg to 520 mg; approximately 430 mg to 530 mg; approximately 440 mg to 540 mg; approximately 450 mg to 550 mg; approximately 460 mg to 560 mg; approximately 470 mg to 570 mg; approximately 480 mg to 580 mg; approximately 490 mg to 590 mg; approximately 500 mg to 600 mg; approximately 600 mg to 700 mg; approximately 700 mg to 800 mg; approximately 800 mg to 900 mg; approximately 150 mg to 650 mg; approximately 350 mg to 850 mg; or any amount limited to these values ​​or within the range between these values.

[0078] In certain embodiments, the pharmaceutical composition contains meloxicam, but compared to dosage forms that do not contain cyclodextrin, antacids, or buffers (such as bicarbonates), it increases the bioavailability of meloxicam from the dosage form (e.g., T max Decrease, C maxresults in an increase in , an increase in AUC, etc.). In some embodiments, the bioavailability of meloxicam is increased after multiple administrations.

[0079] Some of the dosage forms provided herein have an AUC of meloxicam 0-inf of about 40,000 * ng·hr / mL to 70,000 ng * ·hr / mL; about 50,000 * ng·hr / mL to 60,000 ng * ·hr / mL; about 52,000 * ng·hr / mL to 56,000 ng * ·hr / mL; or about 54,000 ng * ·hr / mL, which may provide a desired range of area under the plasma concentration curve (AUC) for meloxicam.

[0080] In some embodiments, the dosage form provides a C of meloxicam of from about 2,500 ng / mL to 3,500 ng / mL, from about 2,700 ng / mL to 3,100 ng / mL, or about 2,900 ng / mL max , which may be achieved.

[0081] The methods described herein may reduce the T of meloxicam max . In some embodiments, the method may comprise treating a patient to achieve the T of meloxicam in the patient's body at about 0.5 hour to 1 hour, about 0.8 hour to 0.9 hour, or about 0.875 hour after administration of the subject combination max .

[0082] Some of the dosage forms have about 70 * ng·hr / mL to 100 ng * ·hr / mL; about 80 * ng·hr / mL to 90 ng * ·hr / mL; or about 86.7 ng * ·hr / mL AUC for rizatriptan 0-inf , which may provide a desired range of area under the plasma concentration curve (AUC) for rizatriptan.

[0083] In some embodiments, this dosage form contains approximately 25 ng / mL to approximately 35 ng / mL, approximately 30 ng / mL to approximately 34 ng / mL, and approximately 31 ng / mL to approximately 31.7 ng / mL of rizatriptan. max This can sometimes lead to problems.

[0084] The method described herein involves the T of lyzatriptan. max This may reduce the T of rizatriptan in the patient's body approximately 0.5 to 1 hour, 0.7 to 0.8 hours, or 0.75 hours after administration. max This can sometimes be achieved.

[0085] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form for direct oral administration), and two hours after administration of meloxicam and rizatriptan, humans experience greater relief from allodynia, such as cutaneous allodynia, than humans would have experienced two hours after ingesting the same amount of meloxicam without rizatriptan.

[0086] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, humans experience a greater relief from allodynia, such as cutaneous allodynia, than they would have experienced 24 hours after taking the same amount of meloxicam without rizatriptan.

[0087] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, humans experience greater relief from allodynia, such as cutaneous allodynia, than humans would have experienced two hours after taking the same amount of rizatriptan without meloxicam.

[0088] In some embodiments, meloxicam and rizatriptan are administered simultaneously (in a single dosage form, such as a single oral dosage form including a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, humans experience greater relief from allodynia, such as cutaneous allodynia, than humans would have experienced 24 hours after taking the same amount of rizatriptan without meloxicam.

[0089] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or encapsulated in a hard or soft-shelled gelatin capsule, compressed into a tablet, or directly incorporated into a food. For oral therapeutic administration, the active compound may be formulated with excipients and used in the form of ingestible tablets, suppositories, coated tablets, lozenges, capsules, elixirs, powders, suspensions, solutions, syrups, wafers, patches, or similar products.

[0090] Tablets, lozenges, tablets, capsules, and similar products may contain one or more of the following: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; or flavorings such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain active compounds, sucrose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavorings such as cherry or orange flavoring. It may be desirable that the materials of a dosage form or pharmaceutical composition be pharmaceutically pure and substantially nontoxic in the amounts used.

[0091] Some compositions or dosage forms may be liquids or may contain a solid phase dispersed in a liquid.

[0092] The dosage form may also include a second therapeutically active agent, such as an antacid or analgesic.

[0093] In some embodiments, the dosage form containing the subject combination may contain about 5 mg to about 15 mg, about 8 mg to about 12 mg, or about 10 mg of rizatriptan.

[0094] For acute migraines, the single dose of meloxicam and / or rizatriptan, or the AUC of meloxicam and / or rizatriptan associated with a single dose, is of particular interest. For example, symptoms may be relieved for a long period after a single dose, and repeated administration may not be necessary in the short term. For more persistent symptoms, including more chronic, persistent, or frequent migraine symptoms, daily, weekly, or monthly doses may be of particular interest.

[0095] For any amount of rizatriptan described herein, the salt form of rizatriptan may exist in the amounts described above, or in amounts equivalent in molar terms to these amounts for rizatriptan free base. For example, considering that the molecular weight of rizatriptan free base is 269.4 g / mol, 10 mg of rizatriptan free base is equivalent to 37.1 mmol of rizatriptan. Therefore, the mass of a rizatriptan salt having the same molar equivalent as 10 mg of rizatriptan free base is the mass of 37.1 mmol of rizatriptan salt. For example, for rizatriptan benzoate (molecular weight = 391.2 g / mol), the molar equivalent (or 37.1 mmol) of 10 mg of rizatriptan free base is 14.5 mg of rizatriptan benzoate. These doses may be safe to administer repeatedly once, twice, three or four times per day, or at intervals of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 4 weeks, 4 to 6 weeks, about 1 to 2 months, about 6 weeks, about 2 to 3 months, about 3 to 4 months, about 4 to 5 months, about 5 to 6 months, about 6 to 7 months, about 7 to 8 months, about 8 to 9 months, about 9 to 10 months, about 10 to 11 months, or about 11 to 12 months.

[0096] Some oral dosage forms may have an enteric coating or a film coating. In some embodiments, the dosage form may include a tablet or capsule having an enteric coating. In some embodiments, the dosage form may include a tablet or capsule having a film coating.

[0097] Dosage forms containing rizatriptan and meloxicam, as described herein, may relieve migraine pain within less than 15 minutes, about 15 minutes, less than 30 minutes, 15 to 30 minutes, less than 1 hour, 0.5 to 0.75 hours, or 0.75 to 1 hour after administration. The combinations of rizatriptan and meloxicam described herein may provide numerically greater migraine pain relief than rizatriptan for periods of less than 15 minutes, about 5 minutes, about 5 to 10 minutes, about 10 to 15 minutes, about 15 minutes, about 15 to 30 minutes, about 30 to 45 minutes, about 45 to 60 minutes, about 1 to 1.5 hours, about 1.5 to 2 hours, about 2 to 2.5 hours, about 2.5 to 3 hours, about 3 to 3.5 hours, about 3.5 to 4 hours, about 4 to 5 hours, about 5 to 6 hours, about 6 to 8 hours, about 8 to 10 hours, about 10 to 12 hours, about 12 to 24 hours, about 24 to 48 hours, or longer. The percentage of migraine patients reporting pain relief with the combination of rizatriptan and meloxicam described herein may be 1% to 100%, 3% to 100%, 4% to 100%, 5% to 100%, 3% to 5%, 5% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, 90% to 95%, or 95% to 100%.

[0098] Migraine patients taking a dosage form containing the combination of rizatriptan and meloxicam described herein ("the subject combination") may achieve pain relief after less than 2 hours, about 2 hours, about 2 to 3 hours, about 3 to 4 hours, about 4 to 6 hours, about 6 to 8 hours, about 8 to 10 hours, about 10 to 12 hours, about 12 to 16 hours, about 16 to 20 hours, about 20 to 24 hours, about 24 to 30 hours, about 30 to 36 hours, about 36 to 40 hours, about 40 to 44 hours, about 44 to 48 hours, or longer periods.

[0099] Example 1 A phase 3 randomized, double-blind, multicenter, placebo- and actively controlled trial was conducted to evaluate the efficacy and safety of the meloxicam and rizatriptan combination (meloxicam / rizatriptan) in the acute treatment of moderate to severe migraine. Eligible patients had to be between 18 and 65 years of age, have a confirmed diagnosis of migraine with or without aura as defined by the ICHD-3 criteria (at least one year), experience moderate to severe migraines 2 to 8 times per month on average, and have a history of inadequate response to previous acute migraine treatment, as assessed by a score of 7 (mean score 3.6) on the Migraine Treatment Optimization Questionnaire (mTOQ-4), corresponding to poor response to previous acute migraine treatment. Exclusion criteria included cluster headache or other types of migraine, chronic daily headache (more than 15 days of non-migraine headache per month), a history of significant cardiovascular disease, and uncontrolled hypertension. In addition to a history of insufficient response, registered patients frequently exhibited features strongly associated with poor treatment outcomes, including cutaneous allodynia (75.4%), severe migraine pain intensity (41.2%), obesity (43.7%), and morning-type migraine (36.6%).

[0100] For the treatment of a single moderate to severe migraine attack, a total of 1,594 patients were randomly assigned in a 2:2:2:1 ratio to receive (1) meloxicam / rizatriptan (meloxicam 20 mg / rizatriptan 10 mg, SBEβCD (approx. 133.6 mg) and sodium bicarbonate (500 mg)), (2) rizatriptan (10 mg) alone, (3) meloxicam (20 mg) and SBEβCD (MoSEIC meloxicam), or (4) placebo. The study had two co-primary endpoints. The endpoints for meloxicam / rizatriptan compared to placebo were the proportion of patients with headache pain resolution at 2 hours post-administration and the proportion of patients with resolution of the most distressing migraine-related symptom (nausea, photophobia, or phonophobia) at 2 hours post-administration. Superiority of meloxicam / rizatriptan over rizatriptan and meloxicam (component contribution) should be established based on sustained headache resolution from 2 to 24 hours post-administration (key secondary endpoint). This study was conducted in accordance with FDA Special Protocol Assessment (SPA). Rizatriptan, the active control in this study, is the fastest-acting oral triptan and is considered one of the most effective acute migraine treatments currently available. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. serotonin 5-HT(1B / 1D) agonists) Acute migraine treatment: a meta-analysis of 53 trials. (Treatment of acute migraine with oral triptans (serotonin 5-HT(1B / 1D) agonists): A meta-analysis of 53 clinical trials.) Lancet. 2001 Nov 17;358(9294):1668-75.

[0101] Meloxicam / rizatriptan rapidly relieved migraine pain. In the meloxicam / rizatriptan group, pain reduction was achieved at a numerically higher rate than in the rizatriptan group at all time points measured from 15 minutes onward, and a statistically significant result (p=0.04) was obtained at 60 minutes (Figure 1). The percentage of patients who experienced pain reduction 1.5 hours after administration was 60.5% in the meloxicam / rizatriptan group, compared to 52.5% in the rizatriptan group and 48.3% in the placebo group (p=0.019, p=0.04, relative to the meloxicam / rizatriptan group) (Figure 1A). Figure 1A shows the percentage of subjects who reported pain reduction at 1 hour and 1.5 hours after administration, excluding the placebo group, for the roxicam, rizatriptan, and meloxicam / rizatriptan groups.

[0102] Meloxicam / rizatriptan met two regulatory co-primary endpoints, with statistically significant differences compared to placebo, resulting in a higher percentage of patients achieving pain relief 2 hours after administration (19.9% ​​vs. 6.7%, p<0.001, Figure 2) and a higher percentage of patients achieving relief from the most bothersome symptoms (36.9% vs. 24.4%, p=0.002).

[0103] The superiority of meloxicam / rizatriptan over rizatriptan (active control) and MoSEIC® meloxicam (component contributing agent) was established as defined in the SPA by demonstrating a higher percentage of patients with sustained pain relief from 2 to 24 hours post-dosing compared to rizatriptan, MoSEIC® meloxicam, and placebo (16.1%, 11.2%, 6%, and 5.3%, respectively, p=0.038, p=0.001, and p<0.001 for meloxicam / rizatriptan, Figure 3A), which was a pre-specified primary secondary endpoint to demonstrate component contribution. Approximately 80% of patients treated with meloxicam / rizatriptan who achieved pain relief at 2 hours maintained pain relief up to 24 hours. These results demonstrated a significant improvement in pain relief in migraine treatment and the superiority of meloxicam / rizatriptan over rizatriptan.

[0104] Meloxicam / rizatriptan provided more significant and sustained migraine pain relief compared to placebo and rizatriptan, and meloxicam / rizatriptan significantly reduced the use of emergency medications compared to placebo and rizatriptan. The proportion of patients who experienced sustained pain relief from 2 to 24 hours after administration was 53.3% with meloxicam / rizatriptan, compared to 33.5% with placebo and 43.9% with rizatriptan (p<0.001 and p=0.006, respectively, for meloxicam / rizatriptan) (Figure 3B).

[0105] Sustained analgesia from 2 to 48 hours was also experienced in a statistically significantly higher proportion (46.5%) of meloxicam / rizatriptan patients compared to placebo patients (31.1%) and rizatriptan patients (36.5%) (p<0.001 and p=0.003, respectively, for the meloxicam / rizatriptan group) (Figure 4B). Figure 4D shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan, excluding the placebo group. Sustained pain relief from 2 to 48 hours was experienced in a statistically significantly higher proportion (15.4%) of meloxicam / rizatriptan patients compared to placebo (5.3%), rizatriptan (8.8%), and MoSEIC® meloxicam (8.1%) patients (p<0.001, p=0.003, and p=<0.001 for meloxicam / rizatriptan, respectively) (Figure 4A). Figure 4C shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan, excluding placebo. Approximately 77% of meloxicam / rizatriptan patients who achieved pain relief at 2 hours maintained pain relief until 48 hours later.

[0106] Emergency medication was used in 23.0% of patients taking meloxicam / rizatriptan, compared to 43.5% of patients taking placebo and 34.7% of patients taking rizatriptan (p<0.001 for meloxicam / rizatriptan, respectively) (Figure 5). Approximately 77% of patients taking meloxicam / rizatriptan did not require emergency medication. These results indicate that meloxicam / rizatriptan is superior to the active control drug rizatriptan in the treatment of migraines.

[0107] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan in several other secondary endpoints, including patients' overall perception of the changes (PGI-C) (p=0.022) and recovery of normal function after 24 hours (p=0.027).

[0108] Table 1 below shows some of the p-values ​​for meloxicam / rizatriptan compared to rizatriptan across various evaluation items, demonstrating the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraines.

[0109] [Table 1]

[0110] Considering that rizatriptan, the active control drug in this study, is the fastest-acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine, and that this study enrolled patients with difficult-to-treat migraines, the therapeutic effect observed with meloxicam / rizatriptan, which provides greater and longer-lasting migraine pain relief than rizatriptan, is highly significant. Many patients experience suboptimal responses to current acute migraine treatments and are at high risk of headache-related disorders and progression to chronic migraine, which are factors associated with increased healthcare costs. The results of this study suggest that meloxicam / rizatriptan may offer an important treatment option for patients with difficult-to-treat migraines. In the MOMENTUM Phase 3 trial, meloxicam / rizatriptan was generally safe and well-tolerated, with adverse events occurring in 1% to 3% of patients. 11.1% of patients experienced some kind of emergency treatment adverse event after taking meloxicam / rizatriptan, and 2.7%, 1.6%, and 1.4% of patients experienced nausea, dizziness, and somnolence, respectively (Table 2). The proportion of patients experiencing treatment-related adverse events after meloxicam / rizatriptan administration was similar to that of other tested treatments (Table 2).

[0111] [Table 2]

[0112] The results of this trial demonstrate the ability of meloxicam / rizatriptan to provide rapid, potent, and sustained migraine pain relief compared to rizatriptan, a potent active control, in a rigorously designed trial involving patients with refractory migraine. These results have potentially significant implications for patient care, given the high rates of inadequate response to current treatments and patient dissatisfaction with current treatments.

[0113] Meloxicam / rizatriptan incorporates multiple mechanisms of action to address various processes in migraine, aiming for greater efficacy. It is thought to work by inhibiting CGRP release, reversing CGRP-mediated vasodilation, neuroinflammation, pain signaling, and central sensitization. The results of this clinical trial validate this approach, demonstrating that meloxicam / rizatriptan can offer greater benefits than current treatments, even in patients with refractory migraine. Meloxicam / rizatriptan may be effectively used for the acute treatment of adult migraine, with or without aura.

[0114] Example 2 Over 70% of those affected report dissatisfaction with existing acute-phase treatments. The most common reasons for patient dissatisfaction are delayed onset of pain relief, inconsistent pain relief, and pain recurrence on the same day. Inadequate acute-phase treatment is associated with an increased risk of chronic migraine, which can sometimes be prevented by improving the outcomes of acute-phase treatment.

[0115] The Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluates the effectiveness of acute treatment based on four items: pain relief, sustained pain reduction, comfort with daily activity planning, and no impairment of daily activities. Previous studies have shown that 12% to 27% of migraine patients report little to no positive response in these items with other medical treatments.

[0116] The clinical trial in Example 1 was analyzed to characterize the areas of greatest need in the acute treatment of migraines by examining the percentage of subjects who answered "never" or "almost never" to each item of the mTOQ-4.

[0117] The mTOQ-4 is a four-item questionnaire designed to assess the validity of current treatment outcomes for the purpose of optimizing treatment, incorporating efficacy, reliability, self-report, and ease of use. The mTOQ-4 is shown in Table 3 below.

[0118] [Table 3]

[0119] Figure 6 shows the percentage of patients who answered "never" or "almost never" to each question on the mTOQ-4.

[0120] Example 3 A phase 3 randomized, double-blind, multicenter, placebo-controlled trial was conducted to evaluate the early treatment of migraine with meloxicam / rizatriptan. A total of 302 patients were randomly assigned in a 1:1 ratio to receive treatment for one migraine attack at the earliest sign of migraine, while the pain was still mild and before it progressed to moderate or severe, with either a single dose of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, supplemented with SBEβCD (approximately 133.6 mg) and sodium bicarbonate (500 mg) as described in Example 1 above) or placebo.

[0121] This clinical trial differs from the clinical trial in Example 1. In the Example 1 trial, only patients with a history of inadequate response to previous acute treatment were enrolled, and patients were expected to wait for treatment only when migraine pain reached moderate or severe. In contrast to this clinical trial, the Example 1 trial enrolled all volunteers, and patients were instructed to administer meloxicam / rizatriptan at the earliest sign of migraine, while the pain was still mild, before it progressed to moderate or severe intensity.

[0122] The patients were adult subjects who had been definitively diagnosed with migraine, regardless of the presence or absence of aura.

[0123] The co-primary endpoints were the absence of headache pain and the absence of the most distressing migraine-related symptoms (nausea, photophobia, or phonophobia) two hours after administration of meloxicam / rizatriptan, compared to placebo.

[0124] Secondary endpoints included sustained pain relief, resolution of migraine pain progression, changes in functional impairment, and use of emergency medications.

[0125] Inclusion criteria included males or females aged 18 to 65 years, a confirmed diagnosis of migraine (for at least one year) with or without aura as defined by the ICHD-3 criteria, and an average of 2 to 8 migraines per month. Exclusion criteria included cluster headache, tension headache, or other types of migraine, chronic daily headache (more than 15 non-migraine headache days per month), a history of significant cardiovascular disease, and uncontrolled hypertension.

[0126] In this 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. In this trial, meloxicam / rizatriptan met the co-primary endpoints of migraine pain relief and relief of the most distressing symptom compared to placebo.

[0127] Meloxicam / rizatriptan demonstrated statistically significant improvement compared to placebo in both co-primary endpoints: resolution of pain 2 hours after administration (32.6% vs. 16.3%, p=0.002) and resolution of the most bothersome symptom (43.9% vs. 26.7%, p=0.003) (Figures 7A and 7B). The most bothersome symptoms were nausea, photophobia, or phonophobia.

[0128] Meloxicam / rizatriptan was numerically superior to placebo at 30 minutes in the resolution of migraine pain (Figure 8) and the resolution of the most bothersome symptoms (Figure 9), and achieved statistical significance for migraine pain resolution at 90 minutes (p=0.003) and at all subsequent time points (Figure 8). At 12 hours, 64% of patients who took meloxicam / rizatriptan had experienced pain relief, compared to 42% of patients who took placebo. At 24 hours, 69% of patients who took meloxicam / rizatriptan had experienced pain relief, compared to 47% of patients who took placebo.

[0129] Meloxicam / rizatriptan provided sustained relief of migraine pain in a statistically significantly higher percentage of patients compared to placebo, achieving sustained pain relief from 2 to 24 hours post-administration (22.7% vs. 12.6%, p=0.030) and sustained pain relief from 2 to 48 hours post-administration (20.5% vs. 9.6%, p=0.013) (Figures 10A and 10B).

[0130] Meloxicam / rizatriptan prevented the progression of mild to severe migraine pain intensity from 2 to 24 hours in 73.5% of patients compared to 47.4% in placebo patients (p<0.001) (Figure 11). A single dose of meloxicam / rizatriptan prevented the progression of mild to severe migraine pain.

[0131] The effect on pain progression manifested as a significant reduction in the use of emergency medications; only 15.3% of patients who took meloxicam / rizatriptan required emergency medication within 24 hours of administration, compared to 42.2% of patients who took placebo (p<0.001) (Figure 12).

[0132] Meloxicam / rizatriptan substantially and significantly reduced functional impairment, demonstrating overall improvement in the disease. After 24 hours, the ability to perform normal activities was achieved in 73.5% of patients treated with meloxicam / rizatriptan compared to 47.4% of patients treated with placebo (p<0.001) (Figure 13).

[0133] On the Patient Global Impression Scale-C (PGI-C), 52.4% of patients who took meloxicam / rizatriptan reported being "significantly improved" or "improved" after 2 hours, compared to only 27.7% of patients who took placebo (p<0.001) (Figure 14).

[0134] Meloxicam / rizatriptan was generally safe and well-tolerated in the study. The most commonly reported adverse events with meloxicam / rizatriptan were somnolence, dizziness, and paresthesia, all occurring in less than 5% of patients (Table 4). No serious adverse events were observed in the study.

[0135] [Table 4]

[0136] In the clinical trial described above, several patients had depression. Tables 5 and 6 summarize the results for pain resolution and resolution of the most distressing migraine symptoms at 2 hours in the patient population with a history of depression and the patient population without a history of depression. The meloxicam / rizatriptan used in the clinical trial contained 20 mg of meloxicam free acid, 10 mg of rizatriptan free base, and the molar equivalent of rizatriptan benzoate.

[0137] [Table 5]

[0138] As shown in Table 5, among responders with a history of depression, 48% experienced relief of headache pain 2 hours after treatment with the meloxicam and rizatriptan combination, while only 4.8% of patients receiving placebo showed relief of headache pain 2 hours after treatment, a difference of 43.2%.

[0139] On the other hand, among patients with no history of depression, 29% experienced relief of headache pain two hours after treatment with the meloxicam and rizatriptan combination, compared to 18.4% of placebo patients, a difference of 10.6%.

[0140] [Table 6]

[0141] Similarly, as shown in Table 6, among responders with a history of depression, 52% experienced relief of the most bothersome migraine symptoms 2 hours after treatment with the meloxicam and rizatriptan combination, compared to only 28.6% of placebo-takers, a difference of 23.4%.

[0142] On the other hand, among responders with no history of depression, 42.1% experienced relief of the most bothersome migraine symptoms two hours after treatment with the meloxicam and rizatriptan combination, compared to 26.3% of placebo-takers, a difference of 15.7%.

[0143] Therefore, among patients who responded to treatment with the combination of meloxicam and rizatriptan as claimed (AXS-07), the percentage of patients with headache pain relief or relief of the most bothersome migraine symptom after 2 hours was significantly higher in patients with a history of depression (excluding those receiving the placebo) than in patients without a history of depression (excluding those receiving the placebo).

[0144] “This study demonstrated a high rate of migraine pain relief with meloxicam / rizatriptan treatment and employed an innovative design to assess the progression of migraine pain. It is noteworthy that early treatment with meloxicam / rizatriptan halted the progression of migraine pain in the majority of patients and enabled a similarly high percentage of patients to return to normal function,” said Dr. Stewart Tepper, professor of neurology at the Geisel School of Medicine, Dartmouth University. "The multiple mechanisms of action of meloxicam / rizatriptan address the disruption of many physiological processes involved in migraine attacks. These results, coupled with previous clinical data demonstrating the superiority of meloxicam / rizatriptan over active control agents, provide clinical evidence that this synergistic, multi-mechanism approach and the rapid absorption of meloxicam / rizatriptan may offer significant benefits to a wide range of patients. Clinicians continue to seek patient options that offer improved efficacy over currently available therapies, and meloxicam / rizatriptan may represent a crucial new treatment for this seemingly helpless condition."

[0145] This Phase 3 trial confirmed the superior and sustained efficacy of meloxicam / rizatriptan. The significant increase in prevention of migraine pain progression and pain relief rates demonstrated by early treatment with meloxicam / rizatriptan expands and enhances its differentiated profile for the acute treatment of migraine. With this Phase 3 trial and the Phase 3 trial described in Example 11, which involved patients with a history of inadequate response to previous acute treatments, meloxicam / rizatriptan is now being evaluated in two well-controlled trials with good outcomes. These trials demonstrated the efficacy of meloxicam / rizatriptan against potent active and placebo controls in a variety of migraine attack situations, regardless of the timing of migraine treatment, disease severity, or baseline pain intensity.

[0146] “Migraines are one of the most debilitating conditions, leaving patients helpless and severely impacting their home life, social activities, and work capacity. Published studies highlight patients’ dissatisfaction with the effectiveness of currently available treatments,” said Dr. Cedric O’Gorman, senior vice president of clinical development and medical affairs at Axsome. “The results of this trial are the first to demonstrate that meloxicam / rizatriptan can halt the progression of migraine pain before it reaches moderate or severe. These data enrich the substance of clinical evidence supporting the potential of meloxicam / rizatriptan as a multi-mechanism treatment for migraines, offering superior efficacy over current standard treatments and rapid, powerful, and sustained symptom relief, enabling patients to return to normal daily activities.”

[0147] Example 4 A long-term, open-label Phase 3 trial of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, containing SBEβCD and sodium bicarbonate as described in Example 4) was conducted. In this trial, treatment with meloxicam / rizatriptan rapidly, substantially, and sustainably reduced migraine pain and associated symptoms. Meloxicam / rizatriptan was well-tolerated over long-term treatment with a safety profile consistent with that observed in previously reported comparative studies.

[0148] This clinical trial evaluated the long-term safety of meloxicam / rizatriptan (MoSEIC® meloxicam 20 mg / rizatriptan 10 mg) administered for up to 12 months in patients with migraine attacks. This trial enrolled patients who had completed the clinical trials described in Example 11 or Example 12. Enrolled patients were permitted to treat up to 10 migraine attacks per month over a period of up to 12 months with one dose of meloxicam / rizatriptan for each migraine that occurred. The safety and efficacy of meloxicam / rizatriptan were evaluated during the trial. A total of 706 patients were enrolled. The trial was conducted once, and as specified, at least 300 patients were treated for at least 2 migraines per month for 6 months, and approximately 100 patients were treated for at least 2 migraines per month for 12 months. At the end of the trial, 515 patients had reached at least 6 months of treatment, and 155 patients had reached at least 12 months of treatment. More than 21,000 migraine attacks were treated with meloxicam / rizatriptan during the trial. Measures of efficacy included reduction of migraine pain and most distressing symptoms (photophobia, phonophobia, nausea), as well as the use of emergency medication.

[0149] In this clinical trial, administration of meloxicam / rizatriptan resulted in rapid and substantial relief of migraine pain and associated symptoms. Within one hour of administration, 39% (range: 37-41%) of patients achieved migraine pain relief, indicating a rapid onset of meloxicam / rizatriptan. Two hours after administration of meloxicam / rizatriptan, 68% (range: 65-71%) of patients achieved migraine pain relief, and 38% (range: 37-40%) achieved pain relief. Within two hours of administration, 47% (range: 46-49%) of patients achieved relief of the most bothersome symptoms (photophobia, phonophobia, nausea).

[0150] Meloxicam / rizatriptan provided sustained migraine pain relief in 85% (range: 84-86%) of patients for 24 hours without the use of emergency medications, and in 83% (range: 82-85%) of patients for 48 hours without the use of emergency medications, following a single dose of meloxicam / rizatriptan. The rates of sustained pain relief at 2 to 24 hours and 2 to 48 hours were 60% (range: 59-62%) and 59% (range: 58-60%), respectively. The rates of sustained pain resolution at 2 to 24 hours and 2 to 48 hours were 33% (range: 33-35%) and 32% (range: 32-34%), respectively.

[0151] Meloxicam / rizatriptan was well-tolerated with long-term administration. The safety profile of meloxicam / rizatriptan over a 12-month treatment period was consistent with that previously reported in short-term comparative studies. The most frequently reported adverse events (≥3%) were nausea, dizziness, and vomiting. During the 12-month study, 1.6% of patients discontinued treatment due to adverse events.

[0152] Example 5 The efficacy of meloxicam / rizatriptan compared to placebo was evaluated in a subgroup of patients with high BMI, allodynia, morning-type migraine, and a history of depression, which are risk factors for inadequate treatment response to acute migraine medication.

[0153] The data were obtained from pooled subgroup analyses of subjects who participated in clinical trials of Example 1 and Example 3 for the acute treatment of migraines.

[0154] As shown in Figure 15, across four subgroups defined by risk factors, treatment with meloxicam / rizatriptan improved the 24-hour sustained pain relief rate compared to placebo.

[0155] BMI above the median BMI of the patients in this study (median 28.8 kg / m²) 2In patients with the above conditions, pain disappeared after 2 hours in 15.8% of treated patients compared to 7.6% of patients who received a placebo (p=0.008).

[0156] In patients with allodynia, defined as an ASC-12 score of 3 or higher, pain disappeared after 2 hours in 18.7% of treated patients compared to 8.1% of patients who received a placebo (p<0.001).

[0157] For patients with morning migraines, defined as migraine attacks occurring before 10:00 a.m., 18.3% of those treated experienced pain relief after 2 hours, compared to 8.1% of those who received a placebo (p=0.005).

[0158] In patients with a history of depression, pain disappeared after 2 hours in 16.7% of those treated, compared to 5.9% of those who received a placebo (p=0.053).

[0159] Unless otherwise noted, all characteristics such as numbers, quantities, and percentages used to express the quantities of components in this specification and the claims should be understood in all cases to represent both the exact value as indicated and the value as modified by the term “approximately.” Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximations, which may vary depending on the desired characteristics to be obtained. Each numerical parameter should be interpreted, at least in light of the reported number of significant figures, by applying common rounding techniques, and not in any attempt to limit the application of the doctrine of equivalents to the claims.

[0160] In the context describing embodiments (in particular, in the context of the following claims), the terms “a,” “an,” “the,” and similar reference terms shall be construed to encompass both singular and plural forms unless otherwise specified herein or unless clearly contradicted by the context. All methods described herein may be performed in any suitable order unless otherwise specified herein or unless clearly contradicted by the context. Any examples or exemplary language used herein (e.g., “such as”) are merely for the purpose of better describing embodiments and shall not limit the scope of any claim. No language in the specification should be construed to indicate a component that is not included in the claims and is essential to the carrying out of the claimed invention.

[0161] The grouping of alternative components or embodiments disclosed herein should not be construed as limitation. Members of each group may be referenced individually or in any combination with other members of the group or other elements found herein, and may be described in the claims. It is anticipated that one or more members of a certain group may be included in or removed from such group for convenience and / or to expedite examination. When such inclusion or removal occurs, this specification shall be deemed to include groups modified to satisfy the description requirements of all Markush groups when used in the appended claims.

[0162] Specific embodiments are described herein, including the best mode known to the inventors for carrying out the embodiments of the claims. Of course, variations of these described embodiments will be obvious to those skilled in the art by reading the preceding description. The inventors anticipate that those skilled in the art will appropriately adopt such variations, and they intend that the embodiments of the claims will be carried out in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described herein that are permitted by applicable law. Furthermore, unless otherwise specifically noted herein or unless it is clearly inconsistent with the context, any combination of the above elements in these possible variations is contemplated.

[0163] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, alternative embodiments may be used in accordance with the teachings herein, not as limitations but as examples. Thus, the claims are not limited to the embodiments shown and described herein.

[0164] [Note] [Note 1] A method for treating migraine, comprising orally administering to a person in need of it about 15 mg to 30 mg of meloxicam or a pharmaceutically acceptable salt thereof and a combination of rizatriptan or a pharmaceutically acceptable salt thereof, wherein the person has a history of depression and suffers from migraine pain or aura.

[0165] [Note 2] The method described in Appendix 1, wherein rizatriptan is administered orally to the human being in doses of approximately 8 mg to approximately 13 mg of free base of rizatriptan or a molar equivalent of the salt of rizatriptan.

[0166] [Note 3] The method according to Appendix 1 or 2, wherein the combination comprises approximately 20 mg of meloxicam free acid or meloxicam in the form of a salt of the same acid.

[0167] [Note 4] The method according to any one of the appendices 1 to 3, wherein the person experiences a reduction in migraine pain one hour after oral administration of the combination.

[0168] [Note 5] The method according to any one of the appendices 1 to 3, wherein the person experiences a reduction in migraine pain 24 hours after oral administration of the combination.

[0169] [Note 6] The method according to any one of the appendices 1 to 3, wherein the person experiences the disappearance of migraine pain two hours after oral administration of the combination.

[0170] [Note 7] The person in question suffers from moderate to severe migraine pain, according to any one of the methods described in Appendix 1 to 6.

[0171] [Note 8] The person in question suffers from photophobia, as described in any one of the methods described in Appendix 1 to 7.

[0172] [Note 9] The method described in Appendix 8, wherein the human subject experiences a reduction in photophobia two hours after oral administration of the combination.

[0173] [Note 10] The person in question suffers from phonophobia, as described in any one of the methods in Appendix 1 to 9.

[0174] [Note 11] The method described in Appendix 10, wherein the person experiences a reduction in phonophobia two hours after oral administration of the combination.

[0175] [Note 12] The person is suffering from nausea, according to one of the methods described in Appendix 1 to 11.

[0176] [Note 13] The method described in Appendix 12, wherein the person experiences a reduction in nausea two hours after oral administration of the combination.

[0177] [Note 14] The aforementioned migraine is accompanied by aura, and is a method described in any one of the appendices 1 to 13.

[0178] [Note 15] The method according to any one of Appendix 1 to 14, wherein the use of analgesics other than meloxicam is reduced compared to the use of analgesics other than meloxicam that would have occurred if the person had not received meloxicam.

[0179] [Note 16] The method according to any one of Appendix 1 to 15, wherein the use of analgesics other than meloxicam is reduced by at least about 20% compared to the use of analgesics other than meloxicam that would have occurred if the person had not received meloxicam.

[0180] [Note 17] The aforementioned human beings received meloxicam within 2 hours after oral administration of the aforementioned combination. max A method according to any one of appendices 1 to 16, wherein the method is provided for the member.

[0181] [Note 18] The aforementioned human beings received meloxicam within 1 hour after oral administration of the aforementioned combination. max A method according to any one of appendices 1 to 16, wherein the method is provided for the member.

[0182] [Note 19] The method according to any one of Appendix 1 to 18, wherein the rizatriptan is rizatriptan benzoate.

[0183] [Note 20] The method according to any one of appendices 1 to 19, wherein the meloxicam is in the free acid form.

[0184] [Note 21] The method according to any one of the appendices 1 to 20, wherein the combination is present in a dosage form when administered orally to a human.

Claims

1. A method for treating migraine, comprising orally administering to a person in need of it about 15 to 30 mg of meloxicam or a pharmaceutically acceptable salt thereof and a combination of rizatriptan or a pharmaceutically acceptable salt thereof, wherein the person has a history of depression and suffers from migraine pain or aura.

2. The method according to claim 1, wherein rizatriptan is administered orally to the human being in an amount of approximately 8 mg to approximately 13 mg of free base of rizatriptan or a molar equivalent of the salt of rizatriptan.

3. The method according to claim 1 or 2, wherein the combination comprises approximately 20 mg of meloxicam free acid or meloxicam in the form of a salt of molar equivalent.

4. The method according to any one of claims 1 to 3, wherein the person experiences a reduction in migraine pain one hour after oral administration of the combination.

5. The method according to any one of claims 1 to 3, wherein the person experiences a reduction in migraine pain 24 hours after oral administration of the combination.

6. The method according to any one of claims 1 to 3, wherein the person experiences the disappearance of migraine pain two hours after oral administration of the combination.

7. The method according to any one of claims 1 to 6, wherein the person suffers from moderate to severe migraine pain.

8. The method according to any one of claims 1 to 7, wherein the person suffers from photophobia.

9. The method according to claim 8, wherein the person experiences a decrease in photophobia two hours after oral administration of the combination.

10. The method according to any one of claims 1 to 9, wherein the person suffers from phonophobia.

11. The method according to claim 10, wherein the person experiences a reduction in phonophobia two hours after oral administration of the combination.

12. The method according to any one of claims 1 to 11, wherein the person is suffering from nausea.

13. The method according to claim 12, wherein the person experiences a reduction in nausea two hours after oral administration of the combination.

14. The method according to any one of claims 1 to 13, wherein the migraine is accompanied by an aura.

15. The method according to any one of claims 1 to 14, wherein the use of analgesics other than meloxicam is reduced compared to the use of analgesics other than meloxicam that would have occurred if the person had not received meloxicam.

16. The method according to any one of claims 1 to 15, wherein the use of analgesics other than meloxicam is reduced by at least about 20% compared to the use of analgesics other than meloxicam that would have occurred if the person had not received meloxicam.

17. The aforementioned human beings received meloxicam within 2 hours after oral administration of the aforementioned combination. ｍａｘ The method according to any one of claims 1 to 16, comprising:

18. The aforementioned human beings received meloxicam within one hour after oral administration of the aforementioned combination. ｍａｘ The method according to any one of claims 1 to 16, comprising:

19. The method according to any one of claims 1 to 18, wherein the rizatriptan is rizatriptan benzoate.

20. The method according to any one of claims 1 to 19, wherein the meloxicam is in the form of a free acid.

21. The method according to any one of claims 1 to 20, wherein the combination is present in a dosage form when administered orally to a human being.

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