Pharmaceutical composition comprising meloxicam

Abstract

Disclosed herein is a method of treating migraine in a patient with a history of inadequate response to a prior migraine treatment, the method comprising: selecting a patient who, in the at least the past month, has: 1) 2 to 8 migraines per month, and 2a) according to the patient, never or rarely feels comfortable enough to plan daily activities without taking the patient’s migraine medication, 2b) according to the patient, never or rarely feels the patient’s migraines are controlled enough after taking migraine medication that the patient feels the patient’s daily activities will not be disrupted, 2c) an mTOQ-4 score of 0, and / or 2d) a history of depression; and administering to the patient a combination of meloxicam and rizatriptan during a migraine attack.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 579,833, filed August 31, 2023, which is incorporated herein by reference in its entirety. Summary of the Invention

[0003] Some implementation methods include a method for treating migraine in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who has: 1) experienced migraines 2 to 8 times per month for at least the past four weeks; and 2) according to the patient, never or rarely felt sufficiently comfortable to plan daily activities while taking the patient's migraine medication; and, after selecting the patient, administering to the patient a combination of 20 mg meloxicam or a pharmaceutically acceptable salt thereof and 10 mg rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

[0004] Some implementation methods include a method for treating migraine in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who has: 1) experienced migraines 2 to 8 times per month for at least the past four weeks; and 2) according to the patient, that the patient has never or rarely felt that the patient's migraines are adequately controlled so that the patient feels that the patient's daily activities will not be interfered with after taking migraine medication; and, after selecting the patient, administering a combination of 20 mg meloxicam or a pharmaceutically acceptable salt thereof and 10 mg rizatriptan or a pharmaceutically acceptable salt thereof to the patient during a migraine attack.

[0005] Some implementation methods include a method for treating migraine in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who has had at least the following conditions in the past four weeks: 1) experiencing migraines 2 to 8 times per month, and 2) having an mTOQ-4 score of 0; and, after selecting the patient, administering a combination of 20 mg meloxicam or a pharmaceutically acceptable salt thereof and 10 mg rizatriptan or a pharmaceutically acceptable salt thereof to the patient during a migraine attack.

[0006] Some implementation methods include a method for treating migraine in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who: 1) has experienced 2 to 8 migraines per month for at least the past four weeks, and 2) has a history of depression; and, after selecting the patient, administering a combination of 20 mg meloxicam or a pharmaceutically acceptable salt thereof and 10 mg rizatriptan or a pharmaceutically acceptable salt thereof to the patient during a migraine attack.

[0007] Some implementation methods include a method for treating migraines, which involves orally administering a combination of about 15 mg to 30 mg of meloxicam or a pharmaceutically acceptable salt thereof and rizatriptan or a pharmaceutically acceptable salt thereof to a person in need, wherein the person has a history of depression and suffers from migraine pain or aura. Attached Figure Description

[0008] Figure 1 The graph shows the percentage of subjects who reported pain relief at various time points within the first 4 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1.

[0009] Figure 1A The percentage of subjects who reported pain relief at 1.0 and 1.5 hours, relative to placebo, for meloxicam, rizatriptan, and meloxicam / rizatriptan.

[0010] Figure 2 The percentage of subjects who achieved pain-free status at 2, 4, 12, and 16 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1 is shown.

[0011] Figure 3A The percentage of subjects who achieved sustained pain-free status 2 to 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1 is shown.

[0012] Figure 3B The percentage of subjects who achieved sustained pain relief 2 to 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1 is shown.

[0013] Figure 4A The percentage of subjects who achieved sustained pain-free status 2 to 48 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1 is shown.

[0014] Figure 4B The percentage of subjects who achieved sustained pain relief 2 to 48 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 1 is shown.

[0015] Figure 4C The percentage of subjects who achieved sustained pain-free status from 2 to 48 hours relative to placebo for meloxicam, rizatriptan, and meloxicam / rizatriptan was shown.

[0016] Figure 4D The percentage of subjects who achieved sustained pain relief from 2 to 48 hours with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo is shown.

[0017] Figure 5 The percentage of subjects who took the rescue medication up to 24 hours after administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo as described in Example 1 is shown.

[0018] Figure 6 The proportion of patients in Example 1 who answered “never” or “rarely” for each mTOQ-4 question is depicted.

[0019] Figure 7A and Figure 7B The percentage of subjects in Example 3 who experienced relief from pain and most bothersome symptoms, including those taking meloxicam / rizatriptan and placebo, is shown.

[0020] Figure 8 The percentage of subjects who achieved pain-free status over time in Example 3, including those taking meloxicam / rizatriptan and placebo, is shown.

[0021] Figure 9 The percentage of subjects in Example 3 who received meloxicam / rizatriptan and placebo achieved no most bothersome symptoms over time is shown.

[0022] Figure 10A and Figure 10B The percentage of subjects in Example 3 who received meloxicam / rizatriptan and placebo achieved pain-free status during the 2-24 hour and 2-48 hour periods is shown.

[0023] Figure 11 The percentage of subjects in Example 3 who received meloxicam / rizatriptan and placebo achieved pain-free progression within 2–24 hours is shown.

[0024] Figure 12 The percentage of subjects who took rescue medication among those taking meloxicam / rizatriptan and placebo in Example 3 is shown.

[0025] Figure 13 The percentage of subjects in Example 3 who did not experience functional disability at 24 hours is shown.

[0026] Figure 14This shows the percentage of subjects in Example 3 who had a “significant improvement” or “gross improvement” in the overall patient change impression (PGI-C) at hour 2 among those taking meloxicam / rizatriptan and placebo.

[0027] Figure 15 The study showed the rate of 24-hour pain-free duration compared to placebo in patients with a high BMI, hyperalgesia, a history of morning migraines, and depression. Detailed Implementation

[0028] Meloxicam has the following structure:

[0029] ,

[0030] It is a nonsteroidal anti-inflammatory drug (NSAID) exhibiting anti-inflammatory, analgesic, and antipyretic activities. The mechanism of action of meloxicam may involve inhibition of prostaglandin synthase (cyclooxygenase, COX), an enzyme involved in the initial steps of the arachidonic acid cascade reaction; this inhibition leads to a reduction in the formation of prostaglandins, thromboxanes, and prostacyclin.

[0031] Meloxicam and some other NSAIDs have poor water solubility, which may reduce bioavailability and delay the onset of pain relief. One way to increase the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cyclic amylose) are typically barrel-shaped cyclic polysaccharides. Cyclodextrins help increase the bioavailability of other molecules because they are hydrophobic on the inside and hydrophilic on the outside, which helps facilitate the transport of molecules such as hydrophobic molecules. Naturally occurring cyclodextrins contain six, seven, and eight glucose units (α-, β-, and γ-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (i.e., inclusion complexes) with drugs by incorporating the drug into the central / hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around drugs in a micellar structure. This ability of cyclodextrins allows them to act as drug carriers to increase the bioavailability of drugs that are difficult to dissolve.

[0032] The combination of rizatriptan and meloxicam (referred to as the “topic combination” for convenience) can be used to treat a variety of pain conditions.

[0033] Rizatritan has the structure shown below.

[0034]

[0035] Rizatrotan

[0036] Some embodiments include a combination of the following: 1) an inclusion complex of meloxicam and cyclodextrin, 2) rizatriptan, and 3) a bicarbonate for treating migraines in humans. Migraines can be treatment-resistant. The person may have a history of inadequate response to previous treatments. In some embodiments, the cyclodextrin is SBEβCD.

[0037] Dosage forms can be administered enterically, including but not limited to oral, sublingual or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal or subcutaneous delivery.

[0038] Unless otherwise stated, any reference to the compounds described herein (such as meloxicam or rizatriptan) by means of structure, name or any other means includes pharmaceutically acceptable salts, alternative solid forms (such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterated forms) or any other chemical substance (such as a prodrug, prodrug or any other chemical substance that can be rapidly converted into the compounds described herein under the conditions of use of the compounds described herein).

[0039] The combination of the ingredients can be administered enterally, including but not limited to oral, sublingual, or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous delivery. In some embodiments, meloxicam and rizatriptan are administered orally.

[0040] Typically, administration of the combination of meloxicam and rizatriptan allows a person to receive meloxicam and rizatriptan over short periods of time relative to each other. 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 of each other. 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).

[0041] The term “treating” or “treatment” broadly includes any kind of therapeutic activity, including any activity that diagnoses, cures, alleviates or prevents disease in a person or other animal, or otherwise affects the structure or any function of the body in a person or other animal.

[0042] Migraine is a disabling neurological disorder characterized by recurrent, throbbing headaches accompanied by nausea and sensitivity to light and sound. The pain can be mild or moderate to severe, but is usually intense and disabling, requiring bed rest. The headache may affect half of the head, may be throbbing in nature, and can last from 2 to 72 hours. Related symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or odors. Migraine pain may be accompanied by visual disturbances. Physical activity can worsen migraine pain. Migraines may be associated with auras, which can be brief visual disturbances indicating that the headache is about to begin. Some migraine sufferers may not have auras.

[0043] In some implementations, people being treated for migraine pain suffer from hyperalgesia, such as cutaneous hyperalgesia accompanying their migraine attacks. Hyperalgesia (e.g., cutaneous hyperalgesia) is pain induced by normal, non-painful stimuli (such as combing hair, wearing glasses, bathing, etc.). Patients with hyperalgesia (e.g., cutaneous hyperalgesia) are considered unlikely to respond well to triptans.

[0044] Current treatment is suboptimal, with over 70% of patients reporting dissatisfaction with their existing acute care. The most common reasons for patient dissatisfaction are slow onset of pain relief, unstable pain relief, and recurrence of pain on the same day. Suboptimal acute care is associated with a significantly increased risk of new-onset chronic migraine, which can be prevented by improving acute care outcomes.

[0045] Administering the combination of themes to a person suffering from migraines (such as an acute attack or aura of migraine pain) can rapidly result in a reduction of migraine symptoms (such as pain, nausea, vomiting, photophobia, or phonophobia), such as within approximately 5 minutes (intended as an abbreviation for "within approximately 5 minutes"), within approximately 10 minutes, within approximately 30 minutes, within approximately 1 hour, within approximately 90 minutes, within approximately 2 hours, within approximately 2.5 hours, or within approximately 3 hours. In some implementations, the person experiences a reduction or complete relief of pain (such as headache or migraine pain, nausea, vomiting, photophobia, and / or phonophobia) within approximately 1 hour, within approximately 90 minutes, within approximately 2 hours, within approximately 2.5 hours, or within approximately 3 hours. In some implementations, the relief experienced is greater than that experienced when receiving the same amount of rizatriptan without meloxicam. In some implementations, the remission experienced is greater than that experienced with the same amount of meloxicam without rizatriptan.

[0046] Thematic combinations can be applied at the earliest signs of migraine pain or shortly after, such as 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 before it progresses to moderate or severe intensity. For some methods, thematic combinations can be applied when the migraine pain has already reached moderate or severe intensity.

[0047] In some implementations, the combination of meloxicam and rizatriptan is administered to migraine patients who have functional disability or are selected due to functional disability. In some implementations, the treatment enables migraine patients to resume normal activities within 24 hours of receiving treatment.

[0048] The combination of meloxicam and rizatriptan can have different dual mechanisms of action for the acute treatment of migraines. Meloxicam is a potent COX-2-preferred NSAID, limited by its slow absorption. Rizatriptan is a potent 5-HT1 inhibitor considered effective for migraines. B / D Agonists.

[0049] Observing symptom relief or reduction within a specific time period (such as "at 2 hours") is useful because it allows for evaluation of treatment effectiveness at specific or consistent time points, which facilitates comparisons between patients. Observing symptom relief or reduction within a specific time period, such as "approximately 2 hours," is useful because it is expected that symptom relief or reduction will occur as early as possible, and specifying relief within a prescribed time sets a criterion for expecting relief.

[0050] For some methods, the application of thematic combinations can achieve relief of migraine pain, nausea, vomiting, photophobia, or phonophobia for at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8 to 24 hours, about 24 hours, or more than 24 hours.

[0051] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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 pain relief experienced by the person is greater than the pain relief experienced by the person two hours after receiving the same amount of meloxicam without rizatriptan.

[0052] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid dosage form), and the pain relief experienced by a person 24 hours after administration of meloxicam and rizatriptan is greater than the pain relief experienced by a person 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0053] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the pain relief experienced by the person is greater than the pain relief experienced by the person two hours after receiving the same amount of rizatriptan without meloxicam.

[0054] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and the pain relief experienced by a person 24 hours after administration of meloxicam and rizatriptan is greater than the pain relief experienced by a person 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0055] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the nausea relief experienced by a person is greater than the nausea relief experienced by a person two hours after receiving the same amount of meloxicam without rizatriptan.

[0056] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and the nausea relief experienced by a person 24 hours after administration of meloxicam and rizatriptan is greater than the nausea relief experienced by a person 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0057] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the nausea relief experienced by a person is greater than the nausea relief experienced by a person two hours after receiving the same amount of rizatriptan without meloxicam.

[0058] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and the nausea relief experienced by a person 24 hours after administration of meloxicam and rizatriptan is greater than the nausea relief experienced by a person 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0059] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the person experiences greater vomiting relief than the person experiences two hours after receiving the same amount of meloxicam without rizatriptan.

[0060] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater vomiting relief than the person experiences within 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0061] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the person experiences greater vomiting relief than the person experiences two hours after receiving the same amount of rizatriptan without meloxicam.

[0062] In some implementations, meloxicam and rizatriptan are administered concurrently (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater relief from vomiting than the person experiences within 24 hours after receiving the same amount of rizatriptan without meloxicam. In some implementations, meloxicam and rizatriptan are administered concurrently (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within two hours after administration of meloxicam and rizatriptan, the person experiences greater relief from photophobia than the person experiences within two hours after receiving the same amount of meloxicam without rizatriptan.

[0063] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater photophobia relief than the person experiences within 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0064] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the person experiences greater relief from photophobia than the person experiences two hours after receiving the same amount of rizatriptan without meloxicam.

[0065] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater photophobia relief than the person experiences within 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0066] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the person experiences greater relief from phonophobia than the person experiences two hours after receiving the same amount of meloxicam without rizatriptan.

[0067] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater relief from phonophobia than the person experiences within 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0068] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the person experiences greater relief from phonophobia than the person experiences two hours after receiving the same amount of rizatriptan without meloxicam.

[0069] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater relief from phonophobia than the person experiences within 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0070] In some implementations, the person has already used triptans before receiving the combination of therapies (such as a combination containing meloxicam and rizatriptan).

[0071] In some implementations, people who receive the topic combination score 0 or 1 on the migraine treatment optimization questionnaire (mTOQ-4).

[0072] In some implementations, the person receiving the theme combination has indicated before receiving the theme combination that he or she has “never” or “rarely” been pain-free within two hours after treatment for most episodes.

[0073] In some implementations, the recipients of the subject combination have indicated before receiving the subject combination that a dose of the medication "never" or "rarely" relieved the respondent's headache and made it disappear for at least 24 hours.

[0074] In some implementations, the person receiving the theme combination has indicated before receiving the theme combination that he or she “never” or “rarely” feels comfortable enough while taking his or her migraine medication to be able to plan his or her daily activities.

[0075] In some implementations, the person receiving the theme combination has indicated before receiving the theme combination that, after taking his or her migraine medication, he or she “never” or “rarely” felt that he or she had sufficient control over his or her migraines so that he or she felt that his or her daily activities would not be interfered with.

[0076] In some implementations, individuals receiving the topic set have a history of depression prior to receiving the topic set.

[0077] In some implementations, the person receiving the combination of therapies (such as a combination containing meloxicam and rizatriptan) suffers from migraines and may have a history of inadequate response to previous migraine treatments. In some implementations, the person suffering from migraines does not experience cluster headaches or other types of migraines. In some implementations, the person suffering from migraines does not have chronic daily headaches. In some implementations, the person suffering from migraines does not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 non-migraine days per month. In some implementations, the person suffering from migraines does not have a significant history of cardiovascular disease. In some implementations, the person suffering from migraines does not have uncontrolled hypertension.

[0078] For some methods, administration of the dosage form can achieve pain relief lasting for at least about one hour, two hours, three hours, four hours, six hours, at least about eight hours, about eight to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form can achieve pain relief observed at approximately 10 minutes, about 30 minutes, about one hour, about two hours, about three hours, about four hours, about five hours, about six hours, less than 15 minutes, less than 20 minutes, 30 minutes, less than one hour, less than two hours, less than three hours, 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, or other time periods within the range defined by any of these values.

[0079] For some methods, administration of the dosage form or theme combination can achieve pain relief lasting for at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about eight to about 24 hours, or about 24 hours. In other embodiments, administration of the theme combination can achieve pain relief observed at approximately 10 minutes, about 30 minutes, about one hour, about two hours, about three hours, about four hours, about five hours, about six 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, two hours or less, three hours or less, or other time periods defined by these ranges.

[0080] The person who treats the disease or condition with the dosage form described herein can be of any age. For example, the age of a person can be approximately 10 to approximately 90 years, approximately 20 to approximately 80 years, approximately 30 to approximately 75 years, approximately 40 to approximately 70 years, approximately 1 to approximately 16 years, approximately 80 to approximately 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 defined by or within the range of these values.

[0081] In some implementations, the person treated with migraines using the dosage forms described herein (e.g., containing meloxicam, rizatriptan, SBEβCD, and bicarbonates such as sodium bicarbonate) may be 18 to 65 years of age, approximately 18–20 years of age, approximately 20–25 years of age, approximately 25–30 years of age, approximately 30–40 years of age, approximately 40–45 years of age, approximately 40–50 years of age, approximately 50–60 years of age, approximately 60–65 years of age, or any other age range defined by or between these values.

[0082] In some embodiments, the person treating migraines with the dosage forms described herein (such as those containing meloxicam, rizatriptan, sulfobutyl ether-β-cyclodextrin (SBEβCD), and bicarbonates (such as sodium bicarbonate)) can 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.

[0083] In some implementations, a person treating a disease or condition with a dosage form containing meloxicam or another NSAID suffers from pain or pain-related symptoms for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or any duration defined by or within the range of these values.

[0084] In some implementations, the person treated with a formulation containing meloxicam and rizatriptan has been diagnosed with migraine with or without aura for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years or longer, or at least 1 year, or any duration defined by or within these values ​​as defined by the ICHD-3 criteria.

[0085] In some implementation schemes, such as at least in the past month, a person has had or has had an average of 2 to 8, 2-3, 3-4, 4-5, 5-6, 6-7 or 7-8 moderate to severe migraines per month.

[0086] Cyclodextrins used in dosage forms with meloxicam can include cyclodextrins, cyclodextrin derivatives, and / or salts thereof. The inclusion complex of meloxicam and cyclodextrin can be more water-soluble than uncompounded meloxicam. The cyclodextrin can be a naturally occurring cyclodextrin (e.g., α-, β-, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, its derivatives, or salts 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, succinoyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0087] In some embodiments, β-cyclodextrin, its derivatives, or salts may be used. β-cyclodextrin may include, but is not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-amino-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-sulfonyl)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl- 6-O-sulfonyl)-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-maltose)-β-cyclodextrin, (6-O-sulfonyl)-β-cyclodextrin, (6-O-tert-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinoyl-(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, random methylated-β-cyclodextrin, branched-β-cyclodextrin, or combinations thereof.

[0088] In other embodiments, the β-cyclodextrin can be a sulfoalkyl ether cyclodextrin, its derivatives, or a salt. 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, each cyclodextrin molecule of SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups.

[0089] In some embodiments, γ-cyclodextrin, its derivatives, or salts 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-O-tert-butyldimethylsilyl)-γ-cyclodextrin, succinoyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

[0090] In some implementations, the dosage form may include bicarbonates, such as sodium bicarbonate, potassium bicarbonate, or combinations thereof. Bicarbonates can help increase the solubility and bioavailability of meloxicam or rizatriptan.

[0091] Unless otherwise stated, any reference to the compounds described herein (such as meloxicam or cyclodextrin) by means of structure, name or any other means includes pharmaceutically acceptable salts, alternative solid forms (such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterated forms) or any other chemical substance that can be rapidly converted into the compounds described herein under the conditions under which the compounds are used as described herein.

[0092] In some embodiments, the dosage form may contain approximately 15-25 mg, approximately 18-22 mg, or approximately 20 mg of meloxicam. These doses may be safe doses for repeated administration, such as once-hourly to once-daily, twice-daily, once to 12 times daily, 3, 4, 5, or 6 times daily. In some embodiments, meloxicam can be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times daily, or approximately 3 to approximately 10 times daily, once daily, or less frequently, such as once weekly, once every two weeks, once monthly, etc.

[0093] For any amount of meloxicam described herein, the salt form of meloxicam may exist in the amounts described above, or in amounts that are molar equivalents of these amounts of meloxicam free acid. For example, considering that the molecular weight of meloxicam free acid is 351.4 g / mol, 20 mg of meloxicam in the free acid form is 56.9 mmol. Therefore, the molar equivalent of 20 mg of meloxicam free acid will be the mass of 56.9 mmol of meloxicam in the salt form. For example, the weight of meloxicam sodium salt (mw = 373.4 g / mol) having the same molar equivalent (or 56.9 mmol) of 20 mg of meloxicam free acid would be 21.25 mg. These dosages may be safe for repeated administration, such as once, twice, three or four times daily, or at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, approximately 1-2 months, approximately 6 weeks, approximately 2-3 months, approximately 3-4 months, approximately 4-5 months, approximately 5-6 months, approximately 6-7 months, approximately 7-8 months, approximately 8-9 months, approximately 9-10 months, approximately 10-11 months, approximately 11-12 months or longer.

[0094] For some dosage forms, meloxicam forms a complex with substituted β-cyclodextrin or other cyclodextrins that can be formulated into solid dosage forms. Such dosage forms may be suitable for oral administration. Meloxicam-cyclodextrin inclusion complexes can also be dissolved in water or another solvent to form parenteral formulations. However, physical mixtures of meloxicam and substituted β-cyclodextrin or other cyclodextrins may also be used in oral or parenteral dosage forms.

[0095] The formation of inclusion complexes of meloxicam and cyclodextrin can help improve the properties of the dosage form. For some inclusion complexes, the molar ratio of meloxicam to cyclodextrin (e.g., SBEβCD) can be about 0.5-2 (0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or any ratio within the range defined by any of these values.

[0096] For some dosage forms, cyclodextrin (e.g., SBEβCD) and meloxicam can be used in weight ratios within the following ranges: about 1-1000 (e.g., the weight ratio of 1 g cyclodextrin / 1 g meloxicam is 1); about 1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio defined by or within the range of these values. For some dosage forms, cyclodextrin (e.g., SBEβCD) and meloxicam can be used in weight ratios within the following ranges: about 0.001-1 (e.g., the weight ratio of 0.1 g cyclodextrin / 1 g meloxicam is 0.1); about 0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weight ratio defined by or within the range of these values. Different ratios can be used for each type of cyclodextrin.

[0097] For some dosage forms, cyclodextrin may be present in the following amounts: about 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about 40-80 mg; about 50-70 mg; about 55-65 mg; about 60-62 mg; or any amount defined by or within the range of these values.

[0098] For some methods, meloxicam and cyclodextrin (such as substituted β-cyclodextrin) are delivered orally (e.g., via tablets, capsules, elixirs, etc.). Other potential routes of administration include intravenous, intramuscular, intranasal, parenteral (lyophilized), subcutaneous, transdermal, transmucosal, or other parenteral routes. Meloxicam can also be delivered alone or not in combination with cyclodextrin.

[0099] Some dosage forms contain the following amounts of bicarbonate (e.g., sodium bicarbonate): approximately 1-2000 mg; approximately 1-1000 mg; approximately 100-1000 mg; approximately 200-800 mg; approximately 1-500 mg; approximately 1-200 mg; approximately 1-100 mg; approximately 50-750 mg; approximately 500-1000 mg; approximately 100-500 mg; approximately 100-300 mg; approximately 500-1000 mg; approximately 300-700 mg; approximately 400-600 mg; approximately 50-250 mg; approximately 250-750 mg; approximately 100-200 mg; approximately 200-300 mg; approximately 300-400 mg; approximately 400-500 mg; approximately 410-510 mg; approximately 420-520 mg; approximately 430-530 mg. 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 amount defined by any of these values ​​or within the range of these values.

[0100] In some embodiments, the pharmaceutical composition results in increased bioavailability of meloxicam from said dosage form (e.g., reduced Tg) compared to dosage forms containing meloxicam but not containing cyclodextrin, acid inhibitors, or buffers (such as bicarbonates). max The increase of C max (Increased AUC). In some implementations, the bioavailability of meloxicam will increase with repeated dosing.

[0101] Some dosage forms can result in expected ranges for the area under the plasma concentration curve (AUC) of meloxicam, such as approximately 40,000–70,000 ng*hr / mL, approximately 50,000–60,000 ng*hr / mL, approximately 52,000–56,000 ng*hr / mL, or approximately 54,000 ng*hr / mL. 0-inf .

[0102] In some implementations, the dosage form can result in meloxicam C at approximately 2,500-3,500 ng / mL, approximately 2,700-3,100 ng / mL, or approximately 2,900 ng / mL. max .

[0103] The method described in this article can reduce meloxicam T levels. maxIn some implementations, the method may include treating the patient to achieve meloxicam T-cell efficacy in the patient approximately 0.5-1 hr, approximately 0.8-0.9 hr, or approximately 0.875 hr after administration of the topic combination. max .

[0104] Some dosage forms can result in expected ranges for the area under the plasma concentration curve (AUC) of rizatriptan, such as approximately 70-100 ng*hr / mL, approximately 80-90 ng*hr / mL, or approximately 86.7 ng*hr / mL. 0-inf .

[0105] In some implementations, the dosage form can result in rizatriptan C at approximately 25-35 ng / mL, approximately 30-34 ng / mL, approximately 31-32 ng / mL, or approximately 31.7 ng / mL. max .

[0106] The method described in this article can reduce T in rizatriptan. max For example, the method can achieve T-cell efficacy of rizatriptan in patients approximately 0.5–1 hr, approximately 0.7–0.8 hr, or approximately 0.75 hr after administration. max .

[0107] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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 relief of hyperalgesia (e.g., cutaneous hyperalgesia) than the person experiences two hours after receiving the same amount of meloxicam without rizatriptan.

[0108] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater relief from pain hypersensitivity (e.g., cutaneous hypersensitivity) than the person experiences within 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0109] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., 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, the person experiences greater relief from pain hypersensitivity (e.g., cutaneous hypersensitivity) than the person experiences two hours after receiving the same amount of rizatriptan without meloxicam.

[0110] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form, including a single solid oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the person experiences greater relief from hyperalgesia (e.g., cutaneous hyperalgesia) than the person experiences within 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0111] In some implementations, the dosage form may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly mixed with food. For oral therapeutic administration, the active compound may be blended with excipients and used in the form of ingestible tablets, sublingual tablets, coated tablets, lozenges, capsules, elixirs, dispersions, suspensions, solutions, syrups, rice paper capsules, patches, etc.

[0112] Tablets, lozenges, pills, capsules, etc., may also contain one or more of the following substances: binders, such as gum arabic, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, or saccharin; or flavorings, such as peppermint, wintergreen oil, or cherry flavorings. When the unit dosage form is a capsule, it may also contain a liquid carrier in addition to the materials of the types mentioned above. 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, dyes, and flavorings, such as cherry or orange flavorings. It may be desirable that the substances in the dosage form or pharmaceutical composition are pharmaceutically pure and substantially non-toxic in the amounts used.

[0113] Some compositions or dosage forms may be liquids, or may contain a solid phase dispersed in a liquid.

[0114] The dosage form may further include a second therapeutic agent, such as an acid inhibitor or analgesic.

[0115] In some implementations, dosage forms containing the subject combination may contain rizatriptan in amounts of about 5-15 mg, about 8-12 mg, or about 10 mg.

[0116] For acute migraines, the amount of a single dose of meloxicam and / or rizatriptan, or the AUC of meloxicam and / or rizatriptan associated with a single dose, is of particular concern. For example, symptoms may be relieved over an extended period after a single dose, potentially eliminating the need for repeated doses in the short term. For more continuous symptoms, including more chronic, persistent, or frequent migraine symptoms, daily, weekly, or monthly doses may be of particular concern.

[0117] For any amount of rizatriptan described herein, the salt form of rizatriptan may exist in the amounts described above, or in amounts that are molar equivalents of these amounts of the free base of rizatriptan. For example, given that the molecular weight of the free base of rizatriptan is 269.4 g / mol, 10 mg of the free base of rizatriptan is 37.1 mmol of rizatriptan. Therefore, the weight of the same molar equivalent of the rizatriptan salt having 10 mg of the free base of rizatriptan would be the mass of 37.1 mmol of the rizatriptan salt. For example, for the benzoate of rizatriptan (mw = 391.2 g / mol), the molar equivalent (or 37.1 mmol) of the free base of rizatriptan would be 14.5 mg of rizatriptan benzoate. These dosages may be safe for repeated administration, such as once, two, three, or four times daily, or at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, approximately 1-2 months, approximately 6 weeks, approximately 2-3 months, approximately 3-4 months, approximately 4-5 months, approximately 5-6 months, approximately 6-7 months, approximately 7-8 months, approximately 8-9 months, approximately 9-10 months, approximately 10-11 months, approximately 11-12 months, etc.

[0118] Some oral dosage forms may have enteric coating or film coating. In some embodiments, the dosage form may comprise tablets or capsules with enteric coating. In some embodiments, the dosage form may comprise tablets or capsules with film coating.

[0119] The formulations of rizatriptan and meloxicam described in this article can provide rapid relief of migraine pain in less than 15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, less than 1 hour, 0.5-0.75 hours, or 0.75-1 hour after administration. Compared to rizatriptan, the combination of rizatriptan and meloxicam described in this article provides numerically greater migraine pain relief in less than 15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes, about 30-45 minutes, about 45-60 minutes, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours, about 5-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-24 hours, about 24-48 hours or longer after administration. The percentage of migraine patients reporting pain relief when treated with the combination of rizatriptan and meloxicam described in this article can be 1%-100%, 3%-100%, 4%-100%, 5%-100%, 3%-5%, 5%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-95%, or 95%-100%.

[0120] Migraine patients receiving the formulation of the combination of rizatriptan and meloxicam described herein (the “Subject Combination”) may experience pain relief in less than 2 hours, approximately 2 hours, approximately 2–3 hours, approximately 3–4 hours, approximately 4–6 hours, approximately 6–8 hours, approximately 8–10 hours, approximately 10–12 hours, approximately 12–16 hours, approximately 16–20 hours, approximately 20–24 hours, approximately 24–30 hours, approximately 30–36 hours, approximately 36–40 hours, approximately 40–44 hours, approximately 44–48 hours or longer after administration.

[0121] Example 1

[0122] A phase 3, randomized, double-blind, multicenter, placebo- and active-controlled trial was conducted to evaluate the efficacy and safety of the combination of meloxicam and rizatriptan (meloxicam / rizatriptan) in the acute treatment of moderate and severe migraine. Eligible patients were aged 18 to 65 years, had a confirmed diagnosis of migraine with or without aura (for at least 1 year) as defined by the ICHD-3 criteria, experienced 2 to 8 moderate to severe migraine episodes per month on average, and had a history of inadequate response to previous acute migraine treatment, assessed by a score of 7 (mean score 3.6) on the migraine treatment optimization questionnaire-4, corresponding to poor response to previous acute treatment. Exclusion criteria included cluster headache or other types of migraine, chronic daily headache (≥ 15 non-migraine days per month), a significant history of cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, enrolled patients also exhibited a high rate of features closely associated with adverse treatment outcomes, including cutaneous hyperalgesia (75.4%), severe migraine pain intensity (41.2%), obesity (43.7%), and morning migraine (36.6%).

[0123] A total of 1,594 patients were randomized in a 2:2:2:1 ratio to receive (1) meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan) with SBEβCD (approximately 133.6 mg) and sodium bicarbonate (500 mg), (2) rizatriptan (10 mg), (3) meloxicam (20 mg) with SBEβCD (MoSEIC meloxicam), or (4) placebo for the treatment of a single moderate or severe migraine attack. The two co-primary endpoints of the trial were the proportion of patients who were headache-free two hours after administration of meloxicam / rizatriptan compared to placebo, and the proportion of patients who were no longer experiencing the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) two hours after administration. Superiority (component contribution) of meloxicam / rizatriptan relative to the rizatriptan group and the meloxicam group will be determined based on the absence of headache for two to 24 hours post-dose (key secondary endpoint). This study was conducted under FDA Special Protocol Evaluation (SPA). Rizatriptan, the active control drug in the trial, is considered one of the fastest-acting oral triptans and is currently one of the most effective drugs available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B / 1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov 17;358(9294):1668-75.)

[0124] Meloxicam / rizatriptan provides rapid relief of migraine pain, with the percentage of patients achieving pain relief using meloxicam / rizatriptan being numerically greater than using rizatriptan at every time point measured starting from 15 minutes, and statistically significant by 60 minutes (p = 0.04). Figure 1 For meloxicam / rizatriptan, the proportion of patients experiencing pain relief 1.5 hours after administration was 60.5%, compared to 52.5% for rizatriptan and 48.3% for placebo (p = 0.019 and p = 0.04, respectively, compared to meloxicam / rizatriptan). Figure 1 ). Figure 1A The percentage of subjects who reported pain relief at 1.0 and 1.5 hours, relative to placebo, for meloxicam, rizatriptan, and meloxicam / rizatriptan.

[0125] Meloxicam / rizatriptan met both regulatory co-primary endpoints with statistically significant results: the percentage of patients achieving pain-free status compared to placebo (19.9% ​​vs. 6.7%, p < 0.001). Figure 2 ), and no most bothersome symptoms were observed 2 hours after administration (36.9% vs. 24.4%, p = 0.002).

[0126] The superiority of meloxicam / rizatriptan over rizatriptan (active control) and MoSEIC™ meloxicam (component contribution) was determined, as per the SPA, by presenting the following results: A significantly higher proportion of patients receiving meloxicam / rizatriptan achieved sustained pain-free status 2 to 24 hours post-dose compared to rizatriptan, MoSEIC™ meloxicam, and placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively; p = 0.038, p = 0.001, and p < 0.001, respectively, compared to meloxicam / rizatriptan). Figure 3A (Pre-specified key secondary endpoints were used to demonstrate component contribution.) Approximately 80% of patients treated with meloxicam / rizatriptan achieved pain-free status at 2 hours and remained pain-free for up to 24 hours. These results demonstrate the significant improvement in pain-free status of meloxicam / rizatriptan compared to rizatriptan and its superiority over rizatriptan in the treatment of migraines.

[0127] Compared with placebo and rizatriptan, meloxicam / rizatriptan provided significantly greater and more durable migraine pain relief, which translated into a significant reduction in rescue medication use for meloxicam / rizatriptan compared with placebo and rizatriptan. The percentage of patients experiencing sustained pain relief 2 hours to 24 hours after administration was 53.3% for meloxicam / rizatriptan, compared to 33.5% for placebo and 43.9% for rizatriptan (p < 0.001 and p = 0.006, respectively, compared with meloxicam / rizatriptan). Figure 3B ).

[0128] Compared with placebo (31.1%) and rizatriptan (36.5%) patients, a statistically significantly higher proportion of meloxicam / rizatriptan patients (46.5%) experienced sustained pain relief between 2 and 48 hours (p < 0.001 and p = 0.003, respectively, compared with meloxicam / rizatriptan). Figure 4B ). Figure 4DThis shows the percentage of subjects who achieved sustained pain relief from 2 to 48 hours with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo. A statistically significantly higher proportion of meloxicam / rizatriptan patients (15.4%) experienced sustained pain relief from 2 to 48 hours compared to placebo (5.3%), rizatriptan (8.8%), and MoSEIC™ meloxicam (8.1%) patients (p < 0.001, p = 0.003, p < 0.001, respectively). Figure 4A ). Figure 4C This shows the percentage of subjects who achieved sustained pain-free status from 2 hours to 48 hours, relative to placebo, for meloxicam, rizatriptan, and meloxicam / rizatriptan. Approximately 77% of patients treated with meloxicam / rizatriptan achieved pain-free status at 2 hours and remained pain-free until 48 hours.

[0129] 23.0% of patients receiving meloxicam / rizatriptan used rescue medication, compared to 43.5% of patients receiving placebo and 34.7% of patients receiving rizatriptan (p < 0.001 for each group compared to meloxicam / rizatriptan). Figure 5 Approximately 77% of patients receiving meloxicam / rizatriptan did not require rescue medication. These results demonstrate the superiority of meloxicam / rizatriptan over the active control drug rizatriptan in the treatment of migraines.

[0130] In several other secondary endpoints, meloxicam / rizatriptan was statistically significantly superior to rizatriptan, including overall patient impression of change (PGI-C) (p = 0.022) and return to normal function within 24 hours (p = 0.027).

[0131] The p-values ​​of meloxicam / rizatriptan compared to rizatriptan for various endpoints are listed in Table 1 below, demonstrating the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraine.

[0132] Table 1. P-values ​​of meloxicam / rizatriptan compared to rizatriptan for different endpoints.

[0133]

[0134] Given that rizatriptan, the active control drug in the trial, is considered one of the fastest-acting oral triptans and one of the most effective drugs currently available for the acute treatment of migraine, and considering that the trial enrolled patients with treatment-resistant migraine, the observed therapeutic effect of meloxicam / rizatriptan was highly significant, providing greater and more durable migraine pain relief than rizatriptan. Many patients experience suboptimal responses to current acute migraine treatments, exposing them to an increased risk of headache-related disability and progression to chronic migraine, factors associated with increased healthcare costs. The results of this study suggest that meloxicam / rizatriptan could provide an important treatment option for patients with treatment-resistant migraine. During 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 any form of treatment-associated adverse event after taking meloxicam / rizatriptan, while 2.7%, 1.6%, and 1.4% of patients, respectively, experienced nausea, dizziness, and somnolence after taking meloxicam / rizatriptan (Table 2). The rate of treatment-associated adverse events after administration of meloxicam / rizatriptan was substantially similar to that of any other tested treatment (Table 2).

[0135] Table 2 a

[0136]

[0137] a Data is presented as a percentage of participants (out of participants).

[0138] The results of this trial demonstrate that, in a rigorously designed trial enriched with patients suffering from treatment-resistant migraine, meloxicam / rizatriptan offers a unique benefit to migraine sufferers compared to the potent, active control drug rizatriptan, providing rapid, powerful, and sustained relief of migraine pain. Given the high rates of inadequate response to current treatments and patient dissatisfaction, these results have potentially significant implications for patient care.

[0139] Meloxicam / rizatriptan combines multiple mechanisms of action to address various migraine processes, aiming to provide enhanced effectiveness. Meloxicam / rizatriptan is believed to work by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and suppressing neuroinflammation, pain signaling, and central sensitization. The results of this trial validate this approach, demonstrating that meloxicam / rizatriptan can provide a significant benefit greater than currently available treatments, even in patients with treatment-resistant migraines. Meloxicam / rizatriptan can be effectively used for the acute treatment of migraines in adults, with or without aura.

[0140] Example 2

[0141] Over 70% of patients reported dissatisfaction with their current acute treatment. The most common reasons for patient dissatisfaction were slow onset of pain relief, unstable pain relief, and recurrence of pain on the same day. Suboptimal acute treatment was associated with an increased risk of chronic migraine, which could be prevented by improving acute treatment outcomes.

[0142] The migraine treatment optimization questionnaire (mTOQ-4) evaluates the efficacy of acute treatments based on four domains: pain-free, sustained pain relief, comfort when planning daily activities, and uninterrupted daily activities. Previous studies have shown that 12%–27% of migraine sufferers report little or no positive response to these items when treated with other medications.

[0143] The clinical trial of Example 1 was analyzed to examine the proportion of subjects who answered “never” or “rarely” to each of the mTOQ-4 items in order to characterize the areas of greatest unmet need in the acute treatment of migraine.

[0144] The mTOQ-4 is a validated, reliable, self-reporting, and easy-to-use four-item questionnaire used to assess the adequacy of current treatment efficacy for the purpose of optimizing treatment. The mTOQ-4 is shown in Table 3 below.

[0145] Table 3

[0146]

[0147] a mTOQ-4 scores were determined based on prior treatment within the previous 4 weeks prior to screening.

[0148] The proportion of patients who answered "never" or "rarely" for each mTOQ-4 question was depicted in Figure 6 middle.

[0149] Example 3

[0150] A phase 3, randomized, double-blind, multicenter, placebo-controlled trial was conducted to evaluate early treatment of migraine with meloxicam / rizatriptan. A total of 302 patients were randomized 1:1 to receive a single dose of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, along with SBEβCD (approximately 133.6 mg) and sodium bicarbonate (500 mg)) or placebo for a single migraine attack at the earliest signs of migraine pain, before the pain progressed to moderate or severe intensity.

[0151] This clinical trial differs from the clinical trial in Example 1. The clinical trial in Example 1 enrolled only patients with a history of inadequate response to previous acute treatment, where patients waited for treatment of their attacks only when migraine pain reached moderate or severe intensity. This clinical trial serves as a control group compared to the one in Example 1. This clinical trial enrolled all participants, and in this clinical trial, patients were instructed to receive meloxicam / rizatriptan at the earliest signs of migraine pain, before the pain progressed to moderate or severe intensity and was at a mild stage.

[0152] The patients were adult subjects diagnosed with migraine with or without aura.

[0153] The co-primary endpoint was the absence of headache and most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) two hours after administration of meloxicam / rizatriptan, compared to placebo.

[0154] Secondary endpoints included persistent pain relief, no progression of migraine pain, changes in functional disability, and use of rescue medications.

[0155] Inclusion criteria included men or women aged 18–65 years (inclusive), a confirmed diagnosis of migraine with or without aura as defined by ICHD-3 criteria (for at least 1 year), and an average of 2–8 migraines per month. Exclusion criteria included cluster headache, tension headache or other types of migraine, chronic daily headache (≥ 15 non-migraine days per month), significant history of cardiovascular disease, and uncontrolled hypertension.

[0156] In this phase 3 trial of meloxicam / rizatriptan for early treatment of migraine, meloxicam / rizatriptan significantly and substantially eliminated migraine pain and significantly and substantially prevented the progression of migraine pain intensity. In this trial, compared with placebo, meloxicam / rizatriptan met the co-primary endpoints of no migraine pain and no most bothersome symptoms.

[0157] Meloxicam / rizatriptan showed statistically significant improvements over placebo in both of the co-primary endpoints at 2 hours post-dose: no pain (32.6% vs. 16.3%, p = 0.002) and no most bothersome symptoms (43.9% vs. 26.7%, p = 0.003). Figure 8 A and Figure 8 B). The most bothersome symptoms are nausea, photophobia, or phonophobia.

[0158] Meloxicam / rizatriptan was numerically superior to placebo, with no migraine pain as early as 30 minutes later. Figure 8 ) and no most annoying symptoms ( Figure 9 At 90 minutes (p = 0.003) and at every subsequent time point ( Figure 8 The study achieved statistical significance for pain relief in patients without migraines. 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.

[0159] Meloxicam / rizatriptan provided sustained relief of migraine pain, achieving a statistically significantly higher percentage of patients with sustained pain relief compared to placebo at 2 to 24 hours post-dose (22.7% vs. 12.6%, p = 0.030) and 2 to 48 hours post-dose (20.5% vs. 9.6%, p = 0.013). Figure 10A and Figure 10B ).

[0160] Within 2 to 24 hours, meloxicam / rizatriptan prevented migraine pain intensity greater than mild in 73.5% of patients, compared to 47.4% in patients taking placebo (p < 0.001). Figure 11 A single dose of meloxicam / rizatriptan can prevent migraine pain from progressing beyond the mild stage.

[0161] The effect on pain progression translated into a significant reduction in rescue medication use; only 15.3% of patients taking meloxicam / rizatriptan required rescue medication up to 24 hours after administration, compared to 42.2% of patients taking placebo (p < 0.001). Figure 12 ).

[0162] Meloxicam / rizatriptan significantly and substantially reduced functional disability and demonstrated overall disease improvement. At 24 hours, 73.5% of patients taking meloxicam / rizatriptan were able to perform normal activities, compared to 47.4% of patients taking placebo (p < 0.001). Figure 13 ).

[0163] On the Patient Global Impression Change-C (PGI-C) scale, 52.4% of patients taking meloxicam / rizatriptan showed significant or substantial improvement at hour 2 (p < 0.001), compared to 27.7% of patients taking placebo. Figure 14 ).

[0164] Meloxicam / rizatriptan was generally safe and well-tolerated in the trial. The most frequently reported adverse events in patients taking meloxicam / rizatriptan were somnolence, dizziness, and paresthesia, all of which occurred in less than 5 percent of patients (Table 4). No serious adverse events occurred in the trial.

[0165] Table 4a

[0166]

[0167] a Data is expressed as the number of participants (% of participants).

[0168] In the aforementioned clinical trials, some patients had depression. Tables 5 and 6 below summarize the results of 2 hours without pain and 2 hours without the most bothersome migraine symptoms in patient groups with and without a history of depression. The meloxicam / rizatriptan used in the clinical trials contained a molar equivalent of 20 mg meloxicam free acid and 10 mg rizatriptan free base in rizatriptan benzoate.

[0169] Table 5. Percentage of subjects without headache at 2 hours

[0170]

[0171] As shown in Table 5, among the responders with a history of depression, 48% of patients were headache-free 2 hours after treatment with the combination of meloxicam and rizatriptan, while only 4.8% of patients who took the placebo showed headache-free 2 hours after treatment, a difference of 43.2%.

[0172] On the other hand, among the responders who had no history of depression, 29% of patients were headache-free 2 hours after treatment with the combination of meloxicam and rizatriptan, compared with 18.4% of patients who took the placebo, a difference of 10.6%.

[0173] Table 6. Percentage of subjects who did not experience the most bothersome migraine symptoms in the second hour.

[0174]

[0175] Similarly, as shown in Table 6, among the responders with a history of depression, 52% of patients were free of most bothersome migraine symptoms 2 hours after treatment with the combination of meloxicam and rizatriptan, compared to only 28.6% of patients who took the placebo, a difference of 23.4%.

[0176] On the other hand, among the responders who had no history of depression, 42.1% of patients did not have the most bothersome migraine symptoms 2 hours after treatment with the combination of meloxicam and rizatriptan, while 26.3% of patients who took the placebo showed no most bothersome migraine symptoms 2 hours after treatment, a difference of 15.7%.

[0177] Therefore, compared with patients without a history of depression in the placebo group, the percentage of patients with a history of depression in the responders treated with the combination of meloxicam and rizatriptan (AXS-07) was significantly higher at hour 2 than in the placebo group.

[0178] “[This] study demonstrates a high rate of migraine pain-free outcomes with meloxicam / rizatriptan treatment and utilizes an innovative design to evaluate migraine pain progression. Notably, early treatment with meloxicam / rizatriptan prevented migraine pain progression in the vast majority of patients and restored normal function to an equally high percentage,” said Dr. Stewart Tepper, Professor of Neurology at Dartmouth Geisel School of Medicine. “The multiple mechanisms of meloxicam / rizatriptan address many of the disordered physiological processes associated with migraine attacks. These results, coupled with previous clinical data showing the superiority of meloxicam / rizatriptan over the active control, provide clinical evidence that this synergistic, multi-mechanism approach and the rapid absorption of meloxicam / rizatriptan may translate into significant benefits for a broad range of patients. As clinicians continue to seek more effective alternatives for patients than currently available therapies, meloxicam / rizatriptan could offer an important new treatment option for this disabling condition.”

[0179] This phase 3 trial confirmed the superior and durable efficacy of meloxicam / rizatriptan. The significant increase in migraine pain progression prevention and pain-free rates demonstrated by early treatment with meloxicam / rizatriptan expands and enhances its differentiating characteristics for acute migraine treatment. Using this phase 3 trial and the phase 3 trial described in Example 11 in patients with a history of inadequate response to previous acute treatment, meloxicam / rizatriptan is now positively evaluated in two well-designed controlled trials. These trials demonstrated that meloxicam / rizatriptan is superior to potent active drugs and placebo in a range of migraine attack settings, regardless of migraine treatment duration, disease severity, or baseline pain intensity.

[0180] “Migraine is one of the most disabling diseases, causing patients to lose their abilities and severely impairing their family life, social activities, and work capacity. Published surveys have highlighted that patients remain dissatisfied with the efficacy of currently available treatments,” said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs at Axsome. “[This] trial’s results demonstrate for the first time that meloxicam / rizatriptan can halt the progression of migraine pain before it reaches moderate or severe intensity. These data add to a large body of clinical evidence supporting the potential of meloxicam / rizatriptan as a multi-mechanism treatment for migraine that is superior to current standard of care and can provide rapid, robust, and lasting symptom relief, enabling patients to return to normal daily activities.”

[0181] Example 4

[0182] A long-term, open-label phase 3 trial of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, together with SBEβCD and sodium bicarbonate, as described in Example 4 above) was conducted. In this trial, meloxicam / rizatriptan provided rapid, significant, and durable relief of migraine pain and related symptoms. Meloxicam / rizatriptan was well tolerated in long-term treatment, and its safety profile was consistent with that observed in previously reported controlled trials.

[0183] This clinical trial evaluated the long-term safety of meloxicam / rizatriptan (20 mg MoSEIC™ meloxicam / 10 mg rizatriptan) for up to 12 months in patients experiencing migraine attacks. The study enrolled patients who had completed the clinical trials described in Example 11 or Example 12. Enrolled patients were allowed to treat up to 10 migraine attacks per month for up to 12 months, with one dose of meloxicam / rizatriptan for each migraine attack. The safety and efficacy of meloxicam / rizatriptan were assessed during the trial. A total of 706 patients were enrolled. The trial ended, as pre-specified, after at least 300 patients had been treated with at least 2 migraine attacks per month for 6 months, and approximately 100 patients had been treated with at least 2 migraine attacks per month for 12 months. At the end of the study, 515 patients had achieved at least 6 months of treatment, and 155 patients had achieved at least 12 months of treatment. During the trial, meloxicam / rizatriptan treated more than 21,000 migraine attacks. Efficacy measures include relief of migraine pain and most bothersome symptoms (photophobia, phonophobia, nausea) as well as the use of rescue medications.

[0184] In this clinical trial, meloxicam / rizatriptan administration resulted in rapid and significant relief of migraine pain and related symptoms. Within one hour of administration, 39% (range: 37%–41%) of patients experienced migraine pain relief, demonstrating the rapid onset of action of meloxicam / rizatriptan. Two hours after administration, 68% (range: 65%–71%) of patients experienced migraine pain relief, and 38% (range: 37%–40%) were pain-free. 47% (range: 46%–49%) of patients experienced no most bothersome symptoms (photophobia, phonophobia, nausea) within two hours of administration.

[0185] Meloxicam / rizatriptan provides sustained relief from migraine pain, with 85% (range: 84%-86%) of patients not requiring rescue medication within 24 hours of a single meloxicam / rizatriptan dose, and 83% (range: 82%-85%) not requiring rescue medication within 48 hours of a single meloxicam / rizatriptan dose. The sustained pain relief rates at 2–24 hours and 2–48 hours were 60% (range: 59%-62%) and 59% (range: 58%-60%), respectively. The rates of sustained pain-free status at 2–24 hours and 2–48 hours were 33% (range: 33%-35%) and 32% (range: 32%-34%), respectively.

[0186] Meloxicam / rizatriptan was well tolerated with long-term administration. The safety profile of meloxicam / rizatriptan during the 12-month treatment period was consistent with previous reports in short-term controlled trials. The most frequently reported adverse events (≥ 3%) were nausea, dizziness, and vomiting. During the 12-month trial, 1.6% of patients discontinued treatment due to adverse events.

[0187] Example 5

[0188] The efficacy of meloxicam / rizatriptan compared to placebo was evaluated in a subgroup of patients with the following risk factors for inadequate response to acute migraine medication: higher BMI, hyperalgesia, morning migraine, and a history of depression.

[0189] Data were obtained from pooled subgroup analyses of subjects who participated in clinical trials of acute treatment for migraine in Examples 1 and 3.

[0190] like Figure 15 As shown, in four subgroups defined by risk factors, meloxicam / rizatriptan treatment improved the rate of 24-hour sustained pain-free status compared to placebo.

[0191] For patients with a BMI greater than or equal to the median BMI in the study (≥ median 28.8 kg / m²), 2Of the patients who received treatment, 15.8% were pain-free at two hours, compared to 7.6% of those who received placebo (p = 0.008).

[0192] For patients with hyperalgesia, as defined by an ASC-12 score ≥ 3, 18.7% of treated patients were pain-free at two hours, compared to 8.1% of patients receiving placebo (p < 0.001).

[0193] For patients with morning migraines, defined as migraine attacks occurring before 10 a.m., 18.3% of treated patients were pain-free two hours later, compared to 8.1% of patients receiving a placebo (p = 0.005).

[0194] For patients with a history of depression, 16.7% of those receiving treatment experienced no pain at two hours, compared to 5.9% of those receiving a placebo (p = 0.053).

[0195] Unless otherwise indicated, all figures representing quantities, characteristics (such as amounts, percentages), etc., of the expressed components used in the specification and claims should in all cases be understood as indicating precise values ​​as shown and modified by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximate values ​​that may vary depending on the desired characteristic being sought. At least and without attempt to limit the application of the doctrine of equivalence to the claims, each numerical parameter should be interpreted at least based on the number of significant figures reported and by applying common rounding techniques.

[0196] Unless otherwise indicated herein or clearly contradicted by the context, the terms “a” and “an”, “described,” and similar pronouns used in the context of describing embodiments (especially in the context of the appended claims) should be interpreted as encompassing both the singular and plural. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of any claim. No language in this specification should be construed as indicating that any unclaimed element is necessary for the practice of the claims.

[0197] The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of the group or other elements found herein. For convenience and / or to expedite the application process, it is contemplated that one or more members of a group may be included in or removed from the group. When any such inclusion or removal occurs, this specification shall be deemed to include the modified group, thereby satisfying the written description of all Markush groups if used in the appended claims.

[0198] This document describes certain embodiments, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these embodiments will be apparent to those skilled in the art after reading the foregoing description. The inventors anticipate that those skilled in the art can employ such variations as needed, and that the claimed embodiments can be practiced in ways other than those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Furthermore, any combination of the foregoing elements in all possible variations is contemplated unless otherwise indicated herein or clearly contradicted by the context.

[0199] 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 of this document, by way of example rather than limitation. Thus, the claims are not precisely limited to the embodiments shown and described.

Claims

1. A method for treating migraine, the method comprising orally administering to a person in need a combination of about 15 mg to 30 mg of meloxicam or a pharmaceutically acceptable salt thereof and 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 of claim 1, wherein the rizatriptan is administered orally to the person in a dose of about 8 mg to about 13 mg of the free rizatriptan base or a molar equivalent of the rizatriptan salt.

3. The method according to claim 1 or 2, wherein the combination contains about 20 mg of meloxicam free acid or molar equivalents of meloxicam salt.

4. The method according to claim 1, 2 or 3, wherein one hour after oral administration of the combination, the person experiences a reduction in migraine pain.

5. The method according to claim 1, 2 or 3, wherein the person experiences a reduction in migraine pain 24 hours after oral administration of the combination.

6. The method according to claim 1, 2 or 3, wherein the person experiences no migraine pain 2 hours after oral administration of the combination.

7. The method according to claim 1, 2, 3, 4, 5 or 6, wherein the person suffers from moderate to severe migraine pain.

8. The method according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the person suffers from photophobia.

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

10. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the person suffers from phonophobia.

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

12. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein the person suffers from nausea.

13. The method of claim 12, wherein the person experiences relief of nausea two hours after oral administration of the combination.

14. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein the migraine is associated with aura.

15. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the person reduces the use of the analgesics other than said meloxicam compared to the use of analgesics that would occur without meloxicam.

16. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the person reduces the use of analgesics other than meloxicam, wherein the use of the analgesics is reduced by at least about 20% compared to the use of the analgesics that would occur without the meloxicam.

17. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the person has meloxicam T at a time two hours or less following oral administration of the combination. max .

18. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the person has meloxicam T at a time when the combination is administered orally one hour or less later. max .

19. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the rizatriptan is rizatriptan benzoate.

20. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein the meloxicam is in the form of a free acid.

21. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the combination is in the form of a dosage form for oral administration to the person.

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