Pharmaceutical composition comprising meloxicam

Abstract

Disclosed herein is a method of treating migraine in a patient having a history of inadequate response to a previous migraine treatment, the method comprising: selecting a patient that, for at least one month in the past: 1) has 2 to 8 migraine per month, and 2a) has 2 to 8 migraine per month according to the patient; the present invention relates to a method for controlling migraine treatment of a patient, said method comprising the following steps: b) in accordance with the patient, after taking a migraine drug, the patient never or rarely feels sufficient control of migraine of the patient such that the patient feels that daily activity of the patient will not be disturbed, and b) after taking a migraine drug, the patient never or rarely feels sufficient control of migraine of the patient; 2c) the score of mTOQ-4 is 0, and / or 2d) the medical history of depression; and administering to the patient a combination of 20 mg meloxicam and 10 mg rizatriptan during the onset of migraine.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 343,982, filed on May 19, 2022, which is expressly incorporated herein by reference in its entirety. Summary of the invention

[0002] Some embodiments include a method of treating migraine in a patient with a history of inadequate response to prior migraine treatments, the method comprising selecting a patient who, for at least the past four weeks: 1) has had 2 to 8 migraines per month, and 2) has never or rarely, depending on the patient, felt comfortable enough on the patient's migraine medication to be able to plan daily activities; and after selecting the patient, administering to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

[0003] Some embodiments include a method of treating migraine in a patient with a history of inadequate response to prior migraine treatments, the method comprising selecting a patient who, for at least the past four weeks: 1) has had 2 to 8 migraines per month, and 2) according to the patient, has never or rarely felt adequate control over the patient's migraines after taking migraine medications such that the patient feels the patient's daily activities will not be interfered with; and after selecting the patient, administering to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

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

[0005] Some embodiments include a method of treating migraine in a patient with a history of inadequate response to prior migraine treatments, the method comprising selecting a patient who: 1) has 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 to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1A graph showing the percentage of subjects reporting pain relief at various time points within the first 4 hours following administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 1.

[0007] Figure 1A The percentages of subjects reporting superior pain relief for meloxicam, rizatriptan, and meloxicam / rizatriptan over placebo at 1.0 hour and 1.5 hours are shown.

[0008] Figure 2 The percentage of subjects achieving pain freedom at 2 hours, 4 hours, 12 hours and 16 hours following administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam and placebo described in Example 1 are shown.

[0009] Figure 3A The percentage of subjects achieving sustained pain freedom from 2 hours to 24 hours following administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 1 are shown.

[0010] Figure 3B The percentage of subjects achieving sustained pain relief from 2 hours to 24 hours following administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 1 are shown.

[0011] Figure 4A The percentage of subjects achieving sustained pain freedom from 2 hours to 48 hours following administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 1 are shown.

[0012] Figure 4B The percentage of subjects achieving sustained pain relief from 2 hours to 48 hours following administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 1 are shown.

[0013] Figure 4C The percentage of subjects achieving sustained pain freedom superior to placebo from 2 hours to 48 hours is shown for meloxicam, rizatriptan, and meloxicam / rizatriptan.

[0014] Figure 4D The percentage of subjects achieving sustained pain relief superior to placebo from 2 hours to 48 hours is shown for meloxicam, rizatriptan, and meloxicam / rizatriptan.

[0015] Figure 5The percentage of subjects who took rescue medication within 24 hours after administration of the dosage forms of meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo described in Example 1 are shown.

[0016] Figure 6 The proportion of patients who answered “never” or “rarely” to each mTOQ-4 question in Example 1 is depicted.

[0017] Fig. 7A and Figure 7B The percentages of subjects who were pain free and had resolution of the most bothersome symptom in Example 3 are shown for subjects taking meloxicam / rizatriptan and placebo.

[0018] Figure 8 The percentage of subjects achieving pain freedom over time for subjects taking meloxicam / rizatriptan and placebo in Example 3 is shown.

[0019] Fig. 9 The percentage of subjects achieving freedom from the most bothersome symptom over time for subjects taking meloxicam / rizatriptan and placebo in Example 3 is shown.

[0020] Fig. 10A and Fig. 10B The percentage of subjects achieving pain freedom within 2-24 hours and 2-48 hours for subjects taking meloxicam / rizatriptan and placebo in Example 3 is shown.

[0021] Fig.11 The percentage of subjects who achieved pain freedom within 2-24 hours for subjects taking meloxicam / rizatriptan and placebo in Example 3 is shown.

[0022] Fig.12 The percentage of subjects taking rescue medication in Example 3 is shown for subjects taking meloxicam / rizatriptan and placebo.

[0023] Fig.13 The percentage of subjects without functional disability at 24 hours for subjects taking meloxicam / rizatriptan and placebo in Example 3 is shown.

[0024] Fig.14 The percentage of subjects with a Patient Global Impression of Change (PGI-C) score of "very much improved" or "much improved" at hour 2 in Example 3 for subjects taking meloxicam / rizatriptan and placebo are shown.

[0025] Fig.15The rates of 24-hour continuous pain freedom compared with placebo are shown for patients with higher BMI, allodynia, morning migraine, and a history of depression. DETAILED DESCRIPTION

[0026] Meloxicam, which has the following structure:

[0027]

[0028] It is a nonsteroidal anti-inflammatory (NSAID) drug that exhibits anti-inflammatory, analgesic and antipyretic activities. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthase (cyclooxygenase, COX), which is involved in the initial step of the arachidonic acid cascade, resulting in a decrease in the formation of prostaglandins, thromboxanes and prostacyclins.

[0029] Meloxicam and some other NSAIDs are poorly soluble in water, which may reduce bioavailability and slow the onset of pain relief resulting from their use. One way to improve the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cyclostarches) are generally cyclic polysaccharides that form a barrel-like shape. Cyclodextrins help improve the bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the outside, which helps promote the transport of molecules (such as hydrophobic molecules). Naturally occurring cyclodextrins include 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 solution, 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 the drug in a micellar-type structure. This ability of cyclodextrins can allow them to become carriers for drugs to improve the bioavailability of poorly soluble drugs.

[0030] The combination of rizatriptan and meloxicam (referred to herein for convenience as the "subject combination") may be used to treat a variety of painful conditions.

[0031] Rizatriptan has the structure shown below.

[0032]

[0033] Some embodiments include a subject combination comprising: 1) a complex of meloxicam and a cyclodextrin, 2) rizatriptan, and 3) a bicarbonate for use in treating migraine in a human. The migraine may be refractory migraine. The human may have a history of inadequate response to previous treatments. In some embodiments, the cyclodextrin is SBEβCD.

[0034] Dosage forms may 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.

[0035] Unless otherwise indicated, any reference to a compound herein, such as meloxicam or rizatriptan, by structure, name, or any other means includes pharmaceutically acceptable salts, alternative solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterated modified forms, or any other chemical species, such as a precursor, prodrug, or any other chemical species that can be rapidly converted to a compound described herein under the conditions under which the compound is used as described herein.

[0036] The subject combination may 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, both meloxicam and rizatriptan are administered orally.

[0037] Typically, the combination of meloxicam and rizatriptan is administered so that a human receives meloxicam and rizatriptan within a short period of time relative to each other. For example, meloxicam and rizatriptan can be administered within about 2 hours, within about 1 hour, within about 30 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, within about 5 minutes, or within about 1 minute of each other. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which for the purposes of this disclosure includes administration within about 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).

[0038] The terms "treating" or "treatment" are used broadly to include any kind of therapeutic activity, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or any function of the human or other animal body.

[0039] Migraine is a disabling neurological disorder characterized by recurrent, throbbing headaches accompanied by nausea and sensitivity to light and sound. The pain may be mild, or moderate to severe, but is usually severe and incapacitating, requiring bed rest. The headache may affect half of the head, may be throbbing, and may last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or smells. Migraines may be accompanied by visual disturbances. Physical activity may make migraines worse. Migraines may be associated with an aura, which may be a brief visual disturbance that indicates that the headache will soon occur. Some people with migraines may not have an aura.

[0040] In some embodiments, the human being treated for migraine has allodynia, such as cutaneous allodynia during a migraine attack. Allodynia, such as cutaneous allodynia, is pain caused by normally non-painful stimuli, such as combing hair, wearing glasses, bathing, etc. Patients with allodynia, such as cutaneous allodynia, are considered unlikely to respond well to triptan medication.

[0041] Current treatments are suboptimal, with more than 70% of patients reporting dissatisfaction with existing acute treatments. The most commonly reported reasons for patient dissatisfaction were slow pain relief, inconsistent pain relief, and same-day pain recurrence. Suboptimal acute treatment is associated with a significantly increased risk of new-onset chronic migraine, which could be prevented by improving acute treatment outcomes.

[0042] Administration of the subject combinations to a human suffering from a migraine (e.g., an acute attack of a migraine or aura) can rapidly result in a reduction in migraine symptoms (e.g., pain, nausea, vomiting, photophobia, or phonophobia), such as within about 5 minutes or less (meaning shorthand for "about 5 minutes or less"), within about 10 minutes or less, within about 30 minutes or less, within about 1 hour or less, within about 90 minutes or less, within about 2 hours or less, within about 2.5 hours or less, or within about 3 hours or less. In some embodiments, the human experiences a reduction or complete relief of pain (e.g., headache or migraine, nausea, vomiting, photophobia, and / or phonophobia) within about 1 hour or less, about 90 minutes or less, about 2 hours or less, about 2.5 hours or less, or about 3 hours or less. In some embodiments, the relief experienced is greater than that experienced by receiving the same amount of rizatriptan without meloxicam. In some embodiments, the relief experienced is greater than that experienced by receiving the same amount of meloxicam without rizatriptan.

[0043] The subject combination may be administered at the earliest signs of a migraine, or shortly after the earliest signs of a migraine, such as within about 1 minute, within about 5 minutes, within about 10 minutes, within about 15 minutes, within about 20 minutes, within about 30 minutes, or within about 1 hour. In this early state, the pain may still be mild, or before the pain progresses to moderate or severe intensity. For some methods, the subject combination may be administered when a migraine reaches moderate or severe intensity.

[0044] In some embodiments, the combination of meloxicam and rizatriptan is administered to a human migraine patient who has or is selected to have functional disability. In some embodiments, the treatment results in the human migraine patient being able to resume normal activities within 24 hours of receiving the treatment.

[0045] The combination of meloxicam and rizatriptan may have a unique dual mechanism of action for the acute treatment of migraine. Meloxicam is a potent COX-2 preferential NSAID that is limited by its slow absorption. Rizatriptan is a potent 5-HT1 B / D Agonists, considered effective for migraines.

[0046] Observing relief or reduction of symptoms over a specific time period, such as "2 hours," is useful because it allows evaluation of the effectiveness of a treatment at a specific or consistent time point, which facilitates comparisons between patients. Observing relief or reduction of symptoms within a specific time period, such as "within about 2 hours," is useful because relief or reduction of symptoms is expected to occur as soon as possible, and specifying that relief occurs within a specific time sets the criterion for expecting relief to occur.

[0047] For some methods, administration of the subject combinations can achieve a reduction in migraine, nausea, vomiting, photophobia, or phonophobia that lasts 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 8-24 hours, about 24 hours, or more than 24 hours.

[0048] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater pain relief than two hours after receiving the same amount of meloxicam without rizatriptan.

[0049] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0050] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater pain relief than two hours after receiving the same amount of rizatriptan without meloxicam.

[0051] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0052] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from nausea than two hours after receiving the same amount of meloxicam without rizatriptan.

[0053] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from nausea compared to 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0054] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from nausea than two hours after receiving the same amount of rizatriptan without meloxicam.

[0055] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from nausea compared to 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0056] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from vomiting than two hours after receiving the same amount of meloxicam without rizatriptan.

[0057] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from vomiting than 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0058] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from vomiting than two hours after receiving the same amount of rizatriptan without meloxicam.

[0059] In some embodiments, 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 24 hours after the administration of meloxicam and rizatriptan, the human experiences greater relief from vomiting than 24 hours after receiving the same amount of rizatriptan without meloxicam. In some embodiments, 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 the administration of meloxicam and rizatriptan, the human experiences greater relief from photophobia than two hours after receiving the same amount of meloxicam without rizatriptan.

[0060] In some embodiments, 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 24 hours after the administration of meloxicam and rizatriptan, the human experiences greater relief from photophobia than 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0061] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from photophobia than two hours after receiving the same amount of rizatriptan without meloxicam.

[0062] In some embodiments, 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 24 hours after the administration of meloxicam and rizatriptan, the human experiences greater relief from photophobia than 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0063] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from phonophobia than two hours after receiving the same amount of meloxicam without rizatriptan.

[0064] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from phonophobia than 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0065] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from phonophobia than two hours after receiving the same amount of rizatriptan without meloxicam.

[0066] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from phonophobia than 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0067] In some embodiments, the human has used a triptan prior to receiving a subject combination (eg, a combination comprising meloxicam and rizatriptan).

[0068] In some embodiments, the human receiving the subject combination has a score of 0 or 1 on the Migraine Treatment Optimization Questionnaire (mTOQ-4).

[0069] In some embodiments, the human being receiving the subject combination has indicated, prior to receiving the subject combination, that he or she is "never" or "rarely" pain free within two hours of treatment for most episodes.

[0070] In some embodiments, the human being receiving the subject combination has indicated, prior to receiving the subject combination, that a single dose of the medication "never" or "rarely" relieves the respondent's headache for at least 24 hours.

[0071] In some embodiments, the human being receiving the subject combination has indicated, prior to receiving the subject combination, that he or she "never" or "rarely" feels comfortable enough with his or her migraine medication to be able to plan his or her daily activities.

[0072] In some embodiments, the human being receiving the subject combination has indicated, prior to receiving the subject combination, that after taking his or her migraine medication, he or she "never" or "rarely" feels sufficient control over his or her migraines such that he or she feels his or her daily activities will not be interfered with.

[0073] In some embodiments, the human receiving the subject combination has a history of depression prior to receiving the subject combination.

[0074] In some embodiments, the human being receiving the subject combination (e.g., a combination comprising meloxicam and rizatriptan) suffers from migraine and may have a history of inadequate response to previous migraine treatments. In some embodiments, the human being suffering from migraine does not have cluster headaches or other types of migraine. In some embodiments, the human being suffering from migraine does not have chronic daily headaches. In some embodiments, the human being suffering from migraine does not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 days of non-migraine headaches per month. In some embodiments, the human being suffering from migraine does not have a history of significant cardiovascular disease. In some embodiments, the human being suffering from migraine does not have uncontrolled hypertension.

[0075] For some methods, administration of the dosage form can achieve pain relief that lasts 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 that is observed at about 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, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes after administration of the dosage form, or other time periods within the range defined by any of these values.

[0076] For some methods, the administration of the dosage form or subject combination can achieve a pain reduction that lasts 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 about 24 hours, or about 24 hours. In other embodiments, the administration of the subject combination can achieve a pain reduction that is observed in about 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 limited by these ranges after the administration of the subject combination.

[0077] The human being treated for a disease or condition with the dosage forms described herein can be of any age. For example, the human can be from about 10 to about 90 years old, from about 20 to about 80 years old, from about 30 to about 75 years old, from about 40 to about 70 years old, from about 1 to about 16 years old, from about 80 to about 95 years old, about 16 years old or older, about 18 years old or older, about 20 years old or older, about 25 years old or older, about 30 years old or older, about 40 years old or older, about 45 years old or older, about 50 years old or older, about 55 years old or older, about 60 years old or older, about 65 years old or older, or any other age within a range limited by or between these values.

[0078] In some embodiments, the human treated for migraine with a dosage form described herein (e.g., comprising meloxicam, rizatriptan, SBEβCD, and bicarbonate (e.g., sodium bicarbonate)) can be between 18 and 65 years old, about 18-20 years old, about 20-25 years old, about 25-30 years old, about 30-40 years old, about 40-45 years old, about 40-50 years old, about 50-60 years old, about 60-65 years old, or any other age within a range bounded by or between these values.

[0079] In some embodiments, the human being treated for migraine with a dosage form described herein (e.g., a dosage form comprising meloxicam, rizatriptan, sulfobutyl ether-β-cyclodextrin (SBEβCD), and a bicarbonate (e.g., sodium bicarbonate)) can be black or African American, white, or Asian. In some embodiments, the human being is black or African American. In some embodiments, the human being is white. In some embodiments, the human being is Asian.

[0080] In some embodiments, the human being treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has been suffering from pain or a pain-related condition for at least 1 day, at least a 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 within a range bounded by or between these values.

[0081] In some embodiments, the human being treated for migraine with a dosage form comprising meloxicam and rizatriptan has been diagnosed with migraine with or without aura as defined by the ICHD-3 criteria for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years or longer, or at least 1 year, or any duration within a range bounded by or between these values.

[0082] In some embodiments, the human suffers or has suffered from an average of 2 to 8, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 moderate to severe migraine headaches per month, such as at least in the past month.

[0083] The cyclodextrin used in the dosage form with meloxicam may include cyclodextrin, cyclodextrin derivatives and / or salts thereof. The inclusion complex of meloxicam and cyclodextrin may be more water-soluble than unincluded meloxicam. The cyclodextrin may 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-cyclodextrin may include, but is 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 a combination thereof.

[0084] In some embodiments, β-cyclodextrin, its derivatives or salts can be used. β-cyclodextrin can include, but is not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl -6-O-sulfo)-β-cyclodextrin, (2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3,6-tri-O-methyl)-β-cyclodextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, (2,3,6-tri-O-benzoyl)-β-cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin, 6-bromo-6-deoxy-β-cyclodextrin, Monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-O-tert-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 ( β-cyclodextrin, (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, branched-β-cyclodextrin, or a combination thereof.

[0085] 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, betadec, ). In some embodiments, the SBEβCD can have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0086] In some embodiments, γ-cyclodextrin, its derivatives or salts can be used. γ-cyclodextrin can 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-butylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin (2-hydroxypropyl)-γ-cyclodextrin, acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or a combination thereof.

[0087] In some embodiments, the dosage form may include bicarbonate, such as sodium bicarbonate, potassium bicarbonate, or a combination thereof. Bicarbonate may help improve the solubility and bioavailability of meloxicam or rizatriptan.

[0088] Unless otherwise indicated, any reference to a compound herein, such as meloxicam or cyclodextrin, by structure, name, or any other means includes pharmaceutically acceptable salts, alternative solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterated modified forms, or any other chemical species that can be rapidly converted to a compound described herein under the conditions under which the compound is used as described herein.

[0089] In some embodiments, the dosage form may contain meloxicam in an amount of about 15-25 mg, about 18-22 mg, or about 20 mg. These doses may be safe doses for repeated administration, such as hourly administration to daily administration, twice daily administration, 1 to 12 times daily administration, 3, 4, 5, or 6 times daily administration, etc. In some embodiments, meloxicam can be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times a day, once a day, or less frequently, such as once a week, once every two weeks, once a month, etc.

[0090] For any amount of meloxicam described herein, meloxicam in salt form may be present in the above amounts, or in an amount that is a molar equivalent to 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 free acid form is 56.9 mmol. Therefore, the molar equivalent of 20 mg of meloxicam free acid would be the mass of 56.9 mmol of meloxicam in salt form. For example, the weight of meloxicam sodium salt (mw = 373.4 g / mol), with the same molar equivalent of 20 mg of meloxicam free acid (or 56.9 mmol), would be 21.25 mg. These doses may be safe for repeated administration, such as 1, 2, 3, or 4 times a day, or 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 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months or longer.

[0091] For some dosage forms, meloxicam forms a complex with a substituted β-cyclodextrin or another cyclodextrin, which can be formulated into a solid dosage form. Such a dosage form can be suitable for oral administration. The meloxicam-cyclodextrin inclusion complex can also be dissolved in water or another solvent to form a parenteral formulation. However, a physical mixture of meloxicam and a substituted β-cyclodextrin or other cyclodextrin can also be used in an oral or parenteral dosage form.

[0092] The formation of inclusion complexes of meloxicam and cyclodextrin may help improve the properties of the dosage form. For some inclusion complexes, the molar ratio of meloxicam to cyclodextrin (e.g., SBEβCD) may be about 0.5-2 (a molar ratio of 0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or any ratio within a range defined by any of these values.

[0093] For some dosage forms, cyclodextrin (e.g., SBEβCD) can be employed in a weight ratio to meloxicam in the range of about 1-1000 (e.g., a 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 within a range bounded by or between any of these values. For some dosage forms, cyclodextrin (e.g., SBEβCD) can be used in a weight ratio with meloxicam in the range of about 0.001-1 (e.g., 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 within the range bounded by or between any of these values. Each type of cyclodextrin used can have a different ratio.

[0094] For some dosage forms, the cyclodextrin can be present in an amount of 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 within a range bounded by or between any of these values.

[0095] For some methods, the inclusion complex of meloxicam and cyclodextrin (such as substituted β-cyclodextrin) is delivered orally (e.g., by tablets, capsules, elixirs, etc.). Other potential routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal or by other parenteral routes. Meloxicam can also be delivered alone or not complexed with cyclodextrin.

[0096] Some dosage forms are about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about 200-800 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about 500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about 400-500 or any amount within a range bounded by or between any of these values.

[0097] In certain embodiments, the pharmaceutical composition results in increased bioavailability (e.g., decreased T ) of meloxicam from the dosage form compared to a dosage form containing meloxicam but not cyclodextrin, an acid inhibitor, or a buffer (e.g., bicarbonate). max , increased C max , increased AUC, etc.). In some embodiments, the bioavailability of meloxicam will increase with multiple dosing.

[0098] Some dosage forms can result in a desired range of the area under the plasma concentration curve (AUC) of meloxicam, such as the AUC of meloxicam 0-inf About 40,000-70,000 ng*hr / mL; about 50,000-60,000 ng*hr / mL; about 52,000-56,000 ng*hr / mL; or about 54,000 ng*hr / mL.

[0099] In some embodiments, the dosage form may result in a C of meloxicam of max About 2500-3500 ng / mL, about 2700-3100 ng / mL or about 2900 ng / mL.

[0100] The methods described herein can reduce the T of meloxicam max In some embodiments, the method may include treating the patient at about 0.5-1 hour, about 0.8-0.9 hour, or about 0.875 hour after administration of the subject combination to achieve a T of meloxicam in the patient.max .

[0101] Some dosage forms can result in a desired range of area under the plasma concentration curve (AUC) of rizatriptan, such as an AUC of rizatriptan 0-inf About 70-100 ng*hr / mL; about 80-90 ng*hr / mL; or about 86.7 ng*hr / mL.

[0102] In some embodiments, the dosage form can result in a C of rizatriptan of max About 25-35 ng / mL, about 30-34 ng / mL, about 31-32 ng / mL or about 31.7 ng / mL.

[0103] The methods described herein can reduce the T max For example, the method can achieve a T of rizatriptan in the patient at about 0.5-1 hour, about 0.7-0.8 hour, or about 0.75 hour after administration. max .

[0104] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief of allodynia (e.g., cutaneous allodynia) than two hours after receiving the same amount of meloxicam without rizatriptan.

[0105] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief of allodynia (e.g., cutaneous allodynia) than 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0106] In some embodiments, 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 the meloxicam and rizatriptan, the human experiences greater relief from allodynia (e.g., cutaneous allodynia) than two hours after receiving the same amount of rizatriptan without meloxicam.

[0107] In some embodiments, 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 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief of allodynia (e.g., cutaneous allodynia) than 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0108] In some embodiments, the dosage form can be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it can be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or directly admixed with food in the diet. For oral therapeutic administration, the active compound can be admixed with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, lozenges, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, and the like.

[0109] Tablets, lozenges, pills, capsules, etc. may also contain one or more of the following: binders, such as gum tragacanth, 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 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 in a coating, 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 flavors. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially nontoxic in the amounts employed.

[0110] Some compositions or dosage forms may be liquid, or may comprise a solid phase dispersed in a liquid.

[0111] The dosage form may further comprise a second therapeutically active agent, such as an acid suppressant or an analgesic.

[0112] In some embodiments; dosage forms comprising the subject combination may contain rizatriptan in an amount of about 5-15 mg, about 8-12 mg, or about 10 mg.

[0113] For acute migraine, the amount of meloxicam and / or rizatriptan in a single dose, or the AUC of meloxicam and / or rizatriptan associated with a single dose, is of particular interest. For example, after a single dose, symptoms may be relieved for a long period of time, such that in the short term, repeated dosing may not be necessary. For more persistent conditions, including more chronic, persistent or frequent migraine symptoms, daily, weekly or monthly doses may be of particular interest.

[0114] For any amount of rizatriptan described herein, the salt form of rizatriptan may be present in the amounts described above, or in an amount that is a molar equivalent to these amounts of 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 37.1 mmol of rizatriptan. Therefore, the weight of the rizatriptan salt, with the same molar equivalent of 10 mg of rizatriptan free base, would be the mass of 37.1 mmol of the rizatriptan salt. For example, for the benzoate salt of rizatriptan (mw=391.2 g / mol), the molar equivalent of 10 mg of rizatriptan free base (or 37.1 mmol) would be 14.5 mg of rizatriptan benzoate. These doses may be safe for repeated administration, such as 1, 2, 3, or 4 times a day, or 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 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, etc.

[0115] 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.

[0116] The dosage forms described herein comprising a combination of rizatriptan and meloxicam can provide rapid relief of migraine headaches 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. The combination of rizatriptan and meloxicam described herein can provide migraine relief that is numerically greater than rizatriptan 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 more after administration. The percentage of migraine patients reporting relief from pain with treatment with the combination of rizatriptan and meloxicam described herein 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%.

[0117] Migraine patients receiving a dosage form comprising a combination of rizatriptan and meloxicam (the "subject combination") described herein can achieve pain freedom in less than 2 hours, about 2 hours, about 2-3 hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about 20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40 hours, about 40-44 hours, about 44-48 hours, or more after administration.

[0118] Example 1

[0119] A phase 3, randomized, double-blind, multicenter, placebo- and active-controlled trial was conducted to evaluate the efficacy and safety of a combination of meloxicam and rizatriptan (meloxicam / rizatriptan) in the acute treatment of moderate and severe migraine. Eligible patients had to be aged 18 to 65 years, with a confirmed history (at least 1 year) of migraine with or without aura as defined by ICHD-3 criteria, an average of 2 to 8 moderate to severe migraines per month, a history of inadequate response to previous acute migraine treatment, and a score of 7 (mean score of 3.6) using the Migraine Treatment Optimization Questionnaire (mTOQ-4), corresponding to an inadequate response to previous acute treatment. Exclusion criteria included cluster headache or other types of migraine, chronic daily headache (≥15 days of non-migraine headache per month), history of major cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, enrolled patients exhibited high rates of characteristics strongly associated with adverse treatment outcomes, including cutaneous allodynia (75.4%), severe migraine pain intensity (41.2%), obesity (43.7%), and morning migraine (36.6%).

[0120] A total of 1594 patients were randomized in a 2:2:2:1 ratio to receive (1) meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan) containing SBEβCD (approximately 133.6 mg) and sodium bicarbonate (500 mg), (2) rizatriptan (10 mg), (3) meloxicam (20 mg) containing SBEβCD (MoSEIC meloxicam), or (4) placebo for the treatment of a single migraine attack of moderate or severe intensity. The two co-primary endpoints of the trial were the proportion of patients who were headache free two hours after dosing and the proportion of patients who no longer had the most bothersome migraine-related symptom (nausea, photophobia, or phonophobia) two hours after dosing for meloxicam / rizatriptan compared with placebo. The superiority of meloxicam / rizatriptan over the rizatriptan and meloxicam group (component contribution) was demonstrated by sustained freedom from headache 2 to 24 hours after dosing (a key secondary endpoint). The study was conducted under an FDA Special Protocol Assessment (SPA). The active comparator in the trial, rizatriptan, is considered the fastest acting oral triptan and one of the most effective drugs currently available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT (1B / 1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov 17; 358(9294): 1668-75.)

[0121] Meloxicam / rizatriptan provided rapid relief of migraine, with the percentage of patients achieving pain relief with meloxicam / rizatriptan being numerically greater than with rizatriptan at every time point measured from 15 minutes onwards and statistically significant at 60 minutes (p=0.04)( Figure 1 The proportion of patients experiencing pain relief 1.5 hours after dosing was 60.5% for meloxicam / rizatriptan, compared to 52.5% for rizatriptan and 48.3% for placebo (p=0.019, p=0.04, respectively, compared to meloxicam / rizatriptan) ( Figure 1 ). Figure 1A The percentages of subjects reporting superior pain relief for meloxicam, rizatriptan, and meloxicam / rizatriptan over placebo at 1.0 hour and 1.5 hours are shown.

[0122] This was demonstrated by demonstrating a higher percentage of patients achieving freedom from pain 2 hours after dosing compared to placebo (19.9% ​​vs 6.7%, p<0.001, Figure 2 ), and the most bothersome symptom disappeared (36.9% vs 24.4%, p = 0.002), with high statistical significance, and meloxicam / rizatriptan met the two regulatory co-primary endpoints.

[0123] Demonstrated superiority of meloxicam / rizatriptan over rizatriptan (active comparator) and MoSEIC as specified in the SPA TM Meloxicam (component contribution), demonstrated by: Rizatriptan, MoSEIC TM A higher percentage of patients achieving sustained pain freedom from 2 hours to 24 hours after dosing were treated with meloxicam / rizatriptan compared with placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively; p=0.038, p=0.001, and p<0.001, respectively, compared with meloxicam / rizatriptan). Figure 3A ), a pre-specified key secondary endpoint to demonstrate component contribution. Approximately 80% of patients treated with meloxicam / rizatriptan achieved pain freedom at 2 hours and remained pain free at 24 hours. These results demonstrate a significant improvement in pain freedom with meloxicam / rizatriptan and superiority to rizatriptan in the treatment of migraine.

[0124] Meloxicam / rizatriptan provided significantly greater and longer-lasting migraine relief compared to placebo and rizatriptan, which meant that rescue medication use was significantly reduced with meloxicam / rizatriptan compared to placebo and rizatriptan. The percentage of patients experiencing sustained pain relief from 2 hours to 24 hours after dosing was 53.3% for meloxicam / rizatriptan, compared to 33.5% for placebo and 43.9% for rizatriptan (p<0.001, p=0.006, respectively, compared to meloxicam / rizatriptan) ( Figure 3B ).

[0125] A statistically significantly greater proportion of meloxicam / rizatriptan patients (46.5%) also experienced sustained pain relief from 2 to 48 hours compared to placebo (31.1%) and rizatriptan (36.5%) patients (p<0.001 and p=0.003, respectively, vs meloxicam / rizatriptan) ( Figure 4B ). Figure 4D The percentage of subjects achieving sustained pain relief superior to placebo from 2 hours to 48 hours is shown for meloxicam, rizatriptan, and meloxicam / rizatriptan. TM A statistically significantly greater proportion of meloxicam / rizatriptan patients (15.4%) also experienced sustained pain freedom from 2 to 48 hours compared to meloxicam (8.1%) patients (p<0.001, p=0.003, p=<0.001, respectively, compared to meloxicam / rizatriptan) ( Figure 4A ). Figure 4C The percentage of subjects achieving sustained pain freedom superior to placebo from 2 hours to 48 hours is shown for meloxicam, rizatriptan, and meloxicam / rizatriptan. Approximately 77% of patients treated with meloxicam / rizatriptan achieved pain freedom at 2 hours and remained pain free at 48 hours.

[0126] Rescue medication was used by 23.0% of patients receiving meloxicam / rizatriptan, compared with 43.5% of patients receiving placebo and 34.7% of patients receiving rizatriptan (p<0.001 for each group, vs meloxicam / rizatriptan) ( Figure 5 ). Approximately 77% of patients receiving meloxicam / rizatriptan did not require rescue medication. These results demonstrate that meloxicam / rizatriptan is superior to the active comparator rizatriptan in the treatment of migraine.

[0127] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan on several other secondary endpoints, including Patient Global Impression of Change (PGI-C) (p=0.022) and return to normal function at 24 hours (p=0.027).

[0128] Table 1 below lists some p values ​​for meloxicam / rizatriptan compared to rizatriptan for different endpoints, demonstrating the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraine.

[0129] Table 1. P values ​​for different endpoints of meloxicam / rizatriptan vs. rizatriptan

[0130]

[0131]

[0132] Given that the active comparator in the trial, rizatriptan, is considered the fastest-acting oral triptan and one of the most effective drugs currently available for the acute treatment of migraine, and that the trial enrolled patients with refractory migraine, the observed treatment effect of meloxicam / rizatriptan, which provided greater and more durable migraine relief than rizatriptan, is significant. Many patients experience a suboptimal response to their current acute migraine treatments, placing them at increased risk for headache-related disability and progression to chronic migraine, factors that are associated with increased health care costs. The results of this study suggest that meloxicam / rizatriptan could provide an important treatment option for patients with refractory migraine. During the Phase 3 MOMENTUM trial, meloxicam / rizatriptan was generally safe and well tolerated, with adverse events occurring in 1-3% of patients. 11.1% of patients experienced any form of treatment-emergent adverse event after taking meloxicam / rizatriptan, while 2.7%, 1.6%, and 1.4% of patients experienced nausea, dizziness, and somnolence after taking meloxicam / rizatriptan, respectively (Table 2). The rate at which patients experienced treatment-emergent adverse events after administration of meloxicam / rizatriptan was generally similar compared to any other treatment tested (Table 2).

[0133] Table 2 a

[0134]

[0135] a Data are expressed as number of subjects (% of subjects)

[0136] The results of this trial demonstrate the ability of meloxicam / rizatriptan to provide unique benefits to patients with migraine, with rapid, intense and durable relief of migraine compared to the effective active comparator rizatriptan in a rigorously designed trial focusing on patients with refractory migraine. These results have potentially important implications for patient care given the high rates of inadequate response and dissatisfaction with current treatments.

[0137] Meloxicam / Rizatriptan combines multiple mechanisms of action to address various migraine processes with the goal of providing enhanced effectiveness. Meloxicam / Rizatriptan is believed to work by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and inhibiting neuroinflammation, pain signaling, and central sensitization. The results of this trial validate this approach, showing that meloxicam / Rizatriptan may provide significant benefit over currently available treatments, even in patients with refractory migraine. Meloxicam / Rizatriptan can be effectively used for the acute treatment of migraine with or without aura in adults.

[0138] Example 2

[0139] More than 70% of patients reported dissatisfaction with existing acute treatments. The most commonly reported reasons for patient dissatisfaction were slow pain relief, inconsistent pain relief, and same-day pain recurrence. Suboptimal acute treatment is associated with an increased risk of chronic migraine, which could be prevented by improving acute treatment outcomes.

[0140] Migraine Treatment Optimization Questionnaire (mTOQ-4); evaluates the therapeutic efficacy of acute therapy based on 4 domains: pain freedom, sustained pain relief, comfort with planned daily activities, and lack of interference with daily activities. Previous studies have shown that between 12-27% of migraine patients report rarely or never using other pharmacological treatments to achieve a positive response to these items.

[0141] The clinical trial of Example 1 was analyzed to examine the proportion of subjects who "never" or "seldom" responded to each of the mTOQ-4 items to characterize the areas of greatest unmet need in the acute treatment of migraine.

[0142] The mTOQ-4 is a validated, reliable, self-report, easy-to-use 4-item questionnaire that assesses the adequacy of current treatment efficacy for the purpose of optimizing treatment. The mTOQ-4 is shown in Table 3 below.

[0143] Table 3

[0144]

[0145]

[0146] a The mTOQ-4 score was determined based on previous treatment in the 4 weeks before screening.

[0147] Figure 6 The proportion of patients who answered “never” or “rarely” to each mTOQ-4 question is depicted.

[0148] Example 3

[0149] A phase 3, randomized, double-blind, multicenter, placebo-controlled trial evaluating the early treatment of migraine with meloxicam / rizatriptan was conducted. A total of 302 patients were randomized in a 1:1 ratio to treat a single migraine attack with a single dose of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, containing SBEβCD (approximately 133.6 mg) and sodium bicarbonate (500 mg), as described in Example 1 above) or placebo at the earliest signs of migraine, when the pain is mild, before it progresses to moderate or severe intensity.

[0150] This clinical trial is different from the clinical trial in Example 1. The clinical trial in Example 1 recruited only patients with a history of inadequate response to previous acute treatments, and the patients waited to treat their attacks only when the migraine reached moderate or severe intensity. The clinical trial in Example 1 is in contrast to this clinical trial, which recruited all participants and in which patients were told to take meloxicam / rizatriptan at the earliest sign of migraine pain, while the pain was mild, and then progressed to moderate or severe intensity.

[0151] The patients were adult subjects diagnosed with migraine with or without aura.

[0152] The co-primary endpoints were freedom from headache and freedom from the most bothersome migraine-related symptom (nausea, photophobia, or phonophobia) two hours after dosing for meloxicam / rizatriptan compared with placebo.

[0153] Inclusion criteria included men or women aged 18-65 years (inclusive), diagnosed (at least 1 year) with migraine with or without aura as defined by ICHD-3 criteria, and an average of 2-8 migraines per month. Exclusion criteria included cluster headaches, tension headaches or other types of migraine, chronic daily headaches (≥15 non-migraine headaches per month), history of major cardiovascular disease, and uncontrolled hypertension.

[0154] In this Phase 3 trial of meloxicam / rizatriptan for the early treatment of migraine, meloxicam / rizatriptan substantially and significantly eliminated migraines and substantially and significantly prevented the progression of migraine intensity. In the trial, meloxicam / rizatriptan met the co-primary endpoints of freedom from migraine and freedom from the most bothersome symptom compared to placebo.

[0155] Meloxicam / rizatriptan demonstrated statistically significant improvements in both pain freedom (32.6% vs. 16.3%, p=0.002) and freedom from the most bothersome symptom (43.9% vs. 26.7%, p=0.003) at 2 hours after dosing compared with placebo ( Fig. 7A and Figure 7B ). The most bothersome symptoms are nausea, photophobia, or phonophobia.

[0156] Meloxicam / Rizatriptan for migraine relief (as early as 30 minutes) Figure 8 ) and the most bothersome symptoms ( Fig. 9 ) was numerically superior to placebo at 90 minutes (p = 0.003) and at each subsequent time point ( Figure 8 ) achieved statistical significance for migraine freedom. 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.

[0157] Meloxicam / rizatriptan provided sustained relief of migraine compared with placebo, with a statistically significantly higher percentage of patients achieving sustained migraine freedom from 2 to 24 hours (22.7% vs. 12.6%, p=0.030) and 2 to 48 hours (20.5% vs. 9.6%, p=0.013) after dosing. Fig. 10A and Fig. 10B ).

[0158] Meloxicam / rizatriptan prevented the progression of migraine intensity beyond mild within 2 to 24 hours in 73.5% of patients, compared with 47.4% of patients taking placebo (p<0.001)( Fig.11 ). A single dose of meloxicam / rizatriptan prevented the migraine from progressing beyond mild severity.

[0159] The effect on pain progression translated into a significant reduction in rescue medication use, with only 15.3% of patients taking meloxicam / rizatriptan requiring rescue medication within 24 hours of dosing, compared with 42.2% of patients taking placebo (p<0.001)( Fig.12 ).

[0160] Meloxicam / rizatriptan substantially and significantly reduced functional disability and demonstrated overall disease improvement. 73.5% of patients taking meloxicam / rizatriptan achieved the ability to perform normal activities at 24 hours compared with 47.4% of patients taking placebo (p<0.001)( Fig.13 ).

[0161] On the Patient Global Impression of Change (PGI-C) scale, at 2 hours, 52.4% of patients taking meloxicam / rizatriptan had very great or great improvement compared with 27.7% of patients taking placebo (p<0.001)( Fig.14 ).

[0162] In the trial, meloxicam / rizatriptan was generally safe and well tolerated. The most commonly reported adverse events with meloxicam / rizatriptan were somnolence, dizziness, and paresthesia, all of which occurred in less than 5% of patients (Table 4). There were no major adverse events in the trial.

[0163] Table 4 a

[0164]

[0165] a Data are expressed as number of subjects (% of subjects)

[0166] "[The] study demonstrated high migraine freedom rates with meloxicam / rizatriptan and utilized an innovative design to evaluate migraine progression. Notably, early treatment with meloxicam / rizatriptan halted migraine progression in the vast majority of patients and resulted in a similarly high percentage of patients returning to normal function," said Stewart Tepper, MD, professor of neurology at Dartmouth's Geisel School of Medicine. "Multiple mechanisms contribute to the percentage of patients returning to normal function," said Stewart Tepper, MD, professor of neurology at Dartmouth's Geisel School of Medicine. "The multiple mechanisms of meloxicam / rizatriptan address many of the disrupted physiological processes involved in migraine attacks. These results, combined with previous clinical data showing the superiority of meloxicam / rizatriptan over active comparators, provide clinical evidence that this synergistic, multi-mechanistic approach and the rapid absorption of meloxicam / rizatriptan can translate into important benefits for a broad range of patients. As clinicians continue to seek options for their patients with increased efficacy over currently available therapies, meloxicam / rizatriptan could provide an important new treatment for this debilitating condition."

[0167] This Phase 3 trial demonstrates the superior and sustained efficacy of meloxicam / rizatriptan. The arrest of migraine progression and the significant improvement in pain freedom demonstrated by early treatment with meloxicam / rizatriptan extend and enhance its differentiated profile for the acute treatment of migraine. Meloxicam / rizatriptan has now been evaluated in two positive well-controlled trials in patients with a history of inadequate response to prior acute treatment using this Phase 3 trial and the Phase 3 trial described in Example 11. These trials demonstrate the efficacy of meloxicam / rizatriptan relative to potent active and placebo comparators across a range of migraine attacks, regardless of duration of migraine treatment, disease severity, or baseline pain intensity.

[0168] “Migraine is one of the most debilitating and disabling disorders, leaving patients incapacitated and significantly impairing their ability to live their family life, engage in social activities, and work. Published surveys underscore that patients remain dissatisfied with the efficacy of currently available therapies,” said Cedric O’Gorman, MD, senior vice president of clinical development and medical affairs at Axsome. “The results of [this] trial demonstrate for the first time that meloxicam / rizatriptan can stop the progression of migraine before it reaches moderate or severe intensity. These data add to the body of clinical evidence supporting the potential of meloxicam / rizatriptan as a multi-mechanism migraine treatment that outperforms the current standard of care and provides rapid, robust and durable symptom relief and allows patients to return to their normal daily activities.”

[0169] Example 4

[0170] The efficacy of meloxicam / rizatriptan compared with placebo was evaluated in subgroups of patients with the following risk factors for inadequate response to acute migraine medication: higher BMI, allodynia, morning migraine, and history of depression.

[0171] The data were obtained from a combined subgroup analysis of subjects who participated in the clinical trials of Example 1 and Example 3 for the acute treatment of migraine.

[0172] like Fig.15 Results showed that treatment with meloxicam / rizatriptan improved the rate of freedom from persistent pain at 24 hours compared with placebo in four subgroups defined by risk factors.

[0173] For patients with a BMI greater than or equal to the median BMI of the patients in the study (≥ median 28.8 kg / m 2 ) of patients treated with levofloxacin, 15.8% of treated patients were pain free at two hours compared with 7.6% of patients receiving placebo (p=0.008).

[0174] For patients with allodynia (as defined by a score of ≥3 on the ASC-12), 18.7% of treated patients were pain free at two hours compared to 8.1% of patients receiving placebo (p<0.001).

[0175] For patients with morning migraine (defined as migraine attacks occurring before 10 am), 18.3% of treated patients were pain free at two hours compared to 8.1% of patients receiving placebo (p=0.005).

[0176] For patients with a history of depression, 16.7% of treated patients were pain free at two hours compared to 5.9% of patients receiving placebo (p=0.053).

[0177] Unless otherwise indicated, all numbers used in the specification and claims to indicate quantities of components, properties such as amounts, percentages, etc. should be understood in all cases to indicate the exact value shown and to be modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the attached claims are approximate values, which may vary depending on the desired properties to be obtained. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in accordance with the number of reported significant digits and applying customary rounding techniques.

[0178] Unless otherwise indicated herein or clearly contradicted by context, the terms "one", "a", "said" and similar references used in the context of describing embodiments (especially in the context of the following claims) should be interpreted as covering singular and plural references. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiments and does not limit the scope of any claim. Any language in this specification should not be interpreted as indicating that any unclaimed element is necessary to practice the claims.

[0179] The grouping of alternative elements or embodiments disclosed herein should not be interpreted as limiting. Each group member may be mentioned and claimed individually, or mentioned and claimed in any combination with other members of the group or other elements found herein. For reasons of convenience and / or accelerating the application process, it is contemplated that one or more members of the group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, this specification is deemed to include the modified group, and therefore satisfies the written description of all Markush groups used in the appended claims.

[0180] Certain embodiments are described herein, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that the skilled person will adopt such variations as appropriate, and the inventors expect 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. In addition, any combination of the above elements in all possible variations is covered unless otherwise indicated herein or clearly contradicted by the context.

[0181] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Therefore, by way of example and not limitation, alternative embodiments may be used in accordance with the teachings herein. Therefore, the claims are not limited to the embodiments exactly shown and described.

Claims

1. A method of treating migraine in a patient with a history of inadequate response to prior migraine treatments, the method comprising selecting a patient who, over at least the past four weeks: 1) has had 2 to 8 migraines per month, and 2) according to the patient, has never or rarely felt comfortable enough on the patient's migraine medication to be able to plan daily activities; and after selecting the patient, administering to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

2. A method of treating migraine in a patient with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who, over at least the past four weeks: 1) has 2 to 8 migraines per month, and 2) according to the patient, after taking migraine medications, the patient never or rarely feels adequate control over the patient's migraines such that the patient feels the patient's daily activities will not be interfered with; and after selecting the patient, administering to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

3. A method of treating migraine in a patient 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 2 to 8 migraines per month, and 2) has an mTOQ-4 score of 0; and after selecting the patient, administering to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

4. A method of treating migraine in a patient with a history of inadequate response to previous migraine treatments, the method comprising selecting a patient who: 1) has had 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 to the patient a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof during a migraine attack.

5. The method according to any preceding claim, wherein the meloxicam and the rizatriptan are present in a single dosage form.

6. The method of claim 5, wherein the dosage form further comprises a bicarbonate salt.

7. The method of claim 5, wherein the dosage form further comprises cyclodextrin.

8. The method according to any preceding claim, wherein the meloxicam and the rizatriptan are administered to the patient orally.

9. The method of claim 1, 2, 3, 4, 5 or 6, wherein the combination is administered when the patient suffers from a mild migraine.

10. The method of claim 1, 2, 3, 4, 5 or 6, wherein the combination is administered when the patient suffers from a moderate migraine.

11. The method of claim 1, 2, 3, 4, 5 or 6, wherein the combination is administered when the patient suffers from a severe migraine.

12. The method of claim 6, wherein the dosage form further comprises cyclodextrin.

13. The method according to claim 7 or 12, wherein the cyclodextrin is sulfobutyl ether-β-cyclodextrin (SBEβCD).

14. The method according to claim 13, wherein the meloxicam forms an inclusion complex with SBEβCD.

15. The method according to any preceding claim, wherein the meloxicam is in the free acid form.

16. A method according to any preceding claim, wherein the rizatriptan is in the form of a salt.

17. The method of claim 16, wherein the rizatriptan is present as rizatriptan benzoate.

18. The method of claim 6 or 12, wherein the bicarbonate salt is sodium bicarbonate or potassium bicarbonate.

19. The method of claim 18, wherein about 500 mg of sodium bicarbonate is present in the combination.

20. The method of claim 13, wherein about 133.6 mg SBE[beta]CD is present in the combination.

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