Pharmaceutical composition containing meloxicam

Abstract

Disclosed herein is a method of treating migraine in patients with a history of inadequate response to previous migraine treatments, wherein the patients have had 1) two to eight migraines per month for at least the past four weeks and 2a) according to the patient, there is no or little control of their migraines after taking migraine medications such that the patient feels unhindered in their daily activities, 2b) according to the patient, there is no or little control of their migraines after taking migraine medications such that the patient feels unhindered in their daily activities, 2c) the mTOQ-4 score is 0, and / or 2d) the patient feels they have a history of depression, and administering to the patient, during a migraine attack, a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] (Related Application) This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 343,982, filed on May 19, 2022, which is hereby incorporated by reference in its entirety.

Summary of the Invention

Means for Solving the Problems

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

[0003] Some embodiments include a method of treating migraine in patients with a history of inadequate response to previous migraine treatments, the method comprising selecting, for at least the past four weeks, 1) patients having two to eight migraines per month, and 2) patients who, according to the patient, feel that they have no or hardly any control over their migraines such that, after taking migraine medication, the patient feels unhindered in their daily activities, and, after the patient is selected, administering to the patient, during a migraine attack, a combination of 20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10 mg of rizatriptan or a pharmaceutically acceptable salt thereof.

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

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

[0006]

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Mode for Carrying Out the Invention

[0007] (Detailed Description of the Invention) Meloxicam having the following structure is a non-steroidal anti-inflammatory drug (NSAID) and exhibits anti-inflammatory, analgesic, and antipyretic effects. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthase (cyclooxygenase, COX), which is involved in the initial stage of the arachidonic acid cascade. As a result, the production of prostaglandins, thromboxanes, and prostacyclin is suppressed.

[0008]

Chemical formula

[0009] Meloxicam and other non-steroidal anti-inflammatory drugs (NSAIDs) have low water solubility, which can lead to reduced bioavailability and a delayed onset of pain relief upon use. One way to improve the solubility and bioavailability of meloxicam is to use cyclodextrin. Cyclodextrin (also known as cycloamylose) is generally a cyclic polysaccharide with a bucket-like shape. Cyclodextrin has a hydrophobic interior and a hydrophilic exterior, which facilitates the transport of molecules such as hydrophobic molecules and helps to enhance the bioavailability of other molecules. Naturally occurring cyclodextrins contain 6, 7, and 8 glucose units (α, β, and γ-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are also possible. In an aqueous solution, cyclodextrin can form a complex (inclusion complex) with a drug by incorporating the drug into the central / hydrophobic part of the cyclodextrin ring; however, cyclodextrin compounds are also known to aggregate around the drug in a micelle-like structure. This ability of cyclodextrin may enable it to act as a carrier for drugs to increase the bioavailability of poorly soluble drugs.

[0010] The combination of rizatriptan and meloxicam (referred to herein for convenience as the "subject combination") may be used in the treatment of various pain symptoms.

[0011] Rizatriptan has the structure shown below.

[0012]

Chemical formula

[0013] Some embodiments include a combination of: 1) an inclusion complex of meloxicam and cyclodextrin, 2) rizatriptan, and 3) a bicarbonate, for treating human migraine. The migraine may be treatment-resistant migraine. The human may have a history of showing an insufficient response to previous treatments. In some embodiments, the cyclodextrin is SBEβCD.

[0014] The dosage form may be enteral administration including, but not limited to, oral, sublingual, or rectal administration, or parenteral administration including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous administration.

[0015] Unless otherwise specified, any reference herein to a compound such as meloxicam or rizatriptan by structure, name, or other means includes any pharmaceutically acceptable salt, polymorph, solvate, hydrate, enantiomer, tautomer, deuterium-modified form, or any other chemical species such as an alternative solid form, a precursor, a prodrug, or any other chemical species that is rapidly convertible to the compound described herein under the conditions under which the compound is used as described herein.

[0016] The combination of the subject may be administered by enteral administration including, but not limited to, oral, sublingual, or rectal administration, or parenteral administration including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous administration. In some embodiments, both meloxicam and rizatriptan are administered orally.

[0017] Typically, a combination of meloxicam and rizatriptan is administered such that a human receives meloxicam and rizatriptan within a short period of time of each other. For example, meloxicam and rizatriptan may be administered within about 2 hours of each other, within about 1 hour of each other, within about 30 minutes of each other, within about 20 minutes of each other, within about 15 minutes of each other, within about 10 minutes of each other, within about 5 minutes of each other, 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).

[0018] The terms “treatment” or “treating” broadly include any kind of treatment activity that involves the diagnosis, treatment, alleviation, or prevention of a disease in a human or other animal, or an activity that affects the structure or function of the body of a human or other animal.

[0019] Migraine is a neurological disorder that renders a person incapacitated, characterized by recurrent episodes of throbbing headache, accompanied by nausea and hypersensitivity to light and sound. The pain can range from mild or moderate to severe, but is often severe and disabling, requiring bed rest. The headache occurs on one side of the head, may be throbbing, and can last from 2 to 72 hours. Associated symptoms can include nausea, vomiting, and hypersensitivity to light (photophobia), sound (phonophobia), or smell. The pain of a migraine can be accompanied by visual disturbances. The pain of a migraine can be worsened by physical activity. Migraine can be preceded by an aura, which is a short-term visual disturbance that warns that a headache is about to occur. Some migraine sufferers may not have an aura.

[0020] In some embodiments, humans being treated for migraine suffer from allodynia, such as cutaneous allodynia associated with migraine attacks. Allodynia, such as cutaneous allodynia, is pain caused by stimuli that normally do not cause pain (such as brushing hair, wearing glasses, taking a shower, etc.). Patients with allodynia, such as cutaneous allodynia, are thought to be less responsive to triptan medications.

[0021] Current treatments are not optimal, and more than 70% of affected patients report dissatisfaction with existing acute treatments. The most frequently reported reasons for patient dissatisfaction are the late onset of pain relief, inconsistent pain relief, and pain recurrence on the same day. Inappropriate acute treatment is associated with a significant increase in the risk of developing new chronic migraines and may be preventable by improving the outcome of acute treatment.

[0022] Administering the subject combination to a human suffering from migraine, such as an acute attack of migraine pain or aura, results in a reduction of migraine symptoms, such as pain, nausea, vomiting, photophobia, or phonophobia, within about 5 minutes (intended as an abbreviated expression for "about 5 minutes later or within about 5 minutes"), within about 10 minutes, within about 30 minutes, within about 1 hour, within about 90 minutes, within about 2 hours, within about 2.5 hours, or within about 3 hours. In some embodiments, the human experiences a reduction or complete relief of headache pain or pain such as migraine, nausea, vomiting, photophobia, and / or phonophobia within about 1 hour, within about 90 minutes, within about 2 hours, within about 2.5 hours, or within about 3 hours. In some embodiments, the relief experienced is greater than that experienced by taking the same amount of rizatriptan without meloxicam. In some embodiments, the relief experienced is greater than that experienced by taking the same amount of meloxicam without rizatriptan.

[0023] The combination of the subject matter may be administered at the earliest sign of migraine pain or shortly after the earliest sign of migraine (e.g., 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 initial state, the pain may still be mild or may be before the pain progresses to moderate or severe intensity. In some methods, the combination of the subject matter may be administered when the pain intensity of the migraine reaches moderate or severe.

[0024] In some embodiments, the combination of meloxicam and rizatriptan is administered to human migraine patients who have or are selected to have a dysfunction. In some embodiments, as a result of the treatment, human migraine patients can return to normal activities within 24 hours after receiving the treatment.

[0025] The combination of meloxicam and rizatriptan may have two different mechanisms of action in the acute treatment of migraine. Meloxicam is a potent COX-2 preferential NSAID but has the limitation of slow absorption. Rizatriptan is a potent 5-HT1 B / D agonist and is considered effective for migraine.

[0026] Observing the reduction or decrease of symptoms at a specific period such as "at 2 hours" is useful because the effectiveness of the treatment can be evaluated at a specific or consistent time point and it is easier to compare between patients. Observing the reduction or alleviation of symptoms within a specific period such as "within about 2 hours" is useful because it is desirable for the reduction or alleviation of symptoms to occur as early as possible, and specifying that the reduction occurs within a specific time sets the guideline that it is desirable for the reduction to occur.

[0027] In some methods, administration of the combination of the subject matter may achieve relief of migraine pain, nausea, vomiting, photophobia, or phonophobia that persists for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8 to 24 hours, about 24 hours, or more than 24 hours.

[0028] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and the human experiences greater pain relief 2 hours after administration of meloxicam and rizatriptan than the human would experience 2 hours after ingesting the same amount of meloxicam without rizatriptan.

[0029] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid dosage form), and the human experiences greater pain relief 24 hours after administration of meloxicam and rizatriptan than the human would experience 24 hours after ingesting the same amount of meloxicam without rizatriptan.

[0030] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and the human experiences greater pain relief 2 hours after administration of meloxicam and rizatriptan than the human would experience 2 hours after ingesting the same amount of rizatriptan without meloxicam.

[0031] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and the human experiences greater pain relief 24 hours after administration of meloxicam and rizatriptan than the human would experience 24 hours after ingesting the same amount of rizatriptan without meloxicam.

[0032] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and two hours after meloxicam and rizatriptan are administered, a human experiences greater relief from nausea than would be experienced by a human two hours after ingesting the same amount of meloxicam without rizatriptan.

[0033] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences greater relief from nausea than would be experienced by a human 24 hours after ingesting the same amount of meloxicam without rizatriptan.

[0034] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and two hours after meloxicam and rizatriptan are administered, a human experiences greater relief from nausea than would be experienced by a human two hours after ingesting the same amount of rizatriptan without meloxicam.

[0035] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences greater relief from nausea than would be experienced by a human 24 hours after ingesting the same amount of rizatriptan without meloxicam.

[0036] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and two hours after meloxicam and rizatriptan are administered, a human experiences greater relief from vomiting than would be experienced by a human two hours after ingesting the same amount of meloxicam without rizatriptan.

[0037] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences a greater reduction in vomiting than would be experienced by a human 24 hours after ingesting the same amount of meloxicam without rizatriptan.

[0038] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 2 hours after meloxicam and rizatriptan are administered, a human experiences a greater reduction in vomiting than would be experienced by a human 2 hours after ingesting the same amount of rizatriptan without meloxicam.

[0039] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences a greater reduction in vomiting than would be experienced by a human 24 hours after ingesting 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 comprising a single solid oral dosage form), and 2 hours after meloxicam and rizatriptan are administered, a human experiences a greater reduction in photophobia than would be experienced by a human 2 hours after ingesting the same amount of meloxicam without rizatriptan.

[0040] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences a greater reduction in photophobia than would be experienced by a human 24 hours after ingesting the same amount of meloxicam without rizatriptan.

[0041] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a human experiences a greater reduction in photophobia than would be experienced by a human two hours after ingesting the same amount of rizatriptan without meloxicam.

[0042] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences a greater reduction in photophobia than would be experienced by a human 24 hours after ingesting the same amount of rizatriptan without meloxicam.

[0043] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a human experiences a greater reduction in phonophobia than would be experienced by a human two hours after ingesting the same amount of meloxicam without rizatriptan.

[0044] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences a greater reduction in phonophobia than would be experienced by a human 24 hours after ingesting the same amount of meloxicam without rizatriptan.

[0045] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and two hours after administration of meloxicam and rizatriptan, a human experiences a greater reduction in phonophobia than would be experienced by a human two hours after ingesting the same amount of rizatriptan without meloxicam.

[0046] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences a greater reduction in phonophobia than would be experienced by a human 24 hours after ingesting the same amount of rizatriptan without meloxicam.

[0047] In some embodiments, a human has a history of triptan use prior to ingesting a combination of the subject matter such as a combination of meloxicam and rizatriptan.

[0048] In some embodiments, a human ingesting a combination of the subject matter has a score of 0 or 1 on the Migraine Treatment Optimization Questionnaire (mTOQ-4).

[0049] In some embodiments, a human ingesting a combination of the subject matter has indicated that for most attacks, it is "not at all" or "hardly" the case that pain goes away within 2 hours after treatment prior to ingesting the combination of the subject matter.

[0050] In some embodiments, a human ingesting a combination of the subject matter has indicated that prior to ingesting the combination of the subject matter, with a single dose, the respondent's headache was "not at all" or "hardly" reduced and the headache did not go away (kept it away) for at least 24 hours.

[0051] In some embodiments, a human ingesting a combination of the subject matter has indicated that prior to ingesting the combination of the subject matter, their migraine medication is "not at all" or "hardly" comfortable enough to allow them to plan their daily activities.

[0052] In some embodiments, a human ingesting a combination of the subject matter has indicated that prior to ingesting the combination of the subject matter, they "not at all" or "hardly" feel that they can control their migraine well enough to feel that there will be no interference with their daily activities after taking migraine medication.

[0053] In some embodiments, the human who ingests the combination of the subject matter has a history of depression prior to ingesting the combination of the subject matter.

[0054] In some embodiments, a human who ingests a combination of the subject matter, such as a combination comprising meloxicam and rizatriptan, may have migraine and a history of inadequate response to previous migraine treatments. In some embodiments, a human having migraine does not have cluster headache or other types of migraine. In some embodiments, a human having migraine does not have chronic daily headache. In some embodiments, a human having migraine does not have headache days exceeding 15 days, 15 to 20 days, 20 to 25 days, 25 to 28 days, 28 to 30 days, or 30 to 31 days per month. In some embodiments, a human having migraine does not have a history of serious cardiovascular disease. In some embodiments, a human having migraine does not have uncontrolled hypertension.

[0055] In some methods, administration of the dosage form may achieve a reduction in pain lasting at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, at least about 8 hours, about 8 to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form may achieve a reduction in pain observed about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, less than 15 minutes, less than 20 minutes, 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, or 60 minutes, or at other times within a range limited to any of these values after dosage form administration.

[0056] In some methods, administration of the dosage form or combination of the subject matter may achieve a reduction in pain that persists for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8 hours to about 24 hours, or about 24 hours. In other embodiments, administration of the combination of the subject matter results in a reduction in pain about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or within about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, or about 60 minutes, within 2 hours, within 3 hours, or other periods bounded by these ranges after administration of the combination of the subject matter.

[0057] A human being receiving treatment of a disease or condition with the dosage form described herein can be of any age. For example, the age of the person can be about 10 years to about 90 years, about 20 years to about 80 years, about 30 years to about 75 years, about 40 years to about 70 years, about 1 year to about 16 years, about 80 years to about 95 years, 16 years or older, 18 years or older, 20 years or older, 25 years or older, 30 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, 65 years or older, or any other age within or between the ranges limited by these values.

[0058] In some embodiments, a human being receiving treatment of migraine with the dosage form described herein that includes a hydrogencarbonate such as, for example, meloxicam, rizatriptan, SBEβCD, and sodium hydrogen carbonate can be 18 years to 65 years, about 18 years to 20 years, about 20 years to 25 years, about 25 years to 30 years, about 30 years to 40 years, about 40 years to 45 years, about 40 years to 50 years, about 50 years to 60 years, about 60 years to 65 years, or any other age within or between the ranges limited by these values.

[0059] In some embodiments, a human being receiving treatment for migraine in a dosage form comprising meloxicam, rizatriptan, sulfobutylether-β-cyclodextrin (SBEβCD), and a hydrogencarbonate such as sodium hydrogencarbonate, as described herein, may 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.

[0060] In some embodiments, a human being being treated for a disease or condition in a dosage form comprising meloxicam or another NSAID has been suffering 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 months, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or for any period within or between these values limited by these values.

[0061] In some embodiments, a human being being treated for migraine in a dosage form comprising meloxicam and rizatriptan has been diagnosed with migraine with aura or migraine without aura, as defined by the ICHD-3 criteria, for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1 to 2 years, 2 to 3 years, or more, or for at least 1 year, or for any period within the range limited by these values, or for any period between these values.

[0062] In some embodiments, a human being has had, or has, moderate to severe migraines 2 to 8 times, 2 to 3 times, 3 to 4 times, 4 to 5 times, 5 to 6 times, 6 to 7 times, or 7 to 8 times per month, such as for at least the past 1 month.

[0063] The cyclodextrin used in the dosage form together with meloxicam may include cyclodextrin, cyclodextrin derivatives, and / or their salts. The inclusion complex of meloxicam and cyclodextrin may have higher water solubility compared to non-complexed meloxicam. The cyclodextrin may be a natural cyclodextrin (e.g., α, β, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, derivatives, or their 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 combinations thereof.

[0064] In some embodiments, β-cyclodextrin, derivatives thereof, or salts thereof may be used. β-cyclodextrin includes hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin, (2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3,6-tri-O-methyl)-β-cyclodextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, (2,3,6-tri-O-benzoyl)-β-cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin, 6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,6 - Di - O - ethyl - β - cyclodextrin, (2 - carboxyethyl) - β - cyclodextrin (CMEβCD), hydroxyethyl - β - cyclodextrin (HEβCD), (2 - hydroxypropyl) - β - cyclodextrin, (2 - hydroxypropyl) - β - cyclodextrin (HPβCD), (3 - hydroxypropyl) - β - cyclodextrin (3HPβCD), (2,3 - hydroxypropyl) - β - cyclodextrin (DHPβCD), butyl - β - cyclodextrin, methyl - β - cyclodextrin, silyl ((6 - O - tert - butyldimethyl) - 2,3, - di - O - acetyl) - β - cyclodextrin, succinyl - β - cyclodextrin, (2 - hydroxyisobutyl) - β - cyclodextrin, randomly methylated - β - cyclodextrin, branched - β - cyclodextrin or combinations thereof, but not limited thereto.,

[0065] In other embodiments, the β - cyclodextrin can be a sulfoalkyl ether cyclodextrin, a derivative, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives can include, but are not limited to, sulfobutyl ether - β - cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In some embodiments, SBEβCD can have from about 4 to 8, from about 5 to 8, from about 4 to 7, from about 6 to 7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.,

[0066] In some embodiments, γ-cyclodextrin, derivatives thereof, or salts thereof may be used. γ-Cyclodextrin may include carboxymethyl-γ-cyclodextrin, (2,3,6-tri-O-acetyl)-γ-cyclodextrin, (2,3,6-tri-O-methyl)-γ-cyclodextrin, (2,6-di-O-pentyl)-γ-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin, 6-bromo-6-deoxy-γ-cyclodextrin, 6-iodo-6-deoxy-γ-cyclodextrin, (6-O-t-butyldimethylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin (2-hydroxypropyl)-γ-cyclodextrin, acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

[0067] In some embodiments, the dosage form may include a bicarbonate such as sodium bicarbonate, potassium bicarbonate, or combinations thereof. The bicarbonate may help increase the solubility and bioavailability of meloxicam or rizatriptan.

[0068] Unless otherwise specified, reference to a compound described herein, such as meloxicam or cyclodextrin, by structure, name, or any other means, includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers, tautomers, alternative solid forms such as forms modified with deuterium, or any other chemical species that may be rapidly converted to the compound described herein under the conditions under which the compound is used as described herein.

[0069] In some embodiments, the dosage form may contain meloxicam in an amount of about 15 mg to 25 mg, about 18 mg to 22 mg, or about 20 mg. These dosages can be safe dosages for repeated administration such as once an hour to once a day, twice a day, once to twelve times a day, three, four, five, or six times a day. In some embodiments, meloxicam can be safely administered two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen times a day, or about three to about ten times a day, once a day, or less frequently such as once a week, once every two weeks, or once a month.

[0070] For any amount of meloxicam described herein, the salt form of meloxicam can be present in the above amount or an amount that is molar equivalent to these amounts for meloxicam free acid. For example, considering that the molecular weight of meloxicam free acid is 351.4 g / mol, 20 mg of meloxicam in free acid form is 56.9 mmol. Thus, the molar equivalent of 20 mg of meloxicam free acid is the mass of 56.9 mmol of meloxicam in salt form. For example, the weight of sodium salt of meloxicam (molecular weight 373.4 g / mol) with the same molar equivalent as 20 mg (or 56.9 mmol) of meloxicam free acid is 21.25 mg. These dosages may be safe for repeated administration once, twice, three, or four times a day, or may be safe for repeated administration at intervals of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty - one, twenty - two, twenty - three, twenty - four, twenty - five, twenty - six, twenty - seven, twenty - eight, twenty - nine, thirty, thirty - one days, four weeks, four to six weeks, about one to two months, about six weeks, about two to three months, about three to four months, about four to five months, about five to six months, about six to seven months, about seven to eight months, about eight to nine months, about nine to ten months, about ten to eleven months, about eleven to twelve months or more.

[0071] For some dosage forms, meloxicam may form a complex with substituted-β-cyclodextrin or other cyclodextrins and may be formulated into solid dosage forms. Such dosage forms may be suitable for oral administration. The meloxicam-cyclodextrin inclusion complex may also be dissolved in water or another solvent to form a parenteral formulation. However, physical mixtures of meloxicam and substituted-β-cyclodextrin or other cyclodextrins may also be used in oral or parenteral dosage forms.

[0072] The formation of the inclusion complex of meloxicam and cyclodextrin may help improve the properties of the dosage form. In some inclusion complexes, the molar ratio of meloxicam and cyclodextrin (e.g., SBEβCD) may be about 0.5 to 2 (a molar ratio of 0.5 means 0.5 moles of meloxicam per 1 mole of cyclodextrin), about 0.5 to 0.7, about 0.6 to 0.8, about 0.7 to 0.9, about 0.8 to 1, about 0.9 to 1.1, about 1 to 1.2, about 1.1 to 1.3, about 1.2 to 1.4, about 1.3 to 1.5, about 1.4 to 1.6, about 1.5 to 1.7, about 1.6 to 1.8, about 1.7 to 1.9, about 1.8 to 2, about 0.8 to 1.2, about 1, or any ratio within the range limited by any of these values.

[0073] For some dosage forms, cyclodextrin (e.g., SBEβCD) is employed at a weight ratio of about 1 to 1000 (e.g., 1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about 1 to 20; about 1 to 10; about 1 to 15; about 2 to 4, about 3 to 5, about 4 to 6, about 5 to 7, about 6 to 8, about 7 to 9, about 8 to 10, or a range limited to any of these values or any weight ratio between these values for meloxicam. For some dosage forms, cyclodextrin (e.g., SBEβCD) is employed at a weight ratio of about 0.001 to 1 (e.g., 0.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about 0.01 to 1; about 0.05 to 1; about 0.1 to 1; about 0.2 to 1; about 0.3 to 1, about 0.4 to 1, about 0.5 to 1, about 0.6 to 1, about 0.7 to 1, about 0.8 to 1, or a range limited to these values or any weight ratio between these values for meloxicam. Each type of cyclodextrin employed may have a different ratio.

[0074] For some dosage forms, cyclodextrin is present in an amount of about 1 mg to 200 mg; 25 mg to 175 mg; about 50 mg to 150 mg; about 25 mg to 100 mg; about 75 mg to 150 mg; about 100 mg to 175 mg; about 20 mg to 80 mg; about 25 mg to 50 mg; about 60 mg to 100 mg; about 80 mg to 100 mg; about 80 mg to 120 mg; about 100 mg to 120 mg; about 100 mg to 140 mg; about 120 mg to 160 mg; about 140 mg to 180 mg; about 30 mg to 90 mg; about 40 mg to 80 mg; about 50 mg to 70 mg, about 55 mg to 65 mg, about 60 mg to 62 mg, or an amount limited to or between these values.

[0075] For some methods, the inclusion complex of meloxicam with a cyclodextrin such as substituted β-cyclodextrin is delivered orally (e.g., by tablets, capsules, elixirs, etc.). Other possible routes of administration include intravenous, intramuscular, nasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal, or other parenteral means. Meloxicam may also be delivered alone or without forming a complex with cyclodextrin.

[0076] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in an amount of about 1 mg to 2000 mg; about 1 mg to 1000 mg; about 100 mg to 1000 mg; about 200 mg to 800 mg; about 1 mg to 500 mg; about 1 mg to 200 mg; about 1 mg to 100 mg; about 50 mg to 750 mg; about 500 mg to 1000 mg; about 100 mg to 500 mg; about 100 mg to 300 mg; about 500 mg to 1000 mg; about 300 mg to 700 mg; about 400 mg to 600 mg; about 50 mg to 250 mg; about 250 mg to 750 mg; about 100 mg to 200 mg; about 200 mg to 300 mg; about 300 mg to 400 mg; about 400 mg to 500 mg; about 410 mg to 510 mg; about 420 mg to 520 mg; about 430 mg to 530 mg; about 440 mg to 540 mg; about 450 mg to 550 mg; about 460 mg to 560 mg; about 470 mg to 570 mg; about 480 mg to 580 mg; about 490 mg to 590 mg; about 500 mg to 600 mg; about 600 mg to 700 mg; about 700 mg to 800 mg; about 800 mg to 900 mg; about 150 mg to 650 mg; about 350 mg to 850 mg; or any amount within a range limited to or between these values.

[0077] In certain embodiments, the pharmaceutical composition contains meloxicam and has an increased bioavailability of meloxicam from the dosage form (e.g., a decrease in T max and a decrease in C maxresulting in an increase in, for example, the AUC. In some embodiments, the bioavailability of meloxicam increases with multiple administrations.

[0078] Some of these dosage forms provide an AUC of meloxicam 0-inf of about 40,000 * hr / mL to 70,000 ng * hr / mL; about 50,000 * hr / mL to 60,000 ng * hr / mL; about 52,000 * hr / mL to 56,000 ng * hr / mL; or about 54,000 ng * hr / mL, resulting in a desired range of the area under the plasma concentration curve (AUC) of meloxicam.

[0079] In some embodiments, the dosage form provides a C of meloxicam of about 2,500 ng / mL to 3,500 ng / mL, about 2,700 ng / mL to 3,100 ng / mL, or about 2,900 ng / mL max which may occur.

[0080] The methods described herein may decrease the T of meloxicam. In some embodiments, the method may include treating a patient to achieve a T of meloxicam in the patient's body at about 0.5 hours to 1 hour, about 0.8 hours to 0.9 hours, or about 0.875 hours after administration of the subject combination. max which may occur. max which may occur.

[0081] Some of these dosage forms provide a desired range of the area under the plasma concentration curve (AUC) of rizatriptan, such as * about 70 * hr / mL to 100 ng * hr / mL; about 80 * hr / mL to 90 ng * hr / mL; or about 86.7 ng 0-inf hr / mL.

[0082] In some embodiments, the dosage form provides a C of rizatriptan of from about 25 ng / mL to about 35 ng / mL, from about 30 ng / mL to about 34 ng / mL, or from about 31 ng / mL to about 31.7 ng / mL. max It may result in.

[0083] The methods described herein may reduce the T of rizatriptan. For example, the method may achieve a T of rizatriptan in the patient's body at about 0.5 to 1 hour, about 0.7 to 0.8 hour, or about 0.75 hour after administration. max It may be reduced. For example, the method may achieve a T of rizatriptan in the patient's body at about 0.5 to 1 hour, about 0.7 to 0.8 hour, or about 0.75 hour after administration. max It may be achieved.

[0084] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, a human experiences greater relief from dysesthesia, such as cutaneous dysesthesia, than would be experienced by a human 2 hours after ingesting the same amount of meloxicam without rizatriptan.

[0085] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences greater relief from dysesthesia, such as cutaneous dysesthesia, than would be experienced by a human 24 hours after ingesting the same amount of meloxicam without rizatriptan.

[0086] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single oral dosage form comprising a single solid oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, a human experiences greater relief from dysesthesia, such as cutaneous dysesthesia, than would be experienced by a human 2 hours after ingesting the same amount of rizatriptan without meloxicam.

[0087] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form such as a single solid oral dosage form), and 24 hours after meloxicam and rizatriptan are administered, a human experiences greater relief from dysesthesia, such as cutaneous allodynia, than a human would experience 24 hours after ingesting the same amount of rizatriptan without meloxicam.

[0088] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into a food of a diet. For oral therapeutic administration, the active compound is incorporated with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, powders, suspensions, solutions, syrups, wafers, patches and the like.

[0089] Tablets, troches, pills, capsules and the like may contain one or more of binders such as tragacanth gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; sweetening agents such as sucrose, lactose, or saccharin; or flavoring agents such as peppermint, wintergreen oil, or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to the above types of materials, a liquid carrier. As coatings, various other materials may be present, for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain the active compound, sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, coloring agents and flavoring agents, such as flavoring agents having a cherry or orange flavor. The materials of the dosage form or pharmaceutical composition are desirably pharmaceutically pure and substantially non-toxic in the amounts employed.

[0090] Some of the compositions or dosage forms may be liquid or may contain a solid phase dispersed in a liquid.

[0091] The dosage form may further contain a second therapeutically active agent, such as an antacid or an analgesic.

[0092] In some embodiments, the dosage form comprising the subject combination may contain about 5 mg to about 15 mg, about 8 mg to about 12 mg, or about 10 mg of rizatriptan.

[0093] For acute migraine, the single dose of meloxicam and / or rizatriptan, or the AUC of meloxicam and / or rizatriptan associated with a single dose, is of particular interest. For example, after a single administration, symptoms may be alleviated over an extended period of time and repeated administration may not be necessary in the short term. For more persistent symptoms, including more chronic, continuous, or frequent migraine symptoms, daily, weekly, or monthly dosages may be of particular interest.

[0094] For any amount of the rizatriptan described in this specification, the salt form of the rizatriptan may be present in the amounts described above, or in amounts that are molar equivalents to these amounts for the rizatriptan free base. For example, considering that the molecular weight of the rizatriptan free base is 269.4 g / mol, 10 mg of the rizatriptan free base corresponds to 37.1 mmol of the rizatriptan. Therefore, the mass of the rizatriptan salt having the same molar equivalent as 10 mg of the rizatriptan free base is the mass of 37.1 mmol of the rizatriptan salt. For example, for rizatriptan benzoate (molecular weight = 391.2 g / mol), the molar equivalent (or 37.1 mmol) of 10 mg of the rizatriptan free base is 14.5 mg of the rizatriptan benzoate. These dosages may be safe with repeated administration once, twice, three times, or four times per day, 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 to 6 weeks, about 1 to 2 months, about 6 weeks, about 2 to 3 months, about 3 to 4 months, about 4 to 5 months, about 5 to 6 months, about 6 to 7 months, about 7 to 8 months, about 8 to 9 months, about 9 to 10 months, about 10 to 11 months, about 11 to 12 months, etc.

[0095] Some of the oral dosage forms may have an enteric coating or a film coating. In some embodiments, the dosage form may include tablets or capsules having an enteric coating. In some embodiments, the dosage form may include tablets or capsules having a film coating.

[0096] The dosage forms containing a combination of rizatriptan and meloxicam described herein may reduce the pain of migraine headache in less than 15 minutes, about 15 minutes, less than 30 minutes, 15 to 30 minutes, less than 1 hour, 0.5 to 0.75 hours, or 0.75 to 1 hour after administration. The combination of rizatriptan and meloxicam described herein may provide a numerically greater reduction in migraine headache pain than rizatriptan in less than 15 minutes, about 5 minutes, about 5 to 10 minutes, about 10 to 15 minutes, about 15 minutes, about 15 to 30 minutes, about 30 to 45 minutes, about 45 to 60 minutes, about 1 to 1.5 hours, about 1.5 to 2 hours, about 2 to 2.5 hours, about 2.5 to 3 hours, about 3 to 3.5 hours, about 3.5 to 4 hours, about 4 to 5 hours, about 5 to 6 hours, about 6 to 8 hours, about 8 to 10 hours, about 10 to 12 hours, about 12 to 24 hours, about 24 to 48 hours, or a longer period after administration. The percentage of migraine patients reporting pain reduction with treatment by the combination of rizatriptan and meloxicam described herein may be 1% to 100%, 3% to 100%, 4% to 100%, 5% to 100%, 3% to 5%, 5% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, 90% to 95%, or 95% to 100%.

[0097] Migraine patients who ingest a dosage form containing a combination of rizatriptan and meloxicam described herein (the "subject combination") may achieve pain freedom after less than 2 hours, about 2 hours, about 2 to 3 hours, about 3 to 4 hours, about 4 to 6 hours, about 6 to 8 hours, about 8 to 10 hours, about 10 to 12 hours, about 12 to 16 hours, about 16 to 20 hours, about 20 to 24 hours, about 24 to 30 hours, about 30 to 36 hours, about 36 to 40 hours, about 40 to 44 hours, about 44 to 48 hours, or a longer period.

[0098] (Example) Example 1 To evaluate the efficacy and safety of the combination of meloxicam and rizatriptan (meloxicam / rizatriptan) in the acute treatment of moderate to severe migraine, a phase 3 randomized, double-blind, multi-center, placebo and active control trial was conducted. Eligible patients were aged 18 to 65 years, with a definite diagnosis of migraine with aura or without aura (for at least 1 year) defined by the ICHD-3 criteria, moderate to severe migraine 2 to 8 times per month on average, and a history of inadequate response to previous acute migraine treatment, as assessed by a score of 7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4) (mean score was 3.6). Exclusion criteria included a history of cluster headache or other types of migraine, chronic daily headache (headache other than migraine for more than 15 days per month), a history of major cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, enrolled patients had a high rate of characteristics strongly correlated with poor treatment outcomes, including cutaneous allodynia (75.4%), severe migraine pain intensity (41.2%), obesity (43.7%), and morning migraine (36.6%).

[0099] For the treatment of moderate to severe single migraine attacks, a total of 1,594 patients were randomly assigned in a 2:2:2:1 ratio to (1) a group that ingested meloxicam / rizatriptan (meloxicam 20 mg / rizatriptan 10 mg, SBEβCD (about 133.6 mg) and sodium bicarbonate (500 mg)), (2) a group that ingested rizatriptan (10 mg), (3) a group that ingested meloxicam (20 mg) and SBEβCD (MoSEIC meloxicam), or (4) a placebo group. The two co-primary endpoints of this trial were, for meloxicam / rizatriptan compared with placebo, the proportion of patients in whom headache pain had disappeared at 2 hours after administration, and the proportion of patients in whom the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) had disappeared at 2 hours after administration. That meloxicam / rizatriptan was superior to the rizatriptan and meloxicam groups (contribution of components) should have been established based on the sustained disappearance of headache from 2 hours to 24 hours after administration (key secondary endpoint). This trial was conducted in accordance with the FDA Special Protocol Assessment (SPA). Rizatriptan, the active comparator in this trial, is the most rapidly effective oral triptan and is considered one of the most effective among currently available acute migraine treatments. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. serotonin 5-HT(1B / 1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov 17;358(9294):1668-75.)

[0100] Meloxicam / rizatriptan rapidly reduces the pain of migraine. In the meloxicam / rizatriptan intake group, pain reduction was achieved at numerically higher rates than in the rizatriptan intake group at all time points measured starting from 15 minutes later, and a statistically significant result (p = 0.04) was obtained after 60 minutes (Figure 1). The percentage of patients who experienced pain reduction 1.5 hours after administration was 60.5% in the meloxicam / rizatriptan intake group, 52.5% in the rizatriptan intake group, and 48.3% in the placebo intake group (p = 0.019, p = 0.04, respectively, compared to the meloxicam / rizatriptan intake group) (Figure 1A). Figure 1A shows the percentages of the placebo intake group of subjects who reported pain reduction after 1 hour and 1.5 hours for the meloxicam intake group, rizatriptan intake group, and meloxicam / rizatriptan intake group.

[0101] Meloxicam / rizatriptan achieved a higher percentage of patients with pain disappearance 2 hours after administration (19.9% vs. 6.7%, p < 0.001, Figure 2) and a higher percentage of patients with disappearance of the most bothersome symptoms (36.9% vs. 24.4%, p = 0.002) with a statistically highly significant difference compared to placebo, achieving the two co-primary evaluation items of the regulatory authorities.

[0102] The superiority of meloxicam / rizatriptan over rizatriptan (active comparator) and MoSEIC (trademark) meloxicam (component contributor) was established as per SPA, as shown by a higher percentage of patients who maintained pain relief from 2 to 24 hours post-dosing (16.1%, 11.2%, 6, and 5.3% for meloxicam / rizatriptan, rizatriptan, MoSEIC (trademark) meloxicam, and placebo respectively, with p = 0.038, p = 0.001, p < 0.001 for meloxicam / rizatriptan, Figure 3A) among patients taking the active comparator meloxicam / rizatriptan, in the predefined primary and secondary assessment items to show component contribution. Approximately 80% of patients treated with meloxicam / rizatriptan who achieved pain relief at 2 hours maintained pain relief until 24 hours. These results demonstrated a significant improvement in pain relief and the superiority of meloxicam / rizatriptan over rizatriptan in migraine treatment.

[0103] Meloxicam / rizatriptan provided greater and more sustained reduction in migraine pain compared to placebo and rizatriptan, and meloxicam / rizatriptan was able to significantly reduce the use of rescue medications compared to placebo and rizatriptan. The proportion of patients experiencing sustained pain reduction from 2 to 24 hours post-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 for meloxicam / rizatriptan, Figure 3B).

[0104] A sustained analgesic effect from 2 to 48 hours was also statistically significantly higher (46.5%) in patients administered meloxicam / rizatriptan compared to placebo - administered patients (31.1%) and rizatriptan - administered patients (36.5%) (p<0.001 and p = 0.003, respectively, for the meloxicam / rizatriptan - administered group) and was experienced by meloxicam / rizatriptan - administered patients (Figure 4B). Figure 4D shows the percentage of subjects who achieved sustained pain reduction from 2 to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo. The disappearance of sustained pain from 2 to 48 hours was statistically significantly higher (15.4%) in meloxicam / rizatriptan patients compared to placebo (5.3%), rizatriptan (8.8%), and MoSEIC (trademark) meloxicam (8.1%) patients (p<0.001, p = 0.003, and p<0.001, respectively, for meloxicam / rizatriptan) and was experienced by meloxicam / rizatriptan patients (Figure 4A). Figure 4C shows the percentage of subjects who achieved sustained pain disappearance from 2 to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo. Approximately 77% of meloxicam / rizatriptan - administered patients who achieved pain disappearance at 2 hours maintained pain disappearance until 48 hours later.

[0105] The rescue medication was used in 23.0% of patients administered meloxicam / rizatriptan compared to 43.5% of patients who took placebo and 34.7% of patients who took rizatriptan (p<0.001, respectively, for meloxicam / rizatriptan) (Figure 5). Approximately 77% of patients administered meloxicam / rizatriptan did not require rescue medication. These results indicate that in the treatment of migraine, meloxicam / rizatriptan is superior to rizatriptan, which is an active - control drug.

[0106] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan in several other secondary evaluation items, including the patient's overall impression of change (PGI - C) (p = 0.022) and recovery of normal function after 24 hours (p = 0.027).

[0107] Table 1 below shows some of the p-values for meloxicam / rizatriptan versus rizatriptan in various evaluation items, demonstrating the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraine.

[0108] [Table 1]

[0109] Considering that rizatriptan, the active drug control in this trial, is the most rapid-acting among oral triptan agents and one of the most effective medications currently available for the acute treatment of migraine, and that this trial enrolled migraine patients who were difficult to treat, the treatment effect observed with meloxicam / rizatriptan, which provides greater and longer-lasting reduction of migraine pain than rizatriptan, is highly significant. Many patients experience suboptimal responses to current acute migraine treatments and are at high 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 may offer an important treatment option for patients with difficult-to-treat migraine. In the MOMENTUM Phase 3 trial, adverse events occurred in 1% to 3% of patients with meloxicam / rizatriptan, and generally, safety and tolerability were good. 11.1% of patients experienced any treatment-emergent adverse event after taking meloxicam / rizatriptan, and 2.7%, 1.6%, and 1.4% of patients experienced nausea, dizziness, and drowsiness, respectively, after taking meloxicam / rizatriptan (Table 2). The percentage of patients experiencing treatment-related adverse events after administration of meloxicam / rizatriptan was similar to that of other treatments tested (Table 2).

[0110] [Table 2]

[0111] The results of this trial demonstrate the ability of meloxicam / rizatriptan to provide rapid, potent, and sustained relief of migraine pain compared to rizatriptan, a potent active comparator, in a tightly planned trial in patients with refractory migraine. These results have potentially important implications for patient care, based on the high rates of inadequate response to current treatments and patient dissatisfaction with current treatments.

[0112] Meloxicam / rizatriptan incorporates multiple mechanisms of action to address various processes of migraine in order to achieve higher efficacy. Meloxicam / rizatriptan is thought to act by inhibiting CGRP release, reversing CGRP-mediated vasodilation, neuroinflammation, pain signaling, and central sensitization. The results of this clinical trial validate this approach and demonstrate that meloxicam / rizatriptan can provide greater benefit than current treatments even in patients with refractory migraine. Meloxicam / rizatriptan may be effectively used for the acute treatment of migraine in adults with or without aura.

[0113] Example 2 More than 70% of affected patients have reported dissatisfaction with existing acute treatments. The most commonly reported reasons for patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and pain recurrence on the same day. {Inadequate acute treatment is associated with an increased risk of chronic migraine}, which may be preventable by improving the outcomes of acute treatment. (Parentheses ({and}) indicate boldface in the original text.)

[0114] Migraine Treatment Optimization Questionnaire (mTOQ-4): Evaluates the treatment efficacy of acute treatment based on four items: pain disappearance, persistence of pain relief, comfort in planning daily activities, and no interference with daily activities. Previous studies have shown that 12% to 27% of migraine patients achieve little or no positive response in these items with treatment by other medications.

[0115] The clinical trial of Example 1 was analyzed to examine the percentage of subjects who responded "none" or "almost none" to each item of mTOQ-4 and to characterize the areas of greatest unmet need in acute migraine treatment.

[0116] mTOQ-4 is a 4-item questionnaire with validity, reliability, self-report, and ease of use that assesses the adequacy of current treatment effects for the purpose of optimizing treatment. mTOQ-4 is shown in Table 3 below.

[0117]

Table 3

[0118] Figure 6 shows the percentage of patients who answered "none" or "almost none" to each question of mTOQ-4.

[0119] Example 3 A Phase 3 randomized, double-blind, multi-center, placebo-controlled trial was conducted to evaluate the early treatment of migraine with meloxicam / rizatriptan. A total of 302 patients were randomly assigned at a 1:1 ratio and received a single dose of meloxicam / rizatriptan (meloxicam 20 mg / rizatriptan 10 mg, with the addition of SBEβCD (approx. 133.6 mg) and sodium bicarbonate (500 mg) as described in Example 1 above) or placebo to treat a single migraine attack at the earliest sign of migraine, while the pain was still mild, before progressing to moderate or severe.

[0120] This clinical trial is different from the clinical trial of Example 1. In the clinical trial of Example 1, only patients with a history of inadequate response to past acute treatment were enrolled, and the patients waited to receive treatment for an attack only when the pain of the migraine reached moderate or severe intensity. The clinical trial of Example 1 is in contrast to this clinical trial, in which all interested participants were enrolled, and the patients were instructed to receive meloxicam / rizatriptan at the earliest sign of migraine, while the pain was still mild, before progressing to moderate or severe intensity.

[0121] The patients were adult subjects who had been definitively diagnosed with migraine, with or without aura.

[0122] The co-primary endpoints were disappearance of headache pain and disappearance of the most bothersome migraine-related symptoms (nausea, photophobia or phonophobia) 2 hours after administration of meloxicam / rizatriptan, compared with placebo.

[0123] The inclusion criteria included men or women aged 18 to 65 years, a definitive diagnosis of migraine (for at least 1 year), with or without aura as defined by the ICHD-3 criteria, and 2 to 8 migraines per month on average. The exclusion criteria included cluster headache, tension-type headache, or other types of migraine, chronic daily headache (more than 15 headache days per month other than migraine), a history of major cardiovascular disease, and uncontrolled hypertension.

[0124] In this phase 3 trial of meloxicam / rizatriptan in the early treatment of migraine, meloxicam / rizatriptan substantially and significantly removed the pain of migraine and substantially and significantly blocked the progression of migraine pain intensity. In this trial, meloxicam / rizatriptan met the co-primary endpoints of disappearance of migraine pain and disappearance of the most bothersome symptoms, compared with placebo.

[0125] Meloxicam / rizatriptan demonstrated statistically significant improvement compared with placebo in both co-primary endpoints of disappearance of pain (32.6% vs 16.3%, p = 0.002) and disappearance of the most bothersome symptoms (43.9% vs 26.7%, p = 0.003) 2 hours after administration (Figures 7A and 7B). The most bothersome symptoms were nausea, photophobia, or phonophobia.

[0126] Meloxicam / rizatriptan was numerically superior to placebo at 30 minutes for the disappearance of headache pain (Figure 8) and the disappearance of the most bothersome symptoms (Figure 9), and achieved statistical significance for the disappearance of headache pain at 90 minutes (p = 0.003) and all subsequent time points (Figure 8). At 12 hours, 64% of patients who took meloxicam / rizatriptan had pain disappearance, compared with 42% of patients who took placebo. At 24 hours, 69% of patients who took meloxicam / rizatriptan had pain disappearance, compared with 47% of patients who took placebo.

[0127] Meloxicam / rizatriptan significantly reduced headache pain in a statistically significantly higher percentage of patients compared to placebo, achieving persistent pain disappearance from 2 hours to 24 hours after administration (22.7% vs 12.6%, p = 0.030), and achieving persistent pain disappearance from 2 hours to 48 hours after administration (20.5% vs 9.6%, p = 0.013) (Figure 10A and Figure 10B).

[0128] Meloxicam / rizatriptan blocked the progression of headache pain intensity beyond mild in 73.5% of patients compared to 47.4% of placebo-taking patients from 2 hours to 24 hours (p < 0.001) (Figure 11). Single-dose meloxicam / rizatriptan blocked the progression of headache pain beyond mild.

[0129] The effect on pain progression was manifested as a significant reduction in the use of rescue medications. Only 15.3% of patients who took meloxicam / rizatriptan needed rescue medications within 24 hours after administration, compared with 42.2% of patients who took placebo (p < 0.001) (Figure 12).

[0130] Meloxicam / rizatriptan substantially and significantly reduced disability, demonstrating an overall improvement in the disease. At 24 hours, the ability to perform normal activities was achieved in 73.5% of patients who took meloxicam / rizatriptan compared to 47.4% of patients who took placebo (p < 0.001) (Figure 13).

[0131] On the scale of the overall impression of change (PGI-C) evaluated by the patients, at 2 hours, 52.4% of the patients who took meloxicam / rizatriptan had "improved very much" or "improved", while only 27.7% of the patients who took placebo (p < 0.001) (Figure 14).

[0132] Meloxicam / rizatriptan was generally safe and well tolerated in the trial. The most frequently reported adverse events with meloxicam / rizatriptan were drowsiness, dizziness, and paresthesia, all with an incidence rate of less than 5% (Table 4). No serious adverse events were observed in the trial.

[0133] [Table 4]

[0134] "This [study] demonstrated a high rate of disappearance of migraine pain with meloxicam / rizatriptan treatment and used an innovative design to evaluate the progression of migraine pain. It is noteworthy that early treatment with meloxicam / rizatriptan prevented the progression of migraine pain in the majority of patients and also enabled a similarly high percentage of patients to return to normal function," said Dr. Stuart Tepper, professor of neurology at Geisel School of Medicine at Dartmouth. "Multiple mechanisms of meloxicam / rizatriptan address disruptions in many of the physiological processes involved in migraine attacks. These results, combined with previous clinical data showing the superiority of meloxicam / rizatriptan over placebo, provide clinical evidence that this synergistic, multi-mechanistic approach and the rapid absorption of meloxicam / rizatriptan may provide important benefits to a wide range of patients. Clinicians continue to seek options for patients with improved efficacy compared to currently available treatments, and meloxicam / rizatriptan may become an important new treatment for symptoms that leave patients with few options."

[0135] This Phase 3 trial confirmed the superior and sustained efficacy of meloxicam / rizatriptan. The prevention of headache pain progression and the substantial increase in pain disappearance rate demonstrated by the early treatment with meloxicam / rizatriptan expand and strengthen the differentiated profile for the acute treatment of headache. Based on this Phase 3 trial and the Phase 3 trial described in Example 11 targeting patients with a history of insufficient response to previous acute treatments, meloxicam / rizatriptan is currently being evaluated in two well-controlled trials with favorable results. These trials demonstrated the efficacy of meloxicam / rizatriptan against strong active drug controls and placebo controls in various situations of headache attacks, regardless of the timing of headache treatment, disease severity, or baseline pain intensity.

[0136] "Migraine is one of the most disabling diseases, leaving patients powerless and causing severe damage to family life, social activities, and work ability. Published surveys have highlighted patients' dissatisfaction with the effectiveness of currently available treatments." said Dr. Cedric O'Gorman, senior vice president of clinical development and medical affairs at Axsome. "[These] trial results are the first to demonstrate that meloxicam / rizatriptan can stop the progression of migraine pain before it reaches moderate or severe levels. These data enrich the substantial body of clinical evidence supporting that meloxicam / rizatriptan is a multi-mechanism treatment for migraine, has superior efficacy compared to current standard treatments, and can rapidly, potently, and sustainably relieve symptoms, enabling patients to return to normal daily activities."

[0137] Example 4 The efficacy of meloxicam / rizatriptan compared to placebo was evaluated in patient subgroups with high BMI, allodynia, morning migraine, and a history of depression, which are risk factors for insufficient treatment response to acute headache drug therapy.

[0138] The data were obtained from a subgroup analysis pooled from subjects who participated in the clinical trials of Examples 1 and 3 regarding the acute treatment of migraine.

[0139] As shown in Figure 15, through four subgroups defined by risk factors, treatment with meloxicam / rizatriptan improved the 24-hour sustained pain remission rate compared to placebo.

[0140] For patients with a BMI above the median BMI (median 28.8 kg / m 2 2) of the patients in this study, pain had disappeared 2 hours later in 15.8% of the treated patients compared to 7.6% of the patients who received placebo (p = 0.008).

[0141] For patients with allodynia defined by an ASC-12 score of 3 or higher, pain had disappeared 2 hours later in 18.7% of the treated patients compared to 8.1% of the patients who received placebo (p < 0.001).

[0142] For morning-type migraine patients defined as having a migraine attack before 10 am, pain had disappeared 2 hours later in 18.3% of the treated patients compared to 8.1% of the patients who received placebo (p = 0.005).

[0143] For patients with a history of depression, pain had disappeared 2 hours later in 16.7% of the treated patients compared to 5.9% of the patients who received placebo (p = 0.053).

[0144] Unless otherwise specified, all numbers, amounts, percentages, and other such characteristics expressing the quantities of ingredients used in this specification and the claims are to be understood in all cases as indicating both the exact value as shown and the value as modified by the term "about". Accordingly, unless otherwise indicated, the numerical parameters set forth in this specification and the appended claims are approximate values that may vary depending on the desired characteristics to be obtained. At a minimum, and without limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the reported number of significant digits and by applying ordinary rounding techniques.

[0145] The terms "a", "an", "the", and similar reference terms used in the context of describing embodiments (particularly in the context of the following claims) are to be construed to include both the singular and plural forms unless otherwise specified in this specification or clearly contradicted by the context. All methods described in this specification can be performed in any suitable order unless otherwise specified in this specification or clearly contradicted by the context. Any examples used in this specification, or exemplary language (e.g., "such as"), are merely for the purpose of better explaining the embodiments and do not limit the scope of any claims. No language in the specification should be construed as indicating a component essential for the practice of the claimed invention that is not included in the claims.

[0146] The grouping of alternative components or embodiments disclosed herein should not be construed as limiting. Members of each group may be referred to individually or in any combination with other members of the group or other elements found herein and may be recited in the claims. It is contemplated that one or more members of a group may, for convenience and / or to expedite examination, be included in or deleted from the group. When such inclusion or deletion occurs, the specification is deemed to include the group as modified so as to meet the recited requirements of all Markush groups when used in the appended claims.

[0147] Certain embodiments are described herein, including the best mode known to the inventors of carrying out the claimed embodiments. Of course, variations to these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims are intended to cover all modifications and equivalents of the subject matter recited in the claims that are permitted by the applicable law. Further, unless otherwise specified herein or clearly contradicted by context, any combination of the above elements in these possible variations is contemplated.

[0148] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Accordingly, alternative embodiments may be utilized in accordance with the teachings of this specification by way of illustration and not limitation. Thus, the claims are not limited to the embodiments precisely shown and described.

[0149] (Appendix) (Appendix 1) A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) according to the patient, are not at all or hardly comfortable enough with their own migraine drug treatment to be able to plan their daily activities, and after the selection of said patient, administering to said 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.

[0150] (Appendix 2) A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) according to the patient, feel that their migraine is not at all or hardly controlled enough for them to feel unhindered in their daily activities after taking migraine treatment drugs, and after the selection of said patient, administering to said 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.

[0151] (Appendix 3) A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) have an mTOQ-4 score of 0, and after the selection of said patient, administering to said 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.

[0152] (Appendix 4) A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising: 1) selecting patients who have had at least 2 to 8 migraines per month for at least the past 4 weeks and 2) have a history of depression, and after selecting said patients, administering to said patients a combination of meloxicam or a pharmaceutically acceptable salt thereof, 20 mg, and rizatriptan or a pharmaceutically acceptable salt thereof, 10 mg, during a migraine attack.

[0153] (Appendix 5) The method according to any of the preceding appendices, wherein the meloxicam and the rizatriptan are present in a single dosage form.

[0154] (Appendix 6) The method according to Appendix 5, wherein the dosage form further comprises bicarbonate.

[0155] (Appendix 7) The method according to Appendix 5, wherein the dosage form further comprises cyclodextrin.

[0156] (Appendix 8) The method according to any of the preceding appendices, wherein the meloxicam and the rizatriptan are orally administered to the patient.

[0157] (Appendix 9) The method according to Appendix 1, 2, 3, 4, 5 or 6, wherein the combination is administered while the patient has mild migraine pain.

[0158] (Appendix 10) The method according to Appendix 1, 2, 3, 4, 5 or 6, wherein the combination is administered while the patient has moderate migraine pain.

[0159] (Appendix 11) The method according to Appendix 1, 2, 3, 4, 5 or 6, wherein the combination is administered while the patient has severe migraine pain.

[0160] (Appendix 12) The method according to appendix 6, wherein the dosage form further comprises cyclodextrin.

[0161] (Appendix 13) The method according to appendix 7 or 12, wherein the cyclodextrin is sulfobutylether-β-cyclodextrin (SBEβCD).

[0162] (Appendix 14) The method according to appendix 13, wherein the meloxicam is an inclusion complex with SBEβCD.

[0163] (Appendix 15) The method according to any of the above appendices, wherein the meloxicam is in the free acid form.

[0164] (Appendix 16) The method according to any of the above appendices, wherein the rizatriptan is in salt form.

[0165] (Appendix 17) The method according to appendix 16, wherein the rizatriptan is present as rizatriptan benzoate.

[0166] (Appendix 18) The method according to appendix 6 or 12, wherein the hydrogen carbonate is sodium hydrogen carbonate or potassium hydrogen carbonate.

[0167] (Appendix 19) The method according to appendix 18, wherein about 500 mg of sodium hydrogen carbonate is present in the combination.

[0168] (Appendix 20) The method according to appendix 13, wherein about 133.6 mg of SBEβCD is present in the combination.

Claims

**Claim 1** A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) according to the patient, are not at all or hardly comfortable enough with their own migraine drug treatment to be able to plan their daily activities, and after selection of said patient, administering to said patient a combination of meloxicam or a pharmaceutically acceptable salt thereof at 20 mg and rizatriptan or a pharmaceutically acceptable salt thereof at 10 mg during a migraine attack. **Claim 2** A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) according to the patient, feel that their migraine is not at all or hardly controlled enough to feel unhindered in their daily activities after taking a migraine treatment drug, and after selection of said patient, administering to said patient a combination of meloxicam or a pharmaceutically acceptable salt thereof at 20 mg and rizatriptan or a pharmaceutically acceptable salt thereof at 10 mg during a migraine attack. **Claim 3** A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) an mTOQ-4 score of 0, and after selection of said patient, administering to said patient a combination of meloxicam or a pharmaceutically acceptable salt thereof at 20 mg and rizatriptan or a pharmaceutically acceptable salt thereof at 10 mg during a migraine attack. **Claim 4** A method for treating migraine in patients with a history of inadequate response to previous migraine treatments, comprising selecting patients who have had 1) two to eight migraines per month for at least the past four weeks and 2) a history of depression, and after selection of said patient, administering to said patient a combination of meloxicam or a pharmaceutically acceptable salt thereof at 20 mg and rizatriptan or a pharmaceutically acceptable salt thereof at 10 mg during a migraine attack. **Claim 5** The method according to any of the preceding claims, wherein the meloxicam and the rizatriptan are present in a single dosage form.

6. The method according to claim 5, wherein the dosage form further comprises a hydrogen carbonate.

7. The method according to claim 5, wherein the dosage form further comprises a cyclodextrin.

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

9. The method according to claim 1, 2, 3, 4, 5 or 6, wherein the combination is administered while the patient has mild migraine pain.

10. The method according to claim 1, 2, 3, 4, 5 or 6, wherein the combination is administered while the patient has moderate migraine pain.

11. The method according to claim 1, 2, 3, 4, 5 or 6, wherein the combination is administered while the patient has severe migraine pain.

12. The method according to claim 6, wherein the dosage form further comprises a 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 is an inclusion complex with SBEβCD.

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

16. The method according to any of the preceding claims, wherein the rizatriptan is in salt form.

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

18. The method according to claim 6 or 12, wherein the hydrogen carbonate is sodium hydrogen carbonate or potassium hydrogen carbonate.

19. The method according to claim 18, wherein about 500 mg of sodium hydrogen carbonate is present in the combination.

20. The method according to claim 13, wherein about 133.6 mg of SBEβCD is present in the combination.

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