Use of compositions containing meloxicam and rizatriptan

Abstract

To provide compositions comprising meloxicam and rizatriptan.SOLUTION: Disclosed herein are compositions comprising an NSAID such as meloxicam and / or rizatriptan in combination with a cyclodextrin and / or a carbonate or a bicarbonate. These compositions may be orally administered, for example, to improve the bioavailability or pharmacokinetics of the NSAID for treatment of pain such as migraine, arthritis and other conditions. Also disclosed herein are methods of treating pain, such as migraine, comprising administering meloxicam and rizatriptan to a human suffering from pain, such as migraine. These methods may be particularly useful when the meloxicam and rizatriptan are administered while the human is suffering from an acute attack or aura of migraine. In some embodiments, the combination of meloxicam and rizatriptan may be administered such that Tmax of meloxicam is 3 hours or less.SELECTED DRAWING: Figure 14

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 62 / 802,198, filed February 6, 2019, U.S. Provisional Application No. 62 / 803,756, filed February 11, 2019, U.S. Provisional Application No. 62 / 835,613, filed April 18, 2019, U.S. Provisional Application No. 62 / 846,311, filed May 10, 2019, U.S. Provisional Application No. 62 / 860,705, filed June 12, 2019, U.S. Provisional Application No. 62 / 895,933, filed September 4, 2019, U.S. Provisional Application No. 62 / 895,956, filed September 4, 2019, and U.S. Provisional Application No. 62 / 955,905, filed December 31, 2019, the disclosures of all of which are incorporated herein by reference in their entireties. [Background technology]

[0002] Meloxicam, having the following structure, is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activity. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthetase (cyclooxygenase, COX), which is involved in the early steps of the arachidonic acid cascade, reducing the formation of prostaglandins, thromboxanes and prostacylin.

[0003] [ka] Summary of the Invention [Means for solving the problem]

[0004] Meloxicam and some other NSAIDs are poorly water soluble, thereby reducing their bioavailability and potentially delaying the onset of pain relief resulting from their use. One means of increasing the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cycloamylose) are generally cyclic polysaccharides that form a bucket-like shape. Cyclodextrins help increase the bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the inside that helps facilitate the transport of the molecule. Naturally occurring cyclodextrins contain six, seven and eight glucose units (α, β and γ-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or less glucose units are possible. In aqueous solution, cyclodextrins can form complexes (i.e., inclusion complexes) with drugs by incorporating the drug into the central / hydrophobic portion of the cyclodextrin ring. Cyclodextrin compounds are also known to aggregate around drugs in micellar-type structures. This ability of cyclodextrins may allow them to act as carriers to increase the bioavailability of less soluble drugs.

[0005] Some embodiments include a method of treating migraine comprising selecting a human migraine patient who has a history of inadequate response to previous migraine treatments and administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan.

[0006] Some embodiments include an inclusion complex of meloxicam in a cyclodextrin.

[0007] Some embodiments include a dosage form comprising 1) an inclusion complex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or bicarbonate salt.

[0008] Some embodiments include a method of orally administering meloxicam comprising orally administering to a patient in need of treatment a dosage form described herein.

[0009] Some embodiments include a method of administering meloxicam intravenously comprising administering a dosage form described herein intravenously to a patient in need of treatment.

[0010] Disclosed herein are formulations of an inclusion complex of cyclodextrin and meloxicam formulated with bicarbonate and methods of use thereof.

[0011] Disclosed herein are formulations and methods for delivering meloxicam together with a cyclodextrin to a subject by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal or other parenteral means.

[0012] Also disclosed are methods of treating pain and pain-related conditions by delivering to a subject a dosage form comprising meloxicam, cyclodextrin and bicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal or other parenteral means.

[0013] The combination of rizatriptan and meloxicam (also referred to herein for convenience as the "subject combination") may be used to treat a variety of pain conditions.

[0014] Rizatriptan has the structure shown below. [ka]

[0015] Some embodiments include a combination comprising 1) an inclusion complex of meloxicam and a cyclodextrin, 2) rizatriptan, and 3) bicarbonate for treating migraine in a human. The human may have a history of inadequate response to previous treatments.

[0016] Some embodiments include a subject combination comprising rizatriptan and meloxicam that has rapid, sustained, substantial, and statistically significant efficacy compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of inadequate response to prior therapy.

[0017] Some embodiments include a subject combination comprising zatriptan and meloxicam that results in significantly less rescue medication use compared to placebo, rizatriptan, or meloxicam. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 is a diagram of the results described in Example 2 and included in Table 6. [Diagram 2] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Diagram 3] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 4] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Diagram 5] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 6] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 7] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 8] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 9] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 10] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 11] 1 is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for one embodiment of a dosage form described herein and a commercially available meloxicam dosage form. [Figure 12]1 is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for the meloxicam / rizatriptan dosage form described in Example 6 and a marketed meloxicam dosage form. [Figure 13] 1 is a plot of rizatriptan plasma concentrations at various time points over the first 12 hours for the meloxicam / rizatriptan dosage form described in Example 6 and a marketed meloxicam dosage form. [Figure 14] 1 shows a plot of the percentage of subjects reporting pain relief at various time points over the first 4 hours following administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 15] 1 shows the percentage of subjects who were pain free at 2, 4, 12, and 16 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 16A] 1 shows the percentage of subjects who were sustained pain free 2-24 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 16B] 1 shows the percentage of subjects with sustained pain relief 2-24 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 17A] 1 shows the percentage of subjects who were sustained pain free 2-48 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 17B] 1 shows the percentage of subjects with sustained pain relief 2-48 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 18]1 shows the percentage of subjects taking the old dose up to 24 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Provided herein are dosage forms and methods of treatment using the dosage forms that include an NSAID (eg, meloxicam) and a cyclodextrin (optionally in an inclusion complex), and / or a bicarbonate.

[0020] 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.

[0021] Some methods include administering a combination product of NSAIDs formulated with a) cyclodextrin and / or b) buffering agent.In some embodiments, the method includes treating the patient with a pharmaceutical formulation that includes meloxicam and cyclodextrin and / or carbonate / bicarbonate.Method embodiments can also include treating the patient to increase the bioavailability of meloxicam in the patient or to increase the rate at which meloxicam becomes bioavailable.

[0022] The combination of meloxicam, a cyclodextrin (such as SBEβCD), and a bicarbonate (such as sodium bicarbonate) substantially increases the solubility and absorption of meloxicam following oral administration, while the plasma half-life in mammals, such as humans, following oral administration remains extended.

[0023] The combination of meloxicam, a cyclodextrin (such as SBEβCD), and a bicarbonate (such as sodium bicarbonate) substantially increases the bioavailability of meloxicam in a mammal, such as a human, following oral administration.

[0024] Unless otherwise indicated, reference to a compound herein, such as meloxicam or rizatriptan, by structure, name, or any other means, includes any chemical species, such as pharma- ceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, optical isomers, tautomers, deuterium-modified forms, or precursors, prodrugs, or any other chemical species that can be rapidly converted to a compound described herein under the conditions used as described herein.

[0025] The subject combinations 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. In some embodiments, meloxicam is administered intravenously and rizatriptan is administered orally. In some embodiments, meloxicam is administered intramuscularly and rizatriptan is administered orally.

[0026] Typically, the combination of meloxicam and rizatriptan is administered so that a person receives meloxicam and rizatriptan within a short period of each other. For example, meloxicam and rizatriptan may be administered within about 2 hours, about 1 hour, about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 1 minute of each other. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which for purposes of this disclosure includes administration within about 5 minutes. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form.

[0027] The term "treat" or "treatment" broadly includes any kind of therapeutic activity, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any activity that, while not a therapeutic activity, affects the structure or any function of the body of a human or other animal.

[0028] The dosage forms or subject combinations may be used to treat or provide relief from any type of pain, including, but not limited to, migraine and other types of headaches, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, generalized pain, cancer-related pain, acute pain, pain due to injury, pain due to illness (e.g., fever), post-operative pain, etc. In some cases, pain relief may be temporary, or pain relief may be provided independent of improvement of the disease or condition or the underlying cause of the disease or condition. For example, an individual suffering from a disease may experience pain relief, even though the underlying disease may not improve or may continue to progress. In some embodiments, the pain affects muscles, nerves, cartilage, bones, ligaments, tendons, tendon sheaths, eardrums, or joints.

[0029] Migraine is a disabling neurological disorder characterized by periodic attacks of throbbing head pain accompanied by nausea and sensitivity to light and sound. The pain ranges from moderate to severe, but is often so severe that it is immobilizing and requires bed rest. The headache may affect one half of the head, is pulsating, and may last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or smell. The pain may be worsened by physical activity. Migraines may have an aura, which can be a brief visual disturbance that signals the onset of a headache. Some migraine sufferers do not have an aura.

[0030] In some embodiments, the person being treated for migraine suffers from allodynia associated with migraine attacks. Allodynia is pain caused by normally non-painful stimuli (such as combing hair, dressing, showering, etc.). Patients with allodynia are thought to be less responsive to triptan medications.

[0031] Current treatments are suboptimal, with over 70% of patients complaining of dissatisfaction with their current acute treatment. The most common reasons for patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and recurrence of pain within the same day. Suboptimal acute treatments are associated with a significantly increased risk of new chronic migraine episodes, which could be prevented by improving acute treatment outcomes.

[0032] By administering a subject combination to a human suffering from a migraine headache, such as an acute attack or aura of a migraine headache, symptoms of the migraine headache, such as pain, nausea, vomiting, photophobia, or phonophobia, may be reduced within about 5 minutes or less (intended as an abbreviation for "within 5 minutes" or "within 5 minutes"), within about 10 minutes or less, within about 30 minutes or less, within about 1 hour or less, within about 90 minutes or less, 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, such as headache or migraine, nausea, vomiting, photophobia, and / or phonophobia, 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 relief experienced is greater than that experienced by administering the same amount of rizatriptan without meloxicam. In some embodiments, the relief experienced is greater than that experienced by administering the same amount of meloxicam without rizatriptan.

[0033] The combination of meloxicam and rizatriptan may have two separate mechanisms of function as an acute treatment for migraine. Meloxicam is a potent, COX-2 preferential NSAID that is limited by its slow absorption. Rizatriptan is a potent 5-HT1 antagonist that is believed to be effective in migraine. B / D It is an agonist.

[0034] Finding relief or reduction of symptoms at a specific time point, such as "2 hours," is useful because it allows the effectiveness of treatment to be evaluated at a specific or consistent time point, facilitating comparisons between patients. Finding relief or reduction of symptoms within a specific time, such as "within 2 hours," is useful because it is desirable for relief or reduction to occur as quickly as possible, and clarifying that relief occurs within a specific time period sets a guideline for the desired relief.

[0035] For some methods, administration of the subject combinations may provide continued relief of pain, nausea, vomiting, photophobia, or phonophobia for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 8-24 hours, at least about 24 hours, or for more than 24 hours.

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

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

[0038] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than would be experienced two hours after administration of the same amount of rizatriptan without meloxicam.

[0039] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater pain relief than would be experienced 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0040] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater relief of nausea than would be experienced two hours after administration of the same amount of meloxicam without rizatriptan.

[0041] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief of nausea than would be experienced 24 hours after administration of the same amount of meloxicam without rizatriptan.

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

[0043] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater relief of nausea than would be experienced 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0044] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, the human experiences greater relief from emesis than would be experienced two hours after administration of the same amount of meloxicam without rizatriptan.

[0045] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief from emesis than would be experienced 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0046] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from emesis than the human would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0047] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief from emesis than would be experienced 24 hours after administration of the same amount of rizatriptan without meloxicam. In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form) and 2 hours after administration of meloxicam and rizatriptan, the human experiences greater relief from photophobia than would be experienced 2 hours after administration of the same amount of meloxicam without rizatriptan.

[0048] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief of photophobia than would be experienced 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0049] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a human experiences greater relief of photophobia than a human would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0050] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief of photophobia than would be experienced 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0051] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, the human experiences greater relief from phonophobia than would be experienced two hours after administration of the same amount of meloxicam without rizatriptan.

[0052] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief from phonophobia than would be experienced 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0053] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater relief from phonophobia than would be experienced two hours after administration of the same amount of rizatriptan without meloxicam.

[0054] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief from phonophobia than the human would experience 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0055] In some embodiments, the human being to whom the subject combination is administered has a history of incomplete response to previous migraine treatments. For example, a human being is asked whether most attacks are pain-free within 2 hours of treatment and given the options "none", "almost none", "less than half", or "more than half", and if the human responds "none", "almost none", or "less than half", then the human has an incomplete response to treatment. Similarly, a human is asked whether most attacks are pain-free and if the human responds "none", "almost none", or "less than half" after one dose, then given the options "none", "almost none", "less than half", or "more than half", then if the human responds "none", "almost none", or "less than half", then the human has an incomplete response to treatment.

[0056] In some embodiments, humans receiving a subject combination demonstrate that for most attacks, "none of" the attacks are pain-free within two hours of treatment. In some embodiments, humans receiving a subject combination demonstrate that for most attacks, "almost none of" the attacks are pain-free within two hours of treatment. In some embodiments, humans receiving a subject combination demonstrate that for most attacks, "less than half of" the attacks are pain-free within two hours of treatment.

[0057] In some embodiments, humans administered the subject combinations indicate that after one dose, respondents were "never" headache-free for at least 24 hours. In some embodiments, humans administered the subject combinations indicate that after one dose, respondents were "almost never" headache-free for at least 24 hours. In some embodiments, humans administered the subject combinations indicate that after one dose, respondents were "less than half" headache-free for at least 24 hours.

[0058] In some embodiments, the human being administered a subject combination has a history of inadequate response to previous migraine treatments, as assessed by a total mean score on the Migraine Treatment Optimization Questionnaire (mTOQ-4) of less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, or 6 to 7. In some embodiments, the human has used a triptan prior to being administered a subject combination, such as a combination comprising meloxicam and rizatriptan.

[0059] In some embodiments, a human receiving a subject combination, such as a combination comprising meloxicam and rizatriptan, has migraine headaches and may have a history of inadequate response to previous migraine treatments. In some embodiments, the human with migraine headaches does not have cluster headaches or other types of migraine headaches. In some embodiments, the human with migraine headaches does not have chronic daily headaches. In some embodiments, the human with migraine headaches does not have more than 15 days, 15-20, 20-25, 25-28, 28-30, or 30-31 days per month without a migraine headache. In some embodiments, the human with migraine headaches does not have a history of significant cardiovascular disease. In some embodiments, the human with migraine headaches does not have uncontrolled hypertension.

[0060] In some embodiments, the dosage form may be administered to relieve arthritis pain. In some embodiments, the dosage form may be administered to relieve other signs and / or symptoms of arthritis. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (small and polyarticular), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid), arthropathy, non-articular rheumatism, periarticular disorders, axonal spondyloarthritis, transient osteoarthropathy of the hip, spinal contusion fracture, osteoporosis, and neuropathic arthropathy including Charcot foot, spondyloarthropathy including ankylosing spondylitis, and SAPHO syndrome. In other embodiments, arthritis pain may be chronic or acute. In some embodiments, the dosage form may be administered to relieve signs and / or symptoms of arthritis including, but not limited to, osteoarthritis.

[0061] In some methods, administration of the dosage form can achieve pain relief that lasts for at least about 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least about 8 hours, about 8 hours to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form can achieve pain relief that is observed for 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, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or other time periods bounded by these ranges, after administration of the dosage form.

[0062] In some embodiments, the dosage form can be administered to relieve neuropathic pain, including diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoapical neuralgia, phantom limb pain, sciatica, pudendal neuralgia and central pain.Other causes of neuropathic pain can include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy and neuropathy associated with radiation therapy or chemotherapy treatment.The neuropathic pain to be treated can be chronic or acute.

[0063] In some methods, the dosage form may be administered to relieve inflammatory pain, including inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndromes. In other embodiments, the inflammatory pain may be chronic or acute.

[0064] Arthritis refers to inflammatory joint disease that may be associated with pain.Arthritis pain examples include, but are not limited to, osteoarthritis, erosive osteoarthritis, chronic rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy including Charcot foot, axonal spondyloarthropathy including ankylosing spondylitis, and the pain associated with SAPHO syndrome.The inflammatory joint disease to be treated can be chronic or acute.

[0065] In some methods, meloxicam can be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain can include, but are not limited to, lower back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, spasm, tendonitis, thyroiditis, carpal tunnel syndrome, joint pain, fibromyalgia, injury pain, carpal tunnel syndrome, fracture-related pain, sprain, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip. In other embodiments, musculoskeletal pain can be chronic or acute.

[0066] In some methods, administration of a dosage form or a subject combination may achieve a reduction in pain that lasts 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 about 24 hours, or about 24 hours. In other embodiments, administration of a subject combination may achieve a reduction in pain that is observed within about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 5 minutes or less, about 10 minutes or less, about 15 minutes or less, about 20 minutes or less, about 25 minutes or less, about 30 minutes or less, about 35 minutes or less, about 40 minutes or less, about 45 minutes or less, about 50 minutes or less, or about 60 minutes or less, 2 hours or less, 3 hours or less, or other time periods bounded by these ranges after administration of a subject combination.

[0067] Humans treated for a disease or condition with the dosage forms described herein can be of any age, for example, about 10 to about 90 years old, about 20 to about 80 years old, about 30 to about 75 years old, about 40 to about 70 years old, about 1 to about 16 years old, about 80 to about 95 years old, about 18 years old or older, about 20 years old or older, about 25 years old or older, about 30 years old or older, about 40 years old or older, about 45 years old or older, about 50 years old or older, about 55 years old or older, about 60 years old or older, about 65 years old or older, or any other age bounded by or within a range between these values.

[0068] In some embodiments, a human being treated for migraine headaches with a dosage form described herein containing, for example, meloxicam, rizatriptan, SBEβCD, and a bicarbonate, such as sodium bicarbonate, can be between 18 and 65 years of age, about 18-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-40 years of age, about 40-45 years of age, about 40-50 years of age, about 50-60 years of age, about 60-65 years of age, or any other age bounded by or within a range between these values.

[0069] In some embodiments, humans treated for migraine headaches with the dosage forms described herein, such as dosage forms containing meloxicam, rizatriptan, SBEβCD, and bicarbonates, such as sodium bicarbonate, can be Caucasian, Black or African-American, or Asian.

[0070] In some embodiments, the human being treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has suffered from pain or a condition associated with pain for at least one day, at least one week, at least two weeks, at least one month, at least six weeks, at least two months, at least three months, at least six months, or at least one year, or any period bounded by or within a range between these values.

[0071] In some embodiments, humans being treated for migraine headaches with a dosage form comprising meloxicam and rizatriptan have had a diagnosis of migraine headaches with or without aura as defined by 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 any time period bounded by or within ranges between these values.

[0072] In some embodiments, the human experiences an average of 2-8, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 moderate to severe migraines.

[0073] The cyclodextrin used in the dosage form containing meloxicam may include cyclodextrin, cyclodextrin derivatives and / or salts thereof. The inclusion complex of meloxicam with cyclodextrin may be more water-soluble than uncomplexed meloxicam. The cyclodextrin may be a natural cyclodextrin (e.g., α-, β- or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, its derivatives or salts may be used. The 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-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0074] In some embodiments, β-cyclodextrin, derivatives or salts thereof may be used. β-cyclodextrin may be, 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-buthyl Bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-Ot-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,The cyclodextrin may comprise 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. ,

[0075] In other embodiments, the β-cyclodextrin can be a sulfoalkyl ether cyclodextrin, derivative or 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, 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.

[0076] In some embodiments, gamma-cyclodextrin, a derivative or a salt thereof may be used. The gamma-cyclodextrin may include carboxymethyl-gamma-cyclodextrin, (2,3,6-tri-O-acetyl)-gamma-cyclodextrin, (2,3,6-tri-O-methyl)-gamma-cyclodextrin, (2,6-di-O-pentyl)-gamma-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-gamma-cyclodextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, 6-iodo-6-deoxy-gamma-cyclodextrin, (6-Ot-butyldimethylsilyl)-gamma-cyclodextrin, succinyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin (2-hydroxypropyl)-gamma-cyclodextrin, acetyl-gamma-cyclodextrin, butyl-gamma-cyclodextrin, or combinations thereof.

[0077] In some embodiments, the dosage form may include a bicarbonate salt, such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or a combination thereof. The bicarbonate salt may help increase the bioavailability of meloxicam.

[0078] In other embodiments, the dosage form may include a carbonate, a derivative or a salt thereof. Examples of carbonates may include aluminum carbonate, ammonium carbonate, barium carbonate, calcium carbonate, cobalt (II) carbonate, lanthanum carbonate, lithium carbonate, magnesium carbonate, manganese (II) carbonate, potassium carbonate, sodium carbonate, or combinations thereof.

[0079] In some embodiments, enhanced bioavailability of the dosage form may be achieved in the treatment of one of these conditions by administering a dosage form containing a salt form of meloxicam, by forming an inclusion complex of meloxicam with a cyclodextrin, and / or by including a bicarbonate salt, which allows for a reduced molar amount of meloxicam to be used compared to other meloxicam dosage forms.

[0080] Unless otherwise indicated, the compounds herein, e.g., meloxicam or cyclodextrins, by structure, name or any other means, include other solid forms, such as pharma- ceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms or any other chemical species that can be rapidly converted to the compounds described herein under the conditions in which the compounds described herein are used.

[0081] In some embodiments, the use of cyclodextrin, carbonate or bicarbonate may increase the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40% at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any amount bounded by or within a range therebetween compared to administration of meloxicam alone.

[0082] Due to the improved bioavailability, the dosage form can contain or be administered to a subject on a molar basis less meloxicam than would otherwise be administered. For example, the dosage form can contain or be administered to a mammal at least about 10% less meloxicam, at least about 20% less meloxicam, at least about 30% less meloxicam, at least about 40% less meloxicam, at least about 50% less meloxicam, at least about 60% less meloxicam, at least about 70% less meloxicam, at least about 80% less meloxicam, at least about 85% less meloxicam, and / or up to about 90% less meloxicam, 95% less meloxicam, or any amount bounded by or within a range between these values, compared to the amount of meloxicam that would otherwise be administered.

[0083] In other embodiments, the use of other NSAIDs, opioids, or other analgesics may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, up to about 100%, compared to the use of other NSAIDs, opioids, or other analgesics without administration of meloxicam with a cyclodextrin, carbonate and / or bicarbonate.

[0084] In some embodiments, the dosage form may contain about 1-50 mg, about 1-10 mg, about 1-5 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg, about 5-10 mg, about 5-15 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 30 mg, or any amount of meloxicam bounded by or within the ranges therebetween. These doses may be safe doses for repeated administration, such as once per hour, twice per day, 1-12 times per day, 3, 4, 5, or 6 times per day. In some embodiments, meloxicam can be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times per day, about 3 to about 10 times per day, once per day, or less frequently, such as once per week, once every two weeks, once per month, etc.

[0085] In some dosage forms, meloxicam is complexed with substituted β-cyclodextrin or other cyclodextrins that can be formulated into solid dosage forms. Such dosage forms may be suitable for oral administration. Meloxicam-cyclodextrin inclusion complexes may also be dissolved in water or another solvent to form parenteral formulations. However, physical mixtures of meloxicam with substituted β-cyclodextrin or other cyclodextrins may also be used in oral or parenteral dosage forms.

[0086] Formation of an inclusion complex between meloxicam and cyclodextrin can help improve the properties of the dosage form. For some inclusion complexes, meloxicam and cyclodextrin (e.g., SBEβCD) can have a molar ratio of 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 range bounded by or between these values.

[0087] In some dosage forms, a cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of about 1-1000 (e.g., 1 gram of cyclodextrin per 1 gram of meloxicam is a weight ratio of 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 range bounded by or between these values. In some dosage forms, a cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of about 0.001-1 (e.g., a weight ratio of 0.1 g of cyclodextrin per 1 g of meloxicam), 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 range bounded by or between these values. Each type of cyclodextrin used may have a different ratio.

[0088] In some dosage forms, the cyclodextrin may be present in an amount of about 1-200 mg, about 25-175 mg, about 50-150 mg, about 25-100 mg, about 75-150 mg, about 100-175 mg, about 20-80 mg, about 25-50 mg, about 60-100 mg, about 80-100 mg, about 80-120 mg, about 100-120 mg, about 100-140 mg, about 120-160 mg, about 140-180 mg, about 30-90 mg, about 40-80 mg, about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount bounded by or within a range therebetween.

[0089] In some methods, an inclusion complex of meloxicam and a cyclodextrin (e.g., a substituted β-cyclodextrin) is delivered orally (e.g., via a tablet, capsule, elixir, etc.). Other possible routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal or other parenteral means. Meloxicam may be delivered alone or as an uncomplexed with a cyclodextrin.

[0090] Some dosage forms include about 1-2000 mg, about 1-1000 mg, about 100-1000 mg, about 200-800 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 250-750 mg, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 410-510 mg, about 420-520 mg, about 430-530 mg, about 440-540 mg, about 450-550 mg, about 460-560 mg, about 470-570 mg, about 480-580 mg, about 490-590 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any amount of bicarbonate (e.g., sodium bicarbonate) bounded by or within a range therebetween.

[0091] Some dosage forms include about 1-1000 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 200-800 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 250-750 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 500-250 mg, about 500-300 mg, about 500-400 mg, about 500-500 mg, about 500-600 mg, about 500-750 mg, about 500-800 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 500-750 mg, about 500-750 mg, about 500-800 mg, about 500-800 mg, about 500-900 mg, about 500-600 mg, about 500-800 mg, about 500-900 mg, about 500-800 mg, about 500-900 mg, about 500-900 mg, about 500-10 ... g, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any amount of carbonate bounded by or within a range therebetween.

[0092] In some embodiments, the daily dose of meloxicam (e.g., oral dose, parenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg About 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount bounded by or within ranges therebetween.

[0093] In some embodiments, the weekly dose of meloxicam (e.g., oral dose) is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30-70 mg, about 40-60 mg, about 50-70 mg, about 70-90 mg, about 90-110 mg, about 50 mg, about 55 mg, about 100-150 mg, about 30-100 mg, or any amount bounded by or within a range therebetween. The weekly dose may be given as a single dose given once a week, or may be given in separate doses 2, 3, 4, 5, 6, or 7 times a week.

[0094] In some embodiments, the monthly dose (e.g., oral dose) of meloxicam, or the dose administered over a monthly period, is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 1-4000 mg, about 1-1000 mg, about 10-1000 mg, about 50-1000 mg, about 10-600 mg, about 40-600 mg, about 50-600 mg, about 40-400 mg, about 50-200 mg, about 20-300 mg, about 30-400 mg, about 40-500 mg, about 50-600 mg, about 50-700 mg, about 50-800 mg, about 50-800 mg, about 50-100 mg, about 50-1000 mg, about 50-1000 mg, about 50-600 mg, about 50-1000 mg, about 50-600 mg, about 50-1000 mg, about 50-200 mg, about 50-200 mg, about 50-200 mg, about 50-300 mg, about 50-300 mg, about 50-400 mg, about 50-500 mg, about 50-600 mg, about 50-600 mg, about 50-2 ...600 mg, about 50-200 mg, about 50- The monthly dose may be about 00-240 mg, about 240-280 mg, about 280-320 mg, about 320-360 mg, about 360-400 mg, about 400-450 mg, about 450-500 mg, about 500-600 mg, about 250-350 mg, about 100-600 mg, about 40-2000 mg, about 40-800 mg, about 100-900 mg, about 100-800 mg, about 40-1000 mg, about 50-1000 mg, about 100-1000 mg, or any amount bounded by or within the ranges therebetween. The monthly dose may be given as a single dose or as two or more separate doses administered during the month. In some embodiments, the monthly dose is administered in two or three biweekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28-31 daily doses, or 56-62 daily doses or more. In some embodiments, the monthly dose is administered in 5-15 separate doses per month. The monthly dose may be administered for only one month, or may be administered repeatedly for two or more months.

[0095] In other embodiments, the dosage form can be administered every week for about 1, 2, 3, 4 or more consecutive weeks, every other week, or once every three weeks. This regimen can be repeated once every week, twice a month, three times a month, once a month, once every two months, once every three months, or as directed by a health care professional.

[0096] In certain embodiments, the pharmaceutical composition provides improved bioavailability (e.g., T ) of meloxicam from a dosage form compared to a dosage form containing meloxicam but not containing a cyclodextrin, an acid inhibitor, or a buffering agent (e.g., bicarbonate). max Decrease in C max In some embodiments, the bioavailability of meloxicam is increased with multiple administrations. For example, the bioavailability of meloxicam in the dosage form may be increased after about 1-10 days after administration, about 2-6 days after administration, about 3-5 days after administration, about 4-6 days after administration, about 5-8 days after administration, about 5 days after administration, about 6 days after administration, about 7 days after administration, about 8 days after administration, about 10 days after administration, about 15 days after administration, or any period bounded by or within the ranges therebetween, as compared to the bioavailability of meloxicam in a dosage form that does not contain a cyclodextrin, an acid inhibitor or a buffering agent (e.g., bicarbonate).

[0097] Some of the dosage forms may provide a desired range of area under the plasma concentration curve (AUC) of meloxicam. For example, doses of meloxicam may range from about 1 to 150 μg·hr / mL, about 10 to 30 μg·hr / mL, about 20 to 40 μg·hr / mL, about 30 to 50 μg·hr / mL, about 40 to 60 μg·hr / mL, about 50 to 70 μg·hr / mL, about 60 to 80 μg·hr / mL, about 70 to 90 μg·hr / mL, about 80 to 100 μg·hr / mL, about 10 to 100 μg·hr / mL, about 50 to 150 μg·hr / mL , may result in an AUC of meloxicam of about 25-125 μg·hr / mL, about 75-150 μg·hr / mL, about 20-50 μg·hr / mL, about 40-70 μg·hr / mL, about 60-90 μg·hr / mL, about 80-110 μg·hr / mL, about 100-130 μg·hr / mL, about 120-150 μg·hr / mL, or any AUC bounded by or within ranges therebetween.

[0098] Unless otherwise indicated, AUC is the AUC over a 6-hour period (AUC 0-6 ), AUC over a 12-hour period (AUC 0-12), AUC over a 24-hour period (AUC 0-24 ) and the last measured concentration (AUC 0-t ) or AUC extrapolated to infinity (AUC 0-inf )

[0099] In Example 3 below, the AUC of meloxicam in humans was compared for oral dosage forms containing sodium bicarbonate and sulfobutyl ether β-cyclodextrin (SBEβCD). 0-24 was approximately 27 μg·hr / mL. This dosage form contained 15 mg of meloxicam.

[0100] The AUC of meloxicam in humans at 15 mg IV and intramuscular administration 0-24 was about 27 μg hr / mL. The AUC of meloxicam is believed to be approximately dose proportional. Thus, for this oral dosage form, or for the IV or intramuscular dosage forms, administration of, for example, about 17 mg to about 30 mg of meloxicam resulted in an AUC of meloxicam of about 27 μg hr / mL. 0-24 is thought to be approximately 30 to 50 μg hr / mL.

[0101] For acute pain symptoms such as migraine or other types of headache, the AUC (AUC 0-6 Of particular interest are AUCs over short periods following administration, such as, for example, AUCs of at least about 6 μg·hr / mL, at least about 7 μg·hr / mL, at least about 8 μg·hr / mL, at least about 9 μg·hr / mL, about 6-10 μg·hr / mL, about 7-11 μg·hr / mL, about 8-12 μg·hr / mL, about 9-13 μg·hr / mL, or any AUC bounded by or within ranges therebetween.

[0102] In some embodiments, the dosage form comprises about 10-2500 ng / mL, about 100-2250 ng / mL, about 500-2000 ng / mL, about 1000-2500 ng / mL, about 1000-2000 ng / mL, about 100-900 ng / mL, about 750-1500 ng / mL, about 1250-2000 ng / mL, about 1500-2300 ng / mL, about 800-1200 ng / mL, about 1900-2400 ng / mL, about 50-500 ng / mL, about 400-950 ng / mL, about 500-500 ng / mL, about 500-600 ng / mL, about 500-700 ng / mL, about 500-800 ng / mL, about 500-900 ng / mL, about 500-1000 ng / mL, about 500-1500 ng / mL, about 600-1000 ng / mL, about 600-1500 ng / mL, about 700-1500 ng / mL, about 800-1200 ng / mL, about 1900-2400 ng / mL, about 50-500 ng / mL, about 500-10 ... / mL, approx. 900~1500ng / mL, approx. 1100~2200ng / mL, approx. 1300~1600ng / mL, approx. 1200~1500ng / mL, approx. 1400~2100ng / mL , about 1500-1900ng / mL, about 1600-2100ng / mL, about 1700-2000ng / mL, about 1800-2000ng / mL, about 1900-2500ng / mL, about 1 Meloxicam C of 50-1700ng / mL, about 1600-1800ng / mL, about 1700-1900ng / mL, about 1800-2000ng / mL, about 1900-2100ng / mL, about 2000-2200ng / mL, about 2100-2300ng / mL, about 2200-2400ng / mL, about 2300-2500ng / mL, about 2500-3000ng / mL max , or any C bounded by or in the range between these values max This may result in:

[0103] For example, the methods described herein can be used to max In some embodiments, the method can reduce the T of meloxicam within about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, about 7-10 hours or thereafter. max , or any T bounded by or in the range between these values max This may include treating the patient to achieve

[0104] In some embodiments, an oral dosage form provides a shorter T of meloxicam than that achieved by administration of meloxicam by intramuscular injection. max In some embodiments, the oral dosage form may have a shorter T of meloxicam that is at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20 times, or about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100 times faster, or any factor between or within the ranges bounded by these values, compared to that observed with intramuscular injection. max or may increase the plasma concentration of meloxicam.

[0105] In some embodiments, the dosage form containing meloxicam is about 0.01 to 0.5 μg / mL, approximately 0.5~0.7μg / mL, approximately 0.6~0.8μg / mL, approximately 0.7~0.9μg / mL, approximately 0.8~1μg / mL, approximately 0.9~1.1μg / mL, approximately 1~1.2μg / mL, approximately 1.1~1.3μg / mL, approximately 1.2~1.4μg / mL, approximately 1.3~1.5μg / m L, about 1.4-1.6μg / mL, about 1.5-1.7μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1.8-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, The present invention may result in a plasma concentration of meloxicam at 12 hours that is about 2.3-2.5 μg / mL, about 2.4-2.6 μg / mL, about 2.5-2.7 μg / mL, about 2.6-2.8 μg / mL, about 2.7-2.9 μg / mL, about 2.8-3 μg / mL, about 2.9-3.1 μg / mL, about 3-3.2 μg / mL, about 3.1-3.3 μg / mL, about 3.2-3.4 μg / mL, about 3.3-3.5 μg / mL, about 3.4-3.6 μg / mL, about 3.5-3.7 μg / mL, about 3.6-3.8 μg / mL, about 3.7-3.9 μg / mL, about 3.8-4 μg / mL, or any plasma concentration bounded by or within the ranges therebetween.

[0106] In some embodiments, meloxicam is about 0.01 to 0.5 μg / mL, about 0.5 to 0.7 μg / mL, about 0.6 to 0.8 μg / mL, about 0.7 to 0.9 μg / mL, about 0.8 to 1 μg / mL, about 0.9 to 1.1 μg / mL, about 1 to 1.2 μg / mL, about 1.1 to 1.3 μg / mL, about 1.2 to 1.4 μg / mL, about 1.3 to 1.5 μg / mL, about 1.4 to 1.6 μg / mL, about 1.5 to 1.7 μg / mL, about 1.6 to 1.8 μg / mL, about 1.8 to 2.0 ... / mL, approximately 1.7~1.9μg / mL, approximately 1.8~2μg / mL, approximately 1.9~2.1μg / mL, approximately 2~2.2μg / mL, approximately 2.1~2.3μg / mL, approximately 2.2~2.4μg / mL, approximately 2.3~2.5μg / mL , about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2.9-3.1μg / mL, about 3-3.2μg / mL, about 3. 1~3.3μg / mL, approx. 3.2~3.4μg / mL, approx. 3.3~3.5μg / mL, approx. 3.4~3.6μg / mL, approx. 3.5~3.7μg / mL, approx. 3.6~3.8μg / mL, approx. 3.7~3.9μg / mL, approx. 3 .8~4μg / mL, approx. 0.1~20μg / mL, approx. 0.5~15μg / mL, approx. 0.5~10μg / mL, approx. 5~15μg / mL, approx. 10~20μg / mL, approx. 7.5~15μg / mL, approx. 2~10μg / mL, approx. 1 ~8 μg / mL, about 1-6 μg / mL, about 1-2 μg / mL, about 0.5-3.5 μg / mL, about 0.5-7 μg / mL, about 12-20 μg / mL, about 8-12 μg / mL, about 1-4 μg / mL, about 4-7 μg / mL, about 7-11 μg / mL, about 11-15 μg / mL, about 15-19 μg / mL, about 16-20 μg / mL, or any meloxicam plasma level bounded by or within a range therebetween (e.g., C avg or mean plasma level).

[0107] Administration of the dosage forms described herein may decrease the time to reach a therapeutic plasma concentration of meloxicam. The therapeutic plasma concentration is C avg In some embodiments, the time to therapeutic plasma concentration of meloxicam (T thera) is about 10 to 30 minutes, about 10 to 15 minutes, about 15 to 20 minutes, about 20 to 25 minutes, about 25 to 30 minutes, about 10 to 20 minutes, about 20 to 30 minutes, about 16 to 18 minutes, or about 17 minutes.

[0108] The methods described herein include administering rizatriptan max For example, the method may reduce the T of rizatriptan in a patient within about 50 minutes, within about 60 minutes, within about 70 minutes, within about 80 minutes, within about 90 minutes, within about 40-60 minutes, within about 40-45 minutes, within about 45-50 minutes, within about 50-55 minutes, or within about 55-60 minutes after administration. max , or any T bounded by these values max can be achieved.

[0109] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than would be experienced two hours after administration of the same amount of meloxicam without rizatriptan.

[0110] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than would be experienced 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0111] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than would be experienced two hours after administration of the same amount of rizatriptan without meloxicam.

[0112] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of the meloxicam and rizatriptan, the human experiences greater pain relief than would be experienced 24 hours after administration of the same amount of rizatriptan without the meloxicam.

[0113] One embodiment is a method for reducing the risk of gastrointestinal side effects and improving the bioavailability of NSAIDs in people taking NSAIDs for pain relief and other conditions, especially during chronic treatment.In one embodiment, the method relates to the administration of a product that combines a) an agent that actively increases intragastric pH, and b) an NSAID formulated with cyclodextrin.In another embodiment, the method relates to the administration of a product that combines a) an agent that actively increases intragastric pH, b) an NSAID formulated with cyclodextrin, and c) a buffering agent.Either short- or long-acting acid inhibitors can be effectively used in the dosage form.This method has the added advantage of being able to protect patients from other sources of gastrointestinal ulcers, the effects of which may be enhanced by the breakdown of gastroprotective prostaglandins caused by NSAID therapy.

[0114] Aqueous parenteral forms of meloxicam formulations may include a buffering agent to adjust the pH of the aqueous formulation to about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or any other pH bounded by or within the ranges between these values. Oral forms of meloxicam formulations may include a buffering agent to adjust the pH of the gastric juice to about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or any other pH bounded by or within the ranges between these values. Examples of buffers suitable for use herein include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, and the like.

[0115] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or an edible carrier, or may be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or included directly in the dietary food. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, and the like.

[0116] Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents 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, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to materials of the above types. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, a dye and flavoring such as cherry flavor or orange flavor. It can be desirable for materials in a dosage form or pharmaceutical composition to be pharma- ceutical pure and substantially non-toxic in the amounts used.

[0117] Some compositions or dosage forms may be liquid or may contain a solid phase dispersed in a liquid.

[0118] The dosage form may contain a second therapeutically active agent, such as an antacid or an analgesic.

[0119] In some embodiments, the dosage form may further comprise an acid inhibitor present in an amount effective to raise the patient's gastric pH to at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and higher at least 5 when one or more unit dosage forms are administered. The term "acid inhibitor" refers to an agent that inhibits gastric acid secretion and raises gastric pH. Specific H2 blockers are also referred to as H2 antagonists or histamine H2 blockers or antagonists, and include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, locstidine, famotidine, or combinations thereof.

[0120] Other drugs that can be effectively used as acid inhibitors are proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments, the daily dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or any amount bounded by or within the ranges therebetween.

[0121] Examples of specific proton pump inhibitors include esomeprazole present in unit dosage form in an amount between 5 mg and 50 mg, omeprazole present in unit dosage form in an amount between 5 mg and 50 mg, lansoprazole present in unit dosage form in an amount between 5 mg and 150 mg (preferably between 5 mg and 30 mg), and pantoprazole present in unit dosage form in an amount between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is present in the dosage form in an amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newer class of acid inhibitors has been developed that compete with potassium for the acid pump. This class of compounds is referred to as "reversible proton pump inhibitors" or "acid pump antagonists" and may be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO 96 / 05177 and WO 96 / 05199). Other compounds in this group are H-335 / 25 (AstraZeneca, Dialog File 128, Accession No. 020806), Sch-28080 (Schering-Plough, Dialog File 128, Accession No. 009663), Sch-32651 (Schering-Plough, Dialog File 128, Accession No. 006883) and SK&F-96067 (CAS Registry No. 115607-61-9).

[0122] The second therapeutically active agent may include a second nonsteroidal anti-inflammatory agent, analgesic agent such as an opioid, a steroid, a triptan, etc. In some embodiments, the dosage form or treatment also further comprises administering a second nonsteroidal anti-inflammatory agent in an amount effective to reduce or eliminate pain or inflammation. NSAIDs include, without limitation, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (which will be considered an NSAID for purposes of this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof. For purposes of this disclosure, acid inhibitors, NSAIDs or analgesics are understood to include all common forms of these compounds, particularly pharma- ceutically acceptable salts thereof. The amount of therapeutically effective NSAID may actually be lower in the current embodiment than found elsewhere due to potential positive kinetic interactions and NSAID absorption in the presence of acid inhibitors or in the presence of buffers.

[0123] In other embodiments, the dosage form or treatment may further comprise administering an opioid in an amount effective to reduce or eliminate pain or inflammation. Opioids include, but are not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprozine, bezitramide, buprenorphine, butorphanol, carfentanil, desmethylprozine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levothymidine ... These may include methoφhan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, omefentanyl, oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenatazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.

[0124] Useful triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, albitriptan, zolmitriptan, and the like. In some embodiments, the triptan includes rizatriptan. In some embodiments, the dosage form may include about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 15-20 mg, or about 20-30 mg of a triptan, such as rizatriptan, or any amount within a range bounded by these values.

[0125] In some embodiments, a dosage form comprising the subject combination is provided in an amount of about 1-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, or about 40-50 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 1-10 mg, about 5-20 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-11 mg, about 9-14 mg, about 10-15 mg, about The amount of rizatriptan may be about 11 to 16 mg, about 12 to 17 mg, about 13 to 18 mg, about 14 to 19 mg, about 15 to 20 mg, about 5 to 15 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or any amount of rizatriptan bounded by or within a range therebetween.

[0126] 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, may be of particular interest. For example, after a single dose, symptoms may be relieved for a long period of time such that repeated administration is not required for a short period of time. For more continuous symptoms, including chronic, ongoing, or frequent migraine symptoms, daily, weekly, or monthly dosages may be of particular interest.

[0127] For the amount of rizatriptan described herein, the salt form of rizatriptan can be present in the amount described above, or the molar equivalent of those amounts for rizatriptan free base.For example, if the molecular weight of rizatriptan free base is 269.3g / mol, 10mg of rizatriptan is 37.1mmol of rizatriptan.Therefore, the molar equivalent of 10mg of rizatriptan free base is the amount of 37.1mmol of salt form.For example, for benzoate (mw=391.2g / mol), the molar equivalent of 10mg of free base (or 37.1mmol) is 14.5mg. These doses may be safe for repeated administration 1, 2, 3, or 4 times daily, or at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, 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.

[0128] The pharmaceutical composition may be in the form of a tablet or capsule having (a) an acid inhibitor, and / or (b) a buffering agent, and (c) a nonsteroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in a patient upon administration of one or more of said unit dosage forms. The components of the pharmaceutical composition, individually or collectively, may be in immediate release or sustained release form.

[0129] The term "unit dosage form" as used herein refers to a single entity for drug administration.For example, a single tablet or capsule that combines both an acid inhibitor and an NSAID would be a unit dosage form.A "unit dosage form" (or "unit dose form") is also called a "fixed dosage form" (or "fixed dose form") or a "combination of fixed dosage forms" (or "combination of fixed dosage forms"), and are interchangeable in other documents.In one embodiment, the unit dosage form is a multi-layer tablet.

[0130] In other embodiments, the unit dosage form is suitable for oral administration to a patient.In yet another embodiment, the unit dosage form is a tablet.In yet another embodiment, the unit dosage form is a multi-layer tablet comprising a single core and one or more layers outside the core.

[0131] Some dosage forms may include a first layer containing meloxicam, SBEβCD, and bicarbonate, and a second layer containing a second therapeutically active agent and bicarbonate.

[0132] The first layer may, for example, contain any amount of meloxicam in one of the ranges described above. For example, all of the meloxicam in the dosage form may be present in the first layer. The second layer may contain all of the second therapeutically active agent, such that any amount in the ranges described above for the second therapeutically active agent may be applied to the second layer.

[0133] In some embodiments, the first layer comprises about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of a bicarbonate salt, such as sodium bicarbonate, or any amount in a range bounded by these values.

[0134] In some embodiments, the second layer comprises about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of a bicarbonate salt, such as sodium bicarbonate, or any amount in a range bounded by these values.

[0135] In some embodiments, the pharmaceutical composition can have an effective amount of meloxicam, a cyclodextrin, and a carbonate or bicarbonate to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition can increase the bioavailability of meloxicam or increase the T of meloxicam. max To reduce the risk of nausea and vomiting, the drug may have effective amounts of meloxicam, sulfobutylether-β-cyclodextrin (SBEβCD), and sodium bicarbonate.

[0136] 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 with an enteric coating. In some embodiments, the dosage form may include a tablet or capsule with a film coating.

[0137] One embodiment of the disclosure is a pharmaceutical composition in a unit dosage form suitable for administration to a patient, comprising: (a) esomeprazole, which may or may not be surrounded by an enteric coating; (b) sodium or potassium bicarbonate and / or sodium or potassium carbonate, and (c) Meloxicam, which may or may not be formulated with a cyclodextrin and may or may not be surrounded by an enteric coating. The present invention relates to a pharmaceutical composition comprising:

[0138] One embodiment of the disclosure is a pharmaceutical composition, in a unit dosage form suitable for administration to a patient, for treating a disease, condition, or disorder, such as migraine, comprising: (1) Inclusion complex of meloxicam with sulfobutyl ether β-cyclodextrin (SBEβCD), (2) Bicarbonates, such as sodium bicarbonate or potassium bicarbonate, and (3) Triptans such as rizatriptan The present invention relates to a pharmaceutical composition comprising:

[0139] In certain embodiments, the pharmaceutical composition provides faster release or dissolution of meloxicam from the dosage form as compared to a dosage form containing meloxicam but without an acid inhibitor or without a buffering agent.

[0140] Dosage forms including a combination of rizatriptan and meloxicam ("the subject combination") may be used to treat migraine headaches. The subject combination may be used for acute treatment of migraine headaches. The subject combination may provide greater and more sustained migraine relief compared to rizatriptan, meloxicam, or placebo. The subject combination may provide rapid relief of migraine pain. The subject combination may significantly reduce rescue medication use compared to rizatriptan, meloxicam, or placebo. Migraine patients treated with the rizatriptan and meloxicam combinations described herein may have a history of inadequate response to previous acute treatments. Migraine patients treated with the rizatriptan and meloxicam combinations described herein may have allodynia. Migraine patients treated with the rizatriptan and meloxicam combinations described herein may have severe pain. Migraine patients treated with the rizatriptan and meloxicam combinations described herein may be obese. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have morning migraines. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have a total mean score of less than 7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4), for example, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have allodynia, severe pain, be obese, have morning migraines, have a total mean score of less than 7 on the mTOQ-4, and have a history of inadequate response to previous acute treatments. Dosage forms containing the combination of rizatriptan and meloxicam described herein are safe and well tolerated by treated patients.

[0141] Dosage forms containing the combination of rizatriptan and meloxicam described herein may provide rapid relief of migraine pain in less than 15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, less than 1 hour, 0.5-0.75 hours, or 0.75-1 hour after administration. The combination of rizatriptan and meloxicam described herein may provide numerically greater relief of migraine pain than rizatriptan for less than 15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes, about 30-45 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 even longer after administration. The percentage of migraine patients reporting pain relief 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%.

[0142] Migraine patients administered a dosage form containing the combination of rizatriptan and meloxicam described herein (the "subject combination") may achieve relief from pain for 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 even longer after administration.

[0143] The percentage of migraine patients who achieve freedom from pain increases over time after administration of a dose of the combination of rizatriptan and meloxicam described herein. For example, at 2 hours after administration, the percentage of migraine patients who achieve freedom from pain can be about 15-25%, about 15-20%, about 20%, about 20-25%. At 4 hours after administration, the percentage of migraine patients who achieve freedom from pain can be about 30-50%, about 30-40%, about 40%, about 40-45%, about 45-47%, about 47-50%. At 12 hours after administration, the percentage of migraine patients who achieve freedom from pain can be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 56-57%, about 60-65%, about 65-70%. At 16 hours after administration, the percentage of migraine patients achieving pain relief can be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 58-59%, about 60-65%, about 65-70%. The combination of rizatriptan and meloxicam described herein can provide a significant improvement over rizatriptan in providing pain relief to migraine patients. About 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8%, 8-9%, or 9-10% or more of migraine patients administered a combination of rizatriptan and meloxicam described herein may achieve freedom from pain 2-16 hours after administration, which is about 10-25%, 10-15%, 14-15%, 15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25% improvement over patients administered rizatriptan. For example, if 4 hours after administration, 40% of migraine patients administered a subject combination achieve freedom from pain and 33% of migraine patients administered rizatriptan achieve freedom from pain, then the improvement with the subject combination is about 21% [((40-33) / 33) x 100%]. In migraine patients achieving relief from pain, the improvement of treatment with the subject combination over meloxicam may be greater than the improvement over rizatriptan.For example, in migraine patients achieving freedom from pain, improvement with the subject combination over meloxicam can be about 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75% at 2-16 hours after administration.

[0144] At least 50%, at least 60%, at least 70%, at least 80%, about 70-80%, about 80-90%, about 90-95%, about 80% of migraine patients administered a combination of rizatriptan and meloxicam described herein ("subject combinations") may be pain-free 2 hours after administration and may remain pain-free for up to 24 hours after administration. The number of migraine patients who achieve sustained pain-free (or improvement) 2-24 hours after administration of a subject combination may be increased by about 35-55%, about 35-40%, about 40-45%, about 45-50%, or about 50-55% compared to administration of rizatriptan. The number of migraine patients who achieve sustained relief from pain 2 to 24 hours after administration of a subject combination (or the degree of improvement) may be increased by about 100-165%, about 100-110%, about 110-120%, about 120-130%, about 130-140%, about 140-150%, about 150-160%, or about 160-165%, as compared to administration of meloxicam.

[0145] The number of migraine patients who achieve sustained pain relief (or the degree of improvement) 2-24 hours after administration of a subject combination may be increased by about 15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-22%, or about 21% compared to administration of rizatriptan. The number of migraine patients who achieve sustained pain relief (or the degree of improvement) 2-24 hours after administration of a subject combination may be increased by about 20-35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-30%, or about 27% compared to administration of meloxicam.

[0146] At least 50%, at least 60%, at least 70%, at least 80%, about 70-80%, about 80-90%, about 90-95%, or about 77% of migraine patients administered a combination of rizatriptan and meloxicam described herein ("subject combinations") may be pain-free 2 hours after administration and may remain pain-free for up to 48 hours after administration. The number of migraine patients who achieve sustained pain-free (or improvement) 2-48 hours after administration of a subject combination may be increased by about 60-90%, about 60-70%, about 70-75%, about 75-80%, about 80-90%, or about 75% compared to administration of rizatriptan. The number of migraine patients who achieve sustained relief from pain 2-48 hours after administration of a subject combination (or the degree of improvement) may be increased by about 70-110%, about 70-80%, about 80-90%, about 90-100%, about 100-110%, or about 90%, as compared to administration of meloxicam.

[0147] The number of migraine patients who achieve sustained pain relief (or the degree of improvement) 2-48 hours after administration of a subject combination may be increased by about 20-35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-20%, or about 27% compared to administration of rizatriptan. The number of migraine patients who achieve sustained pain relief (or the degree of improvement) 2-48 hours after administration of a subject combination may be increased by about 15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%, about 24-25%, or about 23% compared to administration of meloxicam.

[0148] At least 50%, at least 60%, at least 70%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or about 77% of migraine patients administered a combination of rizatriptan and meloxicam described herein ("subject combinations") may not require rescue medication. The number of migraine patients taking rescue medication by 24 hours after administration of a subject combination may be reduced by about 35-60%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 47-48%, or about 47% compared to administration of a placebo. The number of migraine patients taking rescue medication by 24 hours after administration of a subject combination may be reduced by about 25-45%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about 34-36%, or about 35%, compared to administration of meloxicam. The number of migraine patients taking rescue medication by 24 hours after administration of a subject combination may be reduced by about 25-40%, about 25-30%, about 30-35%, about 35-40%, about 33-35%, or about 34%, compared to administration of rizatriptan.

[0149] The following embodiments are contemplated:

[0150] Embodiment 1. Inclusion complex of meloxicam in cyclodextrin.

[0151] Embodiment 2. 1) the inclusion complex of embodiment 1; or 2) a dosage form comprising meloxicam and a carbonate or bicarbonate salt.

[0152] Embodiment 3. The dosage form of embodiment 2, comprising an inclusion complex, wherein the cyclodextrin comprises a substituted β-cyclodextrin.

[0153] Embodiment 4. The dosage form of embodiment 3, wherein the substituted β-cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPβCD).

[0154] Embodiment 5. The dosage form of embodiment 4, wherein the cyclodextrin is SBEβCD.

[0155] Embodiment 6. The dosage form of embodiment 5, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[0156] Embodiment 7. The dosage form of embodiment 6, wherein the meloxicam and SBEβCD have a molar ratio of about 0.8 to about 1.2.

[0157] Embodiment 8. The dosage form of embodiment 6, wherein the meloxicam and SBEβCD have a molar ratio of about 1.

[0158] EMBODIMENT 9. The dosage form of embodiment 2, 3, 4, 5, 6, 7 or 8, comprising bicarbonate.

[0159] Embodiment 10. The dosage form of embodiment 9, wherein the bicarbonate comprises sodium bicarbonate.

[0160] Embodiment 11. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9 or 10, which is an oral dosage form.

[0161] Embodiment 12. The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10 or 11, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form.

[0162] Embodiment 13. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the carbonate or bicarbonate is present in an amount ranging from about 400 mg to about 600 mg.

[0163] Embodiment 14. Meloxicam T max14. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the amount of cyclodextrin in the solution is reduced compared to a dosage form not having the carbonate, bicarbonate, or cyclodextrin.

[0164] EMBODIMENT 15. Meloxicam T max is achieved in the patient at a time ranging from about 10 minutes to about 180 minutes after administration.

[0165] Embodiment 16. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 having a higher oral bioavailability of meloxicam than a dosage form that does not have a carbonate, bicarbonate or cyclodextrin.

[0166] EMBODIMENT 17. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, further comprising an acid inhibitor.

[0167] EMBODIMENT 18. The dosage form of embodiment 17, wherein the acid inhibitor is a proton pump inhibitor.

[0168] EMBODIMENT 19. The dosage form of embodiment 18, wherein the proton pump inhibitor is esomeprazole.

[0169] EMBODIMENT 20. The dosage form of embodiment 19, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form.

[0170] EMBODIMENT 21. A method of orally administering meloxicam comprising orally administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 to a patient in need of treatment.

[0171] EMBODIMENT 22. The method of embodiment 21, wherein the dosage form is administered to treat pain.

[0172] EMBODIMENT 23. The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain.

[0173] EMBODIMENT 24. The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[0174] 25. A method of administering meloxicam intravenously comprising administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 or 15 intravenously to a patient in need of treatment.

[0175] 26. The method of embodiment 21, wherein the dosage form is administered to treat a migraine headache.

[0176] EMBODIMENT 27. A dosage form comprising 1) an inclusion complex of meloxicam in a cyclodextrin, 2) a bicarbonate, and 3) a triptan.

[0177] 28. The dosage form of embodiment 27, wherein the triptan is rizatriptan.

[0178] 29. The dosage form of embodiment 27, wherein the bicarbonate comprises sodium bicarbonate.

[0179] EMBODIMENT 30. The dosage form of embodiment 27, wherein the cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD).

[0180] EMBODIMENT 31. The dosage form of embodiment 30, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[0181] EMBODIMENT 32. The dosage form of embodiment 30, wherein the molar ratio of meloxicam to SBEβCD is about 0.8 to about 1.2.

[0182] EMBODIMENT 33. The dosage form of embodiment 32, wherein the molar ratio of meloxicam to SBEβCD is about 1.

[0183] EMBODIMENT 34. The dosage form of embodiment 27, 28, 29, 30, 31, 32, or 33, which is an oral dosage form.

[0184] EMBODIMENT 35. The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form.

[0185] 36. The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the bicarbonate is present in an amount of about 400 mg to about 1000 mg.

[0186] 37. A method of treating migraine comprising administering to a human suffering from migraine a dosage form comprising meloxicam, at least 400 mg of bicarbonate, and rizatriptan, wherein the T of rizatriptan in the dosage form is max is shorter than that of a reference dosage form that a) contains the same amount of rizatriptan, b) does not contain meloxicam, and c) does not contain bicarbonate.

[0187] 38. 1. A method of treating migraine comprising administering meloxicam and about 8 mg to about 13 mg of rizatriptan, based on the weight of the rizatriptan in free base form, to a human suffering from an acute attack of migraine or migraine aura, wherein the meloxicam and rizatriptan are administered within 30 minutes of each other, and the administration of meloxicam to the human is within a T of 110 minutes or less. max , and the AUC of meloxicam of about 30 μg / mL to about 50 μg / mL0-24 A method for bringing about.

[0188] 39. 1) about 0.028 mmol to about 0.085 mmol of meloxicam in free acid or salt form, 2) about 0.019 mmol to about 0.056 mmol of rizatriptan in free base or salt form, 3) about 100 mg to about 175 mg of sulfobutyl ether β-cyclodextrin (SBEβCD), and 4) about 400 mg to about 600 mg of sodium bicarbonate.

[0189] EMBODIMENT 40. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan.

[0190] EMBODIMENT 41. The method of embodiment 40, wherein the human migraine patient experiences migraine relief as a result of oral administration of the dosage form to the migraine patient.

[0191] EMBODIMENT 42. The method of embodiment 40 or 41, wherein 2 hours after the dosage form is orally administered to the human migraine patient, the human migraine patient is free of migraine pain.

[0192] EMBODIMENT 43. The method of embodiment 40, 41, or 42, wherein the migraine sufferer experiences relief from nausea as a result of oral administration of the dosage form to the migraine sufferer.

[0193] EMBODIMENT 44. The method of embodiment 40, 41, 42 or 43, wherein 2 hours after the dosage form is orally administered to the human migraine patient, the human migraine patient is free of nausea.

[0194] EMBODIMENT 45. The method of embodiment 40, 41, 42, 43, or 44, wherein the migraine patient experiences a reduction in photophobia as a result of oral administration of the dosage form to the migraine patient.

[0195] EMBODIMENT 46. The method of embodiment 40, 41, 42, 43, 44, or 45, wherein 2 hours after the dosage form is orally administered to the human migraine patient, the human migraine patient is free of photophobia.

[0196] EMBODIMENT 47. The method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein the migraine patient experiences relief from phonophobia as a result of oral administration of the dosage form to the migraine patient.

[0197] 48. The method of embodiment 40, 41, 42, 43, 44, 45, 46, or 47, wherein the human migraine patient is free of phonophobia 2 hours after the dosage form is orally administered to the human migraine patient.

[0198] 49. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, or 48, wherein the dosage form comprises 400 mg to 600 mg of bicarbonate.

[0199] EMBODIMENT 50. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, wherein the dosage form comprises about 5 mg to about 50 mg of meloxicam.

[0200] EMBODIMENT 51. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein the dosage form comprises from about 50 mg to about 200 mg of SBEβCD.

[0201] EMBODIMENT 52. The dosage form is the T value of meloxicam in humans. maxis a solid oral dosage form that is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate.

[0202] EMBODIMENT 53. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, wherein about 1 mg to about 50 mg of rizatriptan is present in the oral dosage form, based on the weight of the rizatriptan in free base form.

[0203] EMBODIMENT 54. The method of embodiment 53, wherein the rizatriptan is present in a salt form in an amount of about 10 mg, the molar equivalent of the free base form of rizatriptan.

[0204] EMBODIMENT 55. The method of embodiment 53 or 54, wherein the rizatriptan is present as rizatriptan benzoate.

[0205] EMBODIMENT 56. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, wherein the oral dosage form comprises from about 10 mg to about 30 mg of meloxicam.

[0206] EMBODIMENT 57. The method of embodiment 56, wherein the oral dosage form comprises about 20 mg of meloxicam.

[0207] EMBODIMENT 58. The method of embodiment 56, wherein the oral dosage form comprises about 15 mg of meloxicam.

[0208] EMBODIMENT 59. 59. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[0209] 60. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the oral dosage form comprises from about 50 mg to about 150 mg of SBEβCD.

[0210] 61. The method of embodiment 60, wherein the oral dosage form comprises about 100 mg of SBEβCD.

[0211] 62. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61, wherein the molar ratio of SBEβCD to meloxicam is from about 0.5 to about 2.

[0212] 63. The method of embodiment 62, wherein the molar ratio of SBEβCD to meloxicam is about 0.8 to about 1.2.

[0213] 64. The method of embodiment 62, wherein the molar ratio of SBEβCD to meloxicam is about 1.

[0214] 65. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64, wherein the oral dosage form comprises from about 10 mg to about 40 mg of meloxicam and from about 5 mg to about 50 mg of rizatriptan.

[0215] 66. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, wherein the oral dosage form comprises SBEβCD in a weight ratio of SBEβCD to rizatriptan in the range of about 1 to about 100.

[0216] 67. The method of embodiment 66, wherein the oral dosage form comprises SBEβCD in a weight ratio to rizatriptan of about 10.

[0217] 68. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67, wherein the bicarbonate comprises sodium bicarbonate.

[0218] 69. The method of embodiment 68, wherein the oral dosage form comprises 500 mg of sodium bicarbonate.

[0219] EMBODIMENT 70. The oral dosage form was used to measure the T value of meloxicam in fasting human subjects. max The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69, wherein the median time to complete the treatment is less than about 90 minutes.

[0220] EMBODIMENT 71. The oral dosage form was used to measure the T value of meloxicam in fasting human subjects. max The method of embodiment 70, wherein the median time to effect responsiveness is shown to be less than about 2 hours.

[0221] EMBODIMENT 72. The method of embodiment 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71, wherein the oral dosage form has been shown to have a faster time to reach therapeutic plasma concentrations in humans compared to the reference dosage form.

[0222] EMBODIMENT 73. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the human migraine patient experiences relief from migraine pain as a result of oral administration of the dosage form to the migraine patient.

[0223] 74. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein 2 hours after the dosage form is administered to the human migraine patient, the human migraine patient is free of migraine pain.

[0224] 75. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the migraine patient experiences a reduction in nausea as a result of oral administration of the dosage form to the migraine patient.

[0225] EMBODIMENT 76. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein 2 hours after the dosage form is administered to the human migraine patient, the human migraine patient is free of nausea.

[0226] 77. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the migraine patient experiences a reduction in photophobia as a result of oral administration of the dosage form to the migraine patient.

[0227] 78. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein 2 hours after the dosage form is administered to the human migraine patient, the human migraine patient is free of photophobia.

[0228] 79. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the migraine patient experiences a reduction in phonophobia as a result of oral administration of the dosage form to the migraine patient.

[0229] 80. 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form, the dosage form comprising a combination of 1) meloxicam (optionally complexed with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein 2 hours after the dosage form is administered to the human migraine patient, the human migraine patient is free of phonophobia.

[0230] Example 1 The effect of various amounts of potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) on the pH of an acidic medium was tested. The acidic medium was chosen to simulate gastric conditions. K2CO3 or NaHCO3 was added to 50 mL of 0.01 N HCl solution (pH 2). After the addition of K2CO3 or NaHCO3, the pH of the solution was measured. Deionized water (240 mL) was then added to the mixture and the pH was measured again. The results are shown in Tables 1-4.

[0231] [Table 1]

[0232] [Table 2]

[0233] [Table 3]

[0234] [Table 4]

[0235] Example 2 Tablets containing meloxicam and a combination of sulfobutyl ether β-cyclodextrin (SBEβCD) (a cyclodextrin containing about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin) with K2CO3 or NaHCO3 were prepared and tested for dissolution. Tablets containing meloxicam alone (MOBIC®) were purchased and also tested for dissolution. The tablets tested are listed in Table 5. Meloxicam in the form of a meloxicam / SBEβCD inclusion complex was used in the tablets containing meloxicam and SBEβCD. The inclusion complex was formed by mixing meloxicam and SBEβCD in a pH adjusted aqueous solution. The pH of the solution was adjusted using a buffering agent. The resulting soluble meloxicam / SBEβCD inclusion complex was then spray dried. This spray dried dispersion was used to prepare tablets containing SBEβCD.

[0236] [Table 5]

[0237] Dissolution testing in acidic media (selected to simulate gastric conditions) was performed by placing the tablets in 0.01 N HCl solution at a stirring speed of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 6 and Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90 and 120 minutes) are presented as percent (%) of meloxicam dissolved.

[0238] [Table 6]

[0239] Meloxicam dissolution was greater in tablets containing various combinations of meloxicam and SBEβCD, K2CO3, or NaHCO3 compared to tablets containing meloxicam alone. For example, after 120 minutes, dissolution of meloxicam tablets containing NaHCO3 was 95% compared to 2% for tablets containing meloxicam alone.

[0240] Meloxicam dissolution increased with increasing amounts of K2CO3 in the absence of SBEβCD. However, in the presence of SBEβCD, increasing amounts of K2CO3 did not appear to increase meloxicam dissolution. At the highest dose of potassium carbonate tested, meloxicam dissolution in the presence of SBEβCD was reduced by approximately 50% compared to meloxicam dissolution in the absence of SBEβCD at 120 min.

[0241] Meloxicam dissolution with NaHCO3 was significantly greater than that observed with the highest dose of K2CO3 at 15 min (50% vs. 30%) and 120 min (92% vs. 23%). Meloxicam dissolution in the presence of SBEβCD was also significantly greater with NaHCO3 compared to the highest dose of K2CO3 at 15 min (85% vs. 26%) and 120 min (86% vs. 12%). NaHCO3 in the presence of SBEβCD increased meloxicam dissolution more at 15 min compared to potassium carbonate, which reduced dissolution.

[0242] Example 3 A bilayer tablet was prepared containing 1) an inclusion complex of SBEβCD with meloxicam prepared as described below, and 2) sodium bicarbonate (SBEβCD-meloxicam / bicarbonate). The first layer contained 15 mg of meloxicam inclusion complex with 100 mg of SBEβCD and 100 mg of sodium bicarbonate. The second layer contained 40 mg of esomeprazole and 400 mg of sodium bicarbonate.

[0243] A total of 20 human subjects were randomly assigned in a 1:1 ratio to receive either SBEβCD-meloxicam / bicarbonate tablets as described above or Mobic® tablets (meloxicam 15 mg) once daily for 6 days under fasting conditions.

[0244] Plasma samples were collected on the first day of dosing for analysis of meloxicam concentrations at multiple time points. Meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. Results are shown in Figure 11.

[0245] The primary endpoint of the study was T max The median time to saturation was 9 times faster with SBEβCD-meloxicam / bicarbonate tablets compared to Mobic® (0.5 vs. 4.5 hours, respectively, p<0.0001).

[0246] Additionally, SBEβCD-meloxicam / bicarbonate tablets showed a significantly higher maximum plasma concentration (C max ), faster time to therapeutic plasma concentration (p<0.0001), and faster time to half-maximum plasma concentration (p<0.0001).

[0247] For tablets containing meloxicam and cyclodextrin, meloxicam was used in the form of a meloxicam / SBEβCD inclusion complex. The inclusion complex was formed by mixing meloxicam and SBEβCD in a pH-adjusted aqueous solution. The pH of the solution was adjusted with a buffer. The resulting soluble meloxicam / SBEβCD inclusion complex was then spray dried. The spray-dried dispersion was used to prepare tablets containing SBEβCD.

[0248] Example 4 A monolayer tablet was prepared containing 1) an inclusion complex of SBEβCD with meloxicam, 2) rizatriptan, and 3) sodium bicarbonate (SBEβCD-meloxicam / rizatriptan / bicarbonate). The monolayer tablet contained 20 mg meloxicam, 10 mg rizatriptan, and 500 mg sodium bicarbonate. The inclusion complex was similar to that of Example 3.

[0249] Dissolution testing of the tablets in acidic medium (selected to mimic gastric conditions) was performed by placing the tablets in 0.01 N HCl solution at an agitation speed of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent (%) meloxicam dissolved and percent (%) rizatriptan dissolved.

[0250] [Table 7]

[0251] As shown in Table 7, the dissolution results of the tablets of Example 4 were very similar to those of Example 3. Therefore, the inventors investigated the pharmacokinetic properties (bioavailability, T of meloxicam) of the tablets of Example 4. max ) would be similar to that described in Example 3 and Figure 11. As shown in the Examples below, this prediction proved to be correct.

[0252] Example 5 The monolayer tablet of Example 4 was administered to six subjects. Plasma samples were taken for rizatriptan concentration analysis at multiple time points on the first day of administration. Rizatriptan and meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. Results for meloxicam were comparable to those reported for the bilayer dosage form of Example 3. The T of rizatriptan max The median C of rizatriptan was 0.75 hours. max The mean T value for the commercially available rizatriptan formulation, Maxalt®, was 20.710 ng / mL. max is 1.0-1.5 hours.

[0253] Example 6 A phase 1, randomized, single-dose, parallel-group clinical trial was conducted to evaluate the PK, safety, and tolerability of 1) a combination of meloxicam (20 mg), rizatriptan (10 mg), SBEβCD, and sodium bicarbonate (meloxicam / rizatriptan) compared with 2) Maxalt® (10 mg rizatriptan) in healthy human volunteers after oral administration under fasting conditions. A total of 20 healthy adult male or female volunteers were randomly assigned 1:1 to receive a single dose of meloxicam / rizatriptan or Maxalt® (10 mg rizatriptan).

[0254] Blood samples for PK analysis were collected pre-dose and at multiple time points post-dose. The prespecified primary endpoint was T, defined as the Cavg of meloxicam after administration of the maximum tolerated standard dose of meloxicam (15 mg). thera is the time to therapeutic plasma concentration of meloxicam, approximately 1000 ng / mL. PK results for the rizatriptan component of meloxicam / rizatriptan were compared with those for Maxalt® ( / rizatriptan).

[0255] The PK results for the meloxicam (20 mg) component of Meloxicam / Rizatriptan were compared to the PK results for Mobic® (15 mg meloxicam) in Example 3.

[0256] (Phase 1 results) Meloxicam was rapidly absorbed after oral administration of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan), and the primary endpoint of time to therapeutic plasma concentration (T thera The median time to recovery was 17 minutes (Figure 12 and Table 8). max The median T is 1 hour compared to 4.5 hours with standard meloxicam 15 mg (Mobic®). max suggests the potential for a rapid onset of action for meloxicam / rizatriptan in the treatment of migraine.1 / 2 ) was 18.2 hours after administration of meloxicam / rizatriptan compared with 21.5 hours for standard meloxicam. The longer elimination half-life suggests the potential for enhanced and prolonged efficacy of meloxicam / rizatriptan and reduced recurrence of migraine pain.

[0257] [Table 8]

[0258] Rizatriptan is rapidly absorbed after oral administration of meloxicam / rizatriptan, and T max was 0.64 hours (38 minutes) compared to 0.88 hours for the same dose of standard rizatriptan (Maxalt®) (Figure 13 and Table 9). max Systemic exposure, as measured using and AUC, was numerically greater for rizatriptan following meloxicam / rizatriptan administration versus standard rizatriptan.

[0259] [Table 9]

[0260] Meloxicam / rizatriptan was well tolerated, with no relevant differences in the safety profile between the two treatment arms. There were no serious adverse events in the study.

[0261] Example 7 A phase 3, randomized, double-blind, multicenter, positive- and placebo-controlled study was conducted to evaluate the efficacy and safety of meloxicam / rizatriptan in the acute treatment of moderate and severe migraine headaches in patients with a history of incomplete response to previous acute treatments. Eligible patients were randomly assigned to receive treatment 2:2:2:1 with meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, SBEβCD, and sodium bicarbonate, as described in Example 4 above), rizatriptan (10 mg) (rizatriptan group), meloxicam (20 mg), SBEβCD, and sodium bicarbonate (meloxicam group), or placebo. Co-primary endpoints were freedom from headache pain two hours after dosing and freedom from the most bothersome migraine-related symptom (nausea, photophobia, or phonophobia) for meloxicam / rizatriptan compared with placebo.

[0262] The superiority of the meloxicam / rizatriptan group over the rizatriptan group and the meloxicam group (contribution of ingredients) will be established based on sustained freedom from headache pain from 2 to 24 hours after administration (a key secondary endpoint).

[0263] Eligible patients must have a history of an inadequate response to previous acute migraine treatments, as assessed using the Migraine Treatment Optimization Questionnaire (mTOQ-4), a validated questionnaire that assesses efficacy response to previous acute treatments based on four dimensions: freedom from pain in 2 hours, efficacy for at least 24 hours from a single dose, ability to plan daily activities, and interference with daily living.

[0264] Meloxicam / rizatriptan will demonstrate significant improvement over the placebo group and superiority over the rizatriptan and meloxicam groups due to rapid absorption and the two different mechanisms of action of meloxicam / rizatriptan described herein.

[0265] Example 8 A female migraine sufferer visits her doctor hoping for relief from her migraines. Her doctor prescribes 10 mg rizatriptan (Maxalt®) to be taken during her next acute migraine. This provides some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At her next visit, her doctor prescribes 20 mg meloxicam in a tablet that also contains SBEβCD and 500 mg sodium bicarbonate to be taken during her next acute migraine. This provides some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At her next visit, her doctor prescribes her the tablets of Example 4 above. She reported that at 2 and 24 hours after taking the tablets, her pain, nausea, allodynia, photophobia, and / or phonophobia improved by approximately 10-30% versus the little relief she experienced after taking meloxicam or rizatriptan alone.

[0266] Example 9 A male migraine sufferer visits his doctor hoping for relief from his migraines. His doctor prescribes 10 mg rizatriptan (Maxalt®) to be taken during his next acute migraine. This provides some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At his next visit, his doctor prescribes 20 mg meloxicam, in a tablet that also contains SBEβCD and 500 mg sodium bicarbonate, to be taken during his next acute migraine. This provides some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At his next visit, his doctor prescribes him the tablets of Example 4 above. He reported that at 2 and 24 hours after taking the tablets, his pain, nausea, allodynia, photophobia, and / or phonophobia improved by approximately 30-60% versus the little relief he experienced after taking meloxicam or rizatriptan alone.

[0267] Example 10 A female migraine sufferer visits her doctor hoping for relief from her migraines. Her doctor prescribes 10 mg rizatriptan (Maxalt®) to be taken during her next acute migraine. This provides some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At her next visit, her doctor prescribes 20 mg meloxicam in a tablet that also contains SBEβCD and 500 mg sodium bicarbonate to be taken during her next acute migraine. This provides some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At her next visit, her doctor prescribes her the tablets of Example 4 above. She reported that at 2 and 24 hours after taking the tablets, her pain, nausea, allodynia, photophobia, and / or phonophobia improved by approximately 60% to 100% relative to the improvements she experienced after taking meloxicam or rizatriptan alone.

[0268] Example 11 According to the Centers for Disease Control, 37 million Americans suffer from migraines, making them the number one cause of disability among neurological disorders in the United States, according to the American Migraine Foundation. Migraines are characterized by pulsatile attacks, severe and often disabling pain associated with dizziness, and hypersensitivity to light and / or sound. In the United States, direct (e.g., medical expenses, medication) and indirect (e.g., absenteeism, lost productivity) costs of migraines are estimated to be $78 billion annually [Gooch CL,Pracht E,Borenstein AR,The burden of neurological disease in the United States:A summary report and call to action.Ann Neurol.2017Apr;81(4):479-484]. Published surveys of migraine patients indicate that over 70% are not fully satisfied with their current treatment, nearly 80% are willing to try new treatments, and they want treatments that provide faster, more stable results and less recurrence of symptoms [(1) Smelt AF, Louter MA, Kies DA, Blom JW, Terwindt GM, van der Heijden GJ, De Gucht V, Ferrari MD, Assendelft WJ, What do patients consider to be the most important outcomes for effectiveness studies on migraine treatment? Results of a Delphi study. PLoS One. 2014Jun16;9(6):e98933,6 and (2) Lipton RB, Stewart WF, Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999;39(suppl2):S20-S26].

[0269] The World Health Organization classifies severe migraine attacks as one of the most disabling illnesses, comparable to dementia, quadriplegia, and active psychosis [(1) Menken et al., Arch Neurol. 2000;57:418-420, and (2) Shapiro and Goadsby. Cephalosalgia. 2007;27:991-4]. The debilitating pain and the constant fear of the next migraine attack impair family, social, and work life [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. People with migraine are twice as likely to suffer from depression and anxiety than healthy people [Antonaci et al., J Headache Pain. 2011;12:115-125]. Widespread misperceptions about the severity of migraine contribute to its underrecognition and undertreatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of patients are not fully satisfied with current treatments. Therefore, new treatments offering improved efficacy for this serious neurological disorder are urgently needed.

[0270] We conducted a phase 3, randomized, double-blind, multicenter, placebo- and positive-controlled trial to evaluate the efficacy and safety of the combination of meloxicam and rizatriptan (meloxicam / rizatriptan) in the acute treatment of moderate and severe migraine. Eligible patients must be 18-65 years of age, have a confirmed diagnosis of migraine with or without aura by ICHD-3 criteria (for at least 1 year), have an average of 2-8 moderate-to-severe migraine days per month, and have a history of incomplete response to previous acute migraine treatments, as assessed by the Migraine Treatment Optimization Questionnaire (mTOQ-4) (mean score 3.6) with a score of 7 in response to a poor response to previous acute treatments. Exclusion criteria included cluster migraine or other types of migraine, chronic daily headaches (≥15 non-migraine days per month), history of significant cardiovascular disease, and uncontrolled hypertension. In addition to a history of poor response, enrolled patients exhibited a high proportion of features strongly associated with poor treatment outcome, including cutaneous allodynia (75.4%), severe migraine pain (41.2%), obesity (43.7%), and morning migraine (36.6%).A total of 1,594 patients were randomly assigned in a 2:2:2:1 ratio to receive the monolayer tablet of Example 4 (20 mg meloxicam / 10 mg rizatriptan with SBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg) and SBEβCD (MoSEIC meloxicam), or placebo to treat a single migraine attack of moderate or severe intensity. The two co-primary endpoints of the study were the proportion of patients who were free from headache pain 2 hours after dosing for meloxicam / rizatriptan compared with placebo, and the proportion of patients who no longer suffered from the most bothersome migraine-related symptom (nausea, photophobia, or phonophobia) 2 hours after dosing. The superiority of meloxicam / rizatriptan over the rizatriptan and meloxicam groups (contribution of ingredients) was to be established based on sustained freedom from headache pain 2 to 24 hours after dosing (key secondary endpoint). The study was conducted under the FDA's Special Protocol Assessment (SPA).Rizatriptan, the active comparator in this study, is the fastest acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B / 1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov 17; 358(9294): 1668-75).

[0271] Meloxicam / rizatriptan provided rapid relief of migraine pain, with the proportion of patients achieving pain relief with meloxicam / rizatriptan being numerically greater than that with rizatriptan at all time points measured from 15 minutes onwards, and statistically significant only at 60 minutes (p=0.04) (Figure 14). The proportion of patients experiencing pain relief 1.5 hours after dosing was 60.5% with meloxicam / rizatriptan compared with 52.5% with rizatriptan and 48.3% with placebo (P=0.019 and P=0.004 for meloxicam / rizatriptan, respectively) (Figure 14).

[0272] Meloxicam / rizatriptan met the two pre-specified co-primary endpoints by demonstrating high statistical significance in a higher proportion of patients who were pain free (19.9% ​​vs. 6.7%, p<0.001, FIG. 15) and free of the most bothersome symptoms (36.9% vs. 24.4%, p=0.002) at 2 hours after administration compared to placebo.

[0273] The superiority of meloxicam / rizatriptan over rizatriptan (active comparator) and MoSEIC® meloxicam (contribution of ingredients) was established as specified in the SPA by a higher proportion of patients receiving meloxicam / rizatriptan achieved sustained freedom from pain from 2 to 24 hours post-dose compared with rizatriptan, MoSEIC® meloxicam, and placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively, p=0.038, p=0.001, and p<0.001 for meloxicam / rizatriptan, respectively; Figure 16A), a pre-specified key secondary primary outcome indicating the contribution of ingredients. Approximately 80% of patients treated with meloxicam / rizatriptan who achieved freedom from pain at 2 hours maintained freedom from pain throughout 24 hours. These results demonstrated significant improvement in freedom from pain and superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraine.

[0274] Meloxicam / rizatriptan provided substantially greater and more sustained relief of migraine pain compared to placebo and rizatriptan, which translates into a significant reduction in rescue medication use for meloxicam / rizatriptan compared to placebo and rizatriptan. The percentage of patients experiencing sustained pain relief 2-24 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 for meloxicam / rizatriptan, respectively) (Figure 16B).

[0275] A statistically significantly higher proportion of meloxicam / rizatriptan patients (46.5%) experienced sustained pain relief from 2 to 48 hours compared to placebo (31.3%) and rizatriptan (36.5%) patients (p<0.001, p=0.003 for meloxicam / rizatriptan, respectively) (Figure 17B). A statistically significantly higher proportion of meloxicam / rizatriptan patients (15.4%) experienced sustained freedom from pain from 2 to 48 hours compared to placebo (5.3%), rizatriptan (8.8%), and MoSEIC® meloxicam (8.1%) patients (p<0.001, p=0.003, p<0.001 for meloxicam / rizatriptan, respectively) (Figure 17A). Approximately 77% of patients treated with meloxicam / rizatriptan who achieved pain freedom at 2 hours maintained pain freedom through 48 hours.

[0276] Rescue medication was used by 23.0% of patients receiving meloxicam / rizatriptan compared with 43% of patients receiving placebo and 34.7% of patients receiving rizatriptan (p<0.001 for each group vs. meloxicam / rizatriptan). Approximately 77% of patients receiving meloxicam / rizatriptan did not require rescue medication. These results demonstrated the superiority of meloxicam / rizatriptan over the active comparator, rizatriptan, in the treatment of migraine.

[0277] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan in 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).

[0278] Some of the p-values ​​for meloxicam / rizatriptan versus rizatriptan for various endpoints are listed in Table 10 below, which show the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraine.

[0279] [Table 10]

[0280] Given that the active comparator in this study, rizatriptan, is the fastest acting oral triptan and is considered to be one of the most effective medications currently available for the acute treatment of migraine, and that this study included patients with difficult-to-treat migraines, it is highly significant that the treatment effect of meloxicam / rizatriptan was observed to provide greater and more sustained relief of migraine pain than rizatriptan. Many patients experience suboptimal responses to current acute migraine treatments that place them at higher risk for headache-related disability and progression to chronic migraine, factors associated with increased health care costs. The results of this study suggest that meloxicam / rizatriptan may provide an important treatment option for people with difficult-to-treat migraines.

[0281] Meloxicam / rizatriptan was safe and well tolerated in patients studied in this trial. The most commonly reported adverse events with meloxicam / rizatriptan were nausea, dizziness, and somnolence, none of which occurred in rates greater than placebo or in more than 3% of patients. There was one serious adverse event in the meloxicam / rizatriptan group that the investigator deemed unrelated to study drug.

[0282] The results of this study demonstrated that meloxicam / rizatriptan offers migraine patients the unique benefit of rapid, potent, and sustained relief of migraine pain compared with the potent active comparator, rizatriptan, in a rigorously designed study of patients with difficult-to-treat migraines. These results may have important implications for patient care based on inadequate response to current treatments and high rates of patient dissatisfaction.

[0283] Meloxicam / rizatriptan incorporates multiple mechanisms of action to address various migraine processes and aim to enhance efficacy. Meloxicam / rizatriptan is believed to act by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and inhibiting neuroinflammation, pain signaling, and central sensitization. The results of this study validate this approach and show that meloxicam / rizatriptan may provide significantly greater benefit than currently available treatments, even in patients with difficult-to-treat migraines. Meloxicam / rizatriptan may be used effectively for the acute treatment of migraine in adults with or without aura.

[0284] Example 12 Meloxicam / rizatriptan is also being evaluated in another Phase 3 randomized, double-blind, placebo-controlled study evaluating early treatment of migraine with meloxicam / rizatriptan. In this ongoing study, patients with a history of inadequate response will receive meloxicam / rizatriptan when they experience early signs of migraine pain, as opposed to treating migraine attacks when they develop moderate or severe migraines.

[0285] Eligible patients were randomly assigned 1:1 to receive meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, SBEβCD, and sodium bicarbonate, as described in Example 4 above), or placebo. Adult subjects had a confirmed diagnosis of migraine with or without aura. Treatment with meloxicam / rizatriptan was initiated at the first sign of migraine pain onset.

[0286] Co-primary endpoints were freedom from headache pain two hours after dosing and freedom from the most bothersome migraine-related symptom (nausea, photophobia, or phonophobia) for meloxicam / rizatriptan compared with placebo.

[0287] Unless otherwise indicated, the numbers expressing properties such as amounts, quantities, percentages of ingredients, etc. used in the specification and claims should be understood in all cases as indicating both the exact value indicated and the value modified by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, no attempt is made to limit the application of equivalents to the scope of the claims, and each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0288] The terms "a," "an," "the," and similar references used in the context of describing embodiments (particularly in the context of the claims below) should be construed to cover both the singular and the plural, unless otherwise indicated or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "such as"), are intended to better clarify the embodiments and do not impose limitations on the scope of the claims. Nothing in this specification should be construed as indicating any non-claim element essential to the practice of the claims.

[0289] Groupings of alternative elements or embodiments disclosed herein should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. For reasons of convenience and / or ease of implementation, it is anticipated that one or more members of a group may be included in or deleted from a group. When such inclusion or deletion occurs, the specification is deemed to include the modified group, which, when used in the appended claims, satisfies all of the recitations of the Markush group.

[0290] Several embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of these described embodiments will become apparent to those of skill in the art upon reading the foregoing description. The inventors expect those of skill in the art to make appropriate use of such variations, and the inventors intend to carry out the claimed embodiments in ways other than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, combinations of the above-described elements in all possible variations thereof are contemplated unless otherwise indicated herein or clearly contradicted by context.

[0291] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Thus, alternative configurations of the invention may be utilized in accordance with the teachings herein, by way of example, but not of limitation. Thus, the claims should not be limited to the exact embodiments shown and described.

[0292] (Additional Note) (Appendix 1) 1. A method of treating migraine comprising: selecting a human migraine patient who has a history of incomplete response to previous migraine treatments; and orally administering to the migraine patient a dosage form comprising a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan.

[0293] (Appendix 2) 2. The method of claim 1, wherein the human migraine patient experiences migraine relief as a result of oral administration of the dosage form to the migraine patient.

[0294] (Appendix 3) 3. The method of claim 1 or 2, wherein the human migraine patient is free of migraine pain 2 hours after the dosage form is orally administered to the human migraine patient.

[0295] (Appendix 4) 4. The method of claim 1, 2, or 3, wherein the migraine patient experiences relief from nausea as a result of oral administration of the dosage form to the migraine patient.

[0296] (Appendix 5) 5. The method of claim 1, 2, 3, or 4, wherein the human migraine patient is free of nausea 2 hours after the dosage form is orally administered to the human migraine patient.

[0297] (Appendix 6) 6. The method of claim 1, 2, 3, 4, or 5, wherein the migraine patient experiences a reduction in photophobia as a result of oral administration of the dosage form to the migraine patient.

[0298] (Appendix 7) 7. The method of claim 1, 2, 3, 4, 5, or 6, wherein the human migraine patient is free of photophobia 2 hours after the dosage form is orally administered to the human migraine patient.

[0299] (Appendix 8) The method of claim 1, 2, 3, 4, 5, 6, or 7, wherein the migraine patient experiences relief from phonophobia as a result of oral administration of the dosage form to the migraine patient.

[0300] (Appendix 9) The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the human migraine patient is free of phonophobia 2 hours after the dosage form is orally administered to the human migraine patient.

[0301] (Appendix 10) 10. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the dosage form comprises 400 mg to 600 mg of bicarbonate.

[0302] (Appendix 11) 11. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the dosage form comprises about 5 mg to about 50 mg of meloxicam.

[0303] (Appendix 12) 12. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the dosage form comprises about 50 mg to about 200 mg of SBEβCD.

[0304] (Appendix 13) The dosage form is intended to determine the T value of meloxicam in humans. max is a solid oral dosage form that is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate.

[0305] (Appendix 14) 14. The method of claim 1, wherein about 1 mg to about 50 mg of rizatriptan is present in the oral dosage form, based on the weight of rizatriptan in free base form.

[0306] (Appendix 15) 15. The method of claim 14, wherein the rizatriptan is present in a salt form in an amount of about 10 mg, the molar equivalent of the free base form of rizatriptan.

[0307] (Appendix 16) 16. The method of claim 14 or 15, wherein the rizatriptan is present as rizatriptan benzoate.

[0308] (Appendix 17) 17. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the oral dosage form comprises from about 10 mg to about 30 mg of meloxicam.

[0309] (Appendix 18) 18. The method of claim 17, wherein the oral dosage form comprises about 20 mg of meloxicam.

[0310] (Appendix 19) 18. The method of claim 17, wherein the oral dosage form comprises about 15 mg of meloxicam.

[0311] (Appendix 20) 20. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[0312] (Appendix 21) 21. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the oral dosage form comprises about 50 mg to about 150 mg of SBEβCD.

[0313] (Appendix 22) 22. The method of claim 21, wherein the oral dosage form comprises about 100 mg of SBEβCD.

[0314] (Appendix 23) 23. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the molar ratio of SBEβCD to meloxicam is about 0.5 to about 2.

[0315] (Appendix 24) 24. The method of claim 23, wherein the molar ratio of SBEβCD to meloxicam is about 0.8 to about 1.2.

[0316] (Appendix 25) 24. The method of claim 23, wherein the molar ratio of SBEβCD to meloxicam is about 1.

[0317] (Appendix 26) 26. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the oral dosage form comprises from about 10 mg to about 40 mg of meloxicam and from about 5 mg to about 50 mg of rizatriptan.

[0318] (Appendix 27) 27. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the oral dosage form comprises SBEβCD in a weight ratio of SBEβCD to rizatriptan in the range of about 1 to about 100.

[0319] (Appendix 28) 28. The method of claim 27, wherein the oral dosage form comprises SBEβCD in a weight ratio to rizatriptan of about 10.

[0320] (Appendix 29) 29. The method of claim 1, 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, or 28, wherein the bicarbonate comprises sodium bicarbonate.

[0321] (Appendix 30) 30. The method of claim 29, wherein the oral dosage form comprises 500 mg of sodium bicarbonate.

[0322] (Appendix 31) The oral dosage form has a T of meloxicam in the fasted human subject. max 31. The method of claim 1, 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, or 30, wherein the median time to complete the procedure is less than about 90 minutes.

[0323] (Appendix 32) The oral dosage form has a T of meloxicam in the fasted human subject.max The method of claim 31, wherein the median time to effect immunization has been shown to be less than about 2 hours.

[0324] (Appendix 33) 33. The method of claim 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, wherein the oral dosage form has been shown to have a faster time to reach therapeutic plasma concentrations in humans compared to a reference dosage form.

Claims

1. 2. Use of a combination in the manufacture of a medicament for treating migraine in a human migraine patient, said human migraine patient having a history of incomplete response to previous migraine treatments, said combination comprising meloxicam and rizatriptan, said medicament being orally administered to said migraine patient, and after administration of said medicament, said human migraine patient has a C of about 2500 to about 3000 ng / mL of meloxicam. ｍａｘ To have, to use.

2. 2. The use of claim 1, wherein the human migraine patient experiences migraine relief as a result of oral administration of the medicament to the migraine patient.

3. 3. The use according to claim 1 or 2, wherein the human migraine patient is free of migraine pain 2 hours after the medicament is orally administered to the human migraine patient.

4. 4. The use of claim 1, 2, or 3, wherein the migraine patient has nausea, photophobia, or phonophobia, or a combination thereof, and the migraine patient experiences relief of the nausea, photophobia, or phonophobia, or a combination thereof, as a result of oral administration of the medicament to the migraine patient.

5. 5. The use of claim 4, wherein the human migraine patient is free of nausea, photophobia, or phonophobia, or a combination thereof, 2 hours after the medicament is orally administered to the human migraine patient.

6. The use of claim 1, 2, 3, 4, or 5, wherein the combination comprises about 5 mg to about 50 mg of meloxicam.

7. The medicament is a solid oral medicament comprising a combination of 1) a complex of meloxicam with sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan, and is characterized in that it has been shown to improve the TLR of meloxicam in human migraine patients. ｍａｘ is shorter than a reference medication that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, 3) does not contain rizatriptan, and 4) does not contain bicarbonate.

8. 8. The use of claim 1, 2, 3, 4, 5, 6, or 7, wherein about 1 mg to about 50 mg of rizatriptan is present in the oral medicament, based on the weight of rizatriptan in free base form.

9. 9. The use of claim 8, wherein rizatriptan is present in salt form in an amount of about 10 mg, the molar equivalent of rizatriptan in the free base form.

10. 10. The use according to claim 8 or 9, wherein the rizatriptan is present as rizatriptan benzoate.

11. 11. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the oral medicament comprises from about 10 mg to about 30 mg of meloxicam.

12. The use according to claim 11, wherein the oral medicament comprises about 20 mg of meloxicam.

13. 13. The use according to claim 11 or 12, wherein meloxicam is in the free acid form.

14. 14. The use of claim 7, 8, 9, 10, 11, 12, or 13, wherein the SBEβCD has from about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

15. 15. The use of claim 7, 8, 9, 10, 11, 12, 13, or 14, wherein the oral medicament comprises from about 50 mg to about 200 mg of SBEβCD.

16. 16. The use of claim 15, wherein the oral medicament comprises about 100 mg to about 150 mg of SBEβCD.

17. 17. The use of claim 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, or 16, wherein the oral medicament comprises about 10 mg to about 40 mg of meloxicam and about 5 mg to about 50 mg of rizatriptan.

18. 18. The use of claim 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the bicarbonate comprises 500 mg of sodium bicarbonate.

19. The oral medicament has a T value of meloxicam in the fasted human subject. ｍａｘ The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the median duration of the anti-inflammatory effect is less than about 2 hours.

20. 20. The use of claim 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the oral medicament has been shown to have a faster time to reach therapeutic plasma concentrations in human migraine patients compared to a reference medicament.

21. 21. The use of claim 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, or 20, wherein the combination comprises 400 mg to 600 mg of bicarbonate.

22. 22. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the human migraine patient has a confirmed diagnosis of migraine with or without aura and has been experiencing migraine pain with or without aura for at least one year.

23. 23. The use of claim 22, wherein the human migraine sufferer has an average of 2 to 8 moderate to severe migraines per month.

24. After administration of the medicament, the human migraine patient had a C of about 2900 ng / mL of meloxicam. ｍａｘ 2. The use according to claim 1, having the formula:

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