Use of combinations containing meloxicam and rizatriptan

Abstract

We provide a combination containing meloxicam and rizatriptan. [Solution] A composition is disclosed comprising an NSAID such as meloxicam and / or rizatriptan in combination with cyclodextrin and / or carbonate or bicarbonate. These compositions can be administered orally to improve the bioavailability or pharmacokinetics of NSAIDs for the treatment of pain such as migraines, arthritis, and other conditions. Also provided is a method for treating pain such as migraines, comprising administering meloxicam and rizatriptan to a person suffering from pain such as migraines. These methods may be particularly useful when administering meloxicam and rizatriptan while a person is suffering from an acute migraine attack or aura. In some embodiments, the combination of meloxicam and rizatriptan is used, with meloxicam being T max It may be administered so that the time interval is 3 hours or less.

Description

[Technical Field]

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

[0002] Meloxicam, having the structure shown below, is a non-steroidal 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 stages of the arachidonic acid cascade, thereby reducing the formation of prostaglandins, thromboxanes, and prostacyclins.

[0003] [ka] [Overview of the Initiative] [Means for solving the problem]

[0004] Meloxicam and some other NSAIDs have poor water solubility, which can reduce their bioavailability and delay the onset of pain relief resulting from their use. One way to increase the solubility and bioavailability of meloxicam is by using cyclodextrins. Cyclodextrins (also known as cycloamylose) are cyclic polysaccharides that generally form a bucket-like shape. Cyclodextrins help increase the bioavailability of other molecules because they are hydrophobic internally and hydrophilic internally, which helps facilitate the transport of molecules. Naturally occurring cyclodextrins contain 6, 7, and 8 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 micelle-type structures. This ability of cyclodextrins may allow them to act as carriers, increasing the bioavailability of less soluble drugs.

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

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

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

[0008] Some embodiments include methods of orally administering meloxicam to a patient in need of treatment, comprising orally administering the dosage forms described herein to the patient.

[0009] Some embodiments include methods of intravenously administering meloxicam to a patient in need of treatment, comprising intravenously administering the dosage forms described herein to the patient.

[0010] Formulations in which a cyclodextrin-meloxicam inclusion complex is formulated with a bicarbonate and methods of using the same are disclosed herein.

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

[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 various pain symptoms.

[0014] Rizatriptan has the structure shown below.

Chemical Formula

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

[0016] Some embodiments include a combination of the subject matter, comprising rizatriptan and meloxicam, that exhibits 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 treatment.

[0017] Some embodiments include subject combinations containing zatriptan and meloxicam, which result in significantly less emergency medication use compared to placebo, rizatriptan, or meloxicam. [Brief explanation of the drawing]

[0018] [Figure 1] This is a diagram of the results described in Example 2 and included in Table 6. [Figure 2] This is another figure of the results described in Example 2 and included in Table 6. [Figure 3] This is another figure of the results described in Example 2 and included in Table 6. [Figure 4] This is another figure of the results described in Example 2 and included in Table 6. [Figure 5] This is another figure of the results described in Example 2 and included in Table 6. [Figure 6] This is another figure of the results described in Example 2 and included in Table 6. [Figure 7] This is another figure of the results described in Example 2 and included in Table 6. [Figure 8] This is another figure of the results described in Example 2 and included in Table 6. [Figure 9] This is another figure of the results described in Example 2 and included in Table 6. [Figure 10] This is another figure of the results described in Example 2 and included in Table 6. [Figure 11] This is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for one embodiment of the dosage form described herein and for commercially available meloxicam dosage forms. [Figure 12]This 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 commercially available meloxicam dosage forms. [Figure 13] This 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 the commercially available meloxicam dosage form. [Figure 14] This plot shows the percentage of subjects who reported pain relief at various time points over the first four hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 15] The percentage of subjects who were relieved of pain 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] This shows the percentage of subjects who experienced sustained pain relief 2 to 24 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 16B] This shows the percentage of subjects who experienced sustained pain relief 2 to 24 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 17A] This shows the percentage of subjects who experienced sustained pain relief 2 to 48 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 17B] This shows the percentage of subjects who experienced sustained pain relief 2 to 48 hours after administration of the meloxicam / rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. [Figure 18]This shows the percentage of subjects who took the old medication within 24 hours after administration of the meloxicam / rizatriptan dosage form, rizatriptan, MoSEIC meloxicam, and placebo described in Example 11. [Modes for carrying out the invention]

[0019] This specification provides dosage forms comprising an NSAID (e.g., meloxicam) and a cyclodextrin (optionally in an inclusion complex), and / or a bicarbonate, as well as methods of treatment using such dosage forms.

[0020] The dosage form may be, but is not limited to, oral, enteral (including sublingual or rectal delivery), or parenteral (including intravenous, intramuscular, intranasal or subcutaneous delivery).

[0021] Some methods involve administering a product combining an NSAID formulated with a cyclodextrin and / or a buffer. In some embodiments, the method involves treating a patient with a pharmaceutical formulation comprising meloxicam and cyclodextrin and / or carbonate / bicarbonate. Embodiments of the method may also include treating a 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, cyclodextrin (such as SBEβCD), and bicarbonate (such as sodium bicarbonate) substantially increases solubility and absorption of meloxicam after oral administration, while the half-life of plasma concentrations in mammals such as humans after oral administration remains prolonged.

[0023] The combination of meloxicam, cyclodextrin (such as SBEβCD), and bicarbonate (such as sodium bicarbonate) substantially increases the bioavailability of meloxicam in mammals, including humans, after oral administration.

[0024] Unless otherwise stated, references to the compounds herein, such as meloxicam or lyzatriptan, by structure, name, or any other means, include any chemical species such as pharmaceutically 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 the compounds herein under the conditions under which they are used as described herein.

[0025] The subject matter may be administered by enteral delivery, including oral, sublingual, or rectal delivery, or by parenteral delivery, including intravenous, intramuscular, intranasal, or subcutaneous delivery, but is not limited to these. 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 time from each other. For example, meloxicam and rizatriptan may be administered within approximately 2 hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute from each other. In some embodiments, meloxicam and rizatriptan are administered simultaneously, but for the purposes of this disclosure, administration within approximately 5 minutes is included. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form.

[0027] The terms “to treat” or “to cure” broadly include any type of therapeutic activity, including the diagnosis, cure, alleviation, or prevention of disease in humans or other animals, or any activity that is not therapeutic but affects the structure or any function of the body in humans or other animals.

[0028] The dosage form or combination of themes may be used to treat or provide relief from any type of pain, including but not limited to migraines and other types of headaches, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, systemic pain, cancer-related pain, acute pain, pain due to injury, pain due to illness (e.g., fever), and postoperative pain. In some cases, pain relief may be temporary, or pain relief may be provided independently of improvement of the disease or condition, or the underlying cause of the disease or condition. For example, the underlying disease may not improve or may continue to progress, but the individual suffering from the disease may experience pain relief. In some embodiments, pain affects muscles, nerves, cartilage, bones, ligaments, tendons, tendon sheaths, eardrums, or joints.

[0029] Migraine is a distressing neurological disorder characterized by periodic episodes of throbbing headaches accompanied by nausea and hypersensitivity to light and sound. The pain is moderate to severe, but often severe enough to be immobile and require bed rest. The headache may affect one side of the head, is throbbing, and can last from 2 hours to 72 hours. Associated symptoms may include nausea, vomiting, photophobia (fear of light), phonophobia (fear of sound), or olfactory hypersensitivity. The pain may be worsened by physical activity. Migraines may have an aura, which can be a brief visual disturbance that signals an upcoming headache. Some migraine sufferers do not experience an aura.

[0030] In some embodiments, individuals receiving treatment for migraines suffer from allodynia accompanying migraine attacks. Allodynia is pain triggered by normally painless stimuli (such as combing hair, getting dressed, or showering). Patients with allodynia are thought to be less responsive to triptan medications.

[0031] Current treatments are not optimal, and more than 70% of patients are dissatisfied with their current acute treatments. The most common reasons for patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and pain recurrence within the same day. Suboptimal acute treatments are associated with a significantly increased risk of developing new chronic migraines, which can be prevented by improving the outcomes of acute treatment.

[0032] Administering the subject combination to a person suffering from migraine, such as an acute migraine attack or aura, may reduce migraine symptoms such as pain, nausea, vomiting, photophobia, or phonophobia within approximately 5 minutes or less (intended as “in 5 minutes” or “within 5 minutes”), approximately 10 minutes or less, approximately 30 minutes or less, approximately 1 hour or less, approximately 90 minutes or less, approximately 2 hours or less, approximately 2.5 hours or less, or approximately 3 hours or less. In some embodiments, a person experiences a reduction or complete relief of pain such as headache or migraine, nausea, vomiting, photophobia, and / or phonophobia within approximately 1 hour or less, approximately 90 minutes or less, approximately 2 hours or less, approximately 2.5 hours or less, or approximately 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 distinct mechanisms of action as an acute treatment for migraines. Meloxicam is a potent, COX-2-preferential NSAID, limited by its slow absorption. Rizatriptan is a potent 5-HT1-1 NSAID, which is thought to be effective for migraines. B / D He is an agonist.

[0034] Findings of symptom relief or reduction at a specific point in time, such as "2 hours," are useful because they allow for the evaluation of treatment effectiveness at a specific or consistent point in time, facilitating comparisons between patients. Since it is desirable for symptom relief or reduction to occur as quickly as possible, and clearly defining relief within a specific time frame helps establish guidelines for what relief is desirable, findings of symptom relief or reduction within a specific time frame, such as "within 2 hours," are useful.

[0035] For some purposes, administration of a combination of the themes may relieve pain, nausea, vomiting, photophobia, or phonophobia for at least approximately 1 hour, at least approximately 2 hours, at least approximately 3 hours, at least approximately 4 hours, at least approximately 6 hours, at least approximately 8 hours, at least approximately 8 to 24 hours, at least approximately 24 hours, or for 24 hours or more.

[0036] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater pain relief than they would experience two hours after administration of the same amount of meloxicam without rizatriptan.

[0037] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater pain relief than they would experience within 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0038] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, humans experience greater pain relief than they would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0039] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater pain relief than they would experience within 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0040] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater relief of nausea than they would experience two hours after administration of the same amount of meloxicam without rizatriptan.

[0041] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater relief of nausea than they would experience within 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0042] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater relief of nausea than they would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0043] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater relief of nausea than they would experience within 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0044] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater relief of vomiting 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 (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater relief of vomiting than they would experience within 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0046] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater relief of vomiting than they would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0047] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a person experiences greater relief of vomiting than they would experience 24 hours after administration of the same amount of rizatriptan without meloxicam. In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, a person experiences greater relief of photophobia than they would experience 2 hours after administration of the same amount of meloxicam without rizatriptan.

[0048] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater photophobia relief than they would experience within 24 hours after administration of the same amount of meloxicam without rizatriptan.

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

[0050] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater photophobia relief than they would experience within 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0051] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, humans experience greater relief of phonophobia than they would experience two hours after administration of the same amount of meloxicam without rizatriptan.

[0052] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater relief of phonophobia than they would experience within 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0053] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, humans experience greater relief of phonophobia than they would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0054] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater relief of phonophobia than they would experience within 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0055] In some embodiments, the person administered the subject combination has a history of an incomplete response to previous migraine treatments. For example, if a person is asked whether the pain was gone within two hours of treatment for most attacks and given the options "none at all," "almost none," "less than half," or "more than half," and the person answers "none at all," "almost none," or "less than half," then that person has an incomplete response to treatment. Similarly, if a person is asked whether the headache was mostly relieved with a single dose and did not occur for at least 24 hours and given the options "none at all," "almost none," "less than half," or "more than half," and the person answers "none at all," "almost none," or "less than half," then that person has an incomplete response to treatment.

[0056] In some embodiments, individuals administered the subject combination showed that for most seizures, pain relief within two hours of treatment was "never." In some embodiments, individuals administered the subject combination showed that for most seizures, pain relief within two hours of treatment was "rarely." In some embodiments, individuals administered the subject combination showed that for most seizures, pain relief within two hours of treatment was "less than half."

[0057] In some embodiments, individuals administered the subject combination showed that their headaches were relieved and they were headache-free for at least 24 hours after a single dose, which was "never the case." In some embodiments, individuals administered the subject combination showed that their headaches were relieved and they were headache-free for at least 24 hours after a single dose, which was "rarely the case." In some embodiments, individuals administered the subject combination showed that their headaches were relieved and they were headache-free for at least 24 hours after a single dose, which was "less than half the case."

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

[0059] In some embodiments, a person administered a combination of the subject, such as a combination containing meloxicam and rizatriptan, may have migraines and a history of inadequate response to previous migraine treatments. In some embodiments, a person with migraines does not have cluster headaches or other types of migraines. In some embodiments, a person with migraines does not have chronic daily headaches. In some embodiments, a person with migraines has no migraine-free days for more than 15 days, 15-20, 20-25, 25-28, 28-30, or 30-31 days per month. In some embodiments, a person with migraines has no history of significant cardiovascular disease. In some embodiments, a person with migraines does not have uncontrolled hypertension.

[0060] In some embodiments, the dosage form may be administered to relieve pain of arthritis. 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-rheumatic), arthropathy, non-rheumatoid arthritis, periarthritis, axonal spondyloarthritis, transient osteoarthritis of the hip, vertebral contusion fracture, osteoporosis, and neurogenic arthropathy including Charcot foot, spondyloarthropathy including ankylosing spondylitis, and SAPHO syndrome. In other embodiments, the pain of arthritis 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 embodiments, the administration of the dosage form can achieve pain relief lasting 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, the administration of the dosage form can achieve pain relief observed at about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, 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 after the administration of the dosage form, or other periods bounded by these ranges.

[0062] In some embodiments, the dosage form may be administered to relieve neuropathic pain including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, uniacilitation neuralgia, phantom limb pain, sciatica, pudendal neuralgia, and central pain. Other causes of neuropathic pain may 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 radiotherapy or chemotherapy. The neuropathic pain being treated may be chronic or acute.

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

[0064] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include, but are not limited to, osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthropathy, non-rheumatic arthropathy, periarthritis, neuropathic arthropathy including Charcot foot, axonal spondyloarthropathy including ankylosing spondylitis, and pain associated with SAPHO syndrome. Inflammatory joint diseases treated can be chronic or acute.

[0065] In some cases, meloxicam can be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain may include, but are not limited to, lower back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, spasms, tendinitis, thyroiditis, carpal tunnel syndrome, arthralgia, fibromyalgia, pain due to injury, carpal tunnel syndrome, pain associated with fractures, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of the bone, transient osteoporosis, and transient osteoporosis of the hip. In other embodiments, musculoskeletal pain may be chronic or acute.

[0066] In some ways, administration of a dosage form or combination of themes can achieve a reduction in pain lasting at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8 to about 24 hours, or about 24 hours. In another embodiment, administration of a combination of themes can achieve a reduction in pain observed at about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, within about 5 minutes or less, within about 10 minutes or less, within about 15 minutes or less, within about 20 minutes or less, within about 25 minutes or less, within about 30 minutes or less, within about 35 minutes or less, within about 40 minutes or less, within about 45 minutes or less, within about 50 minutes or less, or within about 60 minutes or less, within 2 hours or less, or within 3 hours or less, or at other periods bounded by these ranges.

[0067] A person receiving treatment for a disease or condition in the dosage form described herein may be of any age. For example, they may be approximately 10 to 90 years old, approximately 20 to 80 years old, approximately 30 to 75 years old, approximately 40 to 70 years old, approximately 1 to 16 years old, approximately 80 to 95 years old, approximately 18 years and older, approximately 20 years and older, approximately 25 years and older, approximately 30 years and older, approximately 40 years and older, approximately 45 years and older, approximately 50 years and older, approximately 55 years and older, approximately 60 years and older, approximately 65 years and older, or any other age bounded by or within these values.

[0068] In some embodiments, a person receiving treatment for migraines with a dosage form described herein, for example, meloxicam, rizatriptan, SBEβCD, and a bicarbonate such as sodium bicarbonate, may be between 18 and 65 years of age, about 18 to 20 years, about 20 to 25 years, about 25 to 30 years, about 30 to 40 years, about 40 to 45 years, about 40 to 50 years, about 50 to 60 years, about 60 to 65 years, or any other age bounded by or within these values.

[0069] In some embodiments, individuals receiving treatment for migraines with the dosage forms described herein, such as meloxicam, rizatriptan, SBEβCD, and dosage forms containing bicarbonates such as sodium bicarbonate, may be Caucasian, Black, African American, or Asian.

[0070] In some embodiments, a person receiving treatment for a disease or condition with a dosage form containing meloxicam or another NSAID suffers from pain-related pain or condition 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 of time bordered by these values ​​or within the range in between.

[0071] In some embodiments, individuals treated for migraines with or without aura, as defined by the ICHD-3 criteria, have been diagnosed with migraine with or without aura for at least three months, at least six months, at least one year, at least two years, about one to two years, two to three years, or longer, or any period bordered by or within these values.

[0072] In some embodiments, humans experience an average of 2-8, 2-3, 3-4, 4-5, 5-6, 6-7, and 7-8 moderate to severe migraines.

[0073] The cyclodextrin used in a dosage form containing meloxicam may include cyclodextrin, cyclodextrin derivatives, and / or salts thereof. Inclusion complexes of meloxicam and 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. α-cyclodextrins may include, but are not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O-tert-butyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0074] In some embodiments, β-cyclodextrin, its derivatives or salts may be used. β-cyclodextrins include, but are 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- Romo-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,This may include 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 may be a sulfoalkyl ether cyclodextrin, a derivative thereof, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-β-cyclodextrins (e.g., SBEβCD, BetaDex, CAPTISOL®). In some embodiments, SBEβCD may have about 4 to 8, about 5 to 8, about 4 to 7, about 6 to 7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

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

[0077] In some embodiments, the dosage form may contain bicarbonates such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or combinations thereof. Bicarbonates may help increase the bioavailability of meloxicam.

[0078] In other embodiments, the dosage form may include carbonates, derivatives thereof, or salts. 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 a dosage form can 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 cyclodextrin, and / or by containing a bicarbonate. This allows for a reduction in the molar amount of meloxicam used compared to other meloxicam dosage forms.

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

[0081] In some embodiments, the use of cyclodextrin, carbonate, or bicarbonate can improve 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 by any amount bounded by these values ​​compared to administration of meloxicam alone, or within the range in between.

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

[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 meloxicam administered with cyclodextrin, carbonate and / or bicarbonate.

[0084] In some embodiments, the dosage form may contain meloxicam in amounts of approximately 1–50 mg, approximately 1–10 mg, approximately 1–5 mg, approximately 10–40 mg, approximately 1–35 mg, approximately 1–25 mg, approximately 1–15 mg, approximately 5–20 mg, approximately 5–10 mg, approximately 5–15 mg, approximately 10–20 mg, approximately 20–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 5 mg, approximately 7.5 mg, approximately 10 mg, approximately 15 mg, approximately 30 mg, or any amount of meloxicam bounded by or within the range between these values. These doses may be safe doses for repeated administration, such as once per hour to once per hour, twice per day, once to 12 times per day, three times, four times, five times, or six 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 a day, about 3 to about 10 times a day, once a day, or less frequently, for example, once a week, once every two weeks, once a month, etc.

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

[0086] The formation of inclusion complexes between meloxicam and cyclodextrin may help improve the properties of the dosage form. For some inclusion complexes, meloxicam and cyclodextrin (e.g., SBEβCD) may have molar ratios of about 0.5–2 (0.5 molar ratio 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 molar ratio bounded by or within these values.

[0087] In some dosage forms, cyclodextrin (e.g., SBEβCD) may be used in weight ratios to meloxicam of approximately 1 to 1000 (e.g., 1 g of cyclodextrin per 1 g of meloxicam in a weight ratio of 1), approximately 1 to 20, approximately 1 to 10, approximately 1 to 15, approximately 2 to 4, approximately 3 to 5, approximately 4 to 6, approximately 5 to 7, approximately 6 to 8, approximately 7 to 9, approximately 8 to 10, or bounded by these values, or within the ranges in between. In some dosage forms, cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of approximately 0.001–1 (e.g., 0.1 g of cyclodextrin per 1 g of meloxicam at a weight ratio of 0.1), approximately 0.01–1, approximately 0.05–1, approximately 0.1–1, approximately 0.2–1, approximately 0.3–1, approximately 0.4–1, approximately 0.5–1, approximately 0.6–1, approximately 0.7–1, approximately 0.8–1, or any weight ratio to meloxicam bounded by these values ​​or within the range between them. Each type of cyclodextrin used may have a different ratio.

[0088] In some dosage forms, cyclodextrin may be present in amounts of approximately 1–200 mg, approximately 25–175 mg, approximately 50–150 mg, approximately 25–100 mg, approximately 75–150 mg, approximately 100–175 mg, approximately 20–80 mg, approximately 25–50 mg, approximately 60–100 mg, approximately 80–100 mg, approximately 80–120 mg, approximately 100–120 mg, approximately 100–140 mg, approximately 120–160 mg, approximately 140–180 mg, approximately 30–90 mg, approximately 40–80 mg, approximately 50–70 mg, approximately 55–65 mg, approximately 60–62 mg, or any amount bounded by these values ​​or within the range between them.

[0089] In some cases, the inclusion complex of meloxicam and cyclodextrin (e.g., substituted β-cyclodextrin) is delivered orally (e.g., by tablets, capsules, elixirs, 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 a non-complex with cyclodextrin.

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

[0091] Several dosage forms are available: approximately 1-1000mg, approximately 1-500mg, approximately 1-200mg, approximately 1-100mg, approximately 50-750mg, approximately 500-1000mg, approximately 100-500mg, approximately 100-300mg, approximately 200-800mg, approximately 500-1000mg, approximately 300-700mg, approximately 400-600mg, approximately 50-250mg, and approximately 250-750mg. g contains approximately 100-200 mg, 200-300 mg, 300-400 mg, 400-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, 150-650 mg, 350-850 mg, or any amount of carbonate bounded by or within these values.

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

[0093] In some embodiments, the weekly dose of meloxicam (e.g., oral dose) is approximately 1–1000 mg, approximately 1–500 mg, approximately 10–250 mg, approximately 100–300 mg, approximately 10–100 mg, approximately 10–150 mg, approximately 10–300 mg, approximately 20–150 mg, approximately 20–60 mg, approximately 30–70 mg, approximately 40–60 mg, approximately 50–70 mg, approximately 70–90 mg, approximately 90–110 mg, approximately 50 mg, approximately 55 mg, approximately 100–150 mg, approximately 30–100 mg, or any amount bounded by or within these values. The weekly dose may be administered as a single dose given once a week, or as separate doses given two, three, four, five, six, or seven times a week.

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

[0095] In other embodiments, the dosage form may be administered approximately 1, 2, 3, 4 or more consecutive weeks, every other week, i.e., every three weeks. This regimen may be repeated once a week, twice a month, three times a month, once a month, once every two months, once every three months, or as directed by a healthcare professional.

[0096] In certain embodiments, the pharmaceutical composition exhibits improved bioavailability of meloxicam from the dosage form (e.g., T) compared to dosage forms that contain meloxicam but do not contain cyclodextrin, acid inhibitors, or buffers (e.g., bicarbonates). max Decrease, C max This results in an increase in (e.g., an increase in AUC). In some embodiments, the bioavailability of meloxicam increases with multiple doses. For example, the bioavailability of meloxicam in a dosage form may increase after about 1–10 days, about 2–6 days, about 3–5 days, about 4–6 days, about 5–8 days, about 5 days, about 6 days, about 7 days, about 8 days, about 10 days, about 15 days, or any period bounded by or within the range between these values, compared to the bioavailability of meloxicam in a dosage form that does not contain cyclodextrin, acid inhibitors, or buffers (e.g., bicarbonates).

[0097] Some dosage forms can provide a desired range of the area under the plasma concentration curve (AUC) of meloxicam. For example, meloxicam doses are approximately 1–150 μg·hr / mL, 10–30 μg·hr / mL, 20–40 μg·hr / mL, 30–50 μg·hr / mL, 40–60 μg·hr / mL, 50–70 μg·hr / mL, 60–80 μg·hr / mL, 70–90 μg·hr / mL, 80–100 μg·hr / mL, 10–100 μg·hr / mL, and 50–150 μg·hr / mL. AUCs of meloxicam can be approximately 25–125 μg·hr / mL, approximately 75–150 μg·hr / mL, approximately 20–50 μg·hr / mL, approximately 40–70 μg·hr / mL, approximately 60–90 μg·hr / mL, approximately 80–110 μg·hr / mL, approximately 100–130 μg·hr / mL, and approximately 120–150 μg·hr / mL, or any AUC bounded by or within these ranges.

[0098] Unless otherwise specified, AUC is calculated over a 6-hour period. 0-6 ), AUC over a 12-hour period (AUC 0-12)、The AUC (AUC 0-24 ) measured at the end, such as the concentration measured at the end over a 24-hour period (AUC 0-t ), or the AUC calculated for the AUC (AUC 0-inf ) extrapolated to infinity.

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

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

[0101] For acute pain symptoms such as headache or other types of headache, the AUC (AUC 0-6 ) measured over 6 hours, i.e., the AUC in the short term after administration, is of particular interest. For example, some dosage forms can result in an AUC of meloxicam of at least approximately 6 μg·hr / mL, at least approximately 7 μg·hr / mL, at least approximately 8 μg·hr / mL, at least approximately 9 μg·hr / mL, approximately 6 - 10 μg·hr / mL, approximately 7 - 11 μg·hr / mL, approximately 8 - 12 μg·hr / mL, approximately 9 - 13 μg·hr / mL, or any AUC bounded by or within the range of these values.

[0102] In some embodiments, the dosage forms are approximately 10-2500 ng / mL, approximately 100-2250 ng / mL, approximately 500-2000 ng / mL, approximately 1000-2500 ng / mL, approximately 1000-2000 ng / mL, approximately 100-900 ng / mL, approximately 750-1500 ng / mL, approximately 1250-2000 ng / mL, approximately 1500-2300 ng / mL, approximately 800-1200 ng / mL, approximately 1900-2400 ng / mL, approximately 50-500 ng / mL, and approximately 400-950 ng / 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 at concentrations of 50-1700 ng / mL, approximately 1600-1800 ng / mL, approximately 1700-1900 ng / mL, approximately 1800-2000 ng / mL, approximately 1900-2100 ng / mL, approximately 2000-2200 ng / mL, approximately 2100-2300 ng / mL, approximately 2200-2400 ng / mL, approximately 2300-2500 ng / mL, and approximately 2500-3000 ng / mL. max , or any C within the range bounded by or between these values max This could lead to...

[0103] For example, the method described herein is for meloxicam T max This method can reduce the T of meloxicam within approximately 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 180 minutes, 1-10 hours, 2-9 hours, 3-7 hours, 4-6 hours, 1-5 hours, 2-7 hours, 3-8 hours, 4-9 hours, 1-4 hours, 2-5 hours, 3-6 hours, 4-7 hours, 5-8 hours, 6-9 hours, or 7-10 hours after administration. max , or any T within the range bounded by or between these values max This may include treating patients in order to achieve this.

[0104] In some embodiments, a certain oral dosage form is shorter than the T of meloxicam achieved by administering meloxicam by intramuscular injection. max In some embodiments, the oral dosage form may have a shorter meloxicam T at a rate of 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 faster than that observed with intramuscular injection, or at a rate of about 1.5 to 1000, about 2 to 100, about 3 to 100, about 4 to 100, about 5 to 100, about 6 to 100, about 7 to 100, about 8 to 100, about 9 to 100, about 10 to 100, about 12 to 100, about 15 to 100, about 20 to 100 times faster, or at any rate bounded by these values ​​or within the range between them. max It may have or may increase the plasma concentration of meloxicam.

[0105] In some embodiments, the dosage form containing meloxicam is approximately 0.01-0.5 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, Plasma concentrations of meloxicam at 12 hours may be approximately 2.3–2.5 μg / mL, 2.4–2.6 μg / mL, 2.5–2.7 μg / mL, 2.6–2.8 μg / mL, 2.7–2.9 μg / mL, 2.8–3 μg / mL, 2.9–3.1 μg / mL, 3–3.2 μg / mL, 3.1–3.3 μg / mL, 3.2–3.4 μg / mL, 3.3–3.5 μg / mL, 3.4–3.6 μg / mL, 3.5–3.7 μg / mL, 3.6–3.8 μg / mL, 3.7–3.9 μg / mL, 3.8–4 μg / mL, or any plasma concentration bounded by or within these values.

[0106] In some embodiments, meloxicam is present in concentrations of approximately 0.01-0.5 μg / mL, 0.5-0.7 μg / mL, 0.6-0.8 μg / mL, 0.7-0.9 μg / mL, 0.8-1 μg / mL, 0.9-1.1 μg / mL, 1-1.2 μg / mL, 1.1-1.3 μg / mL, 1.2-1.4 μg / mL, 1.3-1.5 μg / mL, 1.4-1.6 μg / mL, 1.5-1.7 μg / mL, and 1.6-1.8 μg. / 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, approximately 1~6 μg / mL, approximately 1~2 μg / mL, approximately 0.5~3.5 μg / mL, approximately 0.5~7 μg / mL, approximately 12~20 μg / mL, approximately 8~12 μg / mL, approximately 1~4 μg / mL, approximately 4~7 μg / mL, approximately 7~11 μg / mL, approximately 11~15 μg / mL, approximately 15~19 μg / mL, approximately 16~20 μg / mL, or any meloxicam plasma level bounded by or within the range between these values ​​(e.g., C avg It is administered in doses that result in (or mean plasma levels).

[0107] Administration of the dosage forms described herein may reduce the time to reach therapeutic plasma concentration of meloxicam. The therapeutic plasma concentration is C15 mg with Mobic® meloxicam. avg In some embodiments, the time to reach therapeutic plasma concentration of meloxicam (T thera) are approximately 10-30 minutes, approximately 10-15 minutes, approximately 15-20 minutes, approximately 20-25 minutes, approximately 25-30 minutes, approximately 10-20 minutes, approximately 20-30 minutes, approximately 16-18 minutes, or approximately 17 minutes.

[0108] The method described herein involves the T of lyzatriptan. max This can reduce the T of rizatriptan in patients within approximately 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 40-60 minutes, 40-45 minutes, 45-50 minutes, 50-55 minutes, or 55-60 minutes after administration. max , or any T bounded by these values max It is achievable.

[0109] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a person experiences greater pain relief than they would experience two hours after administration of the same amount of meloxicam without rizatriptan.

[0110] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater pain relief than they would experience within 24 hours after administration of the same amount of meloxicam without rizatriptan.

[0111] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, humans experience greater pain relief than they would experience two hours after administration of the same amount of rizatriptan without meloxicam.

[0112] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single dosage form such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, humans experience greater pain relief than they would experience within 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0113] One embodiment is a method for pain relief and for reducing the risk of gastrointestinal side effects in people taking NSAIDs for other conditions, particularly during chronic treatment, and for improving the bioavailability of NSAIDs. In one embodiment, the method relates to the administration of a product combining a) an agent that actively raises gastric pH, and b) a product combining cyclodextrin and a formulated NSAID. In another embodiment, the method relates to the administration of a product combining a) an agent that actively raises gastric pH, b) a product combining cyclodextrin and a formulated NSAID, and c) a buffer. Either short-acting or long-acting acid inhibitors can be effectively used in dosage forms. This method has the additional advantage of being able to protect patients from other sources of gastrointestinal ulcers whose effects can be enhanced by the breakdown of gastroprotective prostaglandins resulting from NSAID therapy.

[0114] Aqueous parenteral meloxicam formulations may contain buffers to adjust the pH of the aqueous formulation to approximately 2–5, approximately 3.5–5, approximately 5–11, approximately 6–9, approximately 6–8, approximately 6–7, or any other pH bounded by these values ​​or within that range. Oral meloxicam formulations may contain buffers to adjust the pH of gastric juice to approximately 2–5, approximately 3.5–5, approximately 5–11, approximately 6–9, approximately 6–8, approximately 6–7, or any other pH bounded by these values ​​or within that range. 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 food carrier, or may be encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into therapeutic diets. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, lozenges, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, etc.

[0116] Tablets, lozenges, pills, capsules, etc., may also contain one or more of the following: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; or flavorings such as peppermint, wintergreen oil, or cherry flavoring. If the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain active compounds, sucrose as a sweetener, methylparaben and propylparaben as preservatives, and colorants and flavorings such as cherry or orange flavoring. It may be desirable that the substances in a dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amount used.

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

[0118] The dosage form may include a second therapeutic agent, such as an antacid or analgesic.

[0119] In some embodiments, the dosage form may further include 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 at least 5 when one or more unit dosage forms are administered. The term “acid inhibitor” refers to a drug that inhibits gastric acid secretion and raises gastric pH. Certain H2 blockers, also called H2 antagonists or histamine H2 blockers or antagonists, include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, 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, reminoprazole, and tenatoprazole. In some embodiments, the daily dose of an 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 these values.

[0121] Examples of specific proton pump inhibitors include esomeprazole present in unit dosage forms between 5 mg and 50 mg, omeprazole present in unit dosage forms between 5 mg and 50 mg, lansoprazole present in unit dosage forms between 5 mg and 150 mg (preferably between 5 mg and 30 mg), and pantoprazole present in unit dosage forms between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is present in dosage forms 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 that compete with potassium for acid pumps have been developed. Compounds in this class may be referred to and used as “reversible proton pump inhibitors” or “acid pump antagonists.” Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, levaprazan, and soraprazan (see International Publications 96 / 05177 and 96 / 05199). Other compounds in this group include H-335 / 25 (AstraZeneca, Dialogue File 128, Accession No. 020806), Sch-28080 (Schering-Plough, Dialogue File 128, Accession No. 009663), Sch-32651 (Schering-Plough, Dialogue File 128, Accession No. 006883), and SK&F-96067 (CAS Registry No. 115607-61-9).

[0122] The second therapeutic activator may include a second nonsteroidal anti-inflammatory agent, an analgesic such as an opioid, steroid, or triptan. In some embodiments, the dosage form or treatment also further includes administering a second nonsteroidal anti-inflammatory agent in an amount effective to reduce or eliminate pain or inflammation. NSAIDs include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID for the 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, oxyfenbutazone, azapropazone, phenylbutazone, or combinations thereof. For the purposes of this disclosure, it is understood that acid inhibitors, NSAIDs, or analgesics include all common forms of these compounds, in particular their pharmaceutically acceptable salts. The therapeutically effective amount of NSAID may be lower in the present embodiments than actually observed elsewhere, due to potential positive kinetic interactions and NSAID absorption in the presence of acid inhibitors or buffers.

[0123] In other embodiments, the dosage form or treatment may further include administering an opioid in an amount effective to reduce or eliminate pain or inflammation. The opioid is, without limitation, (dextro)propoxifen, A-methylfentanyl, alfentanil, allylprozin, vegitramide, buprenorphine, butorphanol, carfentanil, desmethylprozin, dextromoramide, dezosin, diacetylmorphine, dihydrocodeinone, dihydroethorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, refetamine, levasetylmetadol, levote May contain metorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbufine, nalmefene, naloxone, naltrexone, nicomorphine, omefentanil, olipavin, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenatazosine, pyritramide, prozine, remifentanil, sufentanil, tapentadol, tyridine, tramadol, or combinations thereof.

[0124] Useful triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, alumotriptan, flovatriptan, albitotriptan, zolmitriptan, etc. In some embodiments, the triptan includes rizatriptan. In some embodiments, the dosage form may contain a triptan such as rizatriptan in amounts of 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, or any amount within the range bounded by these values.

[0125] In some embodiments, dosage forms including combinations of the subject matter are approximately 1-50 mg, approximately 1-10 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, or approximately 40-50 mg, approximately 10-40 mg, approximately 1-35 mg, approximately 1-25 mg, approximately 1-15 mg, approximately 1-10 mg, approximately 5-20 mg, approximately 1-5 mg, approximately 2-6 mg, approximately 3-7 mg, approximately 4-8 mg, approximately 5-10 mg, approximately 6-11 mg, approximately 7-12 mg, approximately 8-13 mg, approximately 9-11 mg, approximately 9-14 mg, approximately 10-15 mg, approximately It may contain 11-16 mg, approximately 12-17 mg, approximately 13-18 mg, approximately 14-19 mg, approximately 15-20 mg, approximately 5-15 mg, approximately 0.5 mg, approximately 1 mg, approximately 1.5 mg, approximately 2 mg, approximately 2.5 mg, approximately 3 mg, approximately 3.5 mg, approximately 4 mg, approximately 4.5 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 7.5 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, or any amount of rizatriptan bounded by or within these values.

[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, is of particular interest. For example, symptoms may be relieved over a long period after a single dose, without the need for repeated administration in the short term. Daily, weekly, or monthly doses for more persistent symptoms, including chronic, persistent, or frequent migraine symptoms, may be of particular interest.

[0127] With respect to the amounts of lyzatriptan described herein, the salt form of lyzatriptan may exist in the amounts described above, or in molar equivalents of those amounts relative to the free lyzatriptan base. For example, if the molecular weight of the free lyzatriptan base is 269.3 g / mol, then 10 mg of lyzatriptan is 37.1 mmol of lyzatriptan. Therefore, the molar equivalent of 10 mg of free lyzatriptan base is the amount of 37.1 mmol of the salt form. For example, for benzoate (mw = 391.2 g / mol), the molar equivalent of 10 mg of free base (or 37.1 mmol) is 14.5 mg. These doses may be safe to administer repeatedly at intervals of 1, 2, 3, or 4 times a day, or at intervals of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 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 containing (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 when one or more units of the dosage form are administered. The components of the pharmaceutical composition may be in immediate-release or sustained-release form, individually or as a whole.

[0129] As used herein, the term “unit dosage form” refers to a single entity for drug administration. For example, a single tablet or capsule combining both an acid inhibitor and an NSAID would be a unit dosage form. A “unit dosage form” (or “unit dose dosage form”) is also called a “fixed dosage form” (or “fixed dose dosage form”) or a “combination of fixed dosage forms” (or “combination of fixed dose dosage forms”), and these terms are interchangeable in other literature. In one embodiment, the unit dosage form is a multilayer 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 multilayer tablet comprising a single core and one or more layers outside the core.

[0131] Some dosage forms may comprise a first layer containing meloxicam, SBEβCD, and bicarbonate, as well as a second layer containing a second therapeutic agent and bicarbonate.

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

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

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

[0135] In some embodiments, the pharmaceutical composition may have an effective amount of meloxicam, cyclodextrin, and a carbonate or bicarbonate to enhance the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition may increase the bioavailability of meloxicam or the T max To reduce the risk, the material may contain effective amounts of meloxicam, sulfobutyl ether-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 having an enteric coating. In some embodiments, the dosage form may include a tablet or capsule having a film coating.

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

[0138] One embodiment of the present 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, (1) Inclusion complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), (2) Sodium bicarbonate, or bicarbonates such as potassium bicarbonate, (3) Triptans such as lyzatriptan This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0139] In certain embodiments, the pharmaceutical composition contains meloxicam but accelerates the release or dissolution of meloxicam from the dosage form compared to dosage forms that do not contain an acid inhibitor or a buffer.

[0140] Dosage forms containing the combination of rizatriptan and meloxicam ("the subject combination") may be used to treat migraines. The subject combination may be used for the acute treatment of migraines. 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 the use of emergency medications compared to rizatriptan, meloxicam, or placebo. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may have a history of inadequate response to previous acute treatments. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may have allodynia. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may have severe pain. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may be obese. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may have morning migraines. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may have a mean total 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. Patients with migraines treated with the rizatriptan-meloxicam combination described herein may have allodynia, severe pain, be obese, have morning migraines, have a mean total score of less than 7 on the mTOQ-4, and have a history of inadequate response to previous acute treatments. The dosage forms containing the rizatriptan-meloxicam combination described herein are safe and well-tolerated for the patients being treated.

[0141] Dosage forms comprising the combination of rizatriptan and meloxicam described herein may provide rapid relief of migraine pain within less than 15 minutes, about 15 minutes, less than 30 minutes, 15 to 30 minutes, less than 1 hour, 0.5 to 0.75 hours, or 0.75 to 1 hour after administration. The rizatriptan-meloxicam combination described herein may provide numerically greater migraine pain relief than rizatriptan alone 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 longer. The percentage of migraine patients reporting pain relief with the rizatriptan and meloxicam combination described herein may 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] Patients with migraines who are administered a dosage form containing the combination of rizatriptan and meloxicam described herein ("Subject Combination") may achieve pain relief 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 longer after administration.

[0143] The percentage of migraine patients who achieve pain relief increases with time after administration of the rizatriptan and meloxicam combination described herein. For example, at 2 hours post-administration, the percentage of migraine patients who achieve pain relief may be approximately 15-25%, 15-20%, 20%, and 20-25%. At 4 hours post-administration, the percentage of migraine patients who achieve pain relief may be approximately 30-50%, 30-40%, 40%, 40-45%, 45-47%, and 47-50%. At 12 hours post-administration, the percentage of migraine patients who achieve pain relief may be approximately 45-70%, 45-50%, 50-55%, 55-60%, 56-57%, 60-65%, and 65-70%. At 16 hours post-administration, the percentage of migraine patients achieving pain relief may be approximately 45-70%, 45-50%, 50-55%, 55-60%, 58-59%, 60-65%, and 65-70%. The rizatriptan and meloxicam combination described herein may provide a significant improvement over rizatriptan in pain relief for migraine patients. Approximately 2–10%, 2–3%, 3–5%, 5–7%, 6–7%, 7–8%, 8–9%, or 9–10% or more of migraine patients treated with the rizatriptan-meloxicam combination described herein may achieve pain relief with an improvement of approximately 10–25%, 10–15%, 14–15%, 15–16%, 16–17%, 17–18%, 18–19%, 19–20%, 20–21%, or 21–25% compared to patients treated with rizatriptan alone, 2–16 hours after administration. For example, if 40% of migraine patients treated with the subject combination achieve pain relief 4 hours after administration, and 33% of migraine patients treated with rizatriptan achieve pain relief, the improvement for the subject combination is approximately 21% [((40–33) / 33)×100%]. In migraine patients who have achieved pain relief, the improvement from the combination of the above treatments with meloxicam may be greater than the improvement with rizatriptan.For example, in migraine patients who have achieved pain relief, the improvement with meloxicam by the subject combination may be approximately 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75% 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%, and about 80% of migraine patients administered the combination of rizatriptan and meloxicam described herein ("Subject Combination") may be relieved of pain within 2 hours after administration and maintain that relief up to 24 hours after administration. The number of migraine patients (or degree of improvement) achieving sustained pain relief within 2–24 hours after administration of Subject Combination may increase by about 35–55%, about 35–40%, about 40–45%, about 45–50%, and about 50–55% compared to administration of rizatriptan alone. The number of migraine patients (or degree of improvement) achieving relief from persistent pain 2 to 24 hours after administration of the subject combination may increase by approximately 100–165%, approximately 100–110%, approximately 110–120%, approximately 120–130%, approximately 130–140%, approximately 140–150%, approximately 150–160%, or approximately 160–165% compared to administration of meloxicam alone.

[0145] The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 24 hours after administration of the subject combination may increase by approximately 15–30%, 15–20%, 20–25%, 25–30%, 20–22%, or 21% compared to administration of rizatriptan. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 24 hours after administration of the subject combination may increase by approximately 20–35%, 20–25%, 25–30%, 30–35%, 25–26%, 26–27%, 27–28%, 28–30%, or 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 the combination of rizatriptan and meloxicam described herein ("Subject Combination") may be relieved of pain within 2 hours of administration and maintain that relief for up to 48 hours after administration. The number of migraine patients (or degree of improvement) achieving sustained pain relief within 2-48 hours after administration of Subject Combination may increase by about 60-90%, about 60-70%, about 70-75%, about 75-80%, about 80-90%, or about 75% compared to administration of rizatriptan alone. The number of migraine patients (or degree of improvement) achieving relief from persistent pain 2 to 48 hours after administration of the subject combination may increase by approximately 70–110%, 70–80%, 80–90%, 90–100%, 100–110%, or 90% compared to administration of meloxicam alone.

[0147] The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 48 hours after administration of the subject combination may increase by approximately 20–35%, 20–25%, 25–30%, 30–35%, 25–26%, 26–27%, 27–28%, 28–20%, or 27% compared to administration of rizatriptan. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 48 hours after administration of the subject combination may increase by approximately 15–30%, 15–20%, 20–25%, 25–30%, 20–21%, 21–22%, 22–23%, 23–24%, 24–25%, or 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 the combination of rizatriptan and meloxicam described herein ("Subject Combination") may not require emergency medication. The number of migraine patients taking emergency medication within 24 hours after administration of 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 placebo. The number of migraine patients taking emergency medication within 24 hours after administration of the subject combination may decrease by approximately 25–45%, 25–30%, 30–35%, 35–40%, 40–45%, 34–36%, or 35% compared to administration of meloxicam. The number of migraine patients taking emergency medication within 24 hours after administration of the subject combination may decrease by approximately 25–40%, 25–30%, 30–35%, 35–40%, 33–35%, or 34% compared to administration of rizatriptan.

[0149] The following embodiments are intended.

[0150] Embodiment 1. Meloxicam inclusion complex in cyclodextrin.

[0151] Embodiment 2. 1) The inclusion complex of Embodiment 1, or 2) A dosage form comprising meloxicam and a carbonate or bicarbonate.

[0152] Embodiment 3. The dosage form of Embodiment 2 comprises an inclusion complex in which the cyclodextrin contains 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 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 meloxicam and SBEβCD have a molar ratio of approximately 0.8 to approximately 1.2.

[0157] Embodiment 8. The dosage form of Embodiment 6, wherein meloxicam and SBEβCD are in a molar ratio of approximately 1.

[0158] Embodiment 9. Dosage forms of Embodiments 2, 3, 4, 5, 6, 7, or 8, comprising bicarbonate.

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

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

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

[0162] Embodiment 13. Dosage forms of Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the carbonate or bicarbonate is present in an amount ranging from approximately 400 mg to approximately 600 mg.

[0163] Embodiment 14. Meloxicam T maxHowever, the dosage forms of Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 have reduced amounts compared to dosage forms that do not contain carbonate, bicarbonate, or cyclodextrin.

[0164] Embodiment 15. Meloxicam T max However, the method of Embodiment 14 is achieved in the patient within a time range of approximately 10 minutes to approximately 180 minutes after administration.

[0165] Embodiment 16. Dosage forms of Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 having higher oral bioavailability of meloxicam than dosage forms without carbonate, bicarbonate, or cyclodextrin.

[0166] Embodiment 17. Dosage forms of Embodiments 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, in which approximately 30 mg to approximately 50 mg of esomeprazole is present in the dosage form.

[0170] Embodiment 21. A method for orally administering meloxicam, comprising orally administering the dosage form of Embodiments 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] Embodiment 25. A method for intravenous administration of meloxicam, comprising intravenously administering the dosage form of Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, or 15 to a patient in need of treatment.

[0175] Embodiment 26. The method of Embodiment 21, wherein the dosage form is administered to treat migraines.

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

[0177] Embodiment 28. The dosage form of Embodiment 27 is rizatriptan.

[0178] Embodiment 29. The dosage form of Embodiment 27 contains sodium bicarbonate.

[0179] Embodiment 30. The dosage form of Embodiment 27 is sulfobutyl ether β-cyclodextrin (SBEβCD).

[0180] Embodiment 31. SBEβCD is a dosage form of Embodiment 30, having approximately 6 to 7 sulfobutyl ether groups in each molecule of β-cyclodextrin.

[0181] Embodiment 32. The dosage form of Embodiment 30 has a molar ratio of meloxicam to SBEβCD of approximately 0.8 to approximately 1.2.

[0182] Embodiment 33. The dosage form of Embodiment 32 has a molar ratio of meloxicam to SBEβCD of approximately 1.

[0183] Embodiment 34. The dosage forms of Embodiments 27, 28, 29, 30, 31, 32, or 33, which are oral dosage forms.

[0184] Embodiment 35. Dosage forms of Embodiments 27, 28, 29, 30, 31, 32, 33, or 34, wherein approximately 50 mg to approximately 200 mg of SBEβCD is present in the dosage form.

[0185] Embodiment 36. Dosage forms of Embodiments 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein bicarbonate is present in an amount of approximately 400 mg to approximately 1000 mg.

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

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

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

[0189] Embodiment 40. A method for treating migraine, comprising selecting human migraine patients with a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan.

[0190] Embodiment 41. The method of Embodiment 40, wherein a human migraine patient experiences relief of migraine as a result of oral administration of a dosage form for migraine patients.

[0191] Embodiment 42. The method of Embodiment 40 or 41, wherein, two hours after the dosage form is orally administered to a human migraine patient, the human migraine patient is free from migraine pain.

[0192] Embodiment 43. The method of Embodiments 40, 41, or 42, wherein a migraine patient experiences a reduction in nausea as a result of oral administration of the dosage form for migraine patients.

[0193] Embodiment 44. The method of Embodiments 40, 41, 42, or 43, wherein, two hours after the dosage form is orally administered to a human migraine patient, the human migraine patient is free from nausea.

[0194] Embodiment 45. A migraine patient experiences a reduction in photophobia as a result of oral administration of a dosage form for migraine patients, according to the methods of Embodiments 40, 41, 42, 43, or 44.

[0195] Embodiment 46. The method of Embodiments 40, 41, 42, 43, 44, or 45, wherein two hours after the dosage form is orally administered to a human migraine patient, the human migraine patient is photophobic.

[0196] Embodiment 47. A migraine patient experiences a reduction in phonophobia as a result of oral administration of a dosage form for migraine patients, according to the methods of Embodiments 40, 41, 42, 43, 44, 45, or 46.

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

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

[0199] Embodiment 50. The method of Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, wherein the dosage form contains approximately 5 mg to approximately 50 mg of meloxicam.

[0200] Embodiment 51. The method of Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein the dosage form contains approximately 50 mg to approximately 200 mg of SBEβCD.

[0201] Embodiment 52. The dosage form is the same as that of meloxicam in humans. maxThe method of Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, wherein the solid oral dosage form is shorter than the reference dosage form, 1) containing the same amount of meloxicam, 2) not containing SBEβCD, and 3) not containing bicarbonates.

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

[0203] Embodiment 54. The method of Embodiment 53, wherein lyzatriptan is present in salt form in an amount of approximately 10 mg in molar equivalent of free base lyzatriptan.

[0204] Embodiment 55. The method of embodiment 53 or 54, wherein rizatriptan exists as rizatriptan benzoate.

[0205] Embodiment 56. The oral dosage form is the method of Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, comprising approximately 10 mg to approximately 30 mg of meloxicam.

[0206] Embodiment 57. The oral dosage form is the method of Embodiment 56, containing approximately 20 mg of meloxicam.

[0207] Embodiment 58. The oral dosage form is the method of Embodiment 56, containing approximately 15 mg of meloxicam.

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

[0209] Embodiment 60. The oral dosage form is the method of Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, comprising approximately 50 mg to approximately 150 mg of SBEβCD.

[0210] Embodiment 61. The oral dosage form is the method of Embodiment 60, containing approximately 100 mg of SBEβCD.

[0211] Embodiment 62. The method of Embodiments 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 about 0.5 to about 2.

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

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

[0214] Embodiment 65. The oral dosage form comprises approximately 10 mg to approximately 40 mg of meloxicam and approximately 5 mg to approximately 50 mg of rizatriptan, according to the methods of Embodiments 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.

[0215] Embodiment 66. The oral dosage form is the method of Embodiments 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, comprising SBEβCD in a weight ratio of SBEβCD to rizatriptan in the range of about 1 to about 100.

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

[0217] Embodiment 68. The method of Embodiments 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 contains sodium bicarbonate.

[0218] Embodiment 69. The oral dosage form is the method of Embodiment 68, containing 500 mg of sodium bicarbonate.

[0219] Embodiment 70. The oral dosage form is the T of meloxicam in fasted human subjects. max The methods of Embodiments 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, in which the median time is shown to be less than approximately 90 minutes.

[0220] Embodiment 71. The oral dosage form is the T of meloxicam in fasted human subjects. max The method of embodiment 70, in which the median time is shown to be less than approximately 2 hours.

[0221] Embodiment 72. The method of Embodiments 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 reach therapeutic plasma concentrations in humans more quickly than the reference dosage form.

[0222] Embodiment 73. A method for treating migraine, comprising selecting human migraine patients with a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein the human migraine patients experience relief of migraine pain as a result of oral administration of the dosage form to the migraine patients.

[0223] Embodiment 74. A method for treating migraine, comprising selecting human migraine patients with a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein two hours after administration of the dosage form to the human migraine patients, the human migraine patients are free from migraine pain.

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

[0225] Embodiment 76. A method for treating migraine, comprising selecting human migraine patients with a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein two hours after administration of the dosage form to the human migraine patients, the human migraine patients are free from nausea.

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

[0227] Embodiment 78. A method for treating migraine, comprising selecting human migraine patients with a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, wherein two hours after administration of the dosage form to the human migraine patients, the human migraine patients are photophobic.

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

[0229] Embodiment 80. A method of treating migraine, comprising selecting human migraine patients with a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and wherein two hours after the dosage form is administered to the human migraine patient, the human migraine patient is in a state without phonophobia.

[0230] (Example 1) The effects of various amounts of potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) on the pH of an acidic medium were tested. The acidic medium was selected to simulate the gastric state. K2CO3 or NaHCO3 was added to 50 mL of 0.01N HCl solution (pH 2). After the addition of K2CO3 or NaHCO3, the pH of the solution was measured. Then, deionized water (240 mL) was 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 sulfobutyl ether β-cyclodextrin (SBEβCD) (a cyclodextrin containing approximately 6 to 7 sulfobutyl ether groups per β-cyclodextrin molecule) in combination with K2CO3 or NaHCO3 were prepared and tested for solubility. Tablets containing meloxicam alone (MOBIC®) were purchased and tested for solubility. The tested tablets are listed in Table 5. Meloxicam in the form of a meloxicam / SBEβCD inclusion complex was used in 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 buffer. The resulting soluble meloxicam / SBEβCD inclusion complex was then spray-dried. This spray-dried dispersion was used in the preparation of tablets containing SBEβCD.

[0236] [Table 5]

[0237] Dissolution tests in an acidic medium (selected to simulate stomach conditions) were performed by placing the tablets in a 0.01 N HCl solution at a stirring speed of 75 RPM and a container 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 shown as the percentage (%) of meloxicam dissolved.

[0238] [Table 6]

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

[0240] The dissolution of meloxicam 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 the dissolution of meloxicam. At the highest dose of potassium carbonate tested, the dissolution of meloxicam in the presence of SBEβCD was approximately 50% lower at 120 minutes compared to the dissolution of meloxicam in the absence of SBEβCD.

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

[0242] (Example 3) Two-layer tablets were prepared containing 1) an inclusion complex of SBEβCD containing meloxicam prepared according to the description below, and 2) sodium bicarbonate (SBEβCD-meloxicam / bicarbonate). The first layer contained an inclusion complex of 15 mg of meloxicam and 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 the SBEβCD-meloxicam / bicarbonate tablets described above, or the Mobic® tablets (meloxicam 15 mg) (6 days, once daily, under fasting conditions).

[0244] To analyze meloxicam concentrations at multiple time points, plasma samples were collected on the first day of administration. Meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. The results are shown in Figure 11.

[0245] T for meloxicam, which is a major evaluation item of the test max The median of T was about 9 times faster for SBEβCD-meloxicam / bicarbonate tablets compared to Mobic® (0.5 hours vs. 4.5 hours, respectively, p < 0.0001).

[0246] Also, SBEβCD-meloxicam / bicarbonate tablets showed a higher average value of the maximum plasma concentration (C max max) (p = 0.0018), a more rapid time to reach the therapeutic plasma concentration (p < 0.0001), and a more rapid time to reach the maximum half-value of the plasma concentration (p < 0.0001) compared to Mobic®.

[0247] In the tablets containing meloxicam and cyclodextrin, meloxicam in the form of an inclusion complex of meloxicam / SBEβCD was used. This inclusion complex was formed by mixing meloxicam and SBEβCD in an aqueous solution with adjusted pH. The pH of this solution was adjusted using a buffer. Thereafter, the obtained soluble meloxicam / SBEβCD inclusion complex was spray-dried. This spray-dried dispersion was used for the preparation of tablets containing SBEβCD.

[0248] (Example 4) 1) A single-layer tablet containing an inclusion complex of SBEβCD containing meloxicam, 2) rizatriptan, and 3) sodium bicarbonate (SBEβCD-meloxicam / rizatriptan / bicarbonate) was prepared. This single-layer tablet contained 20 mg of meloxicam, 10 mg of rizatriptan, and 500 mg of sodium bicarbonate. The inclusion complex was the same as the inclusion complex of Example 3.

[0249] Solubility tests of these tablets in acidic media (selected to mimic gastric conditions) were performed by placing the tablets in a 0.01 N HCl solution at a stirring speed of 75 RPM and a container 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 shown as the percentage of dissolved meloxicam (%) and the percentage of dissolved rizatriptan (%).

[0250] [Table 7]

[0251] As shown in Table 7, the dissolution results of the tablets in Example 4 were very similar to those of Example 3. Therefore, the inventors determined the pharmacokinetic properties (bioavailability, meloxicam T) of the tablets in Example 4. max We believe that these examples are similar to those described in Example 3 and Figure 11. As shown in the following examples, this prediction proved to be correct.

[0252] (Example 5) The single-layer tablets of Example 4 were administered to six subjects. Plasma samples were collected at multiple time points on the first day of administration for rizatriptan concentration analysis. The concentrations of rizatriptan and meloxicam were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. The results for meloxicam were comparable to those reported for the two-layer dosage form of Example 3. max The median time for rizatriptan is 0.75 hours. max The average value was 20.710 ng / mL. In contrast, the reported T for Maxalt®, a commercially available rizatriptan dosage form, is... max This is 1.0-1.5 hours.

[0253] (Example 6) A Phase 1, randomized, single-dose, parallel-group clinical trial was conducted to evaluate the pharmacokinetics, safety, and tolerability of 1) meloxicam (20 mg), rizatriptan (10 mg), SBEβCD, and sodium bicarbonate (meloxicam / rizatriptan) compared to 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 in a 1:1 ratio to receive either meloxicam / rizatriptan or Maxalt® (10 mg rizatriptan) as a single dose.

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

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

[0256] (Results of Phase 1) Meloxicam is rapidly absorbed after oral administration of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan), and the primary endpoint, time to reach therapeutic plasma concentration (T), is met. thera The median duration was 17 minutes (Figure 12 and Table 8). max The median timeout is 1 hour, compared to 4.5 hours with standard meloxicam 15 mg (Mobic®). max This suggests the potential for rapid onset of action of meloxicam / rizatriptan in the treatment of migraines. The mean plasma excretion half-life (T) of meloxicam.1 / 2 The elimination half-life was 18.2 hours after administration of meloxicam / rizatriptan, compared to 21.5 hours with standard meloxicam. The longer elimination half-life suggests that it may enhance and prolong the effects of meloxicam / rizatriptan and reduce the recurrence of migraine pain.

[0257] [Table 8]

[0258] Rizatriptan is rapidly absorbed after oral administration of meloxicam / rizatriptan, and T max The response time was 0.64 hours (38 minutes), compared to 0.88 hours with the same amount of standard rizatriptan (Maxalt®) (Figure 13 and Table 9). max Furthermore, systemic exposure, measured using AUC, was numerically higher with rizatriptan after meloxicam / rizatriptan administration compared to standard rizatriptan.

[0259] [Table 9]

[0260] Meloxicam / rizatriptan was well-tolerated, and there were no relevant differences in safety profiles between the two treatment groups. No serious adverse events occurred in this study.

[0261] (Example 7) A phase 3, randomized, double-blind, multicenter, positive-controlled, and placebo-controlled trial was conducted to evaluate the efficacy and safety of meloxicam / rizatriptan in the treatment of moderate and severe acute migraine in patients with a history of incomplete response to previous acute treatment. Eligible patients were randomly assigned in a 2:2:2:1 ratio to receive treatment in the meloxicam / rizatriptan group (20 mg meloxicam / 10 mg rizatriptan, SBEβCD, and sodium bicarbonate as described in Example 4 above), the rizatriptan group (10 mg), the meloxicam group (20 mg), SBEβCD, and sodium bicarbonate (meloxicam group), or the placebo group. The co-primary endpoints for meloxicam / rizatriptan, compared to placebo, were relief from headache pain at 2 hours post-administration and relief from the most distressing migraine-related symptoms (nausea, photophobia, or phonophobia).

[0262] The superiority of the meloxicam / rizatriptan group over the rizatriptan group and the meloxicam group (component contribution) will be established based on sustained relief from headache pain from 2 to 24 hours post-administration (an important secondary endpoint).

[0263] Eligible patients must have a history of inadequate responses to previous acute migraine treatments, as assessed using the Migraine Treatment Optimization Questionnaire (mTOQ-4). The mTOQ-4 is a validated questionnaire that assesses the response to effectiveness of previous acute treatments based on four aspects: pain relief within two hours, effectiveness for at least 24 hours with a single dose, ability to plan daily activities, and impairment in daily life.

[0264] Due to its rapid absorption and the two distinct mechanisms of action of meloxicam / rizatriptan described herein, meloxicam / rizatriptan will show a significant improvement over the placebo group and demonstrate superiority over the rizatriptan and meloxicam groups.

[0265] (Example 8) A female migraine sufferer visited her doctor hoping for relief from her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®) for her to take between her next acute migraines. This provided some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but did not completely alleviate the symptoms. At her next visit, her doctor prescribed 20 mg meloxicam in tablets also containing SBEβCD and 500 mg sodium bicarbonate for her to take between her next acute migraines. This provided some relief from the pain, nausea, allodynia, photophobia, and phonophobia, but did not completely alleviate the symptoms. At her next visit, her doctor prescribed her the tablets described in Example 4 above. She reported that pain, nausea, allodynia, photophobia, and / or phonophobia improved by approximately 10–30% at 2 and 24 hours after taking the tablets compared to the slight relief she experienced after taking meloxicam or rizatriptan alone.

[0266] (Example 9) A male migraine sufferer visited his doctor hoping for relief from his migraines. His doctor prescribed 10 mg rizatriptan (Maxalt®) for him to take between acute migraines. This slightly relieved his pain, nausea, allodynia, photophobia, and phonophobia, but did not completely relieve the symptoms. On his next visit, his doctor prescribed 20 mg meloxicam in tablets also containing SBEβCD and 500 mg sodium bicarbonate for him to take between acute migraines. This slightly relieved his pain, nausea, allodynia, photophobia, and phonophobia, but did not completely relieve the symptoms. On his next visit, his doctor prescribed him the tablets of Example 4 described above. He reported that pain, nausea, allodynia, photophobia, and / or phonophobia improved by approximately 30–60% at 2 and 24 hours after taking the tablets compared to the slight relief he experienced after taking meloxicam or rizatriptan alone.

[0267] (Example 10) A female migraine sufferer visited her doctor hoping for relief from her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®) for her to take between her next acute migraines. This slightly relieved her pain, nausea, allodynia, photophobia, and phonophobia, but did not completely relieve the symptoms. At her next visit, her doctor prescribed 20 mg meloxicam in tablets also containing SBEβCD and 500 mg sodium bicarbonate for her to take between her next acute migraines. This slightly relieved her pain, nausea, allodynia, photophobia, and phonophobia, but did not completely relieve the symptoms. At her next visit, her doctor prescribed her the tablets described in Example 4 above. She reported that pain, nausea, allodynia, photophobia, and / or phonophobia improved by approximately 60–100% at 2 and 24 hours after taking the tablets compared to the improvement she experienced after taking meloxicam or rizatriptan alone.

[0268] (Example 11) According to the Centers for Disease Control and Prevention, 37 million Americans suffer from migraines, and according to the American Migraine Foundation, it is the leading cause of disability among neurological disorders in the United States. Migraines are characterized by pulsating attacks, pain often associated with severe and disabling dizziness, and hypersensitivity to light and / or sound. In the United States, the direct (e.g., doctor visits, medication) and indirect (e.g., absenteeism, loss of productivity) costs of migraines are estimated at $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. 2017 Apr;81(4):479-484]. Published surveys of migraine patients show that over 70% are not fully satisfied with their current treatment, nearly 80% are willing to try new treatments, and they are seeking treatments that provide faster, more stable relief and fewer symptom relapses [(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. 2014 Jun 16;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 debilitating illnesses, comparable to dementia, quadriplegia, and active psychosis [(1) Menken et al., Arch Neurol. 2000;57:418-420, and (2) Shapiro and Goadsby. Cephalalgia. 2007;27:991-4]. Debilitating pain and the constant fear of the next migraine attack impair home life, social life, and work [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. People with migraines are twice as likely to experience depression and anxiety compared to healthy individuals [Antonaci et al., J Headache Pain. 2011;12:115-125]. Misunderstandings about the severity of migraines contribute to a lack of awareness and treatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of patients are not adequately satisfied with current treatments. Therefore, there is an urgent need for new treatments that offer improved effectiveness for this serious neurological disorder.

[0270] A phase 3, randomized, double-blind, multicenter, placebo-controlled, and positive-controlled trial was conducted to evaluate the efficacy and safety of the meloxicam-rizatriptan combination (meloxicam / rizatriptan) in the acute treatment of moderate and severe migraine. Eligible patients were 18–65 years of age, had a confirmed diagnosis of migraine with or without aura according to ICHD-3 criteria (for at least one year), experienced moderate to severe migraines on a mean of 2–8 days per month, had a history of incomplete response to previous acute migraine treatment, and were assessed with a score of 7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4) (mean score 3.6) in response to a poor response to previous acute treatment. Exclusion criteria included cluster migraine or other types of migraine, chronic daily headache (15 or more migraine-free days per month), a history of significant cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, enrolled patients exhibited high proportions of features strongly associated with poor treatment outcomes, 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 either the Example 4 monolayer tablet (20 mg meloxicam / 10 mg rizatriptan with SBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg) and SBEβCD (MoSEIC meloxicam), or placebo, for treatment of a single migraine attack of moderate or severe intensity. The two co-primary endpoints of this study were the proportion of patients who were free from headache pain within 2 hours of administration and the proportion of patients who were no longer suffering from their most distressing migraine-related symptoms (nausea, photophobia, or phonophobia) within 2 hours of administration, compared to placebo. The superiority of meloxicam / rizatriptan over rizatriptan and the meloxicam group (component contribution) was established based on sustained relief from headache pain 2–24 hours after administration (an important 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 migraines. (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, and the proportion of patients achieving pain relief with meloxicam / rizatriptan was numerically higher than that with rizatriptan at all time points measured from 15 minutes onward, with statistical significance only at 60 minutes (p=0.04) (Figure 14). The proportion of patients experiencing pain relief at 1.5 hours post-administration was 60.5% with meloxicam / rizatriptan compared to 52.5% with rizatriptan and 48.3% with placebo (P=0.019 and P=0.004, respectively for meloxicam / rizatriptan) (Figure 14).

[0272] Meloxicam / rizatriptan met two predetermined co-primary endpoints by demonstrating high statistical significance compared to placebo at 2 hours after administration, with a higher percentage of patients freed from pain (19.9% ​​vs. 6.7%, p<0.001, Figure 15) and a higher percentage of patients free from their most bothersome symptoms (36.9% vs. 24.4%, p=0.002).

[0273] The superiority of meloxicam / rizatriptan over rizatriptan (active comparator) and MoSEIC® meloxicam (component contribution) was established, as specified in the SPA, by the achievement of sustained pain relief 2 to 24 hours post-administration, compared to rizatriptan, MoSEIC® meloxicam, and placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively, p=0.038, p=0.001, and p<0.001 for meloxicam / rizatriptan, respectively, Figure 16A), demonstrating a higher proportion of patients treated with meloxicam / rizatriptan and a pre-specified key secondary major item indicating component contribution. Approximately 80% of patients treated with meloxicam / rizatriptan who achieved pain relief at 2 hours maintained pain relief throughout 24 hours. These results demonstrate a significant improvement in pain relief in the treatment of migraines, and the superiority of meloxicam / rizatriptan over rizatriptan.

[0274] Meloxicam / rizatriptan resulted in substantially greater and more sustained relief of migraine pain compared to placebo and rizatriptan, which can be interpreted as a significant reduction in emergency medication use with meloxicam / rizatriptan compared to placebo and rizatriptan. The proportion of patients who experienced sustained pain relief 2 to 24 hours after administration was 53.3% for meloxicam / rizatriptan, compared to 33.5% for placebo and 43.9% for rizatriptan (P<0.001 and P=0.006, respectively, for meloxicam / rizatriptan) (Figure 16B).

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

[0276] Compared to 43% of patients treated with placebo and 34.7% of patients treated with rizatriptan (p<0.001 for each group compared to meloxicam / rizatriptan), 23.0% of patients treated with meloxicam / rizatriptan used emergency medication. Approximately 77% of patients treated with meloxicam / rizatriptan did not require emergency medication. These results demonstrate the superiority of meloxicam / rizatriptan over the active comparator, rizatriptan, in the treatment of migraines.

[0277] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan in several other secondary endpoints, including the patient's overall impression of change (PGI-C) (p=0.022) and return to normal function within 24 hours (p=0.027).

[0278] Table 10 lists some of the p-values ​​for meloxicam / rizatriptan versus rizatriptan for various evaluation items, showing the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraines.

[0279] [Table 10]

[0280] The observation of a greater and more sustained migraine pain relief effect from meloxicam / rizatriptan than from rizatriptan is highly significant, considering that rizatriptan, the active comparator in this study, is the fastest-acting oral triptan and is considered one of the most effective medications currently available for the acute treatment of migraine, and given that this study included patients with ill-treated migraines. Many patients experience a suboptimal response to current acute migraine treatments, which increases the risk of headache-related disorders and progression to chronic migraine, and is a contributing factor to increased healthcare costs. The results of this study suggest that meloxicam / rizatriptan may offer an important treatment option for people with ill-treated migraines.

[0281] In the patients studied in this trial, meloxicam / rizatriptan was safe and well-tolerated. The most commonly reported adverse events with meloxicam / rizatriptan were nausea, dizziness, and somnolence, none of which occurred at a higher rate than placebo or at a rate of more than 3%. There was one serious adverse event in the meloxicam / rizatriptan group that the investigator determined was not related to the study drug.

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

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

[0284] (Example 12) Meloxicam / rizatriptan is also being evaluated in another randomized, double-blind, placebo-controlled phase 3 trial evaluating the early treatment of migraine with meloxicam / rizatriptan. In this ongoing trial, patients with a history of inadequate response are treated with meloxicam / rizatriptan when they experience a moderate or severe migraine attack, in contrast to the other trial, which administers meloxicam / rizatriptan to patients when they show early signs of migraine pain.

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

[0286] The co-primary endpoints for meloxicam / rizatriptan, compared to placebo, were relief from headache pain at 2 hours post-administration and relief from the most distressing migraine-related symptoms (nausea, photophobia, or phonophobia).

[0287] Unless otherwise stated, the numerical values ​​representing properties such as quantities, amounts, and percentages of components used herein and in the claims should be understood in all cases to represent both the exact values ​​shown and values ​​modified by the term “approximately.” Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained. At the very least, without attempting to limit the application as equivalents to the claims, each numerical parameter should be interpreted by applying ordinary rounding methods in light of the number of significant figures reported.

[0288] The terms “a,” “an,” “the,” and similar references used in the context of describing embodiments (particularly in the context of the following claims) should be construed to cover both singular and plural forms unless otherwise stated or unless the context clearly contradicts this. All embodiments or use of exemplary language (e.g., “etc.”) provided herein are intended to better illustrate the embodiments and do not limit the scope of the claims. Nothing described herein should be construed as indicating non-claiming elements that are essential to the implementation of the claims.

[0289] The grouping of alternative elements or embodiments disclosed herein should not be construed as limitation. Each group's components may be referenced and claimed individually or in any combination with other components of the group or other elements found herein. For convenience and / or ease of implementation, it is anticipated that one or more components of a group may be included in or removed from the group. If such inclusion or removal occurs, this specification shall be deemed to include the modified group and, when used in the appended claims, shall satisfy all descriptions of the Markush group.

[0290] This specification describes several embodiments of the present invention, including the best mode for carrying out the embodiments described in the claims as known to the inventor. Of course, variations of these described embodiments will be apparent to those skilled in the art by reading the preceding description. The inventor expects that those skilled in the art will appropriately use such variations, and the inventor intends to carry out the embodiments described in the claims in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described in the claims, as permitted by applicable law. Furthermore, unless otherwise stated herein, or unless it is clearly inconsistent with the context, any possible combination of the above elements is conceivable.

[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. Therefore, alternative configurations of the present invention can be utilized in accordance with the teachings herein, not as limitations but as embodiments. Accordingly, the claims are not limited to the embodiments shown and described.

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

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

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

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

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

[0297] (Note 6) The method according to Appendix 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] (Note 7) The method according to Appendix 1, 2, 3, 4, 5, or 6, wherein two hours after the dosage form is orally administered to the human migraine patient, the human migraine patient is free from photophobia.

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

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

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

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

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

[0304] (Note 13) The aforementioned dosage form is the T2 dosage form of meloxicam in humans. max The method according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the solid oral dosage form is shorter than the reference dosage form, 1) containing the same amount of meloxicam, 2) not containing SBEβCD, and 3) not containing bicarbonate.

[0305] (Note 14) The method according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein approximately 1 mg to approximately 50 mg of rizatriptan is present in the oral dosage form based on the weight of rizatriptan in its free base form.

[0306] (Note 15) The method described in Appendix 14, wherein lyzatriptan is present in salt form in an amount of approximately 10 mg in molar equivalent of free base lyzatriptan.

[0307] (Note 16) Rizatriptan exists as rizatriptan benzoate, according to the method described in Appendix 14 or 15.

[0308] (Note 17) The oral dosage form is the method according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, comprising approximately 10 mg to approximately 30 mg of meloxicam.

[0309] (Note 18) The oral dosage form is the method described in Appendix 17, comprising approximately 20 mg of meloxicam.

[0310] (Note 19) The oral dosage form is the method described in Appendix 17, comprising approximately 15 mg of meloxicam.

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

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

[0313] (Note 22) The oral dosage form is the method described in Appendix 21, comprising approximately 100 mg of SBEβCD.

[0314] (Note 23) The method described in Appendix 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 approximately 0.5 to approximately 2.

[0315] (Note 24) The method described in Appendix 23, wherein the molar ratio of SBEβCD to meloxicam is approximately 0.8 to approximately 1.2.

[0316] (Note 25) The method described in Appendix 23, wherein the molar ratio of SBEβCD to meloxicam is approximately 1.

[0317] (Note 26) The oral dosage form is the method according to Appendix 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, comprising approximately 10 mg to approximately 40 mg of meloxicam and approximately 5 mg to approximately 50 mg of rizatriptan.

[0318] (Note 27) The oral dosage form is the method according to Appendix 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 contains SBEβCD in a weight ratio of about 1 to about 100.

[0319] (Note 28) The method according to Appendix 27, wherein the oral dosage form contains SBEβCD in a weight ratio of approximately 10 to rizatriptan.

[0320] (Note 29) The method described in Appendix 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 includes sodium bicarbonate.

[0321] (Note 30) The oral dosage form is the method described in Appendix 29, comprising 500 mg of sodium bicarbonate.

[0322] (Note 31) The oral dosage form is used in the aforementioned human subjects on an empty stomach, and contains meloxicam T max The method described in Appendix 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, in which the median is shown to be less than approximately 90 minutes.

[0323] (Note 32) The oral dosage form is used in the aforementioned human subjects on an empty stomach, and contains meloxicam Tmax The method described in Appendix 31, which has been shown to have a median of less than approximately 2 hours.

[0324] (Note 33) The method according to Appendix 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 reach therapeutic plasma concentration in humans more quickly than the reference dosage form.

Claims

[Claim 1] A method for treating migraine, comprising selecting human migraine patients who have a history of incomplete response to previous migraine treatments, and orally administering a dosage form to the migraine patients, wherein the dosage form comprises 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) a combination of rizatriptan.

Images