JP7420990B2 - Use of combinations containing meloxicam and rizatriptan - Google Patents

Description

(Cross reference to related applications)
This application is filed in U.S. Provisional Application No. 62/802,198, filed on February 6, 2019, U.S. Provisional Application No. 62/803,756, filed on February 11, 2019, and U.S. Provisional Application No. 62/835,613, filed on May 18, 2019; U.S. Provisional Application No. 62/846,311, filed on May 10, 2019; Application No. 62/860,705, U.S. Provisional Application No. 62/895,933, filed September 4, 2019, and United States Provisional Application No. 62/895,956, filed September 4, 2019. , and U.S. Provisional Application No. 62/955,905, filed December 31, 2019, the entire disclosures of which are incorporated herein by reference.

Meloxicam, which has the following structure, is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activity. Meloxicam's mechanism of action may be related to prostaglandin synthetase (cyclooxygenase, COX) inhibition, which is involved in the early steps of the arachidonic acid cascade, reducing the formation of prostaglandins, thromboxanes and prostacylins.

Meloxicam and some other NSAIDs are poorly water soluble, thereby reducing bioavailability and potentially delaying the onset of pain relief resulting from their use. One means of increasing the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cycloamyloses) are cyclic polysaccharides that generally form a bucket-like shape. Cyclodextrins help increase the bioavailability of other molecules because cyclodextrins are internally hydrophobic and internally hydrophilic 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 with drugs (ie, inclusion complexes) by incorporating the drug into the center/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 and increase the bioavailability of less soluble drugs.

Some embodiments include selecting a human migraine patient with a history of poor response to previous migraine treatments and administering to the migraine patient a dosage form. A method of treating a dosage form comprising a combination of 1) a complex of meloxicam and sulfobutyl ether beta-cyclodextrin (SBEβCD), 2) a bicarbonate salt, and 3) rizatriptan.

Some embodiments include inclusion complexes of meloxicam in cyclodextrin.

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

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

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

Disclosed herein are formulations of inclusion complexes of cyclodextrin and meloxicam with bicarbonate and methods of use thereof.

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

for pain and pain by delivering a dosage form comprising meloxicam, cyclodextrin and bicarbonate to a subject orally, enterally, intravenously, intramuscularly, subcutaneously, intranasally or by other parenteral means. Also disclosed are methods of treating related conditions.

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

Rizatriptan has the structure shown below.

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

Some embodiments provide rapid, sustained, and substantial benefits compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of inadequate response to previous treatments. , and the subject combination including rizatriptan and meloxicam, with statistically significant efficacy.

Some embodiments include the subject combinations comprising zatriptan and meloxicam that require significantly less rescue medication use compared to placebo, rizatriptan, or meloxicam.

FIG. 6 is a diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. FIG. 6 is another diagram of the results described in Example 2 and included in Table 6. 1 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 a commercially available meloxicam dosage form. 2 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 the commercially available meloxicam dosage form. 2 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 12 shows a plot of the percentage of subjects reporting pain relief at various time points over the first 4 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 2 shows the percentage of subjects free from pain at 2 hours, 4 hours, 12 hours, and 16 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 2 shows the percentage of subjects with sustained pain relief 2-24 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 2 shows the percentage of subjects with sustained pain relief 2-24 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 2 shows the percentage of subjects with sustained pain relief from 2 to 48 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 2 shows the percentage of subjects with sustained pain relief from 2 to 48 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo. Figure 2 shows the percentage of subjects taking Old and Old by 24 hours after administration of the meloxicam/rizatriptan dosage form described in Example 11, rizatriptan, MoSEIC meloxicam, and placebo.

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

The dosage form may be administered enterally, including but not limited to oral, sublingual or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal or subcutaneous delivery. Good too.

Some methods include administering a product that combines a) a cyclodextrin and/or b) an NSAID formulated with a buffer. In some embodiments, the method includes treating the patient with a pharmaceutical formulation comprising meloxicam and cyclodextrin and/or carbonate/bicarbonate. Embodiments of the method can also include treating the patient to increase the bioavailability of meloxicam in the patient, or to increase the rate at which meloxicam becomes bioavailable.

The combination of meloxicam, a cyclodextrin (such as SBEβCD), and a bicarbonate (such as sodium bicarbonate) substantially increases the solubility and absorption of meloxicam after oral administration, while increasing the The half-life of the plasma concentration at remains prolonged.

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

Unless otherwise stated, references herein to compounds such as meloxicam or rizatriptan, by structure, name, or any other means, include alternative solid forms, such as pharmaceutically acceptable salts, polymorphs, etc. form, solvate, hydrate, optical isomer, tautomer, deuterated form, or precursor, prodrug, or rapidly under the conditions used as described herein. Any chemical species is included, such as any other chemical species that can be rapidly converted to the compounds described herein.

The subject combinations may be administered by enteral delivery, including but not limited to oral, sublingual, or rectal delivery, or by parenteral delivery, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous delivery. You can. 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.

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

The term "treat" or "treatment" refers to any type of therapeutic activity, including diagnosis, cure, mitigation or prevention of disease in humans or other animals, or non-therapeutic activity, Broadly includes any activity that affects the structure or any function of the body.

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

Migraine is a disabling neurological disorder characterized by periodic attacks of pulsating head pain, accompanied by nausea and sensitivity to light and sound. The pain is moderate to severe, but is often severe enough to immobilize and require bed rest. Headaches can affect half of the head, are pulsatile, and can last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and hypersensitivity to light (photophobia), sound (phonophobia), or smell. Pain may be worsened by physical activity. Migraine headaches may have an aura, which can be a brief visual disturbance that tells you that a headache is about to occur. Some migraine sufferers have no aura.

In some embodiments, the human being treated for migraine suffers from allodynia that accompanies migraine attacks. Allodynia is pain caused by normally non-painful stimuli (such as combing your hair, getting dressed, or taking a shower). Patients with allodynia are thought to be less responsive to triptans.

Current treatments are suboptimal, with more than 70% of patients complaining of current acute treatment. The most common reasons for patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and recurrence of pain within the same day. Suboptimal acute treatment is associated with a significantly increased risk of new onset chronic migraine and may be prevented by improving acute treatment outcomes.

Administration of the subject combinations to a human suffering from migraine, such as an acute attack or aura, reduces migraine symptoms such as pain, nausea, vomiting, photophobia, or phonophobia for about 5 minutes or within (intended as an abbreviation for "in 5 minutes" or "within 5 minutes"), about 10 minutes or less, about 30 minutes or less, about 1 hour or less, about 90 minutes or less , within about 2 hours or less, about 2.5 hours or less, or about 3 hours or less. In some embodiments, the human has a headache or headache within about 1 hour or less, about 90 minutes or less, about 2 hours or less, about 2.5 hours or less, or about 3 hours or less. Experience decreased or complete relief of pain such as migraine, nausea, vomiting, photophobia, and/or phonophobia. In some embodiments, the relief experienced is greater than that experienced by receiving the same amount of rizatriptan without meloxicam. In some embodiments, the relief experienced is greater than that experienced by receiving the same amount of meloxicam without rizatriptan.

The combination of meloxicam and rizatriptan may have two distinct mechanisms of function as an acute treatment for migraine. Meloxicam is a potent, COX-2 preferential NSAID and is limited by slow absorption. Rizatriptan is a potent 5-HT1 _B/D agonist that is thought to be effective for migraine.

Findings of symptom relief or reduction at a specific time point, such as "2 hours", are useful because the effect of treatment can be assessed at a specific or consistent time point, facilitating comparisons between patients. be. It is desirable for symptom relief or relief to occur as soon as possible, and making it clear that relief occurs within a certain amount of time is to set a guideline for when relief is desirable; Findings of alleviation or reduction of symptoms within a specified time period, such as ``within a certain period of time,'' are useful.

For some methods, administration of the subject combinations reduces pain, nausea, vomiting, photophobia, or phonophobia for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least The relief may last for about 6 hours, at least about 8 hours, at least about 8 to 24 hours, at least about 24 hours, or more than 24 hours.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan. experience greater pain relief than would be experienced 2 hours after administering the same amount of meloxicam without.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives meloxicam without meloxicam. experience greater pain relief than would be experienced 2 hours after administering the same amount of rizatriptan.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan. experience greater relief from nausea than would be experienced two hours after administering the same amount of meloxicam without.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives meloxicam without meloxicam. experience greater relief from nausea than would be experienced 2 hours after administering the same amount of rizatriptan.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan. experience greater relief of emesis than would be experienced 2 hours later with the same dose of meloxicam without.

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

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

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

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

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

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan. experience greater relief of phonophobia than would be experienced two hours after administering the same amount of meloxicam without.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives meloxicam without meloxicam. experience greater relief of phonophobia than would be experienced 2 hours after administering the same amount of rizatriptan.

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

In some embodiments, the human receiving the subject combination has a history of incomplete response to previous migraine treatment. For example, people are asked whether they are pain-free within two hours of treatment for most attacks and are given the options of "never," "rarely," "less than half the time," or "more than half the time." If a person answers "none," "almost never," or "less than half of the time," the person has an incomplete response to treatment. Similarly, a single dose usually relieves headaches and asks whether headaches occur for at least 24 hours, with options of "never," "rarely," "less than half the time," or "more than half the time." If a person answers "none," "almost never," or "less than half of the time," the person has an incomplete response to treatment.

In some embodiments, humans receiving the subject combinations demonstrate "never" pain relief within 2 hours of treatment for most attacks. In some embodiments, humans receiving the subject combinations exhibit "very little" pain relief within 2 hours of treatment for most attacks. In some embodiments, humans receiving the subject combinations exhibit "less than half" of most attacks being pain free within 2 hours of treatment.

In some embodiments, humans receiving the subject combinations have shown that after one dose, the respondent's headaches have been alleviated and that they have "never" experienced headaches for at least 24 hours. . In some embodiments, humans receiving the subject combinations show that a single dose provided relief from the respondent's headaches and that they were "almost never" headache-free for at least 24 hours. . In some embodiments, humans receiving the subject combinations showed that one dose relieved the respondent's headaches and that "less than half" of respondents were headache-free for at least 24 hours. ing.

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

In some embodiments, the human being administered a subject combination, such as a combination comprising meloxicam and rizatriptan, has migraine and has a history of poor response to previous migraine treatments. There may be. In some embodiments, the person with migraine does not have cluster headache or other types of migraine. In some embodiments, the human with migraine does not have chronic daily headache. In some embodiments, the human with migraine has more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 migraine-free days per month. . In some embodiments, the person with migraine has no history of significant cardiovascular disease. In some embodiments, the person with migraine does not have uncontrolled hypertension.

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

In some methods, administration of the dosage form provides pain relief that lasts at least about 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least about 8 hours, from about 8 hours to about 24 hours, or about 24 hours. can be achieved. In other embodiments, the administration of the dosage form is about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, after administration of the dosage form. Less than 15 minutes, less than 20 minutes, 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 60 minutes, or Observed pain relief can be achieved for other periods delimited by the range.

In some embodiments, the dosage form is used to alleviate neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, unicuspid neuralgia, phantom pain, sciatica, pudendal neuralgia, and central pain. can be administered. Other causes of neuropathic pain 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 radiation therapy or chemotherapy. May include neuropathies related to therapeutic treatment. The neuropathic pain treated can be chronic or acute.

In some methods, the dosage form can be administered to alleviate inflammatory pain, including inflammatory musculoskeletal pain, injury pain, arthritic pain, and complex regional pain syndromes. In other embodiments, the inflammatory pain can be chronic or acute.

Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain include, but are not limited to, osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-rheumatoid arthritis, These include pain associated with peripheral disorders, neuropathic arthropathy including Charcot's foot, axonal spondyloarthropathies including ankylosing spondylitis, and SAPHO syndrome. The inflammatory joint disease treated can be chronic or acute.

In some methods, meloxicam can be administered to alleviate musculoskeletal pain. Examples of musculoskeletal pain include, but are not limited to, lower back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, spasms, tendonitis, thyroiditis, carpal tunnel syndrome, arthralgia, fibrotic May include myalgia, injury pain, carpal tunnel syndrome, pain associated with fractures, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip. In other embodiments, the musculoskeletal pain can be chronic or acute.

In some methods, administration of the dosage form or subject combinations results in 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 Pain reduction that lasts for 24 hours, or about 24 hours, can be achieved. In another embodiment, administration of the subject combinations results in about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 5 minutes or less, about 10 minutes or less, about 15 minutes or less, about 20 minutes or less, about 25 minutes or less, about 30 minutes or less , about 35 minutes or less, about 40 minutes or less, about 45 minutes or less, about 50 minutes or less, or about 60 minutes or less, up to 2 hours, up to 3 hours, within these ranges. A reduction in pain can be achieved, seen in other periods demarcated by.

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

In some embodiments, the human being treated for migraine with a dosage form described herein comprising, for example, meloxicam, rizatriptan, SBEβCD, and a bicarbonate, such as sodium bicarbonate, is 18 years old to 65 years old, about 18-20 years old, about 20-25 years old, about 25-30 years old, about 30-40 years old, about 40-45 years old, about 40-50 years old, about 50-60 years old, about 60-65 years old or any other age within the range bounded by or between these values.

In some embodiments, a human being treated for migraine with a dosage form described herein, such as a dosage form comprising meloxicam, rizatriptan, SBEβCD, and a bicarbonate, such as sodium bicarbonate, , can be white, black or African American, or Asian.

In some embodiments, a human being treated for a disease or condition with a dosage form that includes meloxicam or another NSAID is treated for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least Suffering from a pain-related pain or condition for 2 months, at least 3 months, at least 6 months, or at least 1 year, or any period of time bounded by or within these values.

In some embodiments, a human being treated for migraine with a dosage form comprising meloxicam and rizatriptan is treated for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1 to 2 years, 2 Diagnosis of migraine with or without aura, as defined by ICHD-3 criteria, for ~3 years, or longer, or any period bounded by or in between these values. is recieving.

In some embodiments, the human has an average of 2-8, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8 moderate to severe migraines occur.

Cyclodextrins used in dosage forms containing meloxicam can include cyclodextrins, cyclodextrin derivatives and/or salts thereof. Inclusion complexes of meloxicam and cyclodextrin may be more water soluble than uncomplexed meloxicam. The cyclodextrin can be a natural cyclodextrin (eg, α, β or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, derivatives or salts thereof may be used. α-Cyclodextrin includes, but is not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin , (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O -tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

In some embodiments, β-cyclodextrin, derivatives or salts thereof may be used. β-cyclodextrin includes, without limitation, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, maltosyl-β-cyclodextrin, O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl- 6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl- 6-O-sulfo)-β-cyclodextrin, (2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3 , 6-tri-O-methyl)-β-cyclodextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, (2,3,6-tri-O-benzoyl)-β- Cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β -Cyclodextrin, 6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6 -di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-O-t-butyldimethylsilyl- 2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,6-di-O-)ethyl-β-cyclodextrin, (2- carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl (6- O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin, succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomly methylated It may include β-cyclodextrin, branched-β-cyclodextrin or combinations thereof.

In other embodiments, the β-cyclodextrin can be a sulfoalkyl ether cyclodextrin, derivative or salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include, without limitation, sulfobutyl ether-β-cyclodextrin (eg, SBEβCD, Betadex, CAPTISOL®). In some embodiments, the SBEβCD has about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule. obtain.

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

In some embodiments, the dosage form can include a bicarbonate, such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or combinations thereof. Bicarbonate may help increase the bioavailability of meloxicam.

In other embodiments, the dosage form may include a carbonate salt, derivative or salt thereof. Examples of carbonates 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. obtain.

In some embodiments, enhanced bioavailability of a dosage form is achieved by administering a dosage form that includes a salt form of meloxicam, by producing an inclusion complex of meloxicam and a cyclodextrin. and/or bicarbonate in the treatment of one of these conditions. This allows the molar amount of meloxicam used to be reduced compared to other meloxicam dosage forms.

Unless otherwise indicated, the compounds herein, such as meloxicam or cyclodextrin, by structure, name, or any other means, include pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers. any other solid state, such as a compound described herein, a tautomer, a deuterium-modified form, or any other species that can be rapidly converted to a compound described herein under the conditions in which the compound described herein is used. Including form.

In some embodiments, the use of a cyclodextrin, carbonate or bicarbonate increases the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40%. 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 bounded by these values compared to administration of meloxicam alone, or by any amount in between.

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

In other embodiments, the use of other NSAIDs, opioids, or other analgesics is 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%, cyclodextrin , not administering meloxicam with carbonate and/or bicarbonate may be reduced compared to the use of other NSAIDs, opioids or other analgesics.

In some embodiments, the dosage form is about 1-50 mg, about 1-10 mg, about 1-5 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg. , about 5-10 mg, about 5-15 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 30 mg, or these may include any amount of meloxicam bounded by or within a range between the values of . These doses may be for repeated dosing, such as once to once per hour, twice per day, 1 to 12 times per day, 3 times, 4 times, 5 times or 6 times per day. may be a safe dose. In some embodiments, meloxicam is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 times per day, from about 3 to about 10 times per day, It can be safely administered once a day or less frequently, such as once a week, once every two weeks, once a month, and the like.

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

Formation of an inclusion complex between meloxicam and cyclodextrin may help improve the properties of the dosage form. For some inclusion complexes, meloxicam and cyclodextrin (e.g., SBEβCD) are about 0.5 to 2 (a molar ratio of 0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0 .5 to 0.7, about 0.6 to 0.8, about 0.7 to 0.9, about 0.8 to 1, about 0.9 to 1.1, about 1 to 1.2, about 1 .1 to 1.3, about 1.2 to 1.4, about 1.3 to 1.5, about 1.4 to 1.6, about 1.5 to 1.7, about 1.6 to 1. 8, about 1.7 to 1.9, about 1.8 to 2, about 0.8 to 1.2, about 1, or any mole ratio within the range bounded by or between these values. may have.

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

In some dosage forms, the cyclodextrin is about 1-200 mg, about 25-175 mg, about 50-150 mg, about 25-100 mg, about 75-150 mg, about 100-175 mg, about 20-80 mg, about 25-50 mg. , about 60-100mg, about 80-100mg, about 80-120mg, about 100-120mg, about 100-140mg, about 120-160mg, about 140-180mg, about 30-90mg, about 40-80mg, about 50-70mg , about 55-65 mg, about 60-62 mg or any amount within the range bounded by or between these values.

In some methods, the inclusion complex of meloxicam and cyclodextrin (eg, substituted β-cyclodextrin) is delivered orally (eg, by tablet, capsule, elixir, etc.). Other possible routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal or other parenteral means. Meloxicam may be delivered alone or uncomplexed with cyclodextrin.

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

Some dosage forms include about 1-1000 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 200- 800mg, about 500-1000mg, about 300-700mg, about 400-600mg, about 50-250mg, about 250-750mg, about 100-200mg, about 200-300mg, about 300-400mg, about 400-500mg, about 500- 600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any amount bounded by or within a range between these values. .

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

In some embodiments, the weekly dose (e.g., oral dose) of meloxicam is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, Approximately 10 to 300 mg, approximately 20 to 150 mg, approximately 20 to 60 mg, approximately 30 to 70 mg, approximately 40 to 60 mg, approximately 50 to 70 mg, approximately 70 to 90 mg, approximately 90 to 110 mg, approximately 50 mg, approximately 55 mg, approximately 100 to 150 mg , about 30-100 mg or any amount bounded by or between these values. Weekly doses may be given as a single dose given once a week, or may be given in 2, 3, 4, 5, 6 or 7 separate doses per week.

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

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

In certain embodiments, the pharmaceutical composition provides improved release of meloxicam from a dosage form as compared to a dosage form containing meloxicam but no cyclodextrin, acid inhibitor, or buffer (e.g., bicarbonate). resulting in bioavailability (eg, lower T _max , increased C _max , increased AUC, etc.). In some embodiments, the bioavailability of meloxicam is increased with multiple administrations. For example, the bioavailability of meloxicam in a dosage form is compared to the bioavailability of meloxicam in a dosage form that does not contain cyclodextrin, acid inhibitors or buffers (e.g., bicarbonate). about 1-10 days after administration, about 2-6 days after administration, about 3-5 days after administration, about 4-6 days after administration, about 5-8 days after administration, about 5 days after administration, about 6 days after administration. days, about 7 days after administration, about 8 days after administration, about 10 days after administration, about 15 days after administration, or any period of time bounded by or within the range between these values.

Some of the dosage forms may provide a desired range of area under the plasma concentration curve (AUC) of meloxicam. For example, the dosage of meloxicam is about 1 to 150 μg・hr/mL, about 10 to 30 μg・hr/mL, about 20 to 40 μg・hr/mL, about 30 to 50 μg・hr/mL, and about 40 to 60 μg・hr/mL. mL, about 50-70μg・hr/mL, about 60-80μg・hr/mL, about 70-90μg・hr/mL, about 80-100μg・hr/mL, about 10-100μg・hr/mL, about 50- 150μg・hr/mL, about 25-125μg・hr/mL, about 75-150μg・hr/mL, about 20-50μg・hr/mL, about 40-70μg・hr/mL, about 60-90μg・hr/mL , about 80 to 110 μg·hr/mL, about 100 to 130 μg·hr/mL, about 120 to 150 μg·hr/mL, or any AUC bounded by or within a range between these values. can bring about

Unless otherwise indicated, AUC refers to AUC over a 6-hour period (AUC _0-6 ), AUC over a 12-hour period (AUC _0-12 ), AUC over a 24-hour period (AUC _0-24 ), etc. refers to the AUC calculated for the last measured concentration (AUC _0-t ) or the AUC extrapolated to infinity (AUC _0-inf ).

In Example 3 below, the AUC _0-24 of meloxicam in humans was approximately 27 μg·hr/mL for an oral dosage form containing sodium bicarbonate and sulfobutyl ether β-cyclodextrin (SBEβCD). This dosage form contained 15 mg of meloxicam.

Even at 15 mg IV and intramuscular administration, the AUC _0-24 of meloxicam in humans was approximately 27 μg·hr/mL. The AUC of meloxicam is believed to be approximately proportional to dose. Thus, for this oral dosage form, or for an IV or intramuscular dosage form, for example, administration of about 17 mg to about 30 mg of meloxicam would result in an AUC _0-24 of meloxicam of about 30-50 μg·hr/mL. .

For acute pain conditions such as migraine or other types of headaches, the AUC over a short period of time after administration is of particular interest, such as the AUC measured over 6 hours (AUC _0-6 ). For example, some dosage forms include at least about 6 μg·hr/mL, at least about 7 μg·hr/mL, at least about 8 μg·hr/mL, at least about 9 μg·hr/mL, about 6-10 μg·hr/mL, An AUC of meloxicam of about 7 to 11 μg·hr/mL, about 8 to 12 μg·hr/mL, about 9 to 13 μg·hr/mL, or any AUC bounded by or within a range between these values. can bring about

In some embodiments, the dosage form is about 10-2500 ng/mL, about 100-2250 ng/mL, about 500-2000 ng/mL, about 1000-2500 ng/mL, about 1000-2000 ng/mL, about 100-900 ng /mL, about 750-1500ng/mL, about 1250-2000ng/mL, about 1500-2300ng/mL, about 800-1200ng/mL, about 1900-2400ng/mL, about 50-500ng/mL, about 400-950ng/mL mL, about 900 to 1500 ng/mL, about 1100 to 2200 ng/mL, about 1300 to 1600 ng/mL, about 1200 to 1500 ng/mL, about 1400 to 2100 ng/mL, about 1500 to 1900 ng/mL, about 1600 to 2100 ng/mL , about 1700-2000ng/mL, about 1800-2000ng/mL, about 1900-2500ng/mL, about 150-1700ng/mL, about 1600-1800ng/mL, about 1700-1900ng/mL, about 1800-2000ng/mL, C _max of meloxicam of about 1900 to 2100 ng/mL, about 2000 to 2200 ng/mL, about 2100 to 2300 ng/mL, about 2200 to 2400 ng/mL, about 2300 to 2500 ng/mL, about 2500 to 3000 ng/mL, or these may result in any C _max bounded by or within a range between.

For example, the methods described herein can lower the T _max of meloxicam. In some embodiments, the method comprises about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes. , about 110 minutes, about 120 minutes, about 180 minutes, about 1 to 10 hours, about 2 to 9 hours, about 3 to 7 hours, about 4 to 6 hours, about 1 to 5 hours, about 2 to 7 hours, about 3 to 8 hours, approximately 4 to 9 hours, approximately 1 to 4 hours, approximately 2 to 5 hours, approximately 3 to 6 hours, approximately 4 to 7 hours, approximately 5 to 8 hours, approximately 6 to 9 hours, approximately 7 to It may include treating the patient to achieve the T _max of meloxicam within 10 hours or after administration thereof, or any T _max bounded by or within a range between these values.

In some embodiments, certain oral dosage forms may have a T _max of meloxicam that is shorter than that achieved by administering meloxicam by intramuscular injection. In some embodiments, the oral dosage form has at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8 , about 9, about 10, about 12, about 15, about 20 times, or about 1.5 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 bounded by or between these values. can have a shorter T _max of meloxicam or increase the plasma concentration of meloxicam by any factor of the rate within the range of .

In some embodiments, the dosage form comprising meloxicam is about 0.01-0.5 μg/mL, about 0.5-0.7 μg/mL, about 0.6-0.8 μg/mL, about 0. 7 to 0.9 μg/mL, about 0.8 to 1 μg/mL, about 0.9 to 1.1 μg/mL, about 1 to 1.2 μg/mL, about 1.1 to 1.3 μg/mL, about 1 .2 to 1.4 μg/mL, approximately 1.3 to 1.5 μg/mL, approximately 1.4 to 1.6 μg/mL, approximately 1.5 to 1.7 μg/mL, approximately 1.6 to 1.8 μg /mL, about 1.7-1.9 μg/mL, about 1.8-2 μg/mL, about 1.9-2.1 μg/mL, about 2-2.2 μg/mL, about 2.1-2. 3μg/mL, about 2.2-2.4μg/mL, about 2.3-2.5μg/mL, about 2.4-2.6μg/mL, about 2.5-2.7μg/mL, about 2 .6 to 2.8 μg/mL, approximately 2.7 to 2.9 μg/mL, approximately 2.8 to 3 μg/mL, approximately 2.9 to 3.1 μg/mL, approximately 3 to 3.2 μg/mL, approximately 3.1-3.3μg/mL, about 3.2-3.4μg/mL, about 3.3-3.5μg/mL, about 3.4-3.6μg/mL, about 3.5-3. 7 μg/mL, about 3.6-3.8 μg/mL, about 3.7-3.9 μg/mL, about 3.8-4 μg/mL, or within a range bounded by or between these values. Any plasma concentration can result in a plasma concentration of meloxicam at 12 hours.

In some embodiments, meloxicam is about 0.01-0.5 μg/mL, about 0.5-0.7 μg/mL, about 0.6-0.8 μg/mL, about 0.7-0. 9 μg/mL, about 0.8 to 1 μg/mL, about 0.9 to 1.1 μg/mL, about 1 to 1.2 μg/mL, about 1.1 to 1.3 μg/mL, about 1.2 to 1 .4μg/mL, about 1.3-1.5μg/mL, about 1.4-1.6μg/mL, about 1.5-1.7μg/mL, about 1.6-1.8μg/mL, about 1.7 to 1.9 μg/mL, about 1.8 to 2 μg/mL, about 1.9 to 2.1 μg/mL, about 2 to 2.2 μg/mL, about 2.1 to 2.3 μg/mL, Approximately 2.2 to 2.4 μg/mL, approximately 2.3 to 2.5 μg/mL, approximately 2.4 to 2.6 μg/mL, approximately 2.5 to 2.7 μg/mL, approximately 2.6 to 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- 3.3 μg/mL, about 3.2 to 3.4 μg/mL, about 3.3 to 3.5 μg/mL, about 3.4 to 3.6 μg/mL, about 3.5 to 3.7 μg/mL, Approximately 3.6 to 3.8 μg/mL, approximately 3.7 to 3.9 μg/mL, approximately 3.8 to 4 μg/mL, approximately 0.1 to 20 μg/mL, approximately 0.5 to 15 μg/mL, approximately 0.5 to 10 μg/mL, about 5 to 15 μg/mL, about 10 to 20 μg/mL, about 7.5 to 15 μg/mL, about 2 to 10 μg/mL, about 1 to 8 μg/mL, about 1 to 6 μg/mL mL, about 1 to 2 μg/mL, about 0.5 to 3.5 μg/mL, about 0.5 to 7 μg/mL, about 12 to 20 μg/mL, about 8 to 12 μg/mL, about 1 to 4 μg/mL, about 4-7 μg/mL, about 7-11 μg/mL, about 11-15 μg/mL, about 15-19 μg/mL, about 16-20 μg/mL, or within a range bounded by or between these values. Meloxicam is administered at a dose that produces a given plasma level (eg, C _avg or average plasma level).

Administration of the dosage forms described herein can reduce the time to reach therapeutic plasma concentrations of meloxicam. The therapeutic plasma concentration is C _avg at 15 mg Mobic® meloxicam. In some embodiments, the time to therapeutic plasma concentration (T _thera ) of meloxicam is about 10-30 minutes, about 10-15 minutes, about 15-20 minutes, about 20-25 minutes, about 25-30 minutes, About 10-20 minutes, about 20-30 minutes, about 16-18 minutes, or about 17 minutes.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan. They experience greater pain relief than they would experience 2 hours after administering the same amount of meloxicam without the triptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human receives rizatriptan. They experience greater pain relief than they would experience 24 hours after administering the same amount of meloxicam without the triptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human receives meloxicam experience greater pain relief than would be experienced 2 hours after administering the same amount of rizatriptan without.

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

One embodiment reduces the risk of gastrointestinal side effects and improves the bioavailability of NSAIDs for pain relief and for other conditions, particularly in people taking NSAIDs during chronic treatment. It's a method. In one embodiment, the method involves administering a product that combines a) an agent that actively increases intragastric pH, and b) an NSAID formulated with a cyclodextrin. In another embodiment, the method involves administering a product that combines a) an agent that actively increases intragastric pH, b) an NSAID formulated with a cyclodextrin, and c) a buffering agent. Either short- or long-acting acid inhibitors can be effectively used in the dosage form. This method has the added advantage of protecting the patient from other sources of gastrointestinal ulcers, the effects of which may be enhanced by the breakdown of gastroprotective prostaglandins due to NSAID therapy.

Aqueous parenteral forms of meloxicam formulations may be prepared by adjusting the pH of the aqueous formulation to about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or any other pH within the range bounded by or between these values. Oral forms of meloxicam formulations may have a dosage of about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or by values thereof. Buffers may be included to adjust the pH of the gastric juices at or between any other pH range. Examples of buffers suitable for use herein include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, and the like.

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

Tablets, troches, pills, capsules, etc. may also contain one or more of the following: gum tragacanth, acacia, a binder such as corn starch or gelatin, an excipient such as dicalcium phosphate, corn starch, potato. Contains one or more of starch, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin, or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. You can. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings, for example, the tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for the substances in the dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts used.

Some compositions or dosage forms may be liquid or may include a solid phase dispersed within a liquid.

The dosage form may include a second therapeutically active agent such as an antacid or analgesic.

In some embodiments, the dosage form increases the pH of the patient's stomach by at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and It can further include an acid inhibitor present in an effective amount to increase the concentration to at least 5. The term "acid inhibitor" refers to an agent that inhibits gastric acid secretion and increases the pH of the stomach. Particular H2 blockers, also referred to as H2 antagonists or histamine H2 blockers or antagonists, include, without limitation, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, locustidine, famotidine or combinations thereof.

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 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 range bounded by or between these values. It's the amount.

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

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

In other embodiments, the dosage form or treatment can further include administering an effective amount of an opioid to reduce or eliminate pain or inflammation. Opioids include, without limitation, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allilprozine, vegitramide, buprenorphine, butorphanol, carfentanil, desmethylprozine, dextromoramide, dezocine, diacetylmorphine, dihydroco Deinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine , nalmefene, naloxone, naltrexone, nicomorphine, omefentanil, oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, fenatazocine, piritramide, prozine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof. obtain.

Useful triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, albitriptan, zolmitriptan, and the like. In some embodiments, the triptan includes rizatriptan. In some embodiments, the dosage form is 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 delimited by these values.

In some embodiments, dosage forms comprising the subject combinations are about 1-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, or about 40-50 mg, about 10- 40mg, about 1-35mg, about 1-25mg, about 1-15mg, about 1-10mg, about 5-20mg, about 1-5mg, about 2-6mg, about 3-7mg, about 4-8mg, about 5- 10mg, about 6-11mg, about 7-12mg, about 8-13mg, about 9-11mg, about 9-14mg, about 10-15mg, about 11-16mg, about 12-17mg, about 13-18mg, about 14- 19mg, about 15-20mg, about 5-15mg, about 0.5mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or any range bounded by or between these values. of rizatriptan.

For acute migraine, the amount of meloxicam and/or rizatriptan in a single dose, or the AUC of meloxicam and/or rizatriptan associated with a single dose, is of particular interest. For example, after a single dose, symptoms may be relieved for an extended period of time such that repeated doses are not required in the short term. For more continuous conditions, including chronic, continuous, or frequent migraine symptoms, daily, weekly, or monthly dosages may be of particular interest.

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

The pharmaceutical composition comprises (a) an acid inhibitor, and/or (b) a buffer, and (c) an amount effective to reduce or eliminate pain or inflammation in a patient upon administration of one or more of said unit dosage forms. It can be in the form of tablets or capsules with non-steroidal anti-inflammatory drugs (NSAIDs) present. The components of the pharmaceutical composition may be individually or collectively in immediate or sustained release form.

The term "unit dosage form" as used herein refers to a single entity for drug administration. For example, a single tablet or capsule that combines both an acid inhibitor and an NSAID would be a unit dosage form. "Unit dosage form" (or "unit dosage form") is also referred to as "fixed dosage form" (or "fixed dosage form") or "fixed dosage form combination" (or "fixed dosage form combination"). and are interchangeable in other documents. In one embodiment, the unit dosage form is a multilayer tablet.

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.

Some dosage forms can include a first layer comprising meloxicam, SBEβCD, and bicarbonate, and a second layer comprising a second therapeutically active agent and bicarbonate.

The first layer can include, for example, any amount of meloxicam in the range mentioned above. For example, all of the meloxicam in the dosage form can be present in the first layer. The second layer may include all of the second therapeutically active agent, such that any amount within the ranges described above for the second therapeutically active agent may be applied to the second layer.

In some embodiments, the first layer is 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 ranges delimited by these values. bicarbonate, such as sodium bicarbonate, in any amount.

In some embodiments, the second layer is about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg, or ranges delimited by these values. bicarbonate, such as sodium bicarbonate, in any amount.

In some embodiments, the pharmaceutical composition can have effective amounts of meloxicam, cyclodextrin, and carbonate or bicarbonate to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition comprises an effective amount of meloxicam, sulfobutyl ether-β-cyclodextrin (SBEβCD) to increase the bioavailability of meloxicam or decrease the T _max of meloxicam; and sodium bicarbonate.

Some oral dosage forms may have enteric or film coatings. In some embodiments, the dosage form may include a tablet or capsule with an enteric coating. In some embodiments, the dosage form may include a tablet or capsule with a film coating.

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

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, comprising:
(1) Inclusion complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD),
(2) a bicarbonate, such as sodium bicarbonate or potassium bicarbonate, and
(3) It relates to a pharmaceutical composition containing a triptan such as rizatriptan.

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

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

Dosage forms comprising the combination of rizatriptan and meloxicam described herein can be administered for 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 after administration. , or may provide rapid relief of migraine pain in 0.75 to 1 hour. The combination of rizatriptan and meloxicam described herein can be administered for less than 15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes, about 30-30 minutes after administration. 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 to 4 hours, about 4 to 5 hours, about 5 to 6 hours, about 6 to 8 hours, about 8 to 10 hours, about 10 to 12 hours, about 12 to 24 hours, about 24 to 48 hours, or It is even longer and may provide numerically greater migraine pain relief than rizatriptan. The percentage of migraine patients reporting pain relief with treatment with the rizatriptan and meloxicam combination described herein is 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 It can be ˜95%, or 95-100%.

A migraine patient who is administered a dosage form comprising a combination of rizatriptan and meloxicam (the "Subject Combination") described herein may receive 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- Freedom from pain may be achieved for 30 hours, about 30-36 hours, about 36-40 hours, about 40-44 hours, about 44-48 hours, or even longer.

The rate at which migraine patients achieve pain relief increases over time after administering the combination of rizatriptan and meloxicam described herein. For example, two hours after administration, the percentage of migraineurs who achieve pain relief can be about 15-25%, about 15-20%, about 20%, about 20-25%. Four hours after administration, the percentage of migraine patients achieving pain relief is approximately 30-50%, approximately 30-40%, approximately 40%, approximately 40-45%, approximately 45-47%, approximately 47%. It can be ~50%. 12 hours after administration, the proportion of migraine patients achieving pain relief is about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 56-57%, It can be about 60-65%, about 65-70%. 16 hours after administration, the proportion of migraine patients achieving pain relief is about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 58-59%, It can be about 60-65%, about 65-70%. The combination of rizatriptan and meloxicam described herein may provide significant improvement over rizatriptan in pain relief for migraine patients. Approximately 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8% of migraine patients administered the combination of rizatriptan and meloxicam described herein , 8-9%, or 9-10% more than patients receiving rizatriptan at 2-16 hours post-dose, about 10-25%, 10-15%, 14-15%, 15-16% , 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25% relief from pain may be achieved. For example, 4 hours after administration, 40% of migraineurs receiving the subject combination achieved pain freedom and 33% of migraineurs receiving rizatriptan achieved pain freedom. In this case, the improvement of thematic combination is about 21% [((40-33)/33)×100%]. The improvement of treatment with the subject combination over meloxicam in migraine patients achieving freedom from pain may be greater than the improvement over rizatriptan. For example, the improvement over meloxicam with the subject combinations in migraineurs achieving pain relief was approximately 25-75%, 25-30%, 27-28%, 25-30%, 27-28%, 2-16 hours after administration. It can be 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75%.

at least 50%, at least 60%, at least 70%, at least 80%, about 70-80% of migraine patients who are administered a combination of rizatriptan and meloxicam (the "Subject Combination") described herein; About 80-90%, about 90-95%, about 80% are pain free 2 hours after administration and can maintain it up to 24 hours after administration. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 24 hours after administration of the subject combinations is approximately 35 to 55%, approximately 35 to 55%, compared to administration of rizatriptan. It may be increased by 40%, about 40-45%, about 45-50%, or about 50-55%. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2-24 hours after administration of the subject combination is approximately 100-165%, approximately 100-110% compared to administration of meloxicam. %, about 110-120%, about 120-130%, about 130-140%, about 140-150%, about 150-160%, or about 160-165%.

The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 24 hours after administration of the subject combinations is approximately 15 to 30%, approximately 15 to 20%, compared to administration of rizatriptan. %, about 20-25%, about 25-30%, about 20-22%, or about 21%. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2-24 hours after administration of the subject combination compared to administration of meloxicam is approximately 20-35%, approximately 20-25% , about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-30%, or about 27%.

at least 50%, at least 60%, at least 70%, at least 80%, about 70-80% of migraine patients who are administered a combination of rizatriptan and meloxicam (the "Subject Combination") described herein; About 80-90%, about 90-95%, or about 77% are pain free at 2 hours after administration and can maintain it for up to 48 hours after administration. The number of migraine patients (or degree of improvement) achieving sustained pain freedom 2 to 48 hours after administration of the subject combinations is approximately 60 to 90%, and approximately 60 to 90%, compared to administration of rizatriptan. It may be increased by 70%, about 70-75%, about 75-80%, about 80-90%, or about 75%. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 48 hours after administration of the subject combinations was approximately 70 to 110%, approximately 70 to 80%, compared to administration of meloxicam. %, about 80-90%, about 90-100%, about 100-110%, or about 90%.

The number of migraine patients (or degree of improvement) achieving sustained pain relief 2 to 48 hours after administration of the subject combination is approximately 20 to 35% compared to administration of rizatriptan; %, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-20%, or about 27%. The number of migraine patients (or degree of improvement) achieving sustained pain relief 2-48 hours after administration of the subject combination is approximately 15-30% compared to administration of meloxicam; approximately 15-20% , may increase by about 20-25%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%, about 24-25%, or about 23%. .

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

The following embodiments are contemplated.

Embodiment 1.
Inclusion complex of meloxicam in cyclodextrin.

Embodiment 2.
A dosage form comprising: 1) the inclusion complex of embodiment 1, or 2) meloxicam and a carbonate or bicarbonate.

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

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

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

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

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

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

Embodiment 9.
The dosage form of embodiment 2, 3, 4, 5, 6, 7 or 8, comprising bicarbonate.

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

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

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

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

Embodiment 14.
Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, wherein the T _max of meloxicam is reduced compared to a dosage form without carbonate, bicarbonate or cyclodextrin. 12 or 13 dosage forms.

Embodiment 15.
15. The method of embodiment 14, wherein the T _max of meloxicam is achieved in the patient at a time ranging from about 10 minutes to about 180 minutes after administration.

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

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

Embodiment 18.
The dosage form of embodiment 17, wherein the acid inhibitor is a proton pump inhibitor.

Embodiment 19.
The dosage form of embodiment 18, wherein the proton pump inhibitor is esomeprazole.

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

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

Embodiment 22.
22. The method of embodiment 21, wherein the dosage form is administered to treat pain.

Embodiment 23.
22. The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain.

Embodiment 24.
22. The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.

Embodiment 25.
administering intravenously the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 or 15 to a patient in need of treatment. How to administer.

Embodiment 26.
22. The method of embodiment 21, wherein the dosage form is administered to treat migraine.

Embodiment 27.
A dosage form comprising: 1) an inclusion complex of meloxicam in a cyclodextrin, 2) a bicarbonate, and 3) a triptan.

Embodiment 28.
28. The dosage form of embodiment 27, wherein the triptan is rizatriptan.

Embodiment 29.
28. The dosage form of embodiment 27, wherein the bicarbonate comprises sodium bicarbonate.

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

Embodiment 31.
The dosage form of embodiment 30, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups on each molecule of β-cyclodextrin.

Embodiment 32.
The dosage form of embodiment 30, wherein the molar ratio of meloxicam to SBEβCD is from about 0.8 to about 1.2.

Embodiment 33.
33. The dosage form of embodiment 32, wherein the molar ratio of meloxicam to SBEβCD is about 1.

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

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

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

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

Embodiment 38.
treating a migraine, the method comprising administering meloxicam and about 8 mg to about 13 mg of rizatriptan, based on the weight of rizatriptan in free base form, to a human suffering from an acute attack of migraine or an aura of migraine; A method, wherein meloxicam and rizatriptan are administered within 30 minutes of each other, and the administration of meloxicam to humans results in a T _max of meloxicam of 110 minutes or less, and an AUC of meloxicam of from about 30 μg/mL to about 50 μg/mL. A method that yields _0-24 .

Embodiment 39.
1) about 0.028 mmol to 0.085 mmol of meloxicam in free acid or salt form; 2) about 0.019 mmol to 0.056 mmol of rizatriptan in free base or salt form; 3) about 100 mg to about 175 mg of sulfobutyl ether beta. - cyclodextrin (SBEβCD), and 4) a pharmaceutical dosage form comprising about 400 mg to about 600 mg of sodium bicarbonate.

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

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

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

Embodiment 43.
43. The method of embodiment 40, 41, or 42, wherein the migraine patient experiences relief from nausea as a result of oral administration of the dosage form to the migraine patient.

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

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

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

Embodiment 47.
The method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein the migraine patient experiences a reduction in phonophobia as a result of oral administration of the dosage form to the migraine patient.

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

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

Embodiment 50.
The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, wherein the dosage form contains about 5 mg to about 50 mg of meloxicam.

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

Embodiment 52.
The dosage form is a solid oral dosage form in which the T _max of meloxicam in humans is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. The method of Form 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51.

Embodiment 53.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, wherein from about 1 mg to about 50 mg of rizatriptan is present in the oral dosage form, based on the weight of rizatriptan in free base form. 50, 51, or 52 methods.

Embodiment 54.
54. The method of embodiment 53, wherein rizatriptan is present in salt form in an amount of about 10 mg molar equivalents of rizatriptan in free base form.

Embodiment 55.
55. The method of embodiment 53 or 54, wherein the rizatriptan is present as rizatriptan benzoate.

Embodiment 56.
The oral dosage form of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 contains about 10 mg to about 30 mg of meloxicam. Method.

Embodiment 57.
57. The method of embodiment 56, wherein the oral dosage form comprises about 20 mg of meloxicam.

Embodiment 58.
57. The method of embodiment 56, wherein the oral dosage form comprises about 15 mg of meloxicam.

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

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

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

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

Embodiment 63.
63. The method of embodiment 62, wherein the molar ratio of SBEβCD to meloxicam is from about 0.8 to about 1.2.

Embodiment 64.
63. The method of embodiment 62, wherein the molar ratio of SBEβCD to meloxicam is about 1.

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

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

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

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

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

Embodiment 70.
Embodiments 40, 41, 42, 43, 44, 45, 46, 47, wherein the oral dosage form has been shown to have a median T _max of less than about 90 minutes for meloxicam in fasted human subjects. , 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69.

Embodiment 71.
71. The method of embodiment 70, wherein the oral dosage form has been shown to have a median T _max of less than about 2 hours for meloxicam in fasting human subjects.

Embodiment 72.
Embodiments 52, 53, 54, 55, 56, 57, 58, 59 wherein oral dosage forms have been shown to achieve faster therapeutic plasma concentrations in humans compared to reference dosage forms , 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71.

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

Embodiment 74.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the dosage form is suitable for human migraineurs. Two hours after administration, the human migraine patient is free of migraine pain.

Embodiment 75.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form contains a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the migraine sufferer A method for migraine patients experiencing a reduction in nausea as a result of oral administration.

Embodiment 76.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the dosage form is suitable for human migraineurs. A method in which the human migraine patient is free of nausea 2 hours after administration.

Embodiment 77.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form contains a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the migraine sufferer A method of experiencing a reduction in photophobia as a result of oral administration to migraine patients.

Embodiment 78.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the dosage form is suitable for human migraineurs. A method wherein the human migraine patient is free of photophobia 2 hours after administration.

Embodiment 79.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form contains a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the migraine sufferer A method whereby migraine patients experience a reduction in phonophobia as a result of oral administration.

Embodiment 80.
1. A method of treating migraine, the method comprising: selecting a human migraine patient with a history of incomplete response to previous migraine therapy; and orally administering a dosage form to the migraine patient. , the dosage form comprises a combination of 1) meloxicam (optionally in complex with sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) bicarbonate, and 3) rizatriptan, and the dosage form is suitable for human migraineurs. A method in which the human migraine patient is free of phonophobia 2 hours after administration.

(Example 1)
The effect of various amounts of potassium carbonate (K ₂ CO ₃ ) and sodium bicarbonate (NaHCO ₃ ) on the pH of acidic media was tested. The acidic medium was chosen to simulate gastric conditions. _K2CO3 or _NaHCO3 was added to 50 mL of 0.01N HCl solution (pH ₂ ). The pH _of the solution was measured after addition of _K2CO3 or _NaHCO3 . Deionized water (240 mL) was then added to the mixture and the pH was measured again. The results are shown in Tables 1 to 4.

(Example 2)
Combinations of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD) (a cyclodextrin containing about 6 to about 7 sulfobutyl ether groups on each molecule of β-cyclodextrin) with K ₂ CO ₃ or NaHCO ₃ Tablets were prepared and tested for dissolution. Tablets containing meloxicam alone (MOBIC®) were purchased and also tested for dissolution. The tablets tested are listed in Table 5. Meloxicam in the form of meloxicam/SBEβCD inclusion complex was used in tablets containing meloxicam and SBEβCD. Inclusion complexes were 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 to manufacture tablets containing SBEβCD.

Dissolution tests in acidic media (selected to simulate gastric conditions) were performed by placing the tablets in a 0.01N HCl solution at an agitation 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 expressed as percentage (%) of meloxicam dissolved.

Meloxicam dissolution was greater for tablets containing meloxicam and various combinations of SBEβCD, K ₂ CO ₃ , or NaHCO ₃ compared to tablets containing meloxicam alone. For example, after 120 minutes, the dissolution of meloxicam tablets containing NaHCO ₃ was 95% compared to 2% for tablets containing meloxicam alone.

Meloxicam dissolution increased with increasing amount _{of K2CO3} in the absence of SBEβCD. However, in the presence of SBEβCD, _increasing the amount of _K2CO3 did not seem to increase the dissolution of meloxicam. At the highest dose of potassium carbonate tested, the dissolution of meloxicam in the presence of SBEβCD was reduced by approximately 50% compared to the dissolution of meloxicam in the absence of SBEβCD at 120 minutes.

The dissolution of meloxicam in _NaHCO3 was significantly greater than that observed with the highest dose _{of K2CO3} at 15 minutes (50% vs. 30%) and 120 minutes (92% vs. 23%). Meloxicam dissolution in the presence of SBEβCD was also significantly greater with _NaHCO3 compared to the highest doses of _K2CO3 at 15 min (85% vs. 26% ₎ and 120 min (86% vs. 12%) . _NaHCO3 in the presence of SBEβCD increased the dissolution of meloxicam more at 15 min compared to potassium carbonate, which had decreased dissolution.

(Example 3)
Bilayer tablets were prepared containing 1) an inclusion complex of SBEβCD containing meloxicam prepared as described below and 2) sodium bicarbonate (SBEβCD-meloxicam/bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam and 100 mg SBEβCD and 100 mg sodium bicarbonate. The second layer contained 40 mg of esomeprazole and 400 mg of sodium bicarbonate.

A total of 20 human subjects were treated either with SBEβCD-meloxicam/bicarbonate tablets as described above or with Mobic® tablets (meloxicam 15 mg) (once daily for 6 days, fasting conditions). Random assignment was made in a 1:1 ratio.

Plasma samples were collected on the first day of dosing for analysis of meloxicam concentrations at multiple time points. The concentration of meloxicam was determined using LC-MS/MS. Pharmacokinetic parameters were calculated. The results are shown in FIG.

The median T _max for meloxicam, the study's primary endpoint, was 9 times faster for SBEβCD-meloxicam/bicarbonate tablets compared to Mobic® (0.5 hours vs. 4.5 hours, respectively). , p<0.0001).

SBEβCD-meloxicam/bicarbonate tablets also showed higher mean maximum plasma concentration (C _max ) (p=0.0018), faster time to reach therapeutic plasma concentration (p <0.0001) and faster time to half-maximal plasma concentration (p<0.0001).

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

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

Solubility testing of the tablets in acidic media (chosen to mimic gastric conditions) was performed by placing the tablets in a 0.01N HCl solution with an agitation 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 percent (%) meloxicam dissolved and percent (%) rizatriptan dissolved.

As shown in Table 7, the dissolution results of the tablets of Example 4 were very similar to those of Example 3. Therefore, the inventors believe that the pharmacokinetic properties (bioavailability, T _max of meloxicam, etc.) of the tablet of Example 4 are similar to those described in Example 3 and FIG. 11. This prediction was found to be correct, as shown in the examples below.

(Example 5)
The monolayer tablet of Example 4 was administered to six subjects. On the first day of dosing, plasma samples were collected for rizatriptan concentration analysis at multiple time points. 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 bilayer dosage form of Example 3. The median T _max of rizatriptan was 0.75 hours and the mean C _max of rizatriptan was 20.710 ng/mL. In contrast, the reported T _max of the commercially available rizatriptan dosage form, Maxalt®, is 1.0-1.5 hours.

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

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

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

(Results of Phase 1)
Meloxicam was rapidly absorbed after oral administration of meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan), with a median time to therapeutic plasma concentration (T _thera ) of 17 minutes, the primary endpoint (Figure 12 and Table 8). Median T _max is 1 hour compared to 4.5 hours for standard meloxicam 15 mg (Mobic®). The very short T _max suggests the potential for rapid onset of action of meloxicam/rizatriptan in migraine treatment. The mean plasma elimination half-life (T _1/2 ) for meloxicam was 18.2 hours after administration of meloxicam/rizatriptan compared to 21.5 hours for standard meloxicam. The long elimination half-life suggests the potential for meloxicam/rizatriptan to enhance and prolong its effects and reduce migraine pain recurrence.

Rizatriptan is rapidly absorbed after oral administration of meloxicam/rizatriptan, with a T _max of 0.88 hours compared to 0.88 hours for the same dose of standard rizatriptan (Maxalt®). The time was 64 hours (38 minutes) (Figure 13 and Table 9). Systemic exposure, measured using C _max and AUC, was numerically greater for rizatriptan after meloxicam/rizatriptan administration versus standard rizatriptan.

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

(Example 7)
We conducted a phase 3, randomized, double-blind, multicenter, positive- and placebo-controlled trial to investigate the effects of moderate and severe disease in patients with a history of incomplete response to previous acute treatment. We evaluated the efficacy and safety of meloxicam/rizatriptan in acute migraine treatment. Eligible patients were in the meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, SBEβCD, and sodium bicarbonate, as described in Example 4 above) group, rizatriptan (10 mg) (rizatriptan group), meloxicam (20 mg), SBEβCD , and sodium bicarbonate (meloxicam group), or the placebo group in a 2:2:2:1 ratio. Co-primary endpoints were freedom from headache pain at 2 hours post-dose and freedom from the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) for meloxicam/rizatriptan compared to placebo. It is.

The superiority of the meloxicam/rizatriptan group over the rizatriptan and meloxicam groups (component contribution) was based on sustained relief from headache pain from 2 to 24 hours post-dose (key secondary endpoint). will be established.

Eligible patients must have a history of inadequate response to previous acute migraine treatment, assessed using the Migraine Treatment Optimization Questionnaire (mTOQ-4). The mTOQ-4 is based on four aspects: pain relief in 2 hours, efficacy for at least 24 hours after a single dose, ability to plan daily activities, and interference with daily living. A validated questionnaire that assesses efficacy response to acute treatment.

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

(Example 8)
A female migraine sufferer visits her physician in hopes of finding relief from her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®), which she takes during her next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At her next visit, her doctor prescribed 20 mg meloxicam, which she takes during her next acute migraine, in a tablet that also contains SBEβCD and 500 mg sodium bicarbonate. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but it does not completely relieve the symptoms. At her next visit, her doctor will prescribe her the tablets of Example 4 above. She reported that her pain, nausea, allodynia, photophobia, and/or phonophobia at 2 and 24 hours after ingesting the tablets were approximately 10% lower than the little relief she experienced after taking meloxicam or rizatriptan alone. They reported an improvement of 10-30%.

(Example 9)
A male migraine patient visits his doctor in hopes of finding relief from his migraines. His doctor prescribed 10 mg rizatriptan (Maxalt®), which he takes during his next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but does not completely relieve the symptoms. At his next visit, his doctor prescribed 20 mg meloxicam, which he takes during his next acute migraine, in a tablet that also contains SBEβCD and 500 mg sodium bicarbonate. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but it does not completely relieve the symptoms. At his next visit, his doctor will prescribe him the tablets of Example 4 above. He reported that pain, nausea, allodynia, photophobia, and/or phonophobia at 2 and 24 hours after taking the tablets were approximately 100% less than the little relief he experienced after taking meloxicam or rizatriptan alone. They reported an improvement of 30-60%.

(Example 10)
A female migraine sufferer visits her physician in hopes of finding relief from her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®), which she takes during her next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but it does not completely relieve the symptoms. At her next visit, her doctor prescribed 20 mg meloxicam, which she takes during her next acute migraine, in a tablet that also contains SBEβCD and 500 mg sodium bicarbonate. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but it does not completely relieve the symptoms. At her next visit, her doctor will prescribe her the tablets of Example 4 above. She reported that at 2 and 24 hours after ingesting the tablets, her pain, nausea, allodynia, photophobia, and/or phonophobia decreased by approximately 60 to 60% compared to the improvement she experienced after taking meloxicam or rizatriptan alone. He reported a 100% improvement.

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

The World Health Organization classifies severe migraine attacks as one of the most disabling illnesses, comparable to dementia, quadriplegia, and active psychosis [(1) Menken et al., Arch Neurol. 2000;57:418-420, and (2) Shapiro and Goadsby. Cephalalgia. 2007;27:991-4]. Debilitating pain and constant fear of the next migraine attack impairs home life, social life, and work [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. People with migraine are twice as likely to be depressed and anxious than healthy individuals [Antonaci et al., J Headache Pain. 2011;12:115-125]. Widespread misconceptions about the seriousness of migraine contribute to under-recognition and under-treatment of migraine [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of patients are not fully satisfied with their current treatment. Therefore, new treatments that provide improved efficacy for this serious neurological disease are urgently needed.

A Phase 3, Randomized, Double-Blind, Multicenter, Placebo-Controlled and Positive-Controlled Study of the Efficacy of the Combination of Meloxicam and Rizatriptan (Meloxicam/Rizatriptan) in the Acute Treatment of Moderate and Severe Migraine and evaluated safety. Eligible patients are between 18 and 65 years old, have a confirmed diagnosis of migraine with or without aura according to ICHD-3 criteria (for at least 1 year), and have an average of 2 to 8 days of moderate to severe headache per month. of migraine, had a history of incomplete response to previous acute migraine treatments, and had a history of incomplete response to previous acute migraine treatments and completed the Migraine Treatment Optimization Questionnaire (mTOQ-4) (mean The score must be rated with a score of 7 using 3.6). Exclusion criteria included cluster migraine or other types of migraine, chronic daily headache (>15 non-migraine days per month), history of significant cardiovascular disease, and uncontrolled Includes high blood pressure. In addition to a history of inadequate response, enrolled patients had cutaneous allodynia (75.4%), severe migraine pain (41.2%), obesity (43.7%), morning migraine ( 36.6%) showed a high proportion of characteristics strongly associated with poor treatment outcomes. A total of 1,594 patients received monolayer tablets of Example 4 (20 mg meloxicam/10 mg rizatriptan with SBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg) and SBEβCD (MoSEIC meloxicam), or Patients were randomly assigned in a 2:2:2:1 ratio to placebo to treat a single migraine attack of moderate or severe intensity. The study's two co-primary endpoints for meloxicam/rizatriptan compared to placebo were the proportion of patients who were free of headache pain at 2 hours post-dose and the most bothersome migraine-related symptoms (nausea) at 2 hours post-dose. percentage of patients who no longer suffer from phobias (e.g., photophobia, photophobia, or phonophobia). The superiority of meloxicam/rizatriptan over rizatriptan and meloxicam groups (component contribution) was to be established based on sustained relief from headache pain 2-24 hours after administration (an important side effect). evaluation items). The study was conducted under the FDA's Special Protocol Assessment (SPA). Rizatriptan, the active comparator in this study, is the fastest acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT (1B/1D) agonists) in acute migraine treatment: a meta-an lysis of 53 trials.Lancet.2001Nov17;358(9294):1668 -75)

Meloxicam/rizatriptan provides rapid relief of migraine pain, with a greater proportion of patients achieving pain relief with meloxicam/rizatriptan than with rizatriptan at all time points measured starting at 15 minutes. It was numerically significant and statistically significant by 60 minutes (p=0.04) (Figure 14). The proportion of patients experiencing pain relief 1.5 hours after administration was 52.5% for rizatriptan and 48.3% for placebo (vs. P=0.019 and P=0.04 for meloxicam/rizatriptan, respectively). compared to 60.5% for meloxicam/rizatriptan (Figure 14).

Meloxicam/rizatriptan showed a higher proportion of patients free of pain compared to placebo (19.9% vs. 6.7%, p<0.001, Figure 15) and the most bothersome after 2 hours of administration. Two predetermined co-primary outcome criteria were met by demonstrating a statistically significant high proportion of patients who became symptom-free (36.9% vs. 24.4%, p=0.002).

The advantage of meloxicam/rizatriptan over rizatriptan (active comparator) and MoSEIC® meloxicam (ingredient contribution) is that rizatriptan achieves sustained pain relief 2 to 24 hours after administration. , MoSEIC® meloxicam, and placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively, vs. meloxicam/rizatriptan, p=0.038, p=0.0. 001; and was established as specified in the SPA. Approximately 80% of patients treated with meloxicam/rizatriptan who achieved pain freedom in 2 hours maintained pain freedom through 24 hours. These results demonstrated significant improvement in pain relief and the superiority of meloxicam/rizatriptan over rizatriptan in the treatment of migraine.

Meloxicam/rizatriptan provides substantially greater and more durable relief of migraine pain compared to placebo and rizatriptan; This can be interpreted as resulting in a significant reduction in drug use. The proportion of patients who experienced sustained pain relief 2-24 hours after administration was 33.5% for placebo and 43.9% for rizatriptan (P<0.001 vs. meloxicam/rizatriptan, respectively; P =0.006)) compared to 53.3% for meloxicam/rizatriptan (Figure 16B).

Sustained pain relief from 2 to 48 hours was also significantly lower in placebo (31.3%) and rizatriptan (36.5%) patients (P < 0.001, P = 0.003 for meloxicam/rizatriptan, respectively). ) experienced a statistically significantly higher proportion of meloxicam/rizatriptan patients (46.5%) (Figure 17B). Sustained pain relief from 2 to 48 hours was also significantly lower for placebo (5.3%) and rizatriptan (8.8%) and MoSEIC® meloxicam (8.1%) patients (vs. A statistically significantly higher proportion of meloxicam/rizatriptan patients (15.4%) experienced (Figure 17A). Approximately 77% of patients treated with meloxicam/rizatriptan who achieved pain freedom at 2 hours maintained pain freedom through 48 hours.

meloxicam/rizatriptan compared with 43% of patients receiving placebo and 34.7% of patients receiving rizatriptan (p<0.001 for each group vs. meloxicam/rizatriptan) 23.0% of patients treated used emergency medicines. Approximately 77% of patients receiving meloxicam/rizatriptan did not require rescue medication. These results demonstrated the superiority of meloxicam/rizatriptan over its active comparator rizatriptan in migraine treatment.

Meloxicam/rizatriptan improved Patient Global Impression of Change (PGI-C) (p=0.022) and several other side effects, including return to normal function at 24 hours (p=0.027). It was statistically significantly superior to rizatriptan in various endpoints.

Some of the p-values for meloxicam/rizatriptan versus rizatriptan for various endpoints are listed in Table 10 below showing the statistically significant superiority of meloxicam/rizatriptan over rizatriptan in the treatment of migraine. .

Rizatriptan, the active comparator in this study, is the fastest-acting oral triptan and is believed to be one of the most effective medications currently available for the acute treatment of migraine; The study observed a therapeutic effect with meloxicam/rizatriptan that provided greater and more sustained migraine pain relief than rizatriptan, given that the trial involved patients with difficult-to-treat migraines. That is very important. Many patients experience suboptimal responses to current acute migraine treatments, which increases the risk of headache-related disability and progression to chronic migraine, factors associated with increased healthcare costs. . The results of this study suggest that meloxicam/rizatriptan may provide an important treatment option for people with difficult-to-treat migraine.

Meloxicam/rizatriptan was safe and well-tolerated in the patients studied in this trial. The most commonly reported adverse events with meloxicam/rizatriptan were nausea, dizziness, and somnolence, none of which occurred at a greater rate than placebo or at a rate greater than 3%. . There was one serious adverse event in the meloxicam/rizatriptan group that was determined by the investigator to be unrelated to study drug.

The results of this study show that meloxicam/rizatriptan rapidly reduced migraine pain compared to its highly active comparator, rizatriptan, in a rigorously designed study in patients with difficult-to-treat migraine. It has been shown to provide unique benefits for migraine sufferers, providing powerful and long-lasting relief. These results may have important implications for patient treatment based on the inadequate response to current treatments and high rates of patient dissatisfaction.

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

(Example 12)
Meloxicam/rizatriptan is also being evaluated in a separate Phase 3 trial, a randomized, double-blind, placebo-controlled study evaluating early treatment of migraine with meloxicam/rizatriptan. This ongoing trial treats migraine attacks when patients with a history of inadequate response develop a moderate or severe migraine, whereas another trial treats migraine attacks when they develop a moderate or severe migraine. Administer meloxicam/rizatriptan to patients at the first sign of pain.

Eligible patients were randomly assigned 1:1 to meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, SBEβCD, and sodium bicarbonate, as described in Example 4 above), or placebo. Adults with a confirmed diagnosis of migraine with or without aura were included. Treatment with meloxicam/rizatriptan begins at the first sign of migraine pain onset.

Co-primary endpoints are freedom from headache pain at 2 hours post-dose and freedom from the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) for meloxicam/rizatriptan compared to placebo. .

Unless otherwise stated, numbers expressing quantities, percentages, or other characteristics of ingredients used in the specification and claims refer in all cases to the exact value shown and to "approximately" ” should be understood as indicating both modified values. Therefore, unless indicated to the contrary, the numerical parameters set forth herein and in the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, without any attempt to limit the application of equivalents to the claims, each numerical parameter should at least be interpreted in light of the number of significant figures reported and by applying normal rounding measures. Should.

The terms "a," "an," "the," and similar references used in the context of describing the embodiments (particularly in the context of the following claims), unless otherwise specified or clear from the context. shall be construed to cover both the singular and the plural unless inconsistent with the above. Any and all examples provided herein or the use of exemplary language (e.g., "such as") are intended to better clarify the embodiments and to provide scope for the claims. It does not set any restrictions. Nothing herein should be construed as indicating any non-claimed element as essential to the practice of a claim.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in or removed from a group for reasons of convenience and/or to facilitate implementation. When such inclusions or deletions occur, the specification is deemed to include the modified group, and as used in the appended claims, fulfills all descriptions of the Markush group.

Several embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the embodiments as recited in the claims. Of course, variations on these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to make appropriate use of such variations, and the inventors do not intend to implement the claimed embodiments in ways other than as specifically described herein. is intended. Accordingly, the claims are intended to include all modifications and equivalents of the claimed subject matter as permitted by applicable law. Furthermore, combinations of the above-described elements in all possible variations are contemplated, unless stated otherwise herein or clearly contradicted by context.

Finally, it is to 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. Accordingly, alternative configurations of the invention may be utilized in accordance with the teachings herein, by way of example and not limitation. Therefore, the claims are not limited to the embodiments precisely as shown and described.

(Additional note)
(Additional note 1)
A method of treating migraine headaches comprising selecting a human migraine patient with a history of incomplete response to previous migraine treatments and orally administering a dosage form to said migraine patient. wherein the dosage form comprises a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate salt, and 3) rizatriptan.

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

(Additional note 3)
3. The method according to appendix 1 or 2, wherein 2 hours after the dosage form is orally administered to the human migraine patient, the human migraine patient is free of migraine pain.

(Additional note 4)
4. The method of clause 1, 2, or 3, wherein the migraine patient experiences relief from nausea as a result of oral administration of the dosage form to the migraine patient.

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

(Appendix 6)
6. The method of clause 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.

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

(Appendix 8)
The method of clause 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. .

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

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

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

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

(Appendix 13)
The dosage form is a solid oral dosage form in which the T _max of meloxicam in humans is shorter than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. The method according to appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

(Appendix 14)
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein from about 1 mg to about 50 mg of rizatriptan is present in the oral dosage form, based on the weight of rizatriptan in free base form; 11, 12, or 13.

(Appendix 15)
15. The method of clause 14, wherein rizatriptan is present in salt form in an amount of about 10 mg molar equivalent of rizatriptan in free base form.

(Appendix 16)
16. The method according to appendix 14 or 15, wherein rizatriptan is present as rizatriptan benzoate.

(Appendix 17)
Said oral dosage form comprises about 10 mg to about 30 mg of meloxicam. Method described.

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

(Appendix 19)
18. The method of clause 17, wherein the oral dosage form contains about 15 mg of meloxicam.

(Additional note 20)
SBEβCD has about 6 to about 7 sulfobutyl ether groups on each molecule of β-cyclodextrin; 13, 14, 15, 16, 17, 18, or 19.

(Additional note 21)
The oral dosage form comprises from about 50 mg to about 150 mg of SBEβCD, , 18, 19, or 20.

(Additional note 22)
22. The method of clause 21, wherein the oral dosage form comprises about 100 mg of SBEβCD.

(Additional note 23)
Supplementary notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, wherein the molar ratio of SBEβCD to meloxicam is from about 0.5 to about 2; 17, 18, 19, 20, 21, or 22.

(Additional note 24)
24. The method of clause 23, wherein the molar ratio of SBEβCD to meloxicam is from about 0.8 to about 1.2.

(Additional note 25)
24. The method of claim 23, wherein the molar ratio of SBEβCD to meloxicam is about 1.

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

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

(Additional note 28)
28. The method of clause 27, wherein the oral dosage form comprises SBEβCD in a weight ratio of about 10 to rizatriptan.

(Additional note 29)
Bicarbonates include sodium bicarbonate, notes 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.

(Additional note 30)
29. The method of clause 29, wherein the oral dosage form comprises 500 mg of sodium bicarbonate.

(Appendix 31)
1, 2, 3, 4, 5, 6, 7, wherein said oral dosage form has been shown to have a median T _max of less than about 90 minutes for meloxicam in said human subjects on an empty stomach. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. .

(Appendix 32)
32. The method of clause 31, wherein said oral dosage form has been shown to have a median T _max of less than about 2 hours for meloxicam in said human subjects on an empty stomach.

(Appendix 33)
13, 14, 15, 16, 17, 18, 19, wherein said oral dosage form has been shown to have a faster time to reach therapeutic plasma concentrations in said human compared to a reference dosage form; 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

Claims (24)

Use of the combination in the manufacture of a medicament for the treatment of migraine in a human migraine patient, said human migraine patient having a history of incomplete response to previous migraine treatment and having severe of migraine pain, obesity, morning migraine, or a combination thereof, said combination comprising meloxicam and rizatriptan, said medicament being orally administered to said migraine patient. 2. The use according to claim 1, wherein the human migraine patient experiences migraine relief as a result of oral administration of the medicament to the migraine patient. 3. The use according to claim 1 or 2, wherein 2 hours after the medicament is orally administered to the human migraine patient, the human migraine patient is free of migraine pain. The migraine patient has nausea, photophobia, or phonophobia, or a combination thereof, and the migraine patient has nausea, photophobia, or phonophobia as a result of oral administration of the medicament to the migraine patient. 4. The use according to claim 1, 2 or 3, wherein the user experiences a reduction in phonophobia, or a combination thereof. 5. The use according to claim 4, wherein two hours after the medicament is orally administered to the human migraine patient, the human migraine patient is free of nausea, photophobia, or phonophobia, or a combination thereof. 6. The use according to claim 1, 2, 3, 4, or 5, wherein the combination includes about 5 mg to about 50 mg of meloxicam. The drug is a solid oral drug containing a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) rizatriptan, which reduces the T of meloxicam in human migraine patients. Claims 1, 2, 3, 4, wherein _max is shorter than the reference medicine that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, 3) does not contain rizatriptan, and 4) does not contain bicarbonate. , 5, or 6. 8. The use according to claim 1, 2, 3, 4, 5, 6, or 7, wherein about 1 mg to about 50 mg of rizatriptan is present in the oral medicament, based on the weight of rizatriptan in free base form. 9. The use according to claim 8, wherein rizatriptan is present in salt form in an amount of about 10 mg molar equivalent of rizatriptan in free base form. 10. Use according to claim 8 or 9, wherein rizatriptan is present as rizatriptan benzoate. 11. The use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the oral medicament comprises about 10 mg to about 30 mg of meloxicam. 12. The use according to claim 11, wherein the oral medicament comprises about 20 mg of meloxicam. 13. Use according to claim 11 or 12, wherein meloxicam is in free acid form. 14. The use according to claim 7, 8, 9, 10, 11, 12, or 13, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups on each molecule of β-cyclodextrin. 15. The use of claim 7, 8, 9, 10, 11, 12, 13, or 14, wherein the oral medicament comprises about 50 mg to about 200 mg of SBEβCD. 16. The use according to claim 15, wherein the oral medicament comprises about 100 mg of SBEβCD. Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, wherein the oral medicament comprises about 10 mg to about 40 mg of meloxicam, and about 5 mg to about 50 mg of rizatriptan. , 13, 14, 15, or 16. 18. The use according to claim 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the bicarbonate comprises 500 mg of sodium bicarbonate. Claims 1, 2, 3, 4, 5, 6, 7, wherein said oral medicament has been shown to have a median T _max of less than about 2 hours for meloxicam in said human subjects on a fasting stomach. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. Claims 7, 8, 9, 10, 11, 12, 13, 14, wherein the oral medicament has been shown to reach therapeutic plasma concentrations faster in the human compared to a reference medicament. , 15, 16, 17, 18, or 19. The use according to claim 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the combination comprises 400 mg to 600 mg of bicarbonate. . Claims 1, 2, 3, 4, wherein the history of incomplete response to previous migraine treatment includes a score of 7 or less on the Migraine Treatment Optimization Questionnaire (mTOQ-4). 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. 23. The use according to claim 22, wherein the human migraine patient has a confirmed diagnosis of migraine with or without aura and has been experiencing migraine pain with or without aura for at least one year. 24. The use according to claim 22 or 23, wherein the human migraine sufferer has an average of 2 to 8 moderate to severe migraines per month.

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