Pharmaceutical compositions containing meloxicam

Abstract

To provide compositions with improved efficacy for treating symptoms of pain (such as migraine).SOLUTION: Disclosed herein are compositions comprising drugs (a triptan, such as rizatriptan, and / or an NSAID, such as meloxicam) in combination with a cyclodextrin and / or a carbonate or bicarbonate. These compositions may be orally administered, for example, to improve the bioavailability, solubility or pharmacokinetics of the drugs for treating symptoms such as pain.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 693,871, filed July 3, 2018, U.S. Provisional Patent Application No. 62 / 860,705, filed June 12, 2019, U.S. Provisional Patent Application No. 62 / 846,311, filed May 10, 2019, U.S. Provisional Patent Application No. 62 / 835,613, filed April 18, 2019, U.S. Provisional Patent Application No. 62 / 803,756, filed February 11, 2019, and U.S. Provisional Patent Application No. 62 / 802,198, filed February 6, 2019, all of which are incorporated herein by reference in their entireties. [Background technology]

[0002] There is a continuing need for therapeutics with improved efficacy in the treatment of pain, inflammation, migraine, and related disorders. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure relates to the use of bicarbonates and / or cyclodextrins (such as sulfobutyl ether β-cyclodextrin (SBEβCD)) to improve the pharmacokinetics or bioavailability of drugs (such as nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam, triptans such as rizatriptan, or combinations thereof).

[0004] For example, some embodiments include dosage forms containing a triptan (such as rizatriptan or frovatriptan) in combination with a cyclodextrin (optionally as an inclusion complex of the triptan and cyclodextrin) and / or a bicarbonate, and methods of treatment using the dosage forms.

[0005] Some embodiments include a dosage form containing meloxicam, sulfobutyl ether β-cyclodextrin (SBEβCD), a bicarbonate, and a triptan, which has a higher T of meloxicam than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. max This includes dosage forms that are short oral dosage forms.

[0006] Some embodiments include an inclusion complex of a triptan (such as rizatriptan or frovatriptan) within a cyclodextrin.

[0007] Some embodiments include dosage forms containing 1) an inclusion complex of a triptan (such as rizatriptan or frovatriptan) with a cyclodextrin, or 2) a triptan (such as rizatriptan or frovatriptan) with a carbonate or bicarbonate.

[0008] Some embodiments include methods of administering a product comprising a triptan in combination with 1) a cyclodextrin and / or 2) a buffering agent. In some embodiments, the methods involve treating a patient with a pharmaceutical formulation containing a triptan (e.g., rizatriptan or frovatriptan) and a cyclodextrin and / or a carbonate / bicarbonate. Some embodiments may also include increasing the bioavailability of the triptan (e.g., rizatriptan or frovatriptan) or increasing the percentage of the triptan that is bioavailable in a subject in need of the triptan compared to a formulation that does not include a cyclodextrin or a carbonate / bicarbonate.

[0009] Some embodiments include a method of improving the pharmacokinetics of a triptan or NSAID comprising orally administering a dosage form described herein to a mammal or human in need of treatment with the triptan or NSAID.

[0010] Some embodiments include a method of treating pain comprising orally administering a dosage form described herein to a mammal or human in need of such treatment.

[0011] Some embodiments include methods of treating pain (e.g., migraine) comprising administering meloxicam and rizatriptan to a human suffering from pain (e.g., migraine). With respect to migraine, these methods may be particularly useful when the meloxicam and rizatriptan are administered while the human is suffering from an acute attack of migraine pain or migraine aura. In some embodiments, about 8-13 mg of rizatriptan is administered to the human. In some embodiments, the combination of meloxicam and rizatriptan (e.g., 8-13 mg of rizatriptan) reduces the T of meloxicam within 3 hours, within 2 hours, or within 110 minutes. max and / or an AUC of meloxicam of approximately 30-50 μg·hr / mL 0-24 The compound may be administered in a manner that results in [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the results described in Example 2 and shown in Table 6. [Figure 2] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 3] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 4] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 5] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 6] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 7] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 8] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 9]Another figure showing the results described in Example 2 and shown in Table 6. [Figure 10] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 11] FIG. 1 is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for an embodiment of a dosage form described herein and a commercially available meloxicam dosage form. DETAILED DESCRIPTION OF THE INVENTION

[0013] Meloxicam and other NSAIDs and other drugs have poor aqueous solubility, which can reduce bioavailability and delay the onset of pain relief. One way to increase the solubility and bioavailability of meloxicam and other drugs is through the use of cyclodextrins in combination with meloxicam.

[0014] This can generally be achieved using a dosage form (e.g., oral dosage form) containing a triptan (e.g., rizatriptan), optionally in combination with an NSAID (e.g., meloxicam), along with 1) a cyclodextrin (optionally in the form of an inclusion complex), and / or 2) a buffering agent (e.g., bicarbonate). Administering this type of dosage form to a patient can increase the bioavailability of the triptan (e.g., rizatriptan) or NSAID (e.g., meloxicam) in the patient, increase the rate at which the triptan (e.g., rizatriptan) or NSAID (e.g., meloxicam) becomes bioavailable, or increase the rate at which the plasma concentration of the triptan or NSAID increases. For example, the triptan or NSAID may experience a shorter T max or increased C max or the area under the plasma concentration curve (AUC).

[0015] Any suitable triptan may be used, such as sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan, zolmatriptan, etc. (including combinations or salts thereof). In some embodiments, the triptan comprises rizatriptan, which has the following structure:

[0016] [ka]

[0017] NSAIDs include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID for purposes of this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, pinoxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof.

[0018] In some embodiments, the NSAID is meloxicam, which has the following structure:

[0019] [ka]

[0020] Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic effects. Its mechanism of action may be related to the inhibition of prostaglandin synthase (cyclooxygenase, COX), which is involved in the first step of the arachidonic acid cascade, leading to decreased formation of prostaglandins, thromboxanes, and prostacyclin.

[0021] The combination of rizatriptan and meloxicam (hereinafter referred to as the "subject combination" for simplicity) can be used to treat a variety of pain conditions.

[0022] Unless otherwise specified, any reference to a compound described herein (e.g., meloxicam or rizatriptan) by structure, name, or any other means includes pharmaceutically acceptable salts, alternative solid forms (e.g., polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms), or any other chemical species (precursors, prodrugs), or any other chemical species that can be rapidly converted to a compound described herein under the conditions of using the compound as described herein.

[0023] The dosage forms or subject combinations may be given enterally (e.g., but not limited to, oral, sublingual, or rectal delivery) or parenterally (e.g., but not limited to, intravenous, intramuscular, nasal, or subcutaneous delivery). In some embodiments, both meloxicam and rizatriptan may be 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.

[0024] Typically, the combination of meloxicam and rizatriptan is administered so that a person receives meloxicam and rizatriptan within a short period of time from each other. For example, meloxicam and rizatriptan may be administered within about 2 hours, about 1 hour, about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 1 minute of each other. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which for purposes of this disclosure includes administration within about 5 minutes. In some embodiments, meloxicam and rizatriptan are administered as a single dosage form.

[0025] The term "treatment" broadly includes any type of therapeutic activity (such as the diagnosis, cure, mitigation, or prevention of disease in humans or other animals) or any activity that otherwise affects the structure or any function of the human or animal body.

[0026] The dosage forms or subject combinations can be used to treat or alleviate any type of pain, including, but not limited to, migraine and other types of headache, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, generalized pain, cancer pain, acute pain, pain due to injury, pain due to illness (e.g., fever), post-operative pain, etc. In some cases, pain relief may be temporary, or pain relief may be provided independently of improvement of the disease or disorder or the underlying cause of the disease or disorder. For example, an individual suffering from a disease may experience pain relief even if the underlying disorder does not improve or continues to progress. In some embodiments, the pain affects muscles, nerves, cartilage, bone, ligaments, tendons, tendon sheaths, bursae, or joints.

[0027] Migraine is a headache disorder characterized by frequent headaches that can be moderate to severe. The headaches may affect one side of the head, be pulsating in nature, and last from 2 to 72 hours. Accompanying symptoms include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), and odors. The pain may be worsened by physical activity. Migraine may be accompanied by aura, which can be a brief visual disturbance that signals an impending headache.

[0028] Administration of a subject combination to a human suffering from a migraine headache (such as an acute attack of migraine pain and aura) may rapidly result in a reduction in migraine symptoms (such as pain, nausea, vomiting, light sensitivity, or sound sensitivity), such as at or within about 5 minutes, at or within about 10 minutes, at or within about 30 minutes, at or within about 1 hour, at or within about 90 minutes, at or within about 2 hours, at or within about 2.5 hours, or at or within about 3 hours. In some embodiments, a human experiences a reduction or complete relief of pain (such as headache or migraine pain, allodynia, nausea, vomiting, photosensitivity, and / or phonosensitivity) within about or within 1 hour, about or within 90 minutes, about or within 2 hours, about or within 2.5 hours, or about or within 3 hours. In some embodiments, the relief experienced is greater than that which would be experienced by receiving the same amount of rizatriptan without meloxicam. In some embodiments, the relief experienced is greater than that which would be experienced by receiving the same amount of meloxicam without rizatriptan.

[0029] Observing symptom relief or reduction over a specific time period (e.g., at 'hour 2') is useful because it allows the effectiveness of treatment to be assessed at specific or consistent time points, facilitating comparisons between patients. Observing symptom relief or reduction within a specific time period (e.g., 'within 2 hours') is useful because it may be desirable for symptom relief or reduction to occur as quickly as possible, and specifying that relief occurs within a specific time period sets guidelines within which relief is desirable.

[0030] For some methods, administration of a subject combination may achieve a reduction in migraine pain, allodynia, nausea, vomiting, photophobia, or phonophobia that lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8-24 hours, about 24 hours, or longer than 24 hours.

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

[0032] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences greater pain relief than a human would experience 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0033] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, a human experiences greater pain relief than a human would experience two hours after receiving the same amount of rizatriptan without the meloxicam.

[0034] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences greater pain relief than a human would experience 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0035] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, the human experiences greater relief of allodynia than the human would experience two hours after receiving the same amount of meloxicam without rizatriptan.

[0036] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief of allodynia than the human would experience 24 hours after receiving the same amount of meloxicam without rizatriptan.

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

[0038] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experiences greater relief of allodynia than the human would experience 24 hours after receiving the same amount of rizatriptan without meloxicam.

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

[0040] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences greater nausea relief than a human would experience 24 hours after receiving the same amount of meloxicam without rizatriptan.

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

[0042] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of the meloxicam and rizatriptan, a human experiences greater nausea relief than a human would experience 24 hours after receiving the same amount of rizatriptan without the meloxicam.

[0043] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and two hours after administration of the meloxicam and rizatriptan, a human experiences greater relief from emesis than a human would experience two hours after receiving the same amount of meloxicam without rizatriptan.

[0044] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences greater relief from emesis than a human would experience 24 hours after receiving the same amount of meloxicam without rizatriptan.

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

[0046] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, a human experiences greater relief from emesis than a human would experience 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0047] In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., as a single dosage form, such as a single oral dosage form), and two hours after administration of meloxicam and rizatriptan, a human experiences greater relief from photosensitivity than a human would experience two hours after receiving the same amount of meloxicam without rizatriptan.

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

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

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

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

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

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

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

[0055] In some embodiments, the person receiving the subject combination has a history of inadequate response to previous migraine treatments. For example, if a person is asked whether pain disappeared within two hours of treatment for the majority of attacks and given the response options of "never disappeared," "rarely disappeared," "less than half of the time," or "more than half of the time," and the person answers "never disappeared," "rarely disappeared," or "less than half of the time," the person will have an inadequate response to treatment. Similarly, if a person is asked whether a single dose of a medication usually relieves the person's headache and maintains this state for at least 24 hours and given the response options of "never," "rarely," "less than half of the time," or "more than half of the time," and the person answers "never," "rarely," or "less than half of the time," the person will have an inadequate response to treatment.

[0056] In some embodiments, humans receiving the subject combination demonstrated that for the majority of attacks, pain was "not gone" within two hours of treatment. In some embodiments, humans receiving the subject combination demonstrated that for the majority of attacks, pain was "rarely gone" within two hours of treatment. In some embodiments, humans receiving the subject combination demonstrated that for the majority of attacks, pain was "less than half gone" within two hours of treatment.

[0057] In some embodiments, humans receiving the subject combination indicated that a single dose of the medication "never" relieved the respondent's headache and maintained that state for at least 24 hours. In some embodiments, humans receiving the subject combination indicated that a single dose of the medication "rarely" relieved the respondent's headache and maintained that state for at least 24 hours. In some embodiments, humans receiving the subject combination indicated that a single dose of the medication "rarely" relieved the respondent's headache and maintained that state for at least 24 hours.

[0058] For some methods, the dosage forms or subject combinations may be administered to relieve inflammatory pain, such as inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndrome. In another embodiment, the inflammatory pain may be chronic or acute.

[0059] In some embodiments, the dosage forms (e.g., dosage forms containing a triptan (e.g., rizatriptan or frovatriptan) and / or an NSAID (e.g., meloxicam)) or subject combinations may be administered to relieve arthritis pain or the signs and / or symptoms of arthritis. Arthritis refers to inflammatory joint diseases that may be accompanied by pain. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (oligoarticular and polyarticular), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic), arthropathy, non-articular rheumatoid arthritis, periarticular disorders, axial spondyloarthritis, simple hip arthritis, vertebral crush fractures, arthritis associated with osteoporosis, and neuropathic arthropathies (e.g., Charcot foot), axial spondyloarthritis (e.g., ankylosing spondylitis and SAPHO syndrome). In other embodiments, the arthritis pain may be chronic or acute. In some embodiments, the dosage forms or subject combinations may be administered to alleviate the signs and / or symptoms of arthritis (including, but not limited to, osteoarthritis).

[0060] In some embodiments, the dosage forms (e.g., dosage forms containing a triptan (e.g., rizatriptan or frovatriptan) and / or an NSAID (e.g., meloxicam)) or subject combinations may be administered to relieve neuropathic pain (e.g., diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, sciatica, pudendal neuralgia, and central pain). Other causes of neuropathic pain include, but are not limited to, cancer pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radiation or chemotherapy-associated neuropathy. The neuropathic pain may be chronic or acute.

[0061] For some methods, the dosage form (e.g., a dosage form containing a triptan (e.g., rizatriptan or frovatriptan) and / or an NSAID (e.g., meloxicam)) or a subject combination may be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain include, but are not limited to, back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, cramps, tendonitis, lateral epicondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, injury pain, tunnel syndrome, fracture pain, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient femoral neck osteoporosis. In other embodiments, the musculoskeletal pain may be chronic or acute.

[0062] For some methods, administration of the dosage form (e.g., a dosage form containing a triptan (such as rizatriptan or frovatriptan) and / or an NSAID (such as meloxicam)) or a subject combination may achieve pain suppression that lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, from about 8 hours to about 24 hours, or about 24 hours. In another embodiment, administration of the dosage form or subject combination may achieve pain suppression that is observed at about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, at about or within 5 minutes, at about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, or about 60 minutes, within 2 hours, within 3 hours, or other time periods bounded by these ranges, after administration of the dosage form or subject combination.

[0063] Humans treated for diseases or disorders, such as migraine, with any of the dosage forms (e.g., dosage forms containing a triptan (e.g., rizatriptan or frovatriptan) and / or an NSAID (e.g., meloxicam)) or subject combinations described herein can be of any age. For example, such individuals can be about 0.1-10 years old, about 10-90 years old, about 20-80 years old, about 30-75 years old, about 40-70 years old, about 1-16 years old, about 80-95 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 range bounded by or between any of these values.

[0064] In some embodiments, a human being treated for a disease or disorder, such as migraine, with a subject combination or dosage form (e.g., a dosage form containing a triptan (e.g., rizatriptan or frovatriptan) and / or an NSAID (e.g., meloxicam)) is one who has suffered from the condition for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years, or any period bounded by or within a range between any of these values.

[0065] Cyclodextrins used in dosage forms containing drugs (such as meloxicam or other NSAIDs, rizatriptan, frovatriptan, or other triptans) can include cyclodextrins, cyclodextrin derivatives, and / or salts thereof. Cyclodextrins (also known as cycloamylose) are generally cyclic polysaccharides that form a bucket-like shape. Cyclodextrins have a hydrophobic interior and a hydrophilic exterior, which helps facilitate the transport of hydrophobic molecules into hydrophilic media, thereby increasing the bioavailability of other molecules. Naturally occurring cyclodextrins include 6, 7, and 8 glucose units (α-, β-, and γ-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are also possible. In aqueous solutions, cyclodextrins are known to aggregate around drugs in micellar structures, but they can also form complexes (i.e., inclusion complexes) with drugs by incorporating them into the central / hydrophobic part of the cyclodextrin ring. This ability allows cyclodextrins to act as carriers for less water-soluble drugs, increasing their bioavailability.

[0066] Inclusion complexes of drugs (e.g., meloxicam or other NSAIDs, rizatriptan, frovatriptan, or other triptans) with cyclodextrins may be more water-soluble than the uncomplexed drug. The cyclodextrin may be a naturally occurring cyclodextrin (e.g., α-, β-, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, its derivatives, or its salts may be used. Examples of α-cyclodextrins include, but are not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0067] In some embodiments, β-cyclodextrin, its derivatives, or salts thereof may be used, including, but not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-diamino-β-cyclodextrin), hydroxypropyl-β-cyclodextrin, ... -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-cyclo Dextrin, (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-Ot-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, Succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,Examples of suitable cyclodextrins include 6-di-O-ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl((6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin, succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomly methylated-β-cyclodextrin, branched-β-cyclodextrin, and combinations thereof. ,

[0068] In another embodiment, the β-cyclodextrin may be a sulfoalkyl ether cyclodextrin, a derivative thereof, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives include, but are not limited to, sulfobutyl ether-β-cyclodextrin (e.g., SBEβCD, Betadex, CAPTISOL®). In some embodiments, the SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0069] In some embodiments, gamma-cyclodextrin, its derivatives, or its salts may be used. Examples of gamma-cyclodextrins include carboxymethyl-gamma-cyclodextrin, (2,3,6-tri-O-acetyl)-gamma-cyclodextrin, (2,3,6-tri-O-methyl)-gamma-cyclodextrin, (2,6-di-O-pentyl)-gamma-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-gamma-cyclodextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, 6-iodo-6-deoxy-gamma-cyclodextrin, (6-Ot-butyldimethylsilyl)-gamma-cyclodextrin, succinyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, (2-hydroxypropyl)-gamma-cyclodextrin, acetyl-gamma-cyclodextrin, butyl-gamma-cyclodextrin, and combinations thereof.

[0070] In some embodiments, the dosage form may include a bicarbonate (such as sodium bicarbonate or potassium bicarbonate), which may help increase the pharmacokinetics or bioavailability of meloxicam or other drugs (such as rizatriptan).

[0071] In some embodiments, enhanced bioavailability of a drug (such as meloxicam or a triptan (e.g., rizatriptan)) in the present dosage forms may be achieved by administering a dosage form containing a salt form of the drug, by forming an inclusion complex of the drug with a cyclodextrin, and / or by including a bicarbonate, which may allow for a reduced molar amount of the drug to be used in the treatment of a disease or disorder compared to other drug-containing dosage forms.

[0072] Unless otherwise specified, any reference to a compound described herein (such as meloxicam, an NSAID, a triptan, a rizatriptan, or a cyclodextrin) by structure, name, or any other means, includes pharmaceutically acceptable salts, alternative solid forms (such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, etc.), or any other chemical species (precursors, prodrugs), or any other chemical species that can be rapidly converted to a compound described herein under the conditions of using the compound as described herein.

[0073] In some embodiments, the use of a cyclodextrin or bicarbonate improves the solubility or oral bioavailability (e.g., higher C) of meloxicam in a subject (human or animal). max and / or higher AUC) compared to administration of meloxicam alone may be improved by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at most about 100%, at most about 200%, or by any amount bounded by or within a range between any of these values.

[0074] In some embodiments, the use of a cyclodextrin or bicarbonate improves the solubility or oral bioavailability (e.g., higher C) of a triptan (such as rizatriptan or frovatriptan) in a subject (human or animal). max and / or higher AUC) compared to administration of the triptan alone may be improved by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at most about 100%, at most about 200%, or by any amount bounded by or within a range between any of these values.

[0075] Due to the improved bioavailability described above, the dosage form may contain, or a subject may be administered, on a molar basis, less drug (such as a triptan (e.g., rizatriptan or frovatriptan) or an NSAID (e.g., meloxicam)) than would be administered alone. For example, the dosage form may contain, or a mammal may be administered, at least about 10 molar%, at least about 20 molar%, at least about 30 molar%, at least about 40 molar%, at least about 50 molar%, at least about 60 molar%, at least about 70 molar%, at least about 80 molar%, at least about 85 molar%, and / or at most about 90 molar%, 95 molar%, 98 molar% less meloxicam than would be administered alone, or any amount within a range bounded by or between any of these values.

[0076] In another embodiment, when a drug (such as a triptan (e.g., rizatriptan) or an NSAID (e.g., meloxicam)) is administered with a cyclodextrin and / or a bicarbonate, the use of other NSAIDs, opioids, or other analgesics may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or at most about 100%, or any amount within a range bounded by or between any of these values, compared to administration of the NSAID, opioid, or other analgesic alone.

[0077] In some embodiments, the dosage form comprises an NSAID (such as celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID in this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, pinoxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, etc.) in an amount of about 1- 1000mg, about 1-500mg, about 1-400mg, about 1-300mg, about 1-200mg, about 1-100mg, about 1-50mg, about 1-10mg, about 1-5mg, about 2-6mg, about 3-7m g, about 4-8mg, about 5-10mg, about 7-12mg, about 5-15mg, about 10-20mg, about 15-25mg, about 20-30mg, about 25-35mg, about 30-40mg, about 35-45mg, about It may be included in an amount of 40-50 mg, about 50-150 mg, about 50-100 mg, about 100-200 mg, about 150-250 mg, about 200-300 mg, about 250-350 mg, about 300-400 mg, about 350-450 mg, about 400-500 mg, about 100 mg, about 200 mg, about 325 mg, or any amount bounded by or within a range between any of these values. These doses may be safe doses for repeated administration (such as 1, 2, 3, or 4 repeated doses per day, or repeated doses repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 1 week, about 4 weeks, about 6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 2 years, etc.).

[0078] In some embodiments, dosage forms comprising meloxicam or combinations of dosage forms, including oral, intravenous, or intramuscular dosage forms, include those containing meloxicam in doses of about 1-50 mg, about 1-10 mg, about 1-5 mg, about 10-40 mg, about 1-35 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 7-12 mg, about 5-15 mg, about 10-20 mg, about 10-30 mg, about 18-20 mg, about 20-30 mg, about 25-30 mg, about 35-4 ... The composition may contain an amount of about 2 mg, about 19-21 mg, about 15-25 mg, about 20-30 mg, about 25-35 mg, about 30-40 mg, about 35-45 mg, about 40-50 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or any amount within a range bounded by or between any of these values. For the amounts of meloxicam (or any other compound) described herein, a salt form of meloxicam (or other compound) may be present in the amounts described above or in an amount that is the molar equivalent of such amount for the non-salt form of meloxicam (or other compound). These doses may be safe for repeated administration (1, 2, 3, or 4 repeated doses per day) or may be administered for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 days. The period may be repeated at intervals of about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 1-2 months, about 4 weeks, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 1-2 years, about 2 years, etc.

[0079] For some dosage forms, the drug (e.g., meloxicam, frovatriptan, or rizatriptan) forms a complex with a substituted-β-cyclodextrin or other cyclodextrin that can be formulated into a solid dosage form. Such dosage forms may be suitable for oral administration. Alternatively, the drug-cyclodextrin inclusion complex may be dissolved in water or other solvent to form a parenteral formulation. However, a physical mixture of the drug and substituted-β-cyclodextrin or other cyclodextrin that is not an inclusion complex may also be used in oral or parenteral dosage forms.

[0080] Forming an inclusion complex between a drug (such as meloxicam, frovatriptan, or rizatriptan) and a cyclodextrin can help improve the properties of the dosage form. For some inclusion complexes, the drug and cyclodextrin (e.g., SBEβCD) may have a molar ratio of about 0.5-2, about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 1.9-2.1, about 2-2.2, about 0.8-1.2, about 1 (a molar ratio of 0.5 is 0.5 moles of drug to 1 mole of cyclodextrin), or any ratio within a range bounded by any of these values.

[0081] In some embodiments, the inclusion complex is formed by (1) mixing a homogeneous solution of the drug (e.g., meloxicam or triptan) with a homogeneous solution of a cyclodextrin to form a homogeneous solution of the drug and cyclodextrin, and (2) removing or evaporating the solvent from the homogeneous solution of the drug and cyclodextrin to form a complex comprising an inclusion complex of the drug within the cyclodextrin. In some embodiments, these solutions can be pH-adjusted aqueous solutions. The pH can be adjusted using a buffer. In some embodiments, the solvent can be removed or evaporated by freeze-drying, spray-drying, or other suitable means. In some embodiments, the solvent can be removed by vacuum drying, etc.

[0082] For some dosage forms, the cyclodextrin (e.g., SBEβCD) may be employed in a weight ratio to meloxicam within the ranges of about 1-1000, about 1-500, about 1-5, about 1-20, about 1-10, about 1-15, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 0.01-1, about 0.05-1, about 0.1-1, about 0.2-1, about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1 (e.g., 1 gram of cyclodextrin per 1 gram of meloxicam would be a weight ratio of 1), or any weight ratio within or between any of these ranges. Each type of cyclodextrin employed may have a different weight ratio to meloxicam in the dosage form.

[0083] For some dosage forms, the cyclodextrin (e.g., SBEβCD) is used in an amount of about 1-1000, about 1-500, about 1-100, about 1-50, about 1-20, about 1-10, about 1-15, about 1-5, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 0.01-1, about 0.05- cyclodextrins may be employed in a weight ratio within the range of about 0.1, about 0.1-1, about 0.2-1, about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1 (e.g., 10 g of cyclodextrin per 1 g of rizatriptan or frovatriptan would yield a weight ratio of 10), or any weight ratio within or between any of these values. Each type of cyclodextrin employed may have a different weight ratio to the triptan in the dosage form.

[0084] For some dosage forms, the cyclodextrin (e.g., SBEβCD) may be present in an amount of about 1-1000, about 1-500, about 1-100, about 1-50, about 1-20, about 1-10, about 1-15, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 9-11, about 10-12, about 11-13, about 12-14, about 13-15, about 14-16, about 15-17, about 16-18, about 17-19, about 18-20, about 21-22, about 22-23, about 23-24, about 24-25, about 25-26, about 26-27, about 27-28, about 28-30, about 30-31, about 31-32, about 32-33, about 33-34, about 34-35, about 35-36, about 36-37, about 37-38, about 38-39, about 40-41, about 42-43, about 44-45, about 46-47, about 48-49, about 50-51, about 51-52, about 52-53, about 53-54, about 54-55, about 55-56, about 56-57, about 57-58, about 58-60, about 60-61, about 61-62, about 62-63, about 63-64, about 64-65, about 65-66, about 66-67, about 6 cyclodextrin may be employed in a weight ratio within the range of about 0.001-1, about 0.01-1, about 0.05-1, about 0.1-1, about 0.2-1, about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1 (e.g., 10 g of cyclodextrin per 1 g of rizatriptan would be a weight ratio of 10), or any weight ratio within or bounded by any of these values. Each type of cyclodextrin employed may have a different weight ratio to rizatriptan in the dosage form.

[0085] In some embodiments, the dosage form or subject combination contains rizatriptan at a dose of about 1-50 mg, about 1-10 mg, 10-20 mg, about 20-30 mg, about 30-40 mg, or about 40-50 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 1-10 mg, about 5-20 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-11 mg, about 9-14 mg, about 10-15 mg , about 11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 5-15 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or any amount bounded by or within a range between any of these values.

[0086] For acute migraine, the amount of meloxicam and / or rizatriptan in a single dose, or the AUC of meloxicam and / or rizatriptan associated with a single dose, may be of particular interest. For example, long-term relief of symptoms may be achieved after a single dose, thereby obviating the need for short-term repeated dosing. For more persistent symptoms (more chronic, ongoing, or frequent migraine symptoms), daily, weekly, or monthly dosing may be of particular interest.

[0087] For any amount of rizatriptan described herein, a salt form of rizatriptan may be present in the amount described above or in an amount that is the molar equivalent of these amounts for rizatriptan free base. For example, when the molecular weight of rizatriptan free base is 269.3 g / mol, 10 mg of rizatriptan corresponds to 37.1 mmol of rizatriptan. Therefore, the molar equivalent of 10 mg of rizatriptan free base is the mass of 37.1 mmol of the salt form. For example, for the benzoate salt (mw=391.2 g / mol), the molar equivalent of 10 mg (or 37.1 mmol) of free base is 14.5 mg. These doses may be safe for repeated administration (such as 1, 2, 3, or 4 repeated doses per day, or repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, etc.).

[0088] The other triptan may be administered to the patient in any dose that is effective for analgesia, and in some embodiments, the dosage form may contain the triptan in any amount bounded by or within a range between any of the values ​​recited above.

[0089] In some embodiments, the dosage form contains frovatriptan or other triptans at about 1-50 mg, about 1-10 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-11 mg, about 9-14 mg, about 10-15 mg, about 1 It may be present in an amount of about 1-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 5-15 mg, about 10-20 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 10 mg, about 15 mg, about 30 mg, or any amount bounded by or within a range between any of these values. These doses may be safe doses for repeated administration (such as 1, 2, 3, or 4 repeated doses per day, or repeated doses repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 4 weeks, about 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 2 years, etc.).

[0090] For some dosage forms, the cyclodextrin (e.g., SBEβCD) may be present in an amount of about 1-200 mg, about 1-100 mg, about 25-175 mg, about 50-150 mg, about 50-100 mg, about 50-200 mg, about 25-100 mg, about 75-150 mg, about 100-175 mg, about 20-80 mg, about 25-50 mg, about 60-100 mg, about 80-100 mg, about 100 mg, about 80-120 mg. The cyclodextrin may be present in an amount of about 100-120 mg, about 100-140 mg, about 120-160 mg, about 140-180 mg, about 150-200 mg, about 100-150 mg, about 30-90 mg, about 40-60 mg, about 40-80 mg, about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount within a range bounded by or between any of these values. max It may be effective to decrease the AUC and / or increase the AUC.

[0091] For some dosage forms, the inclusion complex of the drug (e.g., meloxicam or other NSAID, or rizatriptan, frovatriptan, or other triptan) with the cyclodextrin is about 1-10%, about 5-20%, about 5-15%, about 6-16%, about 7-17%, about 8-18%, about 9-19%, about 10-20%, about 15-30%, about 30-40%, about 40-50%, about 50-70%, or about 70-90%, based on the total weight of the dosage form, or any percentage within a range bounded by any of these values.

[0092] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in an amount of about 1-2000 mg, about 1-1000 mg, about 100-1000 mg, about 200-800 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 50-100 mg, about 250-750 mg, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 41 It may be included in an amount of about 0-510 mg, about 420-520 mg, about 430-530 mg, about 440-540 mg, about 450-550 mg, about 460-560 mg, about 470-570 mg, about 480-580 mg, about 490-590 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1000 mg, about 150-650 mg, about 350-850 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or any amount within a range bounded by or between any of these values.

[0093] The bicarbonate (e.g., sodium bicarbonate) may be at least about 10%, at least about 15%, at least about 20%, about 20-40%, about 30-50%, about 40-60%, about 50-70%, about 60-80%, or about 70-90%, based on the total weight of the dosage form, or any percentage within a range bounded by any of these values.

[0094] In some embodiments, the daily dose of meloxicam, or the amount of meloxicam administered per day (either in a single dose or in two or more divided doses totaling the daily dose), is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-31 mg, about 2-32 mg, about 2-33 mg, about 2-34 mg, about 2-35 mg, about 2-36 mg, about 2-37 mg, about 2-38 mg, about 2-39 mg, about 2-40 mg, about 2-41 mg, about 2-42 mg, about 2-43 mg, about 2-44 mg, about 2-45 mg, about 2-46 mg, about 2-47 mg, about 2-48 mg, about 2-49 mg, about 2-50 mg, about 2-51 mg, about 2-52 mg, about 2-53 mg, about 2-54 mg, about 2-55 mg, about 2-56 mg, about 2-57 mg, about 2-58 mg, about 2-59 mg, about 2-60 mg, about 2-61 mg, about 2-62 mg, about 2-63 6mg, about 2-27mg, about 2-28mg, about 2-29mg, about 2-30mg, about 2-35mg, about 2-40mg, about 2-45mg, about 2-50mg, about 2-55mg, about 2-60mg, about 2-65mg, about 2-70mg, about 2-75mg, about 3-8mg, about 4-9mg, about 5-10mg, about 6-11mg, about 7-12mg, about 8-13mg, about 9-14mg, about 10-15mg, about 11-16mg, about 12-17mg, about 13-18mg, about 14-19mg, about 15-20mg, about 16-21mg, about 17-22mg, about 18-23mg, about 19- 24mg, about 20-25mg, about 21-26mg, about 22-27mg, about 23-28mg, about 24-29mg, about 25-30mg, about 26-31mg, about 27-32mg, about 28-33mg, about 29-34mg, about 30-35mg, about 31-36mg, about 32-37mg, about 33-38mg, about 34-39mg, about 35-40mg, about 36-41mg, about 37-42mg, about 38-43mg, about 39-44mg, about 40-45mg, about 41-46mg, about 42-47mg, about 43-48mg, about 44-49mg, about 45-50mg, about 46-51mg , about 47-52 mg, about 48-53 mg, about 49-54 mg, about 50-55 mg, about 51-56 mg, about 52-57 mg, about 53-58 mg, about 54-59 mg, about 55-60 mg, about 56-61 mg, about 57-62 mg, about 58-63 mg, about 59-64 mg, about 60-65 mg, about 61-66 mg, about 62-67 mg, about 63-68 mg, about 64-69 mg, about 65-70 mg, about 66-71 mg, about 67-72 mg, about 68-73 mg, about 69-74 mg, about 70-75 mg, or any amount within a range bounded by any of these values.The daily dose may be given in a single dose once daily or in divided doses given two, three, four or more times daily.

[0095] In some embodiments, the weekly dose of meloxicam, or the amount of meloxicam administered per week (either in a single dose or in two or more divided doses totaling the weekly dose), is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30- 70mg, about 40-60mg, about 50-70mg, about 70-90mg, about 90-110mg, about 80-450mg, about 80-100mg, about 90-110mg, about 100-120mg, about 110 -130mg, about 120-140mg, about 130-150mg, about 140-160mg, about 150-170mg, about 160-180mg, about 170-190mg, about 180-200mg, about 19 0-210mg, about 200-220mg, about 210-230mg, about 220-240mg, about 230-250mg, about 240-260mg, about 250-270mg, about 260-280mg, about 2 70-290mg, about 280-300mg, about 290-310mg, about 300-320mg, about 310-330mg, about 320-340mg, about 330-350mg, about 340-360mg, about 350-370 mg, about 360-380 mg, about 370-390 mg, about 380-400 mg, about 390-410 mg, about 400-420 mg, about 410-430 mg, about 420-440 mg, about 430-450 mg, about 50 mg, about 55 mg, about 100-150 mg, about 30-100 mg, or any amount within a range bounded by or between any of these values. The weekly dose may be given in a single administration once per week, or in two, three, four, five, six, or seven separate administrations per week.

[0096] In some embodiments, the monthly dose (e.g., oral dose) of meloxicam, or the dose administered over a period of one month, 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 300-2400 mg, about 300-350 mg, about 310-360 mg, about 320-370 mg, about 330-380 mg, about 340-390 mg, about 350-400 mg, about 360-410 mg, about 370-420 mg, about 380-430 mg, about 390-440 mg, about 400- 450mg, about 410-460mg, about 420-470mg, about 430-480mg, about 440-490mg, about 450-500mg, about 460-510mg, about 470-520mg, about 480-530mg, about 490-540mg, about 500-550mg, about 510-560mg, about 520-570mg, about 530-580mg, about 540-590mg, about 550-600mg, about 560-610mg, about 570-620mg, about 580-630mg, about 590-640mg, about 600-650mg, about 610-660mg, about 620-670mg, about 6 30-680mg, about 640-690mg, about 650-700mg, about 660-710mg, about 670-720mg, about 680-730mg, about 690-740mg, about 700-750mg, about 710-760mg, about 720-770mg, about 730-780mg, about 740-7 90mg, about 750-800mg, about 760-810mg, about 770-820mg, about 780-830mg, about 790-840mg, about 800-850mg, about 810-860mg, about 820-870mg, about 830-880mg, about 840-890mg, about 850-900mg , about 860-910mg, about 870-920mg, about 880-930mg, about 890-940mg, about 900-950mg, about 910-960mg, about 920-970mg, about 930-980mg, about 940-990mg, about 950-1000mg, about 960-1010mg, about 970-1020mg, about 980-1030mg, about 990-1040mg, about 1000-1050mg, about 1010-1060mg, about 1020-1070mg, about 1030-1080mg, about 1040-1090mg, about 1050-1100mg, about 1060-1110mg,Approximately 1070-1120mg, approximately 1080-1130mg, approximately 1090-1140mg, approximately 1100-1150mg, approximately 1110-1160mg, approximately 1120-1170mg, approximately 1130-1180mg, approximately 1140-1190mg, approximately 1150-1200mg, approximately 1160-1210mg, approximately 1170-1220mg, approximately 1180-1230mg, approximately 1190-1240mg, approximately 1200-1250mg, approximately 1210-1260mg, approximately 1220-1270mg, approximately 1230-1280mg, approximately 1240-1290mg, approximately 1250-1300mg, approximately 12 60-1310mg, approximately 1270-1320mg, approximately 1280-1330mg, approximately 1290-1340mg, approximately 1300-1350mg, approximately 1310-1360mg, approximately 1320-1370mg, approximately 1330-1380mg, approximately 1340-1390mg, approximately 1350-1400mg, approximately 1360-1410mg, approximately 1370-1420mg, approximately 1380-1430mg, approximately 1390-1440mg, approximately 1400-1450mg, approximately 1410-1460mg, approximately 1420-1470mg, approximately 1430-1480mg, approximately 1440-1490mg, approximately 1450- 1500mg, approximately 1460-1510mg, approximately 1470-1520mg, approximately 1480-1530mg, approximately 1490-1540mg, approximately 1500-1550mg, approximately 1510-1560mg, approximately 1520-1570mg, approximately 1530-1580mg, approximately 1540-1590mg, approximately 1550-1600mg, approximately 1560-1610mg, approximately 1570-1620mg, approximately 1580-1630mg, approximately 1590-1640mg, approximately 1600-1650mg, approximately 1610-1660mg, approximately 1620-1670mg, approximately 1630-1680mg, approximately 1640-1690mg 0mg, approximately 1650-1700mg, approximately 1660-1710mg, approximately 1670-1720mg, approximately 1680-1730mg, approximately 1690-1740mg, approximately 1700-1750mg, approximately 1710-1760mg, approximately 1720-1770mg, approximately 1730-1780mg, approximately 1740-1790mg, approximately 1750-1800mg, approximately 1760-1810mg, approximately 1770-1820mg, approximately 1780-1830mg, approximately 1790-1840mg, approximately 1800-1850mg, approximately 1810-1860mg, approximately 1820-1870mg, approximately 1830-1880mgAbout 1840-1890mg, about 1850-1900mg, about 1860-1910mg, about 1870-1920mg, about 1880-1930mg, about 1890-1940mg, about 1900-1950mg, about 1910-1960mg, about 1920-1970mg, about 1 930-1980mg, about 1940-1990mg, about 1950-2000mg, about 1960-2010mg, about 1970-2020mg, about 1980-2030mg, about 1990-2040mg, about 2000-2050mg, about 2010-2060mg, about 2020 -2070mg, about 2030-2080mg, about 2040-2090mg, about 2050-2100mg, about 2060-2110mg, about 2070-2120mg, about 2080-2130mg, about 2090-2140mg, about 2100-2150mg, about 2110-21 60mg, about 2120-2170mg, about 2130-2180mg, about 2140-2190mg, about 2150-2200mg, about 2160-2210mg, about 2170-2220mg, about 2180-2230mg, about 2190-2240mg, about 2200-2250m g, about 2210-2260mg, about 2220-2270mg, about 2230-2280mg, about 2240-2290mg, about 2250-2300mg, about 2260-2310mg, about 2270-2320mg, about 2280-2330mg, about 2290-2340mg, About 2300-2350mg, about 2310-2360mg, about 2320-2370mg, about 2330-2380mg, about 2340-2390mg, about 2350-2400mg, about 1-4000mg, about 1-1000mg, about 10-1000mg, about 50-1000mg, about 10-600 mg, about 40-600 mg, about 50-600 mg, about 40-400 mg, about 50-200 mg, about 200-240 mg, about 240-280 mg, about 280-320 mg, about 320-360 mg, about 360-400 mg, about 400-450 mg, about 450-500 mg, about 500-600 mg, about 250-350 mg, about 100-600 mg, about 40-2000 mg, about 40-800 mg, about 100-900 mg, about 100-800 mg, about 40-1000 mg, about 50-1000 mg, about 100-1000 mg, orAny of these values ​​may be bounded by or within the range of any monthly dose. The monthly dose may be given in a single dose or as two or more separate doses administered monthly. In some embodiments, the monthly dose is administered every other week in two or three divided doses. In some embodiments, the monthly dose is administered weekly in four or five divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses, or more divided doses. In some embodiments, the monthly dose is administered in 5 to 15 divided doses monthly. The monthly dose may be administered for only one month, or repeatedly over two, three, four, five, six, or more months.

[0097] In some embodiments, the daily dose (e.g., oral dose, parenteral dose, etc.) of frovatriptan or other triptan is about 0.5-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2- 19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount within a range bounded by any of these values.

[0098] In some embodiments, the daily dose of rizatriptan is about 0.5-100 mg, about 5-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 1-5 mg, about 1-6 mg, about 2-7 mg, about 3-8 mg, about 4-9 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 11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 16-21 mg, about 17-22 mg, about 18-23 mg, about 19-24 mg, about 20-25 mg, about 21-26 mg, about 22-27 mg, about 23-26 mg, about 24-27 mg, about 25-26 mg, about 26-27 mg, about 27-28 mg, about 28-30 mg, about 29-33 mg, about 30-31 mg, about 31-32 mg, about 32-33 mg, about 33-34 mg, about 34-35 mg, about 35-36 mg, about 36-37 mg, about 37-38 mg, about 38-39 mg, about 40-41 mg, about 42-43 mg, about 44-45 mg, about 45-46 mg, about 47-48 mg, about 48-49 mg, about 49-50 mg, about 50-51 mg, about 51-52 mg, about 52-53 mg, about 54-55 mg 3-28 mg, about 24-29 mg, about 25-30 mg, about 26-31 mg, about 27-32 mg, about 28-33 mg, about 29-34 mg, about 30-35 mg, about 31-36 mg, about 32-37 mg, about 33-38 mg, about 34-39 mg, about 35-40 mg, about 36-41 mg, about 37-42 mg, about 38-43 mg, about 39-44 mg, about 40-45 mg, about 41-46 mg, about 42-47 mg, about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg, about 47-52 mg, about 48-53 mg, about 49-54 mg, about 50-55 mg, or any amount within a range bounded by any of these values. The daily dose may be given in a single dose once daily or in divided doses given two, three, four or more times daily.

[0099] In some embodiments, the weekly dose (e.g., oral dose) of frovatriptan or other triptan is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30-70 mg, about 40-60 mg, about 50-70 mg, about 70-90 mg, about 90-110 mg, about 50 mg, about 55 mg, about 100-150 mg, about 30-100 mg, about 1-20 mg, about 1-10 mg, about 2-10 mg, about 2-5 mg, about 5-10 mg, about 2.5 mg, about 5 mg, about 7.5 mg, or any amount within or between any of these bounded values. The weekly dose may be given in a single administration once a week, or in two, three, four, five, six, or seven separate administrations over the course of one week.

[0100] In some embodiments, the weekly dose of rizatriptan is about 1-1000 mg, about 10-400 mg, about 50-250 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30-70 mg, about 40-60 mg, about 50-70 mg, about 70-90 mg , about 90-110mg, about 50mg, about 55mg, about 100-150mg, about 30-100mg, about 1-20mg, about 1-10mg, about 2-10mg, about 2-5mg, about 5-10mg, about 1-50mg, about 10-60mg, about 20-70mg, about 30-80mg, about 40-90mg, about 50-100mg, about 60-110mg, about 70-120mg, about 80-130mg, about 9 0-140mg, about 100-150mg, about 110-160mg, about 120-170mg, about 130-180mg, about 140-190mg, about 150-200mg, about 160-210mg , about 170-220mg, about 180-230mg, about 190-240mg, about 200-250mg, about 210-260mg, about 220-270mg, about 230-280mg, about 240-2 90 mg, about 250-300 mg, about 260-310 mg, about 270-320 mg, about 280-330 mg, about 290-340 mg, about 300-350 mg, about 310-360 mg, about 320-370 mg, about 330-380 mg, about 340-390 mg, about 350-400 mg, or any amount within a range bounded by or between any of these values. The weekly dose may be given in a single administration once per week, or in two, three, four, five, six, or seven separate administrations per week.

[0101] In some embodiments, the monthly dose (e.g., oral dose) of frovatriptan or other triptan, or the dose administered over a period of one month, is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 1-4000 mg, about 1-1000 mg, about 10-1000 mg, about 50-1000 mg, about 10-600 mg, about 40-600 mg, about 50-600 mg, about 40-400 mg, about 50-200 mg, about 200-240 mg, about 240- The monthly dose may be 280 mg, about 280-320 mg, about 320-360 mg, about 360-400 mg, about 400-450 mg, about 450-500 mg, about 500-600 mg, about 250-350 mg, about 100-600 mg, about 40-2000 mg, about 40-800 mg, about 100-900 mg, about 100-800 mg, about 40-1000 mg, about 50-1000 mg, about 100-1000 mg, about 10-80 mg, about 10-40 mg, or about 20-30 mg, or any monthly dose bounded by or within any of these values. The monthly dose may be given in a single administration or as two or more separate administrations administered monthly. In some embodiments, the monthly dose is administered in two or three divided doses every other week. In some embodiments, the monthly dose is administered weekly in 4 or 5 divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses, or more. In some embodiments, the monthly dose is administered in 5 to 15 divided doses per month. The monthly dose may be administered for only 1 month, or may be administered repeatedly over 2, 3, 4, 5, 6, or more months.

[0102] In some embodiments, the monthly dose of rizatriptan, or the total dose administered within a month period, is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 1-4000 mg, about 1-1000 mg, about 10-1000 mg, about 50-1000 mg, about 10-600 mg, about 40-600 mg, about 50-600 mg, about 150-2400 mg, about 150-200 mg, about 160-210 mg, about 170-220 mg, about 180-230 mg, or about 190-240 mg. g, about 200-250mg, about 210-260mg, about 220-270mg, about 230-280mg, about 240-290mg, about 250-300mg, about 260-310mg, about 270-320mg, about 280-330mg, about 290-340mg, about 300-350mg, about 3 10-360mg, about 320-370mg, about 330-380mg, about 340-390mg, about 350-400mg, about 360-410mg, about 370-420mg, about 380-430mg, about 390-440mg, about 400-450mg, about 410-460mg, about 420-4 70mg, about 430-480mg, about 440-490mg, about 450-500mg, about 460-510mg, about 470-520mg, about 480-530mg, about 490-540mg, about 500-550mg, about 510-560mg, about 520-570mg, about 530-580mg , about 540-590mg, about 550-600mg, about 560-610mg, about 570-620mg, about 580-630mg, about 590-640mg, about 600-650mg, about 610-660mg, about 620-670mg, about 630-680mg, about 640-690mg, about 65 0-700mg, about 660-710mg, about 670-720mg, about 680-730mg, about 690-740mg, about 700-750mg, about 710-760mg, about 720-770mg, about 730-780mg, about 740-790mg, about 750-800mg, about 760-81 0mg, about 770-820mg, about 780-830mg, about 790-840mg, about 800-850mg, about 810-860mg, about 820-870mg, about 830-880mg, about 840-890mg, about 850-900mg, about 860-910mg, about 870-920mg,Approximately 880-930mg, approximately 890-940mg, approximately 900-950mg, approximately 910-960mg, approximately 920-970mg, approximately 930-980mg, approximately 940-990mg, approximately 950-1000mg, approximately 960-1010mg, approximately 970-1020mg, approximately 980-1030mg, approximately 990-1040mg, approximately 1000-1050mg, approximately 1010-1060mg, approximately 1020-1070mg, approximately 1030-1080mg, approximately 1040-1090mg, approximately 1050-1100mg, approximately 1060-1110mg, approximately 1070-1120mg, approximately 1080-1 130mg, approximately 1090-1140mg, approximately 1100-1150mg, approximately 1110-1160mg, approximately 1120-1170mg, approximately 1130-1180mg, approximately 1140-1190mg, approximately 1150-1200mg, approximately 1160-1210mg, approximately 1170-1220mg, approximately 1180-1230mg, approximately 1190-1240mg, approximately 1200-1250mg, approximately 1210-1260mg, approximately 1220-1270mg, approximately 1230-1280mg, approximately 1240-1290mg, approximately 1250-1300mg, approximately 1260-1310mg, approximately 1270-132 0mg, approximately 1280-1330mg, approximately 1290-1340mg, approximately 1300-1350mg, approximately 1310-1360mg, approximately 1320-1370mg, approximately 1330-1380mg, approximately 1340-1390mg, approximately 1350-1400mg, approximately 1360-1410mg, approximately 1370-1420mg, approximately 1380-1430mg, approximately 1390-1440mg, approximately 1400-1450mg, approximately 1410-1460mg, approximately 1420-1470mg, approximately 1430-1480mg, approximately 1440-1490mg, approximately 1450-1500mg, approximately 1460-1510mg g, approximately 1470-1520mg, approximately 1480-1530mg, approximately 1490-1540mg, approximately 1500-1550mg, approximately 1510-1560mg, approximately 1520-1570mg, approximately 1530-1580mg, approximately 1540-1590mg, approximately 1550-1600mg, approximately 1560-1610mg, approximately 1570-1620mg, approximately 1580-1630mg, approximately 1590-1640mg, approximately 1600-1650mg, approximately 1610-1660mg, approximately 1620-1670mg, approximately 1630-1680mg, approximately 1640-1690mg, approximately 1650-1700mg,Approximately 1660-1710mg, approximately 1670-1720mg, approximately 1680-1730mg, approximately 1690-1740mg, approximately 1700-1750mg, approximately 1710-1760mg, approximately 1720-1770mg, approximately 1730-1780mg, approximately 1740-1790mg, approximately 1750-1800mg, approximately 1760-1810mg, approximately 1770-1820mg, approximately 1780-1830mg, approximately 1790-1840mg, approximately 1800-1850mg, approximately 1810-1860mg, approximately 1820-1870mg, approximately 1830-1880mg, approximately 1840-1890mg, approximately 1 850-1900mg, approximately 1860-1910mg, approximately 1870-1920mg, approximately 1880-1930mg, approximately 1890-1940mg, approximately 1900-1950mg, approximately 1910-1960mg, approximately 1920-1970mg, approximately 1930-1980mg, approximately 1940-1990mg, approximately 1950-2000mg, approximately 1960-2010mg, approximately 1970-2020mg, approximately 1980-2030mg, approximately 1990-2040mg, approximately 2000-2050mg, approximately 2010-2060mg, approximately 2020-2070mg, approximately 2030-2080mg, approximately 204 0-2090mg, approximately 2050-2100mg, approximately 2060-2110mg, approximately 2070-2120mg, approximately 2080-2130mg, approximately 2090-2140mg, approximately 2100-2150mg, approximately 2110-2160mg, approximately 2120-2170mg, approximately 2130-2180mg, approximately 2140-2190mg, approximately 2150-2200mg, approximately 2160-2210mg, approximately 2170-2220mg, approximately 2180-2230mg, approximately 2190-2240mg, approximately 2200-2250mg, approximately 2210-2260mg, approximately 2220-2270mg, approximately 2230- 2280mg, approximately 2240-2290mg, approximately 2250-2300mg, approximately 2260-2310mg, approximately 2270-2320mg, approximately 2280-2330mg, approximately 2290-2340mg, approximately 2300-2350mg, approximately 2310-2360mg, approximately 2320-2370mg, approximately 2330-2380mg, approximately 2340-2390mg, approximately 2350-2400mg, approximately 40-400mg, approximately 50-200mg, approximately 200-240mg, approximately 240-280mg, approximately 280-320mg, approximately 320-360mg, approximately 360-400mg, approximately 400-450mgThe monthly dose may be about 450-500 mg, about 500-600 mg, about 250-350 mg, about 100-600 mg, about 40-2000 mg, about 40-800 mg, about 100-900 mg, about 100-800 mg, about 40-1000 mg, about 50-1000 mg, about 100-1000 mg, about 10-80 mg, about 10-40 mg, about 20-30 mg, or any monthly dose bounded by or within any of these values. The monthly dose may be given in a single dose or as two or more separate doses administered monthly. In some embodiments, the monthly dose is administered in two or three divided doses every other week. In some embodiments, the monthly dose is administered in four or five divided doses every week. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses, or more divided doses. In some embodiments, the monthly dose is administered in 5 to 15 divided doses per month. The monthly dose may be administered for only one month, or may be administered repeatedly over two, three, four, five, six, or more months.

[0103] In another embodiment, the dosage form or subject combination may be administered weekly, or every other week or every other week, or once every three weeks for about 1, 2, 3, 4, or more consecutive weeks. This dosing regimen may be repeated weekly, twice a month, three times a month, monthly, once every two months, once every three months, or as directed by a medical professional.

[0104] In some embodiments, administration of the pharmaceutical compositions may result in, for example, improved pharmacokinetics in fasted human subjects (e.g., increased bioavailability (e.g., decreased T) of the drug in the dosage form compared to a dosage form containing the drug (e.g., meloxicam or other NSAID, rizatriptan, frovatriptan, or other triptan) but without a cyclodextrin, an antacid, or a buffering agent (e.g., bicarbonate). max , increased C max, increased AUC, etc. In some embodiments, the bioavailability of the drug increases with repeated administration. For example, the bioavailability of the drug (e.g., meloxicam or other NSAID, rizatriptan, frovatriptan, or other triptan) at this dosage form can increase, e.g., in fasted human subjects, after about 1-10 days after repeated administration, after about 2-6 days after repeated administration, after about 3-5 days after repeated administration, after about 4-6 days after repeated administration, after about 5-8 days after repeated administration, after about 5 days after repeated administration, after about 6 days after repeated administration, after about 7 days after repeated administration, after about 8 days after repeated administration, after about 10 days after repeated administration, after about 15 days after repeated administration, or any time period bounded by or within a range between any of these values, compared to the bioavailability of the drug in a dosage form that does not include a cyclodextrin, an antacid, or a buffer (e.g., a bicarbonate). Administration of a drug to a human subject or patient in any of the dosage forms described herein may improve or achieve the desired oral pharmacokinetic properties of the drug.

[0105] T max , C max Any reference to , AUC, or any other pharmacokinetic parameter includes the average, mean, or median in humans (e.g., human patients or human subjects).

[0106] Administration of some of the present dosage forms or subject combinations to humans may result in a desired range of area under the plasma concentration curve (AUC) of meloxicam. The subject combinations may be administered in amounts and in a manner intended to target therapeutically effective plasma concentrations. For example, the area under the plasma concentration curve (AUC) of meloxicam (e.g., median, mean, or average AUC of meloxicam in humans) for about 1-150 μg·hr / mL is about 10-30 μg·hr / mL, about 20-40 μg·hr / mL, about 30-50 μg·hr / mL, about 40-60 μg·hr / mL, about 50-70 μg·hr / mL, about 60-80 μg·hr / mL, about 70-90 μg·hr / mL, about 80-100 μg·hr / mL, about 10-100 μg·hr / mL, about 50-150 μg·hr / mL, about 25-125 μg·hr / mL, about 75-150 μg·hr / mL, about 20-50 μg·hr / mL, about 40-70 μg·hr / mL. / mL, about 60-90 μg·hr / mL, about 80-110 μg·hr / mL, about 100-130 μg·hr / mL, about 120-150 μg·hr / mL, about 100-150 μg·hr / mL, about 20-30 μg·hr / mL, about 30-40 μg·hr / mL, about 40-50 μg·hr / mL, about 50-60 μg·hr / mL, about 20-25 μg·hr / mL, about 25-30 μg·hr / mL, about 30-35 μg·hr / mL, about 35-40 μg·hr / mL, about 40-45 μg·hr / mL, about 45-50 μg·hr / mL, etc., or any AUC bounded by or within a range between any of these values ​​may be targeted.

[0107] Administration of some of the dosage forms to humans can result in a desired range of frovatriptan plasma area under the curve (AUC). For example, dosage forms containing frovatriptan or other triptans can provide AUCs of about 1-150 μg·hr / mL, about 10-30 μg·hr / mL, about 20-40 μg·hr / mL, about 30-50 μg·hr / mL, about 40-60 μg·hr / mL, about 50-70 μg·hr / mL, about 60-80 μg·hr / mL, about 70-90 μg·hr / mL, about 80-100 μg·hr / mL, about 10-100 μg·hr / mL, about 50-150 μg·hr / mL, about 25-125 μg·hr / mL, and about 75-150 μg·hr / mL. The AUC may be an AUC of frovatriptan (such as the median, mean, or average AUC of frovatriptan in humans) or an AUC of another triptan of about 20-50 μg·hr / mL, about 40-70 μg·hr / mL, about 60-90 μg·hr / mL, about 80-110 μg·hr / mL, about 100-130 μg·hr / mL, about 120-150 μg·hr / mL, or any AUC bounded by or within a range between any of these values.

[0108] Unless otherwise stated, AUC is the AUC calculated up to the final measured concentration (AUC 0-t ) (AUC calculated over a 6-hour period (AUC 0-6 ), AUC calculated over a 12-hour period (AUC 0-12 ), AUC calculated over a 24-hour period (AUC 0-24 ) or AUC extrapolated to infinite time (AUC 0-inf ) refers to

[0109] In Example 3 below, the AUC of meloxicam in humans for oral dosage forms containing sodium bicarbonate and sulfobutylether-β-cyclodextrin (SBEβCD) is 0-24 was approximately 27 μg·h / mL. This dosage form contained 15 mg of meloxicam.

[0110] The AUC of meloxicam in humans after 15 mg intravenous and intramuscular administration is approximately 27 μg·h / mL. 0-24The AUC of meloxicam appears to be roughly proportional to the dose. For this oral dosage form, or for the intravenous or intramuscular dosage forms, for example, a dose of about 17 mg to about 30 mg of meloxicam results in an AUC of about 30-50 μg·h / mL of meloxicam. 0-24 It is expected to bring about

[0111] For several acute pain disorders (such as migraine and other types of headache), the short-term AUC (AUC measured over 6 hours) after oral administration (or AUC 0-6 ) may be particularly interesting, for example, for rapid analgesia. For example, some dosage forms have an AUC of meloxicam of at least about 5 μg·hr / mL (or 5,000 ng·hr / mL), at least about 6 μg·hr / mL (or 6,000 ng·hr / mL), at least about 7 μg·hr / mL (or 7,000 ng·hr / mL), at least about 8 μg·hr / mL (or 8,000 ng·hr / mL), at least about 9 μg·hr / mL (or 9,000 ng·hr / mL), about 6-10 μg·hr / mL, about 7-11 μg·hr / mL, about 8-12 μg·hr / mL, about 9-13 μg·hr / mL, and about 10-14 μg·hr / mL. 0-6 (Mean, mean, or average AUC of meloxicam in humans) 0-6 ), or any AUC bounded by or in the range between any of these values 0-6 It may also result in:

[0112] In some embodiments, the dosage form or subject combination has a concentration of about 10-2500 ng / mL, about 100-2250 ng / mL, about 500-2000 ng / mL, about 1000-2500 ng / mL, about 1000-2000 ng / mL, about 100-900 ng / mL, about 750-1500 ng / mL, about 1250-2000 ng / mL, about 1500-2300 ng / mL, about 800-1200 ng / mL, about 190 0-2400ng / mL, about 50-500ng / mL, about 400-950ng / mL, about 900-1500ng / mL, about 1100-2200ng / mL, about 1300-1600ng / mL, about 120 0-1500ng / mL, about 1400-2100ng / mL, about 1500-1900ng / mL, about 1600-2100ng / mL, about 1700-2000ng / mL, about 1900-2500ng / mL , about 1500-1700ng / mL, about 1600-1800ng / mL, about 1700-1900ng / mL, about 1800-2000ng / mL, about 1900-2100ng / mL, about 2000-2200ng / mL, about 2100-2300ng / mL, about 2200-2400ng / mL, about 2300-2500ng / mL, about 2500-3000ng / mL, at least about 1400ng / mL, at least C of meloxicam of at least about 1500 ng / mL, at least about 1600 ng / mL, at least about 1700 ng / mL, at least about 1800 ng / mL, at least about 1900 ng / mL, at least about 2000 ng / mL, at least about 2100 ng / mL, at least about 2200 ng / mL, at least about 2300 ng / mL, at least about 2400 ng / mL, at least about 2500 ng / mL max (Mean, or average C of meloxicam in humans) max ), or any C bounded by or in the range between any of these values max It is administered in a manner that produces

[0113] In some embodiments, the dosage form contains a concentration of about 10-2500 ng / mL, about 100-2250 ng / mL, about 500-2000 ng / mL, about 1000-2500 ng / mL, about 1000-2000 ng / mL, about 100-900 ng / mL, about 750-1500 ng / mL, about 1250-2000 ng / mL, about 1500-2300 ng / mL, about 800-1200 ng / mL, about 1900-2400 ng / mL, about 50-500 ng / mL, about 400-950 ng / mL, about 900-1500 ng / mL, about 1100-2200 ng / mL, about 1300-1600 ng / mL, about 120 C of frovatriptan: 0-1500ng / mL, about 1400-2100ng / mL, about 1500-1900ng / mL, about 1600-2100ng / mL, about 1700-2000ng / mL, about 1900-2500ng / mL, about 150-1700ng / mL, about 1600-1800ng / mL, about 1700-1900ng / mL, about 1800-2000ng / mL, about 1900-2100ng / mL, about 2000-2200ng / mL, about 2100-2300ng / mL, about 2200-2400ng / mL, about 2300-2500ng / mL, about 2500-3000ng / mL max (Median, mean, or average C of frovatriptan in humans max ), or any C bounded by or in the range between any of these values max It may also result in:

[0114] For example, the methods described herein may be used to treat T max (Mean, or average T of meloxicam in humans) maxIn some embodiments, the method may include treating a patient to reduce the amount of erythrocyte secretion in the patient within about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-60 minutes, or about 50 minutes after administration of the dosage form. Meloxicam T of about 50-70 minutes, about 60-90 minutes, about 70-100 minutes, about 80-110 minutes, about 90-120 minutes, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, about 7-10 hours max , or any T bounded by or in the range between any of these values. max This may include achieving:

[0115] In some embodiments, the methods described herein provide a method for determining a T of 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 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-60 minutes, about 50-70 minutes, about 60-90 minutes, about 70-100 minutes, about 80-110 minutes, about 90-120 minutes after administration of a subject combination. max , or any T bounded by or in the range between any of these values. max Meloxicam has a relatively short T max The present invention relates to the administration of the subject combination in a human in a manner that results in:

[0116] In some embodiments, the oral dosage form provides a shorter T of meloxicam than is achieved by administration of meloxicam by intramuscular injection. max (Mean, or average T of meloxicam in humans) maxIn some embodiments, the oral dosage form may have a T of meloxicam that is shorter than that observed with intramuscular injection by a factor of at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20, or by a factor of about 1.1-2, about 1.5-3, about 2-4, about 3-5, about 4-6, about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100, or a factor within a range bounded by any of these values. max or may increase meloxicam plasma levels at a faster rate.

[0117] In some embodiments, the oral dosage form or subject combination is administered in a manner that has a meloxicam plasma half-maximum time (median, mean, or average plasma half-maximum time in humans) of less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, less than about 60 minutes, less than about 90 minutes, about 5-15 minutes, about 10-20 minutes, about 15-25 minutes, about 20-30 minutes, about 25-35 minutes, about 30-45 minutes, about 35-50 minutes, about 40-55 minutes, about 45-60 minutes, about 0.5-5 hours, or a time within a range bounded by any of these values.

[0118] For example, the methods described herein may be used to treat frovatriptan T max (Median, mean, or average T of frovatriptan in humans maxIn some embodiments, the method may treat a patient to reduce the amount of erythropoietin (E2) in the patient within about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-60 minutes, about 50-70 minutes, about 60-8 ...100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-60 minutes, about 50-70 minutes, about 100 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, T of frovatriptan within about 70-90 minutes, about 0.1-1 hour, about 0.1-0.5 hours, about 0.5-1 hour, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, and about 7-10 hours max , or any T bounded by or in the range between any of these values. max This may include achieving:

[0119] For example, the methods described herein may be used to treat rizatriptan T max (Median, mean, or average T of rizatriptan in humans max In some embodiments, the methods involve treating a patient to reduce the amount of erythrocyte secretion in the patient within about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 2 hours, about 3 hours, about 4 hours, about 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-60 minutes, about 50-70 minutes, or about 60 minutes after administration of a dosage form or a subject combination described herein. T of rizatriptan: about 60-80 minutes, about 70-90 minutes, about 0.1-1 hour, about 0.1-0.5 hours, about 0.5-1 hour, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, about 7-10 hours max , or any T bounded by or in the range between any of these values. max This may include achieving:

[0120] The oral dosage form of Example 3 below provides a T of meloxicam of approximately 30 minutes. max The T of intravenous meloxicam max The T of intramuscular meloxicam is approximately 30 minutes for infusion and 3 minutes for bolus. max is approximately 60-84 minutes.

[0121] In some embodiments, the dosage form comprising meloxicam (e.g., a dosage form comprising a subject combination) 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 0.8-1 μg / mL, about 0.01-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL, about 1.3- 1.5μg / mL, about 1-1.5μg / mL, about 1.4-1.6μg / mL, about 1.5-1.7μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1.8-2μg / mL, about 1 .5-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, about 2.3-2.5μg / mL, about 2-2.5μg / mL, about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2.5-3μg / mL, about 2.9-3.1μg / mL, about 3-3.2μg / mL, about 3.1-3.3μg / mL, about 3.2-3.4μg / mL, about 3.3-3.5μg / mL, about 3-3.5μg / mL, about 3.4-3.6μg / mL, about 3.5-3.7 The drug may be administered in a manner that results in a 12-hour meloxicam plasma concentration (median, mean, or average meloxicam plasma concentration in humans) of about 3.6-3.8 μg / mL, about 3.7-3.9 μg / mL, about 3.8-4 μg / mL, about 3.5-4 μg / mL, or any 12-hour meloxicam plasma concentration bounded by or within a range between any of these values.

[0122] In some embodiments, meloxicam is administered at a concentration of 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 0.8-1 μg / mL, about 0.01-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL, about 1.3-1.5 μg / mL, about 1.4-1.6 μg / mL, about 1.5-1.7 μg / mL, or about 1.6-1.8 μg / mL. g / mL, approximately 1.7-1.9μg / mL, approximately 1.8-2μg / mL, approximately 1-2μg / mL, approximately 0.01-3μg / mL, approximately 1.9-2.1μg / mL, approximately 2-2.2μg / mL, approximately 2.1-2.3μg / mL, approximately 2.2-2.4μ g / mL, about 2.3-2.5μg / mL, about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2-3μg / mL, about 2.9-3. 1μg / mL, about 3-3.2μg / mL, about 3.1-3.3μg / mL, about 3.2-3.4μg / mL, about 3.3-3.5μg / mL, about 3.4-3.6μg / mL, about 3.5-3.7μg / mL, about 3.6-3.8μg / mL, Approximately 3.7-3.9μg / mL, approximately 3.8-4μg / mL, approximately 3-4μg / mL, approximately 2-4μg / mL, approximately 0.01-4μg / mL, approximately 0.1-20μg / mL, approximately 0.5-15μg / mL, approximately 0.5-10μg / mL, approximately 5-15 Meloxicam average plasma levels (C) of about 10-20 μg / mL, about 7.5-15 μg / mL, about 2-10 μg / mL, about 1-8 μg / mL, about 1-6 μg / mL, about 1-2 μg / mL, about 0.5-3.5 μg / mL, about 0.5-7 μg / mL, about 12-20 μg / mL, about 8-12 μg / mL, about 1-4 μg / mL, about 4-7 μg / mL, about 7-11 μg / mL, about 11-15 μg / mL, about 15-19 μg / mL, and about 16-20 μg / mL. ave or average plasma level), or any meloxicam average plasma level bounded by or within the range between any of these values.

[0123] In some embodiments, the dosage form containing frovatriptan has a concentration of 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 0.8-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, or about 1.2-1.4 μg / 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 1.7-1.9μg / mL, about 1. 8-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, about 2.3-2.5μg / The compound may provide a 12-hour frovatriptan plasma concentration of about 2.4-2.6 μg / mL, about 2.5-2.7 μg / mL, about 2.6-2.8 μg / mL, about 2.7-2.9 μg / mL, about 2.8-3 μg / mL, about 2.9-3.1 μg / mL, about 3-3.2 μg / mL, about 3.1-3.3 μg / mL, about 3.2-3.4 μg / mL, about 3.3-3.5 μg / mL, about 3.4-3.6 μg / mL, about 3.5-3.7 μg / mL, about 3.6-3.8 μg / mL, about 3.7-3.9 μg / mL, or about 3.8-4 μg / mL, or any 12-hour frovatriptan plasma concentration bounded by or within a range between any of these values.

[0124] In some embodiments, frovatriptan is administered at a concentration of 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 0.8-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL, about 1.3-1.5 μg / mL, about 1.4-1.6 μg / mL, about 1.5-1.7 μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1.8-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, about 2.3-2.5μg / mL, about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2.9-3.1μg / mL , about 3-3.2μg / mL, about 3.1-3.3μg / mL, about 3.2-3.4μg / mL, about 3.3-3.5μg / mL, about 3.4-3.6μg / mL, about 3.5-3.7μg / mL, about 3.6-3.8μg / mL mL, about 3.7-3.9μg / mL, about 3.8-4μg / mL, about 0.1-20μg / mL, about 0.5-15μg / mL, about 0.5-10μg / mL, about 5-15μg / mL, about 10-20μg / mL, about 7. Average frovatriptan plasma levels (C) of 5-15 μg / mL, about 2-10 μg / mL, about 1-8 μg / mL, about 1-6 μg / mL, about 1-2 μg / mL, about 0.5-3.5 μg / mL, about 0.5-7 μg / mL, about 12-20 μg / mL, about 8-12 μg / mL, about 1-4 μg / mL, about 4-7 μg / mL, about 7-11 μg / mL, about 11-15 μg / mL, about 15-19 μg / mL, and about 16-20 μg / mL ave or average plasma level), or any amount within the range bounded by or between any of these values.

[0125] The use of bicarbonates may help increase the solubility of NSAIDs (such as meloxicam) and / or triptans (such as rizatriptan) in the human stomach.

[0126] In some embodiments, the amount of NSAID (e.g., meloxicam) dissolved in a human's gastric fluid after oral administration of the dosage form is greater than the amount of NSAID (e.g., meloxicam) that would be dissolved in a human's gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of meloxicam and 2) does not contain bicarbonate.

[0127] In some embodiments, 30 minutes after oral administration of the dosage form, the amount of NSAID (e.g., meloxicam) dissolved in a human's gastric fluid is greater than the amount of NSAID (e.g., meloxicam) that would be dissolved in a human's gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of meloxicam and 2) does not contain bicarbonate.

[0128] In some embodiments, 60 minutes after oral administration of the dosage form, the amount of NSAID (e.g., meloxicam) dissolved in a human's gastric fluid is greater than the amount of NSAID (e.g., meloxicam) that would be dissolved in a human's gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of meloxicam and 2) does not contain bicarbonate.

[0129] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) in the dosage form dissolves in human gastric fluids about 15 minutes after the dosage form is orally administered.

[0130] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) in the dosage form dissolves in human gastric fluids about 30 minutes after the dosage form is orally administered.

[0131] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) in the dosage form dissolves in human gastric fluids about 60 minutes after the dosage form is orally administered.

[0132] In some embodiments, 15 minutes after oral administration of the dosage form, the amount of triptan (e.g., rizatriptan) dissolved in human gastric fluid is greater than the amount of triptan (e.g., rizatriptan) that would be dissolved in human gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of triptan (e.g., rizatriptan) and 2) does not contain bicarbonate.

[0133] In some embodiments, 30 minutes after oral administration of the dosage form, the amount of triptan (e.g., rizatriptan) dissolved in human gastric fluid is greater than the amount of triptan (e.g., rizatriptan) that would be dissolved in human gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of triptan (e.g., rizatriptan) and 2) does not contain bicarbonate.

[0134] In some embodiments, 60 minutes after oral administration of the dosage form, the amount of triptan (e.g., rizatriptan) dissolved in human gastric fluid is greater than the amount of triptan (e.g., rizatriptan) that would be dissolved in human gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of triptan (e.g., rizatriptan) and 2) does not contain bicarbonate.

[0135] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) in the dosage form dissolves in human gastric fluids about 15 minutes after the dosage form is orally administered.

[0136] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) in the dosage form dissolves in human gastric fluids about 30 minutes after the dosage form is orally administered.

[0137] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) in the dosage form dissolves in human gastric fluids about 60 minutes after the dosage form is orally administered.

[0138] Some dosage forms 1) contain the same amount of NSAID (e.g., meloxicam) and 2) have improved solubility of the NSAID (e.g., meloxicam) compared to a reference dosage form that does not contain bicarbonate.

[0139] In some embodiments, improved solubility of an NSAID (such as meloxicam) or triptan (such as rizatriptan) may be determined by a solubility test, in which the dosage form or reference dosage form is added to 500 mL of 0.01 N aqueous HCl, stirred at 75 revolutions per minute (RPM) at 37° C. using a USP paddle II apparatus, and the amount of NSAID (such as meloxicam) or triptan (such as rizatriptan) dissolved in the 0.01 N aqueous HCl solution is determined after a specified time.

[0140] As used herein with respect to solubility testing, the term "defined time" refers to a period of time selected for conducting the solubility test. For example, for an NSAID (such as meloxicam) or a triptan (such as rizatriptan), the defined time can be about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, etc.

[0141] In some embodiments, improved solubility of the NSAID (such as meloxicam) may be observed at defined times, such as 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes.

[0142] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) dissolves in 0.01 N aqueous HCl in a specified time of about 15 minutes when subjected to the above solubility test.

[0143] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) dissolves in 0.01 N aqueous HCl in a specified time of about 30 minutes when subjected to the above solubility test.

[0144] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) dissolves in 0.01 N aqueous HCl in a specified time of about 60 minutes when subjected to the above solubility test.

[0145] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the NSAID (e.g., meloxicam) dissolves in 0.01 N aqueous HCl in a specified time of about 120 minutes when subjected to the above solubility test.

[0146] Some dosage forms may have improved solubility of the triptan (e.g., rizatriptan) compared to a reference dosage form that 1) contains the same amount of triptan (e.g., rizatriptan) and 2) does not contain bicarbonate.

[0147] In some embodiments, 30 minutes after oral administration of the dosage form, the amount of triptan (e.g., rizatriptan) dissolved in human gastric fluid is greater than the amount of triptan (e.g., rizatriptan) that would be dissolved in human gastric fluid as a result of oral administration of a reference dosage form that 1) contains the same amount of triptan (e.g., rizatriptan) and 2) does not contain bicarbonate.

[0148] In some embodiments, improved solubility of the triptan (such as rizatriptan) may be observed at defined times such as 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes.

[0149] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) dissolves in 0.01 N aqueous HCl in a specified time of about 15 minutes when subjected to the above solubility test.

[0150] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) dissolves in 0.01 N aqueous HCl in a specified time of about 30 minutes when subjected to the above solubility test.

[0151] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) dissolves in 0.01 N aqueous HCl in a specified time of about 60 minutes when subjected to the above solubility test.

[0152] In some embodiments, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the triptan (e.g., rizatriptan) dissolves in 0.01 N aqueous HCl in a specified time of about 120 minutes when subjected to the above solubility test.

[0153] In some embodiments, dosage forms containing meloxicam, rizatriptan, or both may be formulated for oral administration, for example, with an inert diluent or an edible carrier, enclosed in hard or soft gelatin capsules, compressed into tablets, or incorporated directly into everyday food. For oral therapeutic administration, the active compound may be incorporated into excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, and the like.

[0154] Tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders (such as tragacanth gum, acacia, corn starch, or gelatin), additives (such as dibasic calcium phosphate), disintegrants (such as corn starch, potato starch, or alginic acid), lubricants (such as magnesium stearate), sweeteners (such as sucrose, lactose, or saccharin), and flavoring agents (such as peppermint, oil of wintergreen, or cherry flavoring). When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above-mentioned types of materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with cereals, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methylparaben and propylparaben as preservatives, a dye, and flavoring such as cherry or orange flavoring. It may be desirable for materials in dosage forms or pharmaceutical compositions to be pharmaceutically pure and substantially non-toxic in the amounts employed.

[0155] In addition to meloxicam, cyclodextrins, triptans, and bicarbonates, Some dosage forms may contain additives such as microcrystalline cellulose (e.g., about 1-20%), starch (e.g., about 1-10%), fumed silica (e.g., 0.1-10%), polyvinylpyrrolidone (e.g., about 1-10%), and / or magnesium stearate (e.g., about 0.1-10%).

[0156] Some single dosage forms contain both meloxicam and rizatriptan, and may further contain meloxicam and bicarbonate, which may form a complex with meloxicam. Some dosage forms may also contain additives such as microcrystalline cellulose (e.g., about 1-20%), starch (e.g., about 1-10%), fumed silica (e.g., about 0.1-10%), polyvinylpyrrolidone (e.g., about 1-10%), and / or magnesium stearate (e.g., about 0.1-10%).

[0157] Some compositions or dosage forms may be liquid or may comprise a solid phase dispersed in a liquid.

[0158] The dosage form may further comprise an additional pharmaceutically active agent, such as an antacid or an analgesic.

[0159] In some embodiments, the dosage form may further comprise an antacid present in an amount effective to raise the gastric pH of a patient to at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and even at least 5 when one or more unit dosage forms are administered. The term "antacid" refers to an agent that reduces gastric acid secretion and raises gastric pH. Specific H2 blockers (also called H2 antagonists or histamine H2 blockers or histamine H2 antagonists) that may be used include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine, or combinations thereof.

[0160] Other drugs that can be effectively used as antacids are proton pump inhibitors (such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole, and tenatoprazole). In some embodiments, the daily dose of the antacid (such as esomeprazole) is about 1-200 mg, about 1-100 mg, about 50-100 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 other amount within a range bounded by or between any of these values.

[0161] Examples of specific proton pump inhibitors include esomeprazole (in an amount between 5 mg and 50 mg per unit dosage form), omeprazole (in an amount between 5 mg and 50 mg per unit dosage form), lansoprazole (in an amount between 5 mg and 150 mg (preferably between 5 mg and 30 mg) per unit dosage form), and pantoprazole (in an amount between 10 mg and 200 mg per unit dosage form). In some embodiments, the proton pump inhibitor (e.g., esomeprazole) is present in the dosage form in an amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a new class of antacids has been developed that compete with potassium for the acid pump. Compounds of this type, also known as "reversible proton pump inhibitors" or "acid pump antagonists," can also be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan, and soraprazan (see WO 9605177 and WO 9605199). Other compounds of this type include H-335 / 25 (AstraZeneca, Dialog File 128, Accession No. 020806), Sch-28080 (Schering Plough, Dialog File 128, Accession No. 009663), Sch-32651 (Schering Plough, Dialog File 128, Accession No. 006883), and SK&F-96067 (CAS Registry No. 115607-61-9).

[0162] Additional therapeutically active agents include analgesics, such as a second nonsteroidal anti-inflammatory drug, an opioid, a steroid, or a triptan. In some embodiments, the dosage form or treatment further comprises administering a second nonsteroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. For purposes of this disclosure, reference to an antacid, an NSAID, or an analgesic should be understood to encompass all conventional forms of these compounds, particularly their pharmaceutically acceptable salts. The amount of pharmaceutically effective NSAID may be less in this embodiment than otherwise practiced due to potential positive kinetic interactions and NSAID absorption in the presence of an antacid and / or buffer.

[0163] In another embodiment, the dosage form or treatment further comprises administering an opioid in an amount effective to reduce or eliminate pain or inflammation, including, but not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine, benzitramide, buprenorphine, butorphanol, carfentanil, desmethylprodine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levoflur ... These include basetilmethadol, levomethorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, omefentanil, oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or a combination thereof.

[0164] The term "unit dosage form" is used herein to refer to a single entity for administering a drug. For example, a single tablet or capsule combining both a triptan and an NSAID is a unit dosage form. "Unit dosage form" may also be referred to as a "fixed dosage form" or a "fixed dose combination," which are interchangeable except for the name. In one embodiment, the unit dosage form is a multi-layer tablet.

[0165] In another embodiment, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In yet another embodiment, the unit dosage form is a multi-layer tablet comprising a single core and one or more layers surrounding the core. In some embodiments, the pharmaceutical composition may comprise a triptan (such as rizatriptan or frovatriptan), a cyclodextrin, and a bicarbonate in amounts effective to increase the bioavailability of the rizatriptan or frovatriptan. In another embodiment, the pharmaceutical composition may comprise a triptan (such as rizatriptan or frovatriptan), a cyclodextrin, and a bicarbonate in amounts effective to increase the bioavailability of the triptan or to decrease the T of the triptan. max The composition may comprise a triptan, sulfobutylether-β-cyclodextrin (SBEβCD), and sodium bicarbonate in amounts effective to reduce

[0166] Some dosage forms may include a first layer comprising meloxicam, SBEβCD and a bicarbonate, and a second layer comprising a triptan and a bicarbonate.

[0167] The first layer may contain, for example, an amount of meloxicam within one of the ranges described above. For example, all of the meloxicam in the dosage form may be present in the first layer. The second layer may contain all of the triptan, such that an amount within one of the ranges described above for the triptan is applicable to the second layer.

[0168] In some embodiments, the first layer contains about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of bicarbonate (e.g., sodium bicarbonate), or any amount within a range bounded by any of these values.

[0169] In some embodiments, the second layer contains about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of bicarbonate (e.g., sodium bicarbonate), or any amount within a range bounded by any of these values.

[0170] Some oral dosage forms may have an enteric coating or a film coating. In some embodiments, the dosage form may comprise a tablet or capsule with an enteric coating. In some embodiments, the dosage form may comprise a tablet or capsule with a film coating.

[0171] One embodiment of the present disclosure is a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: (a) dexketoprofen, with or without an enteric coating; (b) sodium or potassium bicarbonate and / or sodium or potassium carbonate, and (c) frovatriptan, with or without an enteric coating, and with or without being formulated with cyclodextrin; The present invention relates to a pharmaceutical composition comprising:

[0172] In certain embodiments, the pharmaceutical compositions provide for more rapid release or dissolution of a drug (e.g., meloxicam or other NSAID, rizatriptan, frovatriptan, or other triptans) from a dosage form compared to a dosage form containing the same drug but without an antacid or without a buffer.

[0173] Contemplated embodiments are listed below.

[0174] Embodiment 1 An inclusion complex of meloxicam in a 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 per molecule of β-cyclodextrin. Embodiment 7. The dosage form of embodiment 6, wherein said meloxicam and said SBEβCD have a molar ratio of about 0.8 to about 1.2. Embodiment 8. The dosage form of embodiment 6, wherein the meloxicam and the SBEβCD have a molar ratio of about 1. Embodiment 9. The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, which contains a 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 Meloxicam T max 14. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein is reduced compared to a dosage form that does not contain a carbonate, a bicarbonate, or a cyclodextrin. Embodiment 15. The T of meloxicam max is achieved in the patient at a time within the range of about 10 minutes to about 180 minutes after administration. Embodiment 16 The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, which has a higher oral bioavailability of meloxicam than a dosage form that does not contain a carbonate, a bicarbonate, or a cyclodextrin. Embodiment 17. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, further comprising an antacid. Embodiment 18. The dosage form of embodiment 17, wherein the antacid 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 A method of oral administration of meloxicam comprising orally administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need of treatment. Embodiment 22. The method of embodiment 21, wherein the dosage form is administered to treat pain. Embodiment 23. The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain. Embodiment 24 The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis. Embodiment 25 A method of intravenously administering meloxicam comprising intravenously administering the dosage form of Embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 to a patient in need of treatment. Embodiment 26. An inclusion complex of frovatriptan in a cyclodextrin.

[0175] Embodiment 2-1 A dosage form comprising 1) an inclusion complex of frovatriptan in a cyclodextrin, or 2) frovatriptan and a carbonate or bicarbonate. Embodiment 2-2 The dosage form of embodiment 2-1 comprising an inclusion complex, wherein the cyclodextrin comprises sulfobutylether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPβCD). Embodiment 2-3 The dosage form of embodiment 2-2, wherein said cyclodextrin is SBEβCD and has about 6 to about 7 sulfobutyl ether groups per β-cyclodextrin molecule. Embodiments 2-4 The dosage form of embodiment 2-3, further comprising a bicarbonate. Embodiments 2-5. The dosage form of embodiment 2-4, wherein the bicarbonate comprises sodium bicarbonate. Embodiments 2-6 The dosage form of embodiment 2-3, wherein said frovatriptan and said SBEβCD have a molar ratio of about 0.8 to about 1.2. Embodiments 2-7. The dosage form of embodiment 2-6, containing a bicarbonate. Embodiments 2-8. The dosage form of embodiment 2-7, wherein the bicarbonate comprises sodium bicarbonate. Embodiment 2-9 The dosage form of embodiment 2-1, which is an oral dosage form. Embodiment 2-10 The dosage form of embodiment 2-2 comprising an inclusion complex, wherein from about 50 mg to about 200 mg of said SBEβCD is present in the unit dosage form. Embodiment 2-11 The dosage form of embodiment 2-1 comprising the frovatriptan and the carbonate or bicarbonate. Embodiment 2-12 T of Frovatriptan max The dosage form of embodiment 2-1, wherein the amount of cyclodextrin in the hydroxybenzoates is reduced compared to a dosage form that does not contain a carbonate, a bicarbonate, or a cyclodextrin. Embodiment 2-13 T of Frovatriptan max is achieved in the patient at a time within the range of about 10 minutes to about 180 minutes after administration. Embodiment 2-14 The dosage form of embodiment 2-1, having a higher oral bioavailability of frovatriptan than a dosage form that does not contain a carbonate, a bicarbonate, or a cyclodextrin. Embodiments 2-15 The dosage form of embodiment 2-11, wherein said carbonate or said bicarbonate is present in the unit dosage form in an amount ranging from about 400 mg to about 600 mg. Embodiments 2-16. The dosage form of embodiment 2-15, wherein the carbonate or bicarbonate is sodium bicarbonate. Embodiments 2-17. The dosage form of embodiment 2-11, further comprising an NSAID. Embodiments 2-18 The dosage form of embodiment 2-17, wherein the NSAID is dexketoprofen or meloxicam. Embodiments 2-19. The dosage form of embodiment 2-18, wherein the NSAID is dexketoprofen. Embodiments 2-20 The dosage form of embodiment 2-19, wherein there is about 10 mg to about 50 mg of dexketoprofen in the unit dosage form. Embodiment 2-21 A method for oral administration of frovatriptan, comprising orally administering the dosage form of Embodiment 2-1 to a patient in need of treatment. Embodiment 2-22 The method of embodiment 2-21, wherein the dosage form comprises the inclusion complex, the cyclodextrin is SBEβCD, and the dosage form further comprises a bicarbonate. Embodiments 2-23. The method of embodiment 2-22, wherein the bicarbonate is sodium bicarbonate. Embodiments 2-24 The method of any of embodiments 2-23, wherein the unit dosage form contains from about 300 mg to about 600 mg of sodium bicarbonate. Embodiments 2-25 The method of embodiment 2-22, wherein the dosage form further comprises an NSAID. Embodiments 2-26 The method of any of embodiments 2-25, wherein the NSAID is dexketoprofen, meloxicam, naproxen, ibuprofen, or celecoxib. Embodiments 2-27 The method of embodiment 2-21, wherein the dosage form is administered to treat pain. Embodiments 2-28 The method of embodiment 2-21, wherein the dosage form is administered to treat inflammatory pain. Embodiments 2-29 The method of embodiment 2-21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[0176] Embodiment P-1 A dosage form comprising meloxicam, sulfobutyl ether β-cyclodextrin (SBEβCD), a bicarbonate, and a triptan, which has a shorter T of meloxicam than a reference dosage form 1) containing the same amount of meloxicam, 2) not containing SBEβCD, and 3) not containing bicarbonate. max The dosage form is an oral dosage form having the formula: Embodiment P-2 The dosage form of embodiment P-1 comprising an inclusion complex of 1) said meloxicam or said triptan and 2) said SBEβCD. Embodiment P-3 The dosage form of embodiment P-1 or P-2 containing about 10 mg to about 20 mg of meloxicam. Embodiment P-4 The dosage form of embodiment P-3 containing about 15 mg of meloxicam. Embodiment P-5 The dosage form of embodiment P-1, P-2, P-3, or P-4, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin. Embodiment P-6 The dosage form of embodiment P-1, P-2, P-3, P-4, or P-5 containing about 50 mg to about 200 mg of said SBEβCD. Embodiment P-7 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, or P-6, wherein the triptan is rizatriptan. Embodiment P-8 The dosage form of embodiment P-7 containing about 5 mg to about 20 mg of rizatriptan. Embodiment P-9 The dosage form of embodiment P-8 containing about 10 mg of rizatriptan. Embodiment P-10 The dosage form of embodiment P-6 containing about 100 mg of SBEβCD. Embodiment P-11 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, or P-10, wherein the bicarbonate comprises sodium bicarbonate. Embodiment P-12 The dosage form of embodiment P-10 containing about 400 mg to about 600 mg of bicarbonate. Embodiment P-13 The dosage form of embodiment P-12, containing about 500 mg of sodium bicarbonate. Embodiment P-14 The oral dosage form provides a mean T of meloxicam in less than about 3 hours max The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, or P-12, wherein the dosage form is Embodiment P-15 The oral dosage form provides a mean T of meloxicam in less than about 2 hours max The dosage form of embodiment P-14, wherein Embodiment P-16 The oral dosage form provides a mean T of meloxicam in less than about 1 hour max The dosage form of embodiment P-14, wherein Embodiment P-17 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, or P-16, wherein the oral dosage form has increased bioavailability of meloxicam when administered to a mammal compared to the reference dosage form. Embodiment P-18 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, or P-17, wherein the oral dosage form has improved pharmacokinetics of meloxicam when administered to a mammal compared to the reference dosage form. Embodiment P-19 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, or P-18, wherein the oral dosage form has increased bioavailability of the triptan when administered to a mammal compared to the reference dosage form. Embodiment P-20 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, or P-19, wherein the oral dosage form has improved pharmacokinetics of the triptan when administered to a mammal compared to the reference dosage form. Embodiment P-21 A method of improving the pharmacokinetics of a triptan or NSAID comprising orally administering a dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, P-19, or P-20 to a mammal or human in need of treatment with the triptan or NSAID. Embodiment P-22 A method of treating pain comprising orally administering a dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, P-19, or P-20 to a mammal or human in need thereof. Embodiment P-23 The method of embodiment P-22, wherein said pain is a migraine headache. Embodiment P-24 The method of embodiment P-22, wherein said pain is inflammatory pain.

[0177] Example 1 The effect of varying amounts of potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) on the pH of an acidic medium was investigated. The acidic medium was chosen to mimic gastric conditions. K2CO3 or NaHCO3 was added to 50 ml of 0.01 N HCl solution (pH 2). After the addition of K2CO3 or NaHCO3, the pH of the solution was measured. Deionized water (240 mL) was then added to the mixture, and the pH was measured again. The results are shown in Tables 1 to 4.

[0178] [Table 1]

[0179] [Table 2]

[0180] [Table 3]

[0181] [Table 4]

[0182] Example 2 Tablets containing meloxicam and cyclodextrin, K2CO3, or NaHCO3 were prepared and tested for solubility. Tablets containing only meloxicam (MOBIC®) were also purchased and tested for solubility. The tablets tested are listed in Table 5. For tablets containing meloxicam and cyclodextrin, meloxicam was used in the form of a meloxicam / cyclodextrin inclusion complex. This inclusion complex was formed by mixing meloxicam and cyclodextrin in a pH-adjusted aqueous solution. The pH of this solution was adjusted with a buffer. The resulting soluble meloxicam / cyclodextrin inclusion complex was then spray-dried. This spray-dried dispersion was used to prepare tablets containing cyclodextrin.

[0183] [Table 5]

[0184] Dissolution tests in acidic medium (selected to mimic gastric conditions) were performed by placing tablets in 0.01 N HCl solution at a stirring speed of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 6 and Figures 1 to 10. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are shown as percent (%) of meloxicam dissolved.

[0185] [Table 6]

[0186] Meloxicam dissolution was greater in tablets containing meloxicam in various combinations with cyclodextrin, K2CO3, or NaHCO3 compared to tablets containing meloxicam alone. For example, the dissolution of meloxicam tablets containing NaHCO3 was 95% after 120 minutes compared to 2% for tablets containing meloxicam alone.

[0187] Meloxicam solubility increases with increasing amounts of K2CO3 in the absence of cyclodextrin. However, in the presence of cyclodextrin, increasing amounts of K2CO3 do not appear to increase meloxicam solubility. Even at the highest potassium carbonate dose, meloxicam solubility in the presence of cyclodextrin was reduced by approximately 50% compared to meloxicam solubility at 120 minutes in the absence of cyclodextrin.

[0188] Meloxicam solubility with NaHCO3 was significantly higher than that observed with the highest K2CO3 dose (50% vs. 30% at 15 minutes, 92% vs. 23% at 120 minutes). Meloxicam solubility with NaHCO3 in the presence of cyclodextrin was also significantly higher than that observed with the highest K2CO3 dose (85% vs. 26% at 15 minutes, 86% vs. 12% at 120 minutes). NaHCO3 in the presence of cyclodextrin increased meloxicam solubility at 15 minutes compared to potassium bicarbonate, which decreased solubility.

[0189] Example 3 Bilayer tablets containing 1) an inclusion complex of SBEβCD with meloxicam, prepared as described in Example 2 below, and 2) sodium bicarbonate were prepared (SBEβCD-meloxicam / bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam with 100 mg SBEβCD and 100 mg sodium bicarbonate. The second layer contained 40 mg esomeprazole and 400 mg sodium bicarbonate.

[0190] A total of 20 human subjects were randomly assigned in a 1:1 ratio to either treatment with the SBEβCD-meloxicam / bicarbonate tablets described above or treatment with Mobic® tablets (meloxicam 15 mg) once daily for 6 days under fasting conditions.

[0191] Plasma samples were collected on the first day of dosing for analysis of meloxicam concentrations at multiple time points. Meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. The results are shown in Figure 11.

[0192] The primary endpoint of the study was median T for meloxicam. max was 9 times faster with SBEβCD-meloxicam / bicarbonate tablets compared to Mobic® (0.5 vs. 4.5 hours, respectively, p<0.0001).

[0193] Additionally, SBEβCD-meloxicam / bicarbonate tablets demonstrated higher mean maximum plasma concentrations (C max ) (p=0.0018), faster time to therapeutic plasma concentration (p<0.0001), and faster time to half-maximum plasma concentration (p<0.0001).

[0194] For tablets containing meloxicam and cyclodextrin, meloxicam was used in the form of a meloxicam / cyclodextrin inclusion complex. The inclusion complex was formed by mixing meloxicam and cyclodextrin in a pH-adjusted aqueous solution. The pH of the solution was adjusted with a buffer. The resulting soluble meloxicam / cyclodextrin inclusion complex was then spray-dried. The spray-dried dispersion was used to prepare tablets containing cyclodextrin.

[0195] Example 4 A monolayer tablet containing 1) an inclusion complex of SBEβCD with 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 was similar to that of Example 3.

[0196] Dissolution testing of the tablets in an acidic medium (selected to mimic gastric conditions) was performed by placing the tablets in a 0.01 N HCl solution at an agitation rate of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent (%) meloxicam dissolved and percent (%) rizatriptan dissolved.

[0197] [Table 7]

[0198] As shown in Table 7, the dissolution results of the tablets of Example 4 were very similar to those of Example 2. Therefore, the inventors investigated the pharmacokinetic properties (bioavailability, T max ) are believed to be similar to those described in Example 3 and FIG.

[0199] Example 5 The monolayer tablet of Example 4 was administered to six subjects. Plasma samples were collected for rizatriptan concentration analysis at multiple time points on the first day of dosing. Rizatriptan and meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. Results for meloxicam were comparable to those reported for the bilayer dosage form of Example 3. Rizatriptan median T max is 0.75 hours, and the mean C of rizatriptan max The reported T of the commercially available rizatriptan formulation, Maxalt®, was 20.710 ng / mL. maxis 1.0-1.5 hours.

[0200] Unless otherwise indicated, all numbers used in the specification and claims expressing quantities of ingredients, properties such as molecular weights, reaction conditions, and the like, are to be understood as referring in each instance to both the exact value as indicated and to values ​​modified by the word "about." Accordingly, unless inconsistent, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. While not limiting the application of the doctrine of equivalents to the scope of the claims, at the very least, each numerical parameter should at least be construed as applying ordinary rounding techniques based on the number of reported significant digits.

[0201] When describing the present invention (particularly in the claims), terms referring to the singular should be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any examples or illustrative statements (e.g., statements such as "etc.") described herein are intended to further clarify the invention and are not intended to limit the scope of any claim. The description of the invention should not be construed as referring to any element essential to the practice of the invention not defined in the claims.

[0202] Groupings of alternative elements or embodiments described herein should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or elements described herein. For reasons of convenience and / or patentability, one or more members of a group may be added to or deleted from a group. When such additions or deletions occur, the specification is considered to include the group so modified, thereby satisfying the description requirement of all Markush groups used in the claims.

[0203] Several embodiments are described herein, including the inventors' best mode for carrying out the invention. Of course, variations on the embodiments described herein will be apparent to those skilled in the art in light of the foregoing description. The inventors expect that those skilled in the art will adopt such variations as appropriate, and intend that the invention may be practiced other than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the claimed subject matter as permitted by applicable law. Moreover, any combination of the above-described elements is contemplated in all possible variations of the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0204] Finally, it should be understood that the embodiments described herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not limitation, alternative embodiments may be employed in accordance with the teachings herein. Accordingly, the claims should not be limited to the precise embodiments shown and disclosed.

[0205] [Note] [Appendix 1] Administering a dosage form containing meloxicam, at least 400 mg of bicarbonate, and rizatriptan to a person suffering from migraine, wherein the T of rizatriptan in said dosage form is max is shorter than that of a reference dosage form that a) contains the same amount of rizatriptan, 2) does not contain meloxicam, and c) does not contain bicarbonate.

[0206] [Appendix 2] 2. The method of claim 1, wherein about 8 mg to about 13 mg of rizatriptan is present in the dosage form based on the amount of rizatriptan in free base form.

[0207] [Appendix 3] 3. The method of claim 2, wherein the rizatriptan is present in salt form in an amount equivalent to about 10 mg of the rizatriptan in free base form.

[0208] [Appendix 4] 4. The method of claim 3, wherein the rizatriptan is present as rizatriptan benzoate.

[0209] [Appendix 5] 2. The method of claim 1, wherein the dosage form comprises about 15 mg to about 25 mg of meloxicam.

[0210] [Appendix 6] 6. The method of claim 5, wherein the dosage form comprises about 20 mg of meloxicam.

[0211] [Appendix 7] 2. The method of claim 1, wherein the dosage form further comprises a cyclodextrin.

[0212] [Appendix 8] 8. The method of claim 7, wherein the dosage form comprises about 100 mg to about 175 mg of the cyclodextrin.

[0213] [Appendix 9] 8. The method of claim 7, wherein the dosage form comprises about 100 mg to about 140 mg of the cyclodextrin.

[0214] [Appendix 10] 2. The method of claim 1, wherein the bicarbonate comprises sodium bicarbonate.

[0215] [Appendix 11] 2. The method of claim 1, wherein the dosage form comprises about 400 mg to about 600 mg of the bicarbonate.

[0216] [Appendix 12] 2. The method of claim 1, wherein the dosage form comprises about 500 mg of sodium bicarbonate.

[0217] [Appendix 13] 2. The method of claim 1, wherein the dosage form comprises about 50% to about 90% by weight of the bicarbonate.

[0218] [Appendix 14] 2. The method of claim 1, wherein the dosage form has the property that, 15 minutes after addition of the dosage form to the simulated gastric fluid, the amount of meloxicam dissolved in the simulated gastric fluid of a human is greater than the amount of meloxicam dissolved in the simulated gastric fluid of a reference dosage form that 1) contains the same amount of meloxicam and 2) does not contain bicarbonate.

[0219] [Appendix 15] 2. The method of claim 1, wherein the dosage form has the property that 15 minutes after the dosage form is added to the simulated gastric fluid, the amount of rizatriptan dissolved in the simulated gastric fluid is greater than the amount of meloxicam.

[0220] [Appendix 16] 2. The method of claim 1, wherein the human experiences pain relief more quickly than would be experienced as a result of oral administration of a reference dosage form that 1) contains the same amount of meloxicam and 2) does not contain bicarbonate.

[0221] [Appendix 17] 2. The method of claim 1, wherein the dosage form has the property that at least about 50% of the rizatriptan in the dosage form is dissolved in the simulated gastric fluid 30 minutes after the dosage form is added to the simulated gastric fluid.

[0222] [Appendix 18] 2. The method of claim 1, wherein the dosage form has the property that at least about 50% of the meloxicam in the dosage form is dissolved in the simulated gastric fluid 30 minutes after the dosage form is added to the simulated gastric fluid.

[0223] [Appendix 19] T of meloxicam in the dosage form max is less than about 1 hour.

[0224] [Appendix 20] T of rizatriptan in the dosage form max is less than about 2 hours.

Claims

1. 1. A method for treating migraine in a human experiencing an acute attack of migraine pain or aura, comprising: an inclusion complex of meloxicam or a pharmaceutically acceptable salt thereof and sulfobutyl ether beta-cyclodextrin; 400 mg to 600 mg of bicarbonate; and rizatriptan or a pharmaceutically acceptable salt thereof, wherein the human has a history of an inadequate response to previous migraine treatments, the composition being in oral dosage form, the oral dosage form comprising 10 mg to 30 mg of the meloxicam, based on the amount of the meloxicam in free acid form, and 8 mg to 13 mg of the rizatriptan, based on the amount of the rizatriptan in free base form.

2. 10. The composition of claim 1, wherein the human has experienced frequent headaches that are moderate to severe.

3. The composition of claim 1, wherein the oral dosage form is a single-layer tablet.

4. 2. The composition of claim 1, comprising 10 mg of rizatriptan in free base form or its molar equivalent in salt form, and 20 mg of meloxicam in free acid form or its molar equivalent in salt form.

5. 5. The composition of claim 1, wherein the bicarbonate comprises sodium bicarbonate.

6. 2. The composition of claim 1, wherein 10 mg of rizatriptan is present in the oral dosage form based on the amount of rizatriptan in free base form.

7. 7. The composition of claim 6, wherein the rizatriptan is present in salt form in an amount equivalent to 10 mg of the free base form of the rizatriptan.

8. 8. The composition of claim 7, wherein the rizatriptan is present as about 14.5 mg of rizatriptan benzoate.

9. 10. The composition of claim 1, wherein the oral dosage form comprises 20 mg of the meloxicam in free acid form.

10. 6. The composition of claim 5, wherein the oral dosage form comprises 500 mg of sodium bicarbonate.

11. 10. The composition of claim 1, wherein the oral dosage form comprises 50% to 90% by weight of bicarbonate.

12. 10. The composition of claim 1, wherein the human experiences a reduction in migraine pain 30 minutes after oral administration of the composition that is greater than what the human would experience 30 minutes after oral administration of the same amount of rizatriptan alone.

13. 10. The composition of claim 1, wherein the human experiences a reduction in migraine pain 2 hours after orally administering the composition that is greater than what the human would experience 2 hours after orally administering the same amount of rizatriptan alone, and the human experiences a reduction in migraine pain 24 hours after orally administering the composition that is greater than what the human would experience 24 hours after orally administering the same amount of rizatriptan alone.

14. A composition comprising 20 mg of meloxicam in free acid form or its molar equivalent in salt form, 400 mg to 600 mg of bicarbonate or 500 mg of sodium bicarbonate, and 10 mg of rizatriptan in free base form or its molar equivalent in salt form or about 14.5 mg of rizatriptan benzoate for use in a method for treating migraine in a human experiencing an acute attack of migraine pain or aura, wherein the human has a history of inadequate response to previous migraine treatments.

Images