CN113423397A

CN113423397A - Pharmaceutical composition comprising meloxicam

Info

Publication number: CN113423397A
Application number: CN202080012487.9A
Authority: CN
Inventors: 赫里奥特·塔布提奥
Original assignee: Axsome Therapeutics Inc
Current assignee: Axsome Therapeutics Inc
Priority date: 2019-02-06
Filing date: 2020-02-06
Publication date: 2021-09-21
Also published as: MX2021009435A; EP3920909A4; MA54904A; WO2020163620A1; ECSP21060962A; CO2021010380A2; EP3920909A1; JP2023062144A; JP2022519670A; AU2020218253A1; CA3128940A1; SG11202107926XA; CR20210420A; JP2024026732A; AU2020218253B2; JP7237386B2; IL285389A; BR112021015467A2; JP7420990B2; AU2023202545A1

Abstract

Disclosed herein are compositions comprising an NSAID, such as meloxicam and/or rizatriptan, in combination with a cyclodextrin and/or a carbonate or bicarbonate salt. These compositions may be administered orally, for example, to improve the bioavailability or pharmacokinetics of NSAIDs used to treat pain, such as migraine, arthritis and other conditions. Also disclosed herein are methods of treating pain, e.g., migraine, comprising administering meloxicam and rizatriptan to a human suffering from pain, e.g., migraine. For migraine, these methods may be particularly useful when meloxicam and rizatriptan are administered in humans with migraine or an acute attack of migraine aura. In some embodiments, T may be such that meloxicam results in_maxThe combination of meloxicam and rizatriptan is administered in a 3 hour or less manner.

Description

Pharmaceutical composition comprising meloxicam

Cross Reference to Related Applications

The present application claims the benefit of united states provisional patent application No. 62/802,198 filed on 6/2/2019, 62/803,756 filed on 11/2/2019, 62/835,613 filed on 18/4/2019, 62/846,311 filed on 10/5/2019, 62/860,705 filed on 12/6/2019, 62/895,933 filed on 4/9/2019, 62/895,956 filed on 4/9/2019, and 62/955,905 filed on 31/12/2019, all of which are incorporated by reference in their entireties.

Background

Meloxicam, the structure of which is as follows:

is a non-steroidal anti-inflammatory drug (NSAID) exhibiting anti-inflammatory, analgesic and antipyretic activity. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthase (cyclooxygenase, COX), which inhibits the initial steps involved in the arachidonic acid cascade, leading to a reduction in the formation of prostaglandins, thromboxanes and prostacyclins.

Disclosure of Invention

Meloxicam and some other NSAIDs have poor water solubility, which may reduce bioavailability and slow pain relief from their use. One way to increase the dissolution and bioavailability of meloxicam is by using cyclodextrins. Cyclodextrins (also known as cycloamylose) are generally cyclic polysaccharides that form a barrel shape. Cyclodextrins help to increase the bioavailability of other molecules, since cyclodextrins are hydrophobic on the inside and hydrophilic on the outside, which helps to facilitate the transport of molecules. Naturally occurring cyclodextrins include six, seven, and eight glucose units (alpha, beta, and gamma-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or less glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (i.e., inclusion complexes) with drugs by incorporating the drug into the central/hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to accumulate around drugs in micelle-type structures. This ability of cyclodextrins can allow them to act as carriers to increase the bioavailability of poorly soluble drugs.

Some embodiments include a method of treating migraine, the method comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) a complex of meloxicam with sulfobutyl ether beta-cyclodextrin (SBE β CD), 2) bicarbonate and 3) rizatriptan.

Some embodiments include inclusion complexes of meloxicam in cyclodextrins.

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

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

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

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

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

Also disclosed are methods of treating pain and pain-related conditions by delivering a dosage form having meloxicam, cyclodextrin, and bicarbonate to a subject orally, enterally, intravenously, intramuscularly, subcutaneously, intranasally, or otherwise parenterally.

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

Rizatriptan has the structure shown below.

Rizatriptan

Some embodiments include a subject combination for treating migraine in a human, the subject combination comprising: 1) an inclusion compound of meloxicam and cyclodextrin, 2) rizatriptan, and 3) bicarbonate. The migraine may be a refractory migraine. Humans may have a history of inadequate response to previous treatments.

Some embodiments include a subject combination comprising rizatriptan and meloxicam having rapid, sustained, substantial, and statistically significant efficacy in acute treatment of migraine in patients with a history of insufficient prior acute treatment response as compared to placebo, rizatriptan, or meloxicam.

Some embodiments include a subject combination comprising rizatriptan and meloxicam that requires significantly less rescue medication use than rizatriptan, meloxicam or placebo.

Drawings

Figure 1 is a depiction of the results depicted in example 2 and contained in table 6.

Figure 2 is another depiction of the results depicted in example 2 and contained in table 6.

Figure 3 is another depiction of the results depicted in example 2 and contained in table 6.

Figure 4 is another depiction of the results depicted in example 2 and contained in table 6.

Figure 5 is another depiction of the results depicted in example 2 and contained in table 6.

Figure 6 is another depiction of the results depicted in example 2 and contained in table 6.

FIG. 7 is another depiction of the results depicted in example 2 and contained in Table 6.

FIG. 8 is another depiction of the results depicted in example 2 and contained in Table 6.

FIG. 9 is another depiction of the results depicted in example 2 and contained in Table 6.

FIG. 10 is another depiction of the results depicted in example 2 and contained in Table 6.

Fig. 11 is a graph of plasma meloxicam concentrations at various time points over the first 24 hours for embodiments of the dosage forms described herein and for a commercially available meloxicam dosage form.

Figure 12 is a graph of the plasma concentration of meloxicam at various time points over the first 24 hours for the meloxicam/rizatriptan dosage form described in example 6 and the commercially available meloxicam dosage form.

Figure 13 is a graph of plasma concentrations of rizatriptan over the first 12 hours for the meloxicam/rizatriptan dosage form described in example 6 and the commercially available meloxicam dosage form.

Figure 14 shows a graph of the percentage of subjects reporting pain relief at different time points within the first 4 hours after administration of the meloxicam/rizatriptan, MoSEIC meloxicam and placebo dosage forms described in example 11.

Figure 15 shows the percentage of subjects achieving analgesia at 2 hours, 4 hours, 12 hours, and 16 hours after administration of the dosage forms of meloxicam/rizatriptan, MoSEIC meloxicam, and placebo described in example 11.

Figure 16A shows the percentage of subjects achieving sustained analgesia between 2 hours and 24 hours after administration of the dosage forms of meloxicam/rizatriptan, MoSEIC meloxicam and placebo described in example 11.

Figure 16B shows the percentage of subjects achieving sustained pain relief 2 to 24 hours after administration of the dosage forms of meloxicam/rizatriptan, MoSEIC meloxicam and placebo described in example 11.

Figure 17A shows the percentage of subjects achieving sustained analgesia between 2 hours and 48 hours after administration of the dosage forms of meloxicam/rizatriptan, MoSEIC meloxicam and placebo described in example 11.

Figure 17B shows the percentage of subjects achieving sustained pain relief 2 to 48 hours after administration of the dosage forms of meloxicam/rizatriptan, MoSEIC meloxicam and placebo described in example 11.

Figure 18 shows the percentage of subjects taking rescue medication within 24 hours after administration of the dosage forms of meloxicam/rizatriptan, MoSEIC meloxicam and placebo described in example 11.

Detailed Description

Provided herein are dosage forms having an NSAID (e.g., meloxicam) and a cyclodextrin (optionally in an inclusion complex) and/or a bicarbonate salt, as well as methods of treatment using the dosage forms.

Dosage forms may be administered enterally, including but not limited to oral, sublingual, or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous delivery.

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

The combination of meloxicam, cyclodextrin (e.g., SBE β CD), and a bicarbonate salt (e.g., sodium bicarbonate) can significantly increase the dissolution and absorption rates of meloxicam upon oral administration, while maintaining an extended half-life of plasma concentrations in a mammal (e.g., a human) upon oral administration.

The combination of meloxicam, cyclodextrin (e.g., SBE β CD), and a bicarbonate salt (e.g., sodium bicarbonate) can significantly increase the oral bioavailability of meloxicam in a mammal (e.g., a human) following oral administration.

Unless otherwise indicated, any reference to a compound herein, e.g., meloxicam or rizatriptan, by structure, name or in any other manner, includes pharmaceutically acceptable salts, alternative solid forms, e.g., polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium modified forms, or any other chemical substance, e.g., precursors, prodrugs or any other chemical substance that can be rapidly converted to the compounds described herein under the conditions in which the compound is used as described herein.

The subject combinations may be administered enterally, including but not limited to oral, sublingual, or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous delivery. In some embodiments, both meloxicam and rizatriptan are administered orally. In some embodiments, meloxicam is administered intravenously and rizatriptan is administered orally. In some embodiments, meloxicam is administered intramuscularly and rizatriptan is administered orally.

Typically, administration of a combination of meloxicam and rizatriptan results in a human receiving meloxicam and rizatriptan within a short time of each other. For example, meloxicam and rizatriptan can be administered within about 2 hours, within about 1 hour, within about 30 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, within about 5 minutes, or within about 1 minute of one another. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which for purposes of this disclosure includes administration within about 5 minutes. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form.

The term "treating" or "treatment" broadly includes any kind of therapeutic activity, including any activity that diagnoses, cures, alleviates or prevents a disease in a human or other animal, or otherwise affects the structure or any function of the body of a human or other animal.

The dosage form or subject combination may 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, systemic pain, cancer-related pain, acute pain, pain resulting from injury, pain resulting from disease (e.g., fever), post-operative pain, and the like. In some cases, pain relief may be palliative, or pain relief may be provided independently of the improvement of the disease or condition or the root cause of the disease or condition. For example, while the underlying disease may not improve or may continue to progress, an individual with the disease may experience pain relief. In some embodiments, the pain affects a muscle, nerve, cartilage, bone, ligament, tendon sheath, bursa, or joint.

Migraine is a disabling neurological disease characterized by recurrent episodes of throbbing head pain with nausea and sensitivity to light and sound. This pain can be moderate to severe, but is usually severe and immobile, requiring bed rest. Headache may affect half of the head, may be pulsatile in nature, and may last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or odor. Pain can be exacerbated by physical activity. Migraine headaches may be associated with aura, which may be a transient visual disturbance that indicates that the headache is rapidly taking place. Some migraine sufferers may not have aura.

In some embodiments, the person being treated for migraine headache has allodynia associated with a migraine attack. Allodynia is typically pain caused by non-painful stimuli (e.g., combing the head, wearing glasses, bathing, etc.). Patients with allodynia are considered unlikely to respond well to triptans.

Current treatments are poor, and over 70% of patients report dissatisfaction with existing acute treatments. The most common causes of patient dissatisfaction are slow pain relief, inconsistent pain relief, and recurrence of pain on the same day. Poor acute treatment is associated with a significant increase in the risk of new onset chronic migraine, which can be prevented by improving the acute treatment outcome.

Administration of the subject combination to a person suffering from migraine, e.g., migraine or an acute attack of aura, can rapidly result in a reduction in migraine symptoms, e.g., pain, nausea, vomiting, photophobia, or phonophobia, e.g., at or within about 5 minutes (a shorthand meaning "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, the human experiences pain relief or complete relief, such as headache or migraine, nausea, vomiting, photophobia and/or phonophobia, 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, the remission experienced is greater than the remission experienced by receiving the same amount of rizatriptan in the absence of meloxicam. In some embodiments, the relief experienced is greater than the relief experienced by receiving the same amount of meloxicam without rizatriptan.

The combination of meloxicam and rizatriptan can have a unique dual effect on acute treatment of migraineA mechanism of re-action. Meloxicam is a potent COX-2 preferred nonsteroidal anti-inflammatory drug, but is absorbed slowly. Lizatriptan is a potent 5-HT1_B/DAgonists, believed to be effective against migraine.

It is useful to observe the relief or alleviation of symptoms at a particular time period (e.g., "2 hours") because it allows the effectiveness of the treatment to be assessed at a particular or consistent point in time, which facilitates comparison between patients. It is useful to observe the relief or reduction of symptoms over a specified period of time (e.g., "within about 2 hours"), since it is desirable to have relief or reduction of symptoms occur as early as possible, and to specify that relief occurs at a specified time to set a guideline in which relief is desired.

For some methods, administration of the subject combination can achieve a reduction in migraine, nausea, vomiting, photophobia, or phonophobia for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8-24 hours, about 24 hours, or more than 24 hours.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the aversion relief experienced by a human is greater than the aversion relief experienced by a human 2 hours after receiving the same amount of meloxicam without rizatriptan.

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

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the aversive relief experienced by a human is greater than the aversive relief experienced by a human 2 hours after receiving the same amount of rizatriptan without meloxicam.

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

In some embodiments, the person receiving the subject combination has a history of insufficient response to prior migraine treatments. For example, if the person is asked if he or she is pain free within 2 hours of treatment for most episodes and gives the option to answer "never", "rarely", "less than half the time" or "more than half the time", the person answers "never", "rarely" or "less than half the time", then the person is not responding adequately to the treatment. Similarly, if a human is asked whether a dose of medication can generally alleviate headache in humans and hold it for at least 24 hours, and given the option of answering "never", "rarely", "less than half the time" or "more than half the time", the human answers "never", "rarely" or "less than half the time", then the human is not responding adequately to the treatment.

In some embodiments, a person receiving the subject combination has shown that he or she is "never" pain free within 2 hours of treatment for most episodes. In some embodiments, a person receiving the subject combination has shown that he or she is "rarely" painless within 2 hours of treatment for most episodes. In some embodiments, the person receiving the subject combination has shown that he or she is pain free within 2 hours of treatment for most episodes of "less than half the time".

In some embodiments, the person receiving the subject combination has indicated that a dose of the drug "never" alleviates and keeps the headache in the interviewee away from the headache for at least 24 hours. In some embodiments, a person receiving the subject combination has shown that a dose of the drug "rarely" alleviates and keeps a subject away from headache for at least 24 hours. In some embodiments, the person receiving the subject combination has indicated that a dose of the drug alleviates the headache in the subject and keeps it away from the headache for less than half of at least 24 hours ".

In some embodiments, a person receiving the subject combination has a history of insufficient response to prior migraine treatment, as assessed by the migraine treatment optimization questionnaire (mTOQ-4) for a total average score of less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. In some embodiments, the human has used triptan prior to receiving the subject combination, e.g., a combination comprising meloxicam and rizatriptan.

In some embodiments, a human receiving a subject combination, e.g., a combination comprising meloxicam and rizatriptan, has migraine and may have a history of insufficient responsiveness to previous migraine treatments. In some embodiments, the person with migraine headache is free of cluster headache or other types of migraine headache. In some embodiments, the person having migraine headache does not have chronic daily headache. In some embodiments, the person with migraine does not exceed 15, 15-20, 20-25, 25-28, 28-30, or 30-31 non-migraine days per month. In some embodiments, the person with migraine has no history of major cardiovascular disease. In some embodiments, the person with migraine is free of uncontrolled hypertension.

In some embodiments, the dosage form may also be administered to relieve pain from arthritis. In some embodiments, the dosage form may be administered to alleviate other signs and/or symptoms of arthritis. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (both oligoarticular and polyarticular), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthritis, arthropathy, non-articular rheumatism, periarticular disease, central spine arthritis, transient hip osteoarthritis, vertebral crush fractures, osteoporosis and neurological arthropathy (including charcot's foot), central spine arthritis (including ankylosing spondylitis), and SAPHO syndrome. In other embodiments, the arthritis pain can be chronic or acute. In some embodiments, the dosage form may be administered to alleviate signs and/or symptoms of arthritis (including but not limited to osteoarthritis).

For some methods, administration of the dosage form can achieve pain relief for at least about 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least about 8 hours, from about 8 to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form may achieve a reduction in pain observed at about 10 minutes, at about 30 minutes, at about 1 hour, at about 2 hours, at about 3 hours, at about 4 hours, at about 5 hours, at about 6 hours, at less than 15 minutes, at less than 20 minutes, at 30 minutes, at less than 1 hour, at less than 2 hours, at less than 3 hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or other time periods limited by these ranges, after administration of the dosage form.

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

In some methods, the dosage form can be administered to relieve inflammatory pain, including inflammatory musculoskeletal pain, pain resulting from injury, arthritic pain, and complex local pain syndromes. In other embodiments, inflammatory pain may be chronic or acute.

Arthritis refers to inflammatory joint disease that may be associated with pain. Examples of arthritic pain include, but are not limited to, pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disease, neuropathic arthropathy (including charcot's foot), central spine arthritis (including ankylosing spondylitis), and SAPHO syndrome. The inflammatory joint disease treated may be chronic or acute.

For some methods, meloxicam may be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain may include, but are not limited to, back pain, low back pain (e.g., lumbosacral pain), neck pain, infection, spasm, tendonitis, epididymitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain caused by injury, siphunculus syndrome, pain associated with bone fracture, sprain, fibrodysplasia, osteogenesis imperfecta, paget's disease of bone, transient osteoporosis, and transient hip osteoporosis. In other embodiments, the musculoskeletal pain may be chronic or acute.

For some methods, administration of a dosage form or subject combination can achieve pain relief 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 to about 24 hours, or about 24 hours. In other embodiments, administration of the subject combination can achieve pain relief observed at about 10 minutes, at about 30 minutes, at about 1 hour, at about 2 hours, at about 3 hours, at about 4 hours, at about 5 hours, at about 6 hours, at about 5 minutes or less, at about 10 minutes or less, at about 15 minutes or less, at about 20 minutes or less, at about 25 minutes or less, at about 30 minutes or less, at about 35 minutes or less, at about 40 minutes or less, at about 45 minutes or less, at about 50 minutes or less, or at about 60 minutes or less, at 2 hours or less, at 3 hours or less, or other time periods limited by these ranges, after administration of the subject combination.

The person treated for a disease or condition with a dosage form described herein can be of any age. For example, the human may be about 10 to about 90 years old, about 20 to about 80 years old, about 30 to about 75 years old, about 40 to about 70 years old, about 1 to about 16 years old, about 80 to about 95 years old, about 18 years old or older, about 20 years old or older, about 25 years old or older, about 30 years old or older, about 40 years old or older, about 45 years old or older, about 50 years old or older, about 55 years old or older, about 60 years old or older, about 65 years old or older, or any other age between these values.

In some embodiments, a human being treated for migraine with a dosage form described herein, e.g., a dosage form comprising meloxicam, rizatriptan, SBE β CD and a bicarbonate salt, e.g., sodium bicarbonate, can be between 18-65 years of age, about 18-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-40 years of age, about 40-45 years of age, about 40-50 years of age, about 50-60 years of age, about 60-65 years of age, or any other age bounded by or ranging between these values.

In some embodiments, the person treated for migraine with a dosage form described herein, e.g., a dosage form comprising meloxicam, rizatriptan, SBE β CD and a bicarbonate salt, e.g., sodium bicarbonate, can be a white person, a black person, or an asian american or asian person.

In some embodiments, a human having pain or a condition associated with pain treated with a dosage form comprising meloxicam or another NSAID has pain or a condition associated with pain for at least 1 day, at least one 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, or at least 1 year, or any duration bounded by or ranging between these values.

In some embodiments, a human treated for migraine with a dosage form comprising meloxicam and rizatriptan has been diagnosed with migraine with or without aura as defined by the ICHD-3 standard for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years, or longer, or at least 1 year, or any duration within these values or ranges between these values.

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

The cyclodextrin used in the dosage form with meloxicam may include cyclodextrin, cyclodextrin derivatives and/or salts thereof. The inclusion complex of meloxicam and cyclodextrin may be more soluble in water than uncomplexed meloxicam. The cyclodextrin can be a naturally occurring cyclodextrin (e.g., alpha, beta, or gamma-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, alpha-cyclodextrin, derivatives or salts thereof may be used. The alpha-cyclodextrin can include, but is not limited to, (2,3, 6-tri-O-acetyl) -alpha-cyclodextrin, (2,3, 6-tri-O-methyl) -alpha-cyclodextrin, (2,3, 6-tri-O-octyl) -alpha-cyclodextrin, 6-bromo-6-deoxy-alpha-cyclodextrin, 6-iodo-6-deoxy-alpha-cyclodextrin, (6-O-tert-butyl-dimethylsilyl) -alpha-cyclodextrin, butyl-alpha-cyclodextrin, succinyl-alpha-cyclodextrin, (2-hydroxypropyl) -alpha-cyclodextrin, or a combination thereof.

In some embodiments, β -cyclodextrin, derivatives or salts thereof may be used. Beta-cyclodextrins may include, but are not limited to, hydroxypropyl-beta-cyclodextrin, 6-monodeoxy-6-monoamino-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, 6-O-alpha-D-glucosyl-beta-cyclodextrin, 6-O-alpha-maltosyl-beta-cyclodextrin, 6-azido-6-deoxy-beta-cyclodextrin, (2, 3-di-O-acetyl-6-O-sulfo) -beta-cyclodextrin, methyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin (DM beta CD), trimethyl-beta-cyclodextrin (TM beta CD), and mixtures thereof, (2, 3-di-O-methyl-6-O-sulfo) -beta-cyclodextrin, (2, 6-di-O-methyl) -beta-cyclodextrin, (2, 6-di-O-ethyl) -beta-cyclodextrin, (2,3, 6-tri-O-methyl) -beta-cyclodextrin, (2,3, 6-tri-O-acetyl) -beta-cyclodextrin, - (2,3, 6-tri-O-benzoyl) -beta-cyclodextrin, (2,3, 6-tri-O-ethyl) -beta-cyclodextrin, 6-iodo-6-deoxy-beta-cyclodextrin, 6- (dimethyl-tert-butylsilyl) -6-deoxy-beta-cyclodextrin Cyclodextrin, 6-bromo-6-deoxy-beta-cyclodextrin, monoacetyl-beta-cyclodextrin, diacetyl-beta-cyclodextrin, triacetyl-beta-cyclodextrin, (3-O-acetyl-2, 6-di-O-methyl) -beta-cyclodextrin, (6-O-maltosyl) -beta-cyclodextrin, (6-O-sulfo) -beta-cyclodextrin, (6-O-t-butyldimethylsilyl-2, 3-di-O-acetyl) -beta-cyclodextrin, succinyl- (2-hydroxypropyl) -beta-cyclodextrin, (2, 6-di-O-) ethyl-beta-cyclodextrin, and pharmaceutically acceptable salts thereof, (2-carboxyethyl) -beta-cyclodextrin (CME beta CD), hydroxyethyl-beta-cyclodextrin (HE beta CD), (2-hydroxypropyl) -beta-cyclodextrin (HP beta CD), (3-hydroxypropyl) -beta-cyclodextrin (3HP beta CD), (2, 3-hydroxypropyl) -beta-cyclodextrin (DHP beta CD), butyl-beta-cyclodextrin, methyl-beta-cyclodextrin, silyl ((6-O-tert-butyldimethyl) -2,3, -di-O-acetyl) -beta-cyclodextrin, succinyl-beta-cyclodextrin, (2-hydroxyisobutyl) -beta-cyclodextrin, and mixtures thereof, Randomly methylated-beta-cyclodextrin, branched-beta-cyclodextrin, or a combination thereof.

In other embodiments, the beta-cyclodextrin can be a sulfoalkyl ether cyclodextrin, a derivative, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives can include, but are not limited to, sulfobutyl ether-beta-cyclodextrin (e.g., SBE beta CD, betadex (betadex)),

In some embodiments, SBE β CD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

In some embodiments, gamma-cyclodextrin, derivatives or salts thereof may be used. The gamma-cyclodextrin may include carboxymethyl-gamma-cyclodextrin, (2,3, 6-tri-O-acetyl) -gamma-cyclodextrin, (2,3, 6-tri-O-methyl) -gamma-cyclodextrin, (2, 6-di-O-pentyl) -gamma-cyclodextrin, 6- (dimethyl-t-butylsilyl) -6-deoxy-gamma-cyclodextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, 6-iodo-6-deoxy-gamma-cyclodextrin, (6-O-t-butyldimethylsilyl) -gamma-cyclodextrin, succinyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin (2-hydroxypropyl) -gamma-cyclodextrin, beta-cyclodextrin, and beta-cyclodextrin, Acetyl-gamma-cyclodextrin, butyl-gamma-cyclodextrin, or a combination thereof.

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

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

In some embodiments, enhanced bioavailability of the dosage form may be achieved in treating one of these conditions by administering a dosage form comprising a meloxicam salt form, by forming an inclusion complex with meloxicam and a cyclodextrin, and/or by comprising a bicarbonate salt. This may allow for the use of reduced molar amounts of meloxicam compared to other meloxicam dosage forms.

Unless otherwise indicated, any reference to a compound herein, for example meloxicam or a cyclodextrin, by structure, name or in any other manner includes pharmaceutically acceptable salts, alternative solid forms, for example polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium modified forms, or any other chemical substance that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein.

In some embodiments, the use of a cyclodextrin, a carbonate, or a bicarbonate salt can increase the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any amount bounded by or ranging between these values, as compared to meloxicam alone.

Due to the improved bioavailability, the dosage form may contain, or the subject may receive, on a molar basis, less meloxicam than would otherwise be administered. For example, a dosage form may contain, or be acceptable to a mammal for, at least about 10 mole% less, at least about 20 mole% less, at least about 30 mole% less, at least about 40 mole% less, at least about 50 mole% less, at least about 60 mole% less, at least about 70 mole% less, at least about 80 mole% less, at least about 85 mole% less, and/or at most about 90 mole%, 95 mole%, or any amount of meloxicam defined by or within the range of these values than would otherwise be administered.

In other embodiments, the use of other NSAIDs, opioids, or other analgesics may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, up to about 100% as compared to the use of other non-steroidal anti-inflammatory drugs, opioids, or other analgesics without the administration of meloxicam with cyclodextrins, carbonates, and/or bicarbonates.

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

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

The formation of inclusion complexes of meloxicam and cyclodextrins may contribute to improved dosage form properties. For some clathrates, the molar ratio of meloxicam to cyclodextrin (e.g., SBE β CD) can be about 0.5-2(0.5 molar ratio is 0.5 molar meloxicam to 1 molar cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or any ratio within a range bounded by any of these values.

For some dosage forms, cyclodextrin (e.g., SBE β CD) can be used with meloxicam in a weight ratio within the following range: about 1 to 1000 (e.g., 1g cyclodextrin per 1g meloxicam by weight of 1); about 1 to about 20; about 1 to about 10; about 1 to about 15; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio defined by or within the range of any of these values. For some dosage forms, cyclodextrin (e.g., SBE β CD) can be used with meloxicam in a weight ratio within the following range: about 0.001-1 (e.g., 0.1g cyclodextrin per 1g meloxicam by weight of 0.1); about 0.01 to about 1; about 0.05 to about 1; about 0.1 to about 1; about 0.2 to about 1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weight ratio defined by or within the range of any of these values. Each type of cyclodextrin used may have a different ratio.

For some dosage forms, the cyclodextrin may be present in the following amounts: about 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about 80-100 mg; about 80-120 mg; about 100 and 120 mg; about 100 and 140 mg; about 120-160 mg; about 140 and 180 mg; about 30-90 mg; about 40-80 mg; about 50-70mg, about 55-65mg, about 60-62mg, or any amount bounded by or within a range of any of these values.

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

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

Some dosage forms contain the following amounts of carbonate: about 1-1000 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500 and 1000 mg; about 100 and 500 mg; about 100 and 300 mg; about 200 and 800 mg; about 500 and 1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about 250 and 750 mg; about 100 and 200 mg; about 200 and 300 mg; about 300 and 400 mg; about 400-500 mg; about 500 and 600 mg; about 600 and 700 mg; about 700 and 800 mg; about 800 and 900 mg; about 150-650 mg; about 350-850 mg; or any amount bounded by or within a range of any of these values.

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

In some embodiments, the weekly dose (e.g., oral dose) of meloxicam is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100 and 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 and 150 mg; about 30-100 mg; or any amount bounded by or within a range of any of these values. The weekly dose may be administered as a single dose, once during a week, or may be administered in 2,3, 4, 5,6 or 7 separate doses during a week.

In some embodiments, the monthly dose (e.g., oral dose) of meloxicam or the dose administered during a month is about 5000mg or less; about 4000mg or less; about 3000mg or less; about 2000mg or less; about 1000mg or less; about 700mg or less; about 600mg 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 and 240 mg; about 240 and 280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450 and 500 mg; about 500 and 600 mg; about 250 and 350 mg; about 100 and 600 mg; about 40-2000 mg; about 40-800 mg; about 100 and 900 mg; about 100 and 800 mg; about 40-1000 mg; about 50-1000 mg; about 100 and 1000 mg; or any monthly dose defined by or within a range of any of these values. The monthly dose can be administered as a single dose, or in two or more separate doses administered during the month. In some embodiments, the monthly dose is administered in 2 or 3 bi-weekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28 to 31 daily doses, or 56 to 62 or more daily doses. In some embodiments, a monthly dose is administered at 5 to 15 individual doses during the month. The monthly dose may be administered for only 1 month, or may be repeated for 2 months or longer.

In other embodiments, the dosage form may be administered weekly for about one, two, three, four or more consecutive weeks, once every other week or every two weeks, or once every three weeks. This regimen may be repeated once a week, twice a month, three times a month, once every two months, once every three months, or as directed by a medical professional.

In certain embodiments, the pharmaceutical composition results in an increase in bioavailability (e.g., a decreased T) of meloxicam from the dosage form as compared to a dosage form containing meloxicam but no cyclodextrin, acid inhibitor, or buffer (e.g., bicarbonate)_maxIncreased C_maxIncreased AUC, etc.). In some embodiments, the bioavailability of meloxicam will increase with multiple administrations. For example, the bioavailability of meloxicam in a dosage form can increase after about 1 to 10 days of administration, about 2 to 6 days of administration, about 3 to 5 days of administration, about 4 to 6 days of administration, about 5 to 8 days of administration, about 5 days of administration, about 6 days of administration, about 7 days of administration, about 8 days of administration, about 10 days of administration, about 15 days of administration, or a time defined by or within any range of any of these values as compared to the bioavailability of meloxicam in a dosage form that does not contain a cyclodextrin, acid inhibitor, or buffer (e.g., bicarbonate).

Some dosage forms may result in the desired range of the area under the plasma concentration curve (AUC) of meloxicam. For example, the dose of meloxicam may result in a meloxicam AUC of about 1-150 μ g-hr/mL, about 10-30 μ g-hr/mL, about 20-40 μ g-hr/mL, about 30-50 μ g-hr/mL, about 40-60 μ g-hr/mL, about 50-70 μ g-hr/mL, about 60-80 μ g-hr/mL, about 70-90 μ g-hr/mL, about 80-100 μ g-hr/mL, about 10-100 μ g-hr/mL, about 50-150 μ g-hr/mL, about 25-125 μ g-hr/mL, about 75-150 μ g-hr/mL, about 20-50 μ g-hr/mL, about 40-70 μ g-hr/mL, about 60-90 μ g-hr/mL, about, About 80-110. mu.g-hr/mL, about 100-130. mu.g-hr/mL, about 120-150. mu.g-hr/mL, or any AUC defined by or within a range of any of these values.

Unless otherwise indicated, AUC refers to the AUC calculated from the last measured concentration (AUC)_0-t) E.g. over 6 hours (AUC)_0-6) Within 12 hours (AUC)_0-12) Over 24 hours (AUC)_0-24) Or extrapolated to infinite time period (AUC)_0-inf)。

In example 3 below, the AUC of meloxicam in humans for oral dosage forms containing sodium bicarbonate and sulfobutyl ether β -cyclodextrin (SBE β CD)_0-24About 27. mu.g-hr/mL. The dosage form contains 15mg of meloxicam.

The 15mg intravenous and intramuscular dose also provided the AUC of meloxicam in humans_0-24And about 27 mg-hr/mL. The AUC of meloxicam is considered to be dose-proportional. Thus, for such an oral dosage form, or for an intravenous or intramuscular dosage form, a meloxicam dose of, for example, about 17mg to about 30mg would be expected to result in a meloxicam AUC of about 30-50 μ g-hr/mL_0-24。

For some acute pain conditions, such as migraine and other types of headache, AUC (or AUC) measured over a short period of time, such as 6 hours, after oral administration_0-6) May be of particular interest. For example, some dosage forms may produce AUC's of at least about 6. mu.g-hr/mL, at least about 7. mu.g-hr/mL, at least about 8. mu.g-hr/mL, at least about 9. mu.g-hr/mL, about 6-10. mu.g-hr/mL, about 7-11. mu.g-hr/mL, about 8-12. mu.g-hr/mL, about 9-13. mu.g-hr/mL_0-6Or any AUC bounded by or within a range of any of these values.

In some embodiments, the dosage form can result in a C of meloxicam_maxAbout 10-2500ng/mL, about 100-2250ng/mL, about 500-2000ng/mL, about 1000-2500ng/mL, about 1000-2000ng/mL, about 100-900ng/mL, about 750-1500ng/mL, about 1250-2000ng/mL, about 1500-2300ng/mL, about 800-1200 ng/mL2400/mL, about 1900-2400ng/mL, about 50-500ng/mL, about 400-950ng/mL, about 900-1500ng/mL, about 1100-2200ng/mL, about 1300-1600ng/mL, about 1200-1500ng/mL, about 1400-2100ng/mL, about 1500-1900ng/mL, about 1600-2100ng/mL, about 1700-2000ng/mL, about 1800-2000ng/mL, about 1900-2500ng/mL, about 150-1700ng/mL, about 1600-1800ng/mL, about 1700-1900-2000-mL, about 1900-2000-mL, about 1900-2100-ng/mL, about 2000-2200ng/mL, about 2100-2300-mL, about 2200-2400/mL, about, About 2300 and 2500ng/mL, about 2500 and 3000ng/mL, or any C defined by or within any of these values_max。

For example, the methods described herein can reduce the T of meloxicam_max. In some embodiments, the method may comprise treating the patient to reach the T of meloxicam of 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 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 after administration_maxOr any T defined by or within the range of any of these values_max。

In some embodiments, the T of meloxicam is in an oral dosage form_maxCan be compared to T achieved by intramuscular administration of meloxicam_maxShorter. In some embodiments, the oral dosage form may have a shorter T of meloxicam_maxOr may increase the meloxicam plasma level at a faster rate by 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-fold, or about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100-fold, or a multiple within a range bounded by any of these values.

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

In some embodiments, meloxicam causes meloxicam plasma levels (e.g., C)_avgOr mean plasma level) is about 0.01-0.5 μ g/mL; about 0.5-0.7 μ g/mL; about 0.6-0.8 μ g/mL; about 0.7-0.9 μ g/mL; about 0.8-1 μ g/mL; about 0.9-1.1 μ g/mL; about 1-1.2 μ g/mL; about 1.1-1.3 μ g/mL; about 1.2-1.4 μ g/mL; about 1.3-1.5 μ g/mL; about 1.4-1.6 μ g/mL; about 1.5-1.7 μ g/mL; about 1.6-1.8 μ g/mL; about 1.7-1.9 μ g/mL; about 1.8-2 μ g/mL; about 1.9-2.1 μ g/mL; about 2-2.2 μ g/mL; about 2.1-2.3 μ g/mL; about 2.2-2.4 μ g/mL; about 2.3-2.5 μ g/mL; about 2.4-2.6 μ g/mL; about 2.5-2.7 μ g/mL; about 2.6-2.8 μ g/mL; about 2.7-2.9 μ g/mL; about 2.8-3 μ g/mL; about 2.9-3.1 μ g/mL; about 3-3.2 μ g/mL; about 3.1-3.3 μ g/mL; about 3.2-3.4 μ g/mL; about 3.3-3.5 μ g/mL; about 3.4-3.6 μ g/mL; about 3.5-3.7 μ g/mL; about 3.6-3.8 μ g/mL; about 3.7-3.9 μ g/mL; about 3.8-4 μ g/mL; about 0.1-20 μ g/mL; about 0.5-15 μ g/mL; about 0.5-10 μ g/mL; about 5-15 μ g/mL; about 10-20 μ g/mL; about 7.5-15 μ g/mL; about 2-10 μ g/mL; about 1-8 μ g/mL; about 1-6 μ g/mL; about 1-2 μ g/mL; about 0.5-3.5 μ g/mL; about 0.5-7 μ g/mL; about 12-20 μ g/mL; about 8-12 μ g/mL; about 1-4 μ g/mL; about 4-7 μ g/mL; about 7-11 μ g/mL; about 11-15 μ g/mL; about 15-19 μ g/mL; about 16-20 μ g/mL; or any amount of meloxicam plasma levels bounded by or within the range of any of these values.

Administration of a dosage form as described herein can result in a reduction in the time to achieve a therapeutic plasma concentration of meloxicam. The therapeutic plasma concentration is 15mg

Meloxicam C_avg. In some embodiments, the time (T) for meloxicam to reach a therapeutic plasma concentration_thera) About 10-30 minutes, about 10-15 minutes, about 15-20 minutes, about 20-25 minutes, about 25-30 minutes, about 10-20 minutes, about 20-30 minutes, about 16-18 minutes, or about 17 minutes.

The methods described herein can reduce the T of rizatriptan_max. For example, the method may achieve the T of rizatriptan in a patient within about 50 minutes, within about 60 minutes, within about 70 minutes, within about 80 minutes, or within about 90 minutes, at about 40-60 minutes, at about 40-45 minutes, at about 45-50 minutes, at about 50-55 minutes, or at about 55-60 minutes after administration_maxOr any T within a range bounded by any of these values_max。

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, a human experiences greater allodynia relief than does a human receiving the same amount of meloxicam 2 hours after administration without rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the allodynia relief experienced by a human is greater than the allodynia relief experienced by a human 24 hours after receiving the same amount of meloxicam without rizatriptan.

In some embodiments, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the allodynia relief experienced by a human is greater than the allodynia relief experienced by a human 2 hours after receiving the same amount of rizatriptan without meloxicam.

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

One embodiment is a method of reducing the risk of gastrointestinal side effects and improving the bioavailability of NSAIDs in humans taking NSAIDs to alleviate pain and other conditions, particularly during chronic treatment. In one embodiment, the method comprises applying a product that combines: a) agents that actively increase the pH in the stomach; and b) an NSAID formulated with a cyclodextrin. In another embodiment, the method comprises applying a product that combines: a) agents that actively increase the pH in the stomach; b) NSAIDs formulated with cyclodextrins; and c) a buffering agent. Either short-acting or long-acting acid inhibitors can be effectively used in the dosage form. This approach has the added benefit of protecting the patient from other GI ulcerations that might otherwise be enhanced by destruction of the gastroprotective prostaglandin by NSAID treatment.

The aqueous parenteral form of meloxicam formulation may comprise a buffering agent to adjust the pH of the aqueous formulation between about 2 and about 5; about 3.5 to about 5; from about 5 to about 11; about 6 to about 9; about 6 to about 8; in the range of about 6 to about 7; or any other pH defined by or within the range of any of these values. The meloxicam formulation in oral form may comprise a buffering agent to adjust the pH of the gastric juice to about 2 to about 5; about 3.5 to about 5; from about 5 to about 11; about 6 to about 9; about 6 to about 8; in the range of about 6 to about 7; or any other pH defined by or within the range of any of these values. Examples of buffers suitable for use herein include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, and the like.

In some embodiments, the dosage form may be formulated for oral administration, e.g., with an inert diluent or an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet. For oral therapeutic administration, the active compounds may be combined with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches and the like.

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

Some compositions or dosage forms may be liquid, or may comprise a solid phase dispersed in a liquid.

The dosage form may also comprise a second therapeutically active agent, such as an acid inhibitor or an analgesic.

In some embodiments, when one or more unit dosage forms are administered, the dosage form may further comprise an acid inhibitor present in an amount effective to raise the gastric pH of the patient to at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and further to at least 5. The term "acid inhibitor" refers to an agent that inhibits gastric acid secretion and increases gastric pH. Specific H that can be used₂Retarders, also known as H₂Antagonists or Histamine H₂Blocking or antagonistic agents, including but not limited toCimetidine, ranitidine, ibutidine, pabuttidine, lafutidine, loxetidine, famotidine, or combinations thereof.

Other agents that may be effectively used as acid inhibitors are proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments, the daily dose of acid inhibitor is about 1-200mg, about 1-100mg, about 1-50mg, about 40-80mg, about 5-50mg, about 20-40mg, about 10-50mg, about 10-20mg, about 20-40mg, about 15-50mg, about 30-60mg, about 10mg, about 20mg, about 30mg, about 40mg or any other amount defined by or within the range of any of these values.

Examples of specific proton pump inhibitors include esomeprazole, present in a unit dosage form of 5mg to 50 mg; omeprazole in a unit dosage form of 5mg to 50 mg; lansoprazole in a unit dosage form of 5mg to 150mg (and preferably 5mg to 30 mg); and pantoprazole in a unit dosage form of 10mg to 200 mg. In some embodiments, the proton pump inhibiting agent is present in the dosage form in an amount of about 10-30mg, about 20-40mg, about 30-50mg, about 40-60mg, about 50-70mg, about 60-80mg, about 70-90mg, or about 80-100 mg. More recently, a newer acid inhibitor has been developed that can compete with potassium in the acid pump. Such compounds are known as "reversible proton pump inhibitors" or "acid pump antagonists" and may also be used. Examples include AZD-0865, AR-H047108, CS-526, Primazole, Revaprazan and Soprarazan (see WO9605177 and WO 9605199). Other compounds in this group are H-335/25(AstraZeneca, dialog document 128, accession number 020806); sch-28080(Schering Plough, dialog document 128, accession number 009663); sch-32651(Schering Plough, dialog document 128, accession number 006883) and SK & F-96067(CAS registry number 115607-61-9).

The second therapeutically active agent may include an analgesic, such as a second non-steroidal anti-inflammatory drug, an opioid, a steroid, a triptan, or the like. In some embodiments, the dosage form or treatment further comprises administering a second non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. The NSAID may include, but is not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (for the purposes of this disclosure to be considered an NSAID), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamic acid, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, acetyl-clofenamic acid, tolfenamic acid, oxybutyzone, azapropazone, phenylbutazone, or combinations thereof. It will be understood that for the purposes of this disclosure, reference to an acid inhibitor, NSAID or analgesic will include all common forms of these compounds, particularly their pharmaceutically acceptable salts. Due to potential positive kinetic interactions and NSAID absorption in the presence of acid inhibitors and/or in the presence of buffering agents, the amount of therapeutically effective non-steroidal anti-inflammatory drugs in the current embodiment may be lower than found in practice.

In other embodiments, the dosage form or treatment may further comprise administering an opioid in an amount effective to reduce or eliminate pain or inflammation. Opioids may include, but are not limited to, (dextro) propoxyphene, A-methylfentanyl, alfentanil, allylrid, benzonitrile mite, buprenorphine, butorphanol, carfentanil, norpraline, dextro-morphine, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, hydromorphone, diphenoxylate, dipiperidone, etorphine, fentanyl, ketobemidone, lexamine, levomethamidone, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, hydroxyfentanyl, oripavine, oxycodone, oxymorphone, PEPAP, paraporphine, tebuconazole, benzazepine, pemidt, ansoprene (phenmedine), ryfentanil, prophenil, tapentadine, tiprex, penethazine, phenformin, phenformide, norpropafenib, phenformide, and/or a, Tramadol or a combination thereof.

Useful triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan, donitaptan, almotriptan, frovatriptan, avitriptan, zolmitriptan and the like. In some embodiments, the triptan drug comprises rizatriptan. In some embodiments, the dosage form may contain about 1-5mg, about 2-6mg, about 3-7mg, about 4-8mg, about 5-10mg, about 6-11mg, about 7-12mg, about 8-13mg, about 9-14mg, about 10-15mg, about 15-20mg, or about 20-30mg of a triptan drug, such as rizatriptan, or any amount within a range defined by any one of these values.

In some embodiments, a dosage form comprising the subject combination may contain about 1-50 mg; about 1-10 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; or about 40-50 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 1-10 mg; about 5-20 mg; about 1-5 mg; about 2-6 mg; about 3-7 mg; about 4-8 mg; about 5-10 mg; about 6-11 mg; about 7-12 mg; about 8-13 mg; about 9-11 mg; about 9-14 mg; about 10-15 mg; about 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 8mg, about 9mg, about 10 mg; about 15 mg; rizatriptan in an amount of about 20mg, about 25mg, about 30mg or any amount defined by or within the range of any of these values.

For acute migraine, the amount of a single dose of meloxicam and/or rizatriptan, or the AUC of meloxicam and/or rizatriptan associated with a single dose, is of particular concern. For example, after a single dose, symptoms may be alleviated over a longer period of time, so that repeated dosing may not be required in a short period of time. For more continuous conditions, including more chronic, continuous or frequent migraine symptoms, daily, weekly or monthly doses may be of particular interest.

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

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

As used herein, the term "unit dosage form" refers to a single entity for administration of a drug. For example, a single tablet or capsule that combines both an acid inhibitor and a non-steroidal anti-inflammatory drug would be a unit dosage form. "Unit dose form/unit dose form)" may also be referred to as a "fixed dose form/fixed dose form") or a "fixed dose combination/fixed dose combination" and may be interchanged. In one embodiment, the unit dosage form is a multilayer tablet.

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 multilayer tablet comprising a single core and one or more layers outside the core.

Some dosage forms may comprise a first layer comprising meloxicam, SBE β CD and bicarbonate; and a second layer comprising a second therapeutically active agent and bicarbonate.

The first layer can comprise meloxicam, for example, in any amount 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 comprise all of the second therapeutically active agent such that any amount within the ranges described above for the second therapeutically active agent may be applied to the second layer.

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

In some embodiments, the second layer contains about 100-, 500-, 200-, 500-, 300-, 500-, 350-, 450-, 380-, 420-, or 400mg of bicarbonate, such as sodium bicarbonate, or any amount of bicarbonate within a range defined by any of these values.

In some embodiments, the pharmaceutical composition can have an effective amount of meloxicam, cyclodextrin, and a carbonate or bicarbonate salt to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition can have an effective amount of meloxicam, sulfobutyl ether- β -cyclodextrin (SBE β CD), and sodium bicarbonate to increase the bioavailability of meloxicam or decrease the T of meloxicam_max。

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.

One embodiment of the present disclosure relates to a pharmaceutical composition in unit dosage form suitable for administration to a patient, the pharmaceutical composition comprising:

(a) esomeprazole, which may or may not be surrounded by an enteric coating;

(b) sodium or potassium bicarbonate and/or sodium or potassium carbonate; and

(c) meloxicam, which may or may not be formulated with cyclodextrins, and which may or may not be surrounded by an enteric coating

One embodiment of the present disclosure is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient for treating a disease, condition, or disorder, such as migraine, comprising:

(1) an inclusion complex of meloxicam and sulfobutyl ether β -cyclodextrin (SBE β CD);

(2) bicarbonates, such as sodium bicarbonate or potassium bicarbonate; and

(3) triptans, such as rizatriptan.

In certain embodiments, the pharmaceutical composition results in a faster release or dissolution of meloxicam from the dosage form as compared to a dosage form containing meloxicam but not containing an acid inhibitor or not containing a buffer.

A dosage form comprising a combination of rizatriptan and meloxicam ("the subject combination") is useful for the treatment of migraine. The subject combinations are useful for acute treatment of migraine. The subject combinations can provide significantly greater and more sustained migraine relief than rizatriptan, meloxicam or placebo. The subject combinations may provide rapid relief from migraine. The subject combination can significantly reduce the use of rescue medication compared to rizatriptan, meloxicam and placebo. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have a history of inadequate response to prior acute treatments. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have allodynia. Migraine patients treated with the combination of rizatriptan and meloxicam described herein can have severe pain intensity. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may be obese. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have morning migraine. The overall average score for the migraine treatment optimized questionnaire (mTOQ-4) for migraine patients treated with the combination of rizatriptan and meloxicam described herein may be less than 7, e.g., 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. Migraine patients treated with the combination of rizatriptan and meloxicam described herein may have allodynia, severe pain intensity, obesity, morning migraine, a total mean score of mTOQ-4 of less than 7, and a history of inadequate response to prior acute treatment. Dosage forms comprising the combination of rizatriptan and meloxicam described herein are safe and well tolerated in migraine sufferers to be treated.

A dosage form comprising the combination of rizatriptan and meloxicam described herein can provide rapid relief of migraine less than 15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, less than 1 hour, 0.5-0.75 hours, or 0.75-1 hour after administration. The combination of rizatriptan and meloxicam described herein can provide migraine relief numerically greater than rizatriptan at times less than 15 minutes, about 5-10 minutes, about 10-15 minutes, about 15-30 minutes, about 30-45 minutes, about 45-60 minutes, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours, about 5-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-24 hours, about 24-48 hours or more after administration. The percentage of migraine patients reporting pain relief treated with the combination of rizatriptan and meloxicam described herein can be 1-100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, or 95-100%.

A migraine sufferer receiving a dosage form comprising a combination of rizatriptan and meloxicam as described herein ("the subject combination") can achieve analgesia less than 2 hours, about 2-3 hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about 20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40 hours, about 40-44 hours, about 44-48 hours or more after administration.

The percentage of migraine sufferers who achieve analgesia after receiving a dose of the combination of rizatriptan and meloxicam described herein increases over time. For example, the percentage of migraine sufferers who achieve analgesia at 2 hours post-administration may be about 15-25%, about 15-20%, about 20-25%. The percentage of migraine sufferers who achieve analgesia at 4 hours post-administration may be about 30-50%, about 30-40%, about 40-45%, about 45-47%, about 47-50%. The percentage of migraine sufferers who achieve analgesia at 12 hours post-administration may be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 56-57%, about 60-65%, about 65-70%. The percentage of migraine sufferers who achieve analgesia at 16 hours post-administration may be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 58-59%, about 60-65%, about 65-70%. The combination of rizatriptan and meloxicam described herein can provide significant improvements over rizatriptan in the analgesia of migraine sufferers. A migraine sufferer receiving a combination of rizatriptan and meloxicam as described herein may achieve analgesia in about 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8%, 8-9%, or 9-10% more migraine sufferers receiving rizatriptan 2-16 hours post-administration, with an improvement of about 10-25%, 10-15%, 14-15%, 15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25%. For example, at 4 hours post-administration, if about 40% of migraine sufferers receiving the subject combination achieve analgesia, and 33% of migraine sufferers receiving rizatriptan achieve analgesia, the improvement in the subject combination is about 21% [ ((40-33)/33) x 100% ]. The improvement in meloxicam by the subject combination may be greater than rizatriptan in migraine sufferers who achieve analgesia. For example, the improvement in achieving analgesia in a migraine sufferer compared to meloxicam at 2-16 hours post-administration of the subject combination may be about 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75% or 70-75%.

There may be at least 50%, at least 60%, at least 70%, at least 80%, about 70-80%, about 80-90%, about 90-95%, about 80% of migraine patients who receive the combination of rizatriptan and meloxicam described herein ("the subject combination"), who achieve pain free at 2 hours, may be maintained until 24 hours post-administration. The increase (or improvement) in the number of migraine sufferers who achieve sustained analgesia 2-24 hours after administration of the subject combination may be about 35-55%, about 35-40%, about 40-45%, about 45-50%, or about 50-55% compared to administration of rizatriptan. The increase (or improvement) in the number of migraine sufferers achieving sustained analgesia from 2-24 hours post administration of the subject combination compared to administration of meloxicam can be about 100-.

The increase in the number of migraine sufferers (or improvement) who achieve sustained pain relief 2-24 hours after administration of the subject combination may be about 15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-22% or about 21% compared to administration of rizatriptan. The increase in the number of migraine sufferers (or improvement thereof) achieving sustained pain relief 2-24 hours after administration of the subject combination may be about 20-35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-30% or about 27% compared to administration of meloxicam.

There may be at least 50%, at least 60%, at least 70%, at least 80%, about 70-80%, about 80-90%, about 90-95%, or about 77% of migraine sufferers who receive the combination of rizatriptan and meloxicam described herein ("the subject combination") who achieve pain free at 2 hours may remain within 48 hours after administration. The increase (or improvement) in the number of migraine sufferers who achieve sustained analgesia 2-48 hours after administration of the subject combination may be about 60-90%, about 60-70%, about 70-75%, about 75-80%, about 80-90%, or about 75% compared to administration of rizatriptan. The increase (or improvement) in the number of migraine sufferers who achieve sustained analgesia 2-48 hours after administration of the subject combination compared to administration of meloxicam may be about 70-110%, about 70-80%, about 80-90%, about 90-100%, about 100-110%, or about 90%.

The increase (or improvement) in the number of migraine sufferers achieving sustained pain relief 2-48 hours post-administration of the subject combination can be about 20-35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-20%, or about 27% compared to administration of rizatriptan. The increase (or improvement) in the number of migraine sufferers who achieve sustained pain relief 2-48 hours after administration of the subject combination compared to administration of meloxicam may be about 15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%, about 24-25%, or about 23%.

There may be at least 50%, at least 60%, at least 70%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or about 77% of migraine sufferers who receive the combination of rizatriptan and meloxicam described herein ("the subject combination") may not require rescue medication. The reduction in the number of migraine sufferers taking rescue medication within 24 hours after administration of the subject combination may be about 35-60%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 47-48%, or about 47% compared to administration of a placebo. The reduction in the number of migraine sufferers taking rescue medication within 24 hours after administration of the subject combination may be about 25-45%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about 34-36%, or about 35% as compared to administration of meloxicam. The reduction in the number of migraine sufferers taking rescue medication within 24 hours after administration of the subject combination may be about 25-40%, about 25-30%, about 30-35%, about 35-40%, about 33-35%, or about 34% as compared to administration of rizatriptan.

The following embodiments are envisaged:

embodiment 1. inclusion complex of meloxicam in cyclodextrin.

Embodiment 2. a dosage form comprising: 1) the clathrate 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 sulfobutylether β -cyclodextrin (SBE β CD) or hydroxypropyl β -cyclodextrin (HP β CD).

Embodiment 5 the dosage form of embodiment 4, wherein the cyclodextrin is SBE β CD.

Embodiment 6 the dosage form of embodiment 5, wherein SBE β CD has about 6 to about 7 sulfobutyl ether groups per β -cyclodextrin molecule.

Embodiment 7 the dosage form of embodiment 6, wherein the molar ratio of meloxicam to SBE β CD is about 0.8 to about 1.2.

Embodiment 8 the dosage form of embodiment 6, wherein the molar ratio of meloxicam to SBE β CD is about 1.

Embodiment 9 the dosage form of

embodiment

2,3, 4, 5,6, 7 or 8 comprising bicarbonate.

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

Embodiment 11 the dosage form of

embodiments

2,3, 4, 5,6, 7, 8, 9 or 10 which is an oral dosage form.

Embodiment 12 the dosage form of

embodiments

2,3, 4, 5,6, 9, 10, or 11, wherein from about 50mg to about 200mg of SBE β CD is present in the dosage form.

Embodiment 13 the dosage form of

embodiments

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

Embodiment 14,

embodiment

2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, or 13, wherein the T of meloxicam_maxReduced compared to a dosage form without the carbonate, bicarbonate, or cyclodextrin.

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

Embodiment 16 the dosage form of

embodiments

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

Embodiment 17 the dosage form of

embodiments

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

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

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

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

Embodiment 21 a method of orally administering meloxicam comprising orally administering to a patient in need of treatment a dosage form of

embodiment

2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

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

embodiments

2,3, 4, 5,6, 7, 8, 9, 10, 12, 13, 14, or 15 to a patient in need of treatment.

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

Embodiment 27. a dosage form comprising: 1) inclusion compounds of meloxicam in cyclodextrins, 2) bicarbonate, and 3) triptans.

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

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

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

Embodiment 31 the dosage form of embodiment 30, wherein SBE β CD has about 6 to about 7 sulfobutyl ether groups per β -cyclodextrin molecule.

Embodiment 32 the dosage form of embodiment 30, wherein the molar ratio of meloxicam to SBE β CD is about 0.8 to about 1.2.

Embodiment 33 the dosage form of embodiment 32, wherein the molar ratio of meloxicam to SBE β CD is about 1.

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

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

Embodiment 36 the dosage form of

embodiments

27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the bicarbonate is present in an amount from about 400mg to about 1000 mg.

A method of treating migraine comprising administering to a human suffering from migraine a dosage form comprising meloxicam, at least 400mg of bicarbonate, and rizatriptan; wherein the T of rizatriptan in the dosage form_maxShorter than T in a reference dosage form comprising a) the same amount of rizatriptan, 2) no meloxicam and c) no bicarbonate_max。

Embodiment 38 a method of treating migraine, comprising administering to a human suffering from migraine or an acute attack of migraine aura meloxicam and rizatriptan in a free base form in an amount of about 8mg to about 13mg by weight, wherein meloxicam and rizatriptan are administered within about 30 minutes of each other, wherein administration of meloxicam to the human results in the T of meloxicam_maxIs 110 minutes or less and AUC of meloxicam_0-24From about 30 mg-hr/mL to about 50 mg-hr/mL.

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

Embodiment 40 a method of treating migraine, the method comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether β -cyclodextrin (SBE β CD)), 2) bicarbonate and 3) rizatriptan.

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

Embodiment 42 the method of embodiment 40 or 41, wherein the human migraine patient is free of migraine headache 2 hours after oral administration of the dosage form to the human migraine patient.

Embodiment 43 the method of embodiment 40, 41 or 42, wherein the migraine sufferer experiences a reduction in nausea as a result of oral administration of the dosage form to the migraine sufferer.

Embodiment 44 the method of embodiment 40, 41, 42 or 43, wherein the human migraine patient does not have nausea 2 hours after oral administration of the dosage form to the human migraine patient.

Embodiment 45 the method of embodiments 40, 41, 42, 43 or 44, wherein said migraine sufferer experiences reduced photophobia as a result of oral administration of said dosage form to said migraine sufferer.

Embodiment 46 the method of embodiment 40, 41, 42, 43, 44 or 45, wherein the human migraine sufferer is not photophobic 2 hours after oral administration of the dosage form to the human migraine sufferer.

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

Embodiment 48 the method of embodiments 40, 41, 42, 43, 44, 45, 46, or 47, wherein the human migraine patient is not phonophobic 2 hours after oral administration of the dosage form to the human migraine patient.

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

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

Embodiment 51 the method of

embodiment

40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50, wherein the dosage form contains from about 50mg to about 200mg of SBE β CD.

Embodiment 52 the method of

embodiments

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51, wherein the dosage form is meloxicam T in humans_maxA solid oral dosage form that is shorter than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain SBE beta CD, and 3) does not contain bicarbonate.

Embodiment 53 the method of

embodiments

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

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

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

Embodiment 56 the method of

embodiments

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55, wherein the oral dosage form contains from about 10mg to about 30mg of meloxicam.

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

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

Embodiment 59 the method of

embodiments

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, wherein SBE β CD has about 6 to about 7 sulfobutyl ether groups per β -cyclodextrin molecule.

Embodiment 60 the method of

embodiments

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the oral dosage form contains from about 50mg to about 150mg of SBE β CD.

Embodiment 61 the method of embodiment 60, wherein the oral dosage form contains about 100mg SBE β CD.

Embodiment 62 the method of

embodiments

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

Embodiment 63 the method of embodiment 62, wherein the molar ratio of SBE β CD to meloxicam is about 0.8 to about 1.2.

Embodiment 64 the method of embodiment 62, wherein the molar ratio of SBE β CD to meloxicam is about 1.

Embodiment 65,

embodiment

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

Embodiment 66 the method of

embodiments

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

Embodiment 67 the method of embodiment 66, wherein the oral dosage form comprises SBE β CD at a weight ratio to rizatriptan of about 10.

Embodiment 68 the method of

embodiments

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

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

Embodiment 70 the method of

embodiments

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 or 69, wherein the method is as described hereinOral dosage forms have shown a median meloxicam value T in fasted human subjects_maxLess than about 90 minutes.

Embodiment 71. the method of embodiment 70, wherein the oral dosage form has shown a median T of meloxicam in fasted human subjects_maxLess than about 2 hours.

Embodiment 72 the method of

embodiments

52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71, wherein the oral dosage form has been shown to achieve a therapeutic plasma concentration in a human more quickly than a reference dosage form.

Embodiment 73 a method of treating migraine, comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein a human migraine patient experiences migraine relief as a result of oral administration of the dosage form to the migraine patient.

Embodiment 74. a method of treating migraine, comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in a complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein a human migraine patient is free of migraine headache pain after 2 hours of oral administration of the dosage form to the human migraine patient.

Embodiment 75. a method of treating migraine, comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein a migraine patient experiences a reduction in nausea as a result of oral administration of the dosage form to the migraine patient.

Embodiment 76 a method of treating migraine, the method comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein the human migraine sufferer is free of nausea 2 hours after oral administration of the dosage form to the human migraine sufferer.

Embodiment 77 a method of treating migraine, the method comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein a migraine patient experiences photophobia relief as a result of oral administration of the dosage form to the migraine patient.

Embodiment 78 a method of treating migraine, the method comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in a complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein a human migraine patient is not photophobic after 2 hours of oral administration of the dosage form to the human migraine patient.

Embodiment 79. a method of treating migraine, comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein a migraine patient experiences a reduction in daunting sounds as a result of oral administration of the dosage form to the migraine patient.

Embodiment 80. a method of treating migraine, comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) meloxicam (optionally in complex with sulfobutyl ether beta-cyclodextrin (SBE β CD)), 2) a bicarbonate salt, and 3) rizatriptan, wherein 2 hours after oral administration of the dosage form to a human migraine patient, said human migraine patient is not daunting.

Example 1

Different amounts of potassium carbonate (K) were tested₂CO₃) And sodium bicarbonate (NaHCO)₃) Influence on the pH of acidic media. The acidic medium is selected to simulate gastric conditions. Will K₂CO₃Or NaHCO₃To 50mL of 0.01N HCl solution (pH 2) was added. At the addition of K₂CO₃Or NaHCO₃The pH of the solution was then measured. Deionized water (240mL) was then added to the mixture and the pH was measured again. The results are shown in tables 1 to 4.

₂ ₃TABLE 1 treatment with KCO (0.01N) HCl) results

K₂CO₃(mg)	pH
		25	2.84
35	6.29
		45	8.05
50	8.29
		100	9.43
200	10.14
		300	10.39
400	10.55
		450	10.58

₂ ₃TABLE 2 use of KCO (0.01N) HCl + water) results

K₂CO₃(mg)	pH
		200	10.27
300	10.46
		400	10.57
450	10.63

₃TABLE 3 NaHCO (0.01N) HCl) results

NaHCO₃(mg)	pH
		200	5.28
300	5.90
		400	6.44
450	6.86
		500	8.23
750	8.30
		1000	8.36

₃TABLE 4 NaHCO (0.01N) HCl + water) results

NaHCO₃(mg)	pH
		200	5.41
300	5.89
		400	6.11
450	6.46
		500	8.33
750	8.54
		1000	8.60

Example 2

Manufacture of a pharmaceutical composition comprising meloxicam and sulfobutyl ether-beta-cyclodextrin (SBE beta CD) (a cyclodextrin having from about 6 to about 7 sulfobutyl ether groups per beta-cyclodextrin molecule), K₂CO₃Or NaHCO₃Tablets of the combination of (a) and tested for dissolution. Purchasing tablets containing meloxicam alone

And tested for dissolution. The tablets tested are listed in table 5. Meloxicam in the form of a meloxicam/SBE β CD clathrate is used in a tablet containing meloxicam and SBE β CD. The inclusion complex is formed by mixing meloxicam and SBE β CD in a pH-adjusted aqueous solution. The pH of the solution was adjusted using a buffer. The resulting soluble meloxicam/SBE β CD clathrate was then spray dried. This spray-dried dispersion was used to make SBE β CD containing tablets.

TABLE 5 tablets

Dissolution testing was performed in acidic media (selected to simulate gastric conditions) by placing the tablets in 0.01N HCl solution at a stirring rate of 75RPM and a vessel temperature of about 37 ℃. The results are presented in table 6 and fig. 1-10. The results at the various time points (0, 15, 30, 45, 60, 90 and 120 minutes) are expressed as the percentage (%) of meloxicam dissolved out.

TABLE 6 dissolution results

0mins

15mins

30mins

45mins

60mins

90mins

120mins

Tablet A

0％

23％

17％

15％

13％

12％

11％

Tablet B

0％

27％

20％

17％

16％

17％

15％

Tablet C

0％

31％

26％

25％

24％

23％

21％

Tablet D

0％

30％

26％

25％

24％

23％

22％

Tablet E

0％

50％

66％

77％

84％

92％

95％

Tablet F

0％

26％

17％

14％

12％

11％

10％

Tablet G

0％

48％

39％

26％

20％

16％

14％

Tablet H

0％

44％

30％

22％

17％

16％

13％

Tablet I

0％

32％

33％

27％

21％

16％

15％

Tablet J

0％

26％

27％

19％

15％

12％

11％

Tablet K

0％

85％

86％

Tablet L

0％

2％

Contains meloxicam and SBE beta CD, K, in comparison to a tablet containing meloxicam alone₂CO₃Or NaHCO₃The dissolution rate of meloxicam in the tablets of the various combinations is higher. For example, after 120 minutes, NaHCO is contained₃The dissolution rate of the meloxicam tablet is 95%, while the dissolution rate of the tablet containing meloxicam alone is 2%.

Dissolution of meloxicam in the absence of SBE beta CD with K₂CO₃The amount increases. However, in the presence of SBE beta CD, K is increased₂CO₃The amount does not appear to increase the dissolution of meloxicam. The dissolution of meloxicam in the presence of SBE β CD was reduced by about 50% compared to the dissolution of meloxicam at 120 minutes in the absence of SBE β CD at the highest dose of potassium carbonate tested.

With NaHCO₃The dissolution rate of the meloxicam is obviously higher than the highest dosage K₂CO₃Dissolution observed at 15 minutes (50% to 30%) and 120 minutes (92% to 23%). With NaHCO in the presence of SBE beta CD₃The dissolution rate and the highest dose K of the meloxicam₂CO₃There was also a significant increase in 15 minutes (85% vs. 26%) compared to 120 minutes (86% vs. 12%). NaHCO in the Presence of SBE beta CD in comparison with Potassium carbonate₃The dissolution of meloxicam increased even more at 15 minutes, which resulted in a decrease in dissolution.

Example 3

A bilayer tablet (SBE β CD-meloxicam/bicarbonate) was prepared comprising 1) a clathrate of SBE β CD with meloxicam prepared as described below, and 2) sodium bicarbonate. The first layer contained a clathrate of 15mg meloxicam and 100mg SBE β CD with 100mg sodium bicarbonate. The second layer contained 40mg esomeprazole and 400mg sodium bicarbonate.

A total of 20 human subjects were randomly assigned at a ratio of 1:1 to SBE β CD-meloxicam/bicarbonate tablets or tablets

Treatment of tablets (15mg meloxicam) was performed once daily under fasting conditions for 6 days.

On the first day of dosing, plasma samples were collected at several time points for concentration analysis of meloxicam. The concentration of meloxicam was determined using LC-MS/MS. Pharmacokinetic parameters were calculated. The results are shown in FIG. 11.

Median value of meloxicam T for SBE beta CD-meloxicam/bicarbonate tablets_maxI.e. the ratio of the primary end-points of the test

9 times faster (0.5 hours and 4.5 hours, respectively, p)<0.0001)。

SBE beta CD-meloxicam/bicarbonate tablets also exhibit compatibility with

In contrast, higher mean maximum plasma concentration (C)_max) (p-0.0018), faster time to therapeutic plasma concentrations (p<0.0001) and faster time to half-maximal plasma concentration (p)<0.0001)。

Meloxicam in the form of a meloxicam/SBE β CD clathrate is used in a tablet containing meloxicam and SBE β CD. The inclusion complex is formed by mixing meloxicam and SBE β CD in a pH-adjusted aqueous solution. The pH of the solution was adjusted using a buffer. The resulting soluble meloxicam/SBE β CD clathrate was then spray dried. This spray-dried dispersion was used to make SBE β CD containing tablets.

Example 4

Preparing a clathrate comprising 1) SBE β CD and meloxicam; 2) rizatriptan; and 3) a single layer tablet of sodium bicarbonate (SBE β CD-meloxicam/rizatriptan/bicarbonate). The mono-layer tablet contains 20mg meloxicam, 10mg rizatriptan and 500mg sodium bicarbonate. The clathrate is the same as that of example 3.

Dissolution testing of the tablets was performed by placing the tablets in 0.01N HCl solution in acidic medium (selected to simulate gastric conditions) at a stirring rate of 75RPM and a vessel temperature of about 37 ℃. The results are listed in table 7. The results at different time points (0, 15, 30, 45, 60, 90 and 120 minutes) are expressed as a percentage (%) of meloxicam and a percentage (%) of rizatriptan dissolved out.

TABLE 7 dissolution results

Time points (minutes)

0min

15min

30min

45min

60min

90min

120min

Rizatriptan

0％

89％

102％

103％

Meloxicam

0％

79％

92％

93％

94％

As shown in table 7, the dissolution results for the tablets in example 4 are very similar to those in example 3. Thus, we expect the pharmacokinetic properties of the tablet of example 4, including the bioavailability, T, of meloxicam_maxEtc. are similar to those described in example 3 and fig. 11. This expectation has proven to be correct, as shown in the examples below.

Example 5

The monolayer tablet of example 4 was administered to 6 human subjects. On the first day of dosing, plasma samples were collected at several time points for concentration analysis of rizatriptan. The concentrations of rizatriptan and meloxicam were determined using LC-MS/MS. Pharmacokinetic parameters were calculated. The results for meloxicam are comparable to those reported for the bilayer dosage form of example 3. Median value T of rizatriptan_max0.75 hours, and the average C of rizatriptan_maxIt was 20.710 ng/mL. In contrast, commercial rizatriptan dosage forms

Report T of_maxIs 1.0-1.5 hours.

Example 6

And 2) and

(10mg rizatriptan) in a randomized, single dose, parallel group of phase 1 clinical studies to evaluate a group of 1) meloxicam (20mg), rizatriptan (10mg), SBE β CD and sodium bicarbonate (meloxicam/rizatriptan) in comparison to healthy human volunteers following oral administration under fasting conditionsPK compliance, safety and tolerability. A total of 20 healthy adult male or female volunteers received randomly a single dose of meloxicam/rizatriptan or

(10mg rizatriptan).

Blood samples for PK analysis were collected at various time points before and after dosing. The pre-specified primary endpoint is T_theraI.e., the time to reach a therapeutic plasma concentration of meloxicam, is defined as the C of meloxicam after administration of the highest approved dose (15mg) of standard meloxicam_avgAnd is about 1000 ng/mL. The PK results of the rizatriptan component of meloxicam/rizatriptan were compared with

PK results for (rizatriptan) were compared.

The PK results for the meloxicam (20mg) component of meloxicam/rizatriptan from this test were compared to the results from example 3

PK results for (15mg meloxicam) were compared.

Stage 1 results

After oral administration of meloxicam/rizatriptan (20mg meloxicam/10 mg rizatriptan), meloxicam is rapidly absorbed, reaching the median time to therapeutic plasma concentrations (T)_thera) I.e., the primary endpoint (fig. 12 and table 8) was 17 minutes. Median value T _max1 hour, 15mg of standard meloxicam

It was 4.5 hours. Very short T_maxShows that the meloxicam/rizatriptan has the potential of quick effect in treating migraine. Mean plasma elimination half-life (Thalf-life) of meloxicam after administration of meloxicam/rizatriptan_1/2) 18.2 hours versus 21.5 hours for standard meloxicam. Longer elimination half-life indicates enhanced and sustained efficacy of meloxicam/rizatriptan and reduced biasPotential for headache recurrence.

TABLE 8 Meloxicam pharmacokinetic parameters of Meloxicam/Rizatriptan

^aT_maxAnd T_theraValues are expressed as median or range.

After oral administration of meloxicam/rizatriptan, rizatriptan is rapidly absorbed, T_max0.64 h (38min), and the same dose of standard rizatriptan

It was 0.88 hr (FIG. 13 and Table 9). Use of C after administration of meloxicam/rizatriptan compared to standard rizatriptan_maxAnd AUC measured systemic exposure to rizatriptan was also higher numerically.

TABLE 9 Rizatriptan pharmacokinetic parameters for meloxicam/Rizatriptan and Standard Rizatriptan

^aT_maxThe values are expressed as median numbers or ranges.

Meloxicam/rizatriptan tolerates well with no relevant differences in safety between the two treatment groups. There were no serious adverse events in the study.

Example 7

A phase 3, randomized, double-blind, multicenter, active and placebo-controlled trial was performed to evaluate the efficacy and safety of acute treatment of moderate and severe migraine in patients with a history of inadequate previous acute migraine treatment. Eligible patients were randomized to treatment with meloxicam/rizatriptan (20mg meloxicam with SBE β CD and sodium bicarbonate/10 mg rizatriptan as described in example 4 above), rizatriptan (10mg) (rizatriptan group), meloxicam with SBE β CD and sodium bicarbonate (20mg) (meloxicam group) or placebo at a ratio of 2:2:2: 1. The common primary endpoints of meloxicam/rizatriptan at 2 hours post-administration compared to placebo were no headache and no most disturbing migraine-related symptoms (nausea, photophobia or phonophobia).

The superiority of meloxicam/rizatriptan over the rizatriptan and meloxicam groups (component contribution) will be determined based on the duration of absence of headache (critical secondary endpoint) from 2 to 24 hours after administration.

Eligible patients must have a history of inadequate response to prior acute migraine treatment and be evaluated using the migraine treatment optimization questionnaire (mTOQ-4). mTOQ-4 is a validated questionnaire that assesses the response of therapeutic treatment to prior acute treatments based on four aspects (2 hours painless, efficacy of at least 24 hours with one dose, ability to plan daily activities, and interruption of daily activities).

Due to the rapid absorption and unique dual mechanism of action of meloxicam/rizatriptan described herein, it is expected that meloxicam/rizatriptan will show significant improvements over placebo and advantages over both the rizatriptan and meloxicam groups.

Example 8

A female migraine sufferer looks at her physician and wishes to relieve her migraine. Her doctor gives her 10mg rizatriptan

She took the drug during the next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia and phonophobia, but does not provide complete relief from these symptoms. At her next visit, her doctor given her 20mg meloxicam tablets, which also contained SBE β CD and 500mg sodium bicarbonate, during her next acute migraine headache. It may provide some relief from pain, nausea, allodynia, photophobia and phonophobia, but does not provide complete relief from these symptoms. At the next visit, her physician gives her the information described in example 4 aboveAnd (4) tablets. She reported about a 10-30% improvement in her pain, nausea, allodynia, photophobia and/or phonophobia at 2 and 24 hours of administration of the tablet compared to that experienced after either meloxicam or rizatriptan alone.

Example 9

A male migraine sufferer looks at his physician and wishes to relieve his migraine. His doctor gave him 10mg rizatriptan

He took during the next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia and phonophobia, but does not provide complete relief from these symptoms. At his next visit, his physician gave him a 20mg meloxicam tablet, which also contained SBE β CD and 500mg sodium bicarbonate, which he took during the next acute migraine headache. It provides some relief from pain, nausea, allodynia, photophobia and phonophobia, but does not provide complete relief from these symptoms. At his next visit, his doctor gave him the tablet described in example 4 above. He reported about a 30-60% improvement in his pain, nausea, allodynia, photophobia and/or phonophobia at 2 and 24 hours of administration of the tablet compared to that experienced after either meloxicam or rizatriptan alone.

Example 10

She took the drug during the next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia and phonophobia, but does not provide complete relief from these symptoms. At her next visit, her doctor given her 20mg meloxicam tablets, which also contained SBE β CD and 500mg sodium bicarbonate, during her next acute migraine headache. It provides some relief from pain, nausea, allodynia, photophobia and phonophobia, but does not provide complete reliefAnd (4) forming. At the next visit, her doctor gave her tablets described in example 4 above. She reported about 60-100% improvement in her pain, nausea, allodynia, photophobia and/or phonophobia at 2 and 24 hours after taking the tablet compared to that experienced after either meloxicam or rizatriptan alone.

Example 11

More than 3700 million americans suffer from migraine according to the data of the centers for disease control, and it is the leading cause of disability in american neurological disorders according to the data of the american migraine foundation. Migraine is characterized by recurrent attacks of pulsatility, often severe and disabling nausea-associated head pain, and sensitivity to light and/or sound. Migraine headache is estimated to cause losses of up to 780 billion dollars per year in the united states, both direct (e.g., medical visits, medications) and indirect (e.g., miswork, decreased productivity) [ Gooch CL, Pracht E, Borenstein AR, neurological disease burden in the united states: summary report and call to action, Ann neurol.2017 month 4; 81(4): 479-484]. Published investigations of migraine patients indicate that more than 70% are not fully satisfactory for their current treatment, nearly 80% will try new therapies, and they wish to treat more quickly, consistently, and result in fewer symptom relapses [ (1) Smelt AF, Louter MA, Kies DA, Blom JW, terrwindow GM, van der Heijden GJ, De Gucht V, Ferrari MD, assendedelft WJ, at do patients contract to be the same as the most important drugs for efficacy reasons on migraines projects tables of a Delphi study. plos. 2014jun 16; 9(6): e98933, 6; and (2) Lipton RB, Stewart WF, Acute migraine therapy: do doctors underpant places with particulate matter from thermal Headrache.1999; 39(suppl 2): S20-S26 ].

The world health organization classifies severe migraine attacks as the most disabling disease, comparable to dementia, quadriplegia, and active mental disorder [ (1) Menken et al, Arch neuron.2000; 57: 418-420; and (2) Shapiro and goadsby. cephalolgia.2007; 27: 991-4]. Debilitating pain, and a persistent fear of the next migraine attack, impairing family life, social life, and employment [ Global Burden of Disease study.lancet.2017; 390: 1211-1259]. Depression and anxiety in people with migraine are twice those in healthy individuals [ Antonaci et al, J Headache pain.2011; 12: 115-125]. Widespread misconception of migraine severity has prompted understandings and under-treatments [ Global Burden of Disease study.lancet.2017; 390: 1211-1259]. Most patients are not completely satisfied with their current treatments. Therefore, new therapies that provide improved therapeutic effects on this severe neurological disease are urgently needed.

A phase 3, randomized, double-blind, multicenter, placebo and active drug-controlled trial was performed to evaluate the efficacy and safety of meloxicam and rizatriptan (meloxicam/rizatriptan) combinations in the acute treatment of moderate and severe migraine. Eligible patients must be between 18 and 65 years of age, have a definitive diagnosis of migraine with or without aura as defined by the ICHD-3 standard (at least 1 year), average 2 to 8 moderate to severe migraines per month, have a history of inadequate response to previous acute migraine treatments, and be assessed 7 points (mean score 3.6) using the migraine treatment optimization questionnaire (mTOQ-4), corresponding to poor response to previous acute treatments. Exclusion criteria included cluster headache or other types of migraine, chronic daily headache (more than 15 non-migraine days per month), history of severe cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, the enrolled patients also exhibited a high rate of characteristics closely associated with poor treatment outcome, including cutaneous allodynia (75.4%), severe migraine intensity (41.2%), obesity (43.7%) and morning migraine (36.6%). A total of 1,594 patients were randomly assigned to the monolayer tablet of example 4 (20mg meloxicam/10 mg rizatriptan with SBE β CD and sodium bicarbonate), rizatriptan (10mg), meloxicam with SBE β CD (20mg) (MoSEIC meloxicam) or placebo at a ratio of 2:1 to treat single attacks of moderate or severe migraine. The two common primary endpoints of this trial were the proportion of patients who had no headache 2 hours after dosing and who no longer had the most disturbing symptoms associated with migraine (nausea, photophobia or phonophobia) 2 hours after dosing for meloxicam/rizatriptan compared to placebo. The superiority of meloxicam/rizatriptan over the rizatriptan and meloxicam groups (component contribution) was determined based on the duration of absence of headache (critical secondary endpoint) from 2 to 24 hours after administration. The study was conducted according to FDA special protocol evaluation (SPA). Rizatriptan is one of the activity comparators in the trial and is considered to be the fastest acting oral triptan drug and one of the most effective drugs currently available for acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (Serotonin 5-HT (1B/1D) agonsts) in acid migraine stream of a meta-analysis of 53 trials. Lancet.2001 Nov 17; 358 (9294): 1668-75.)

Meloxicam/rizatriptan provides rapid relief from migraine headaches, with the percentage of patients achieving pain relief using meloxicam/rizatriptan being numerically higher than with rizatriptan at each time point measured from 15 minutes on, and statistically significant at 60 minutes (p 0.04) (fig. 14). The proportion of patients with pain relief at 1.5 hours post-administration was 60.5% for meloxicam/rizatriptan, 52.5% for rizatriptan and 48.3% for placebo (equivalent to meloxicam/rizatriptan, p 0.019, p 0.04, respectively) (fig. 14).

Meloxicam/rizatriptan achieved analgesia by demonstrating a higher percentage of patients compared to placebo 2 hours post-dose with high statistical significance (19.9% versus 6.7%, p <0.001, fig. 15), and no most annoying symptoms (36.9% versus 24.4%, p ═ 0.002) met both regulatory common primary endpoints.

Meloxicam/rizatriptan versus rizatriptan (activity comparator and MoSEIC)^TMThe superiority of meloxicam (component contribution) is determined according to the regulations in SPA, by the percentage of sustained analgesia achieved with rizatriptan, MoSEIC by patients receiving meloxicam/rizatriptan within 2 hours to 24 hours after administration^TMHigher meloxicam compared to placebo (16.1%, 11.2%, 6.8% and 5.3%, respectively; p 0.038, p 0.001 and p <0.001, respectively, relative to meloxicam/rizatriptan, fig. 16A), previously indicatedKey secondary endpoints were determined to demonstrate component contribution. About 80% of patients receiving meloxicam/rizatriptan treatment achieved analgesia within 2 hours and remained painless within 24 hours. These results indicate that meloxicam/rizatriptan significantly improved pain relief in treating migraine and outperformed rizatriptan.

Meloxicam/rizatriptan provides substantially greater and longer lasting migraine relief compared to placebo and rizatriptan, which means that there is a significant reduction in the rescue medication use of meloxicam/rizatriptan compared to placebo and rizatriptan. The percentage of patients who experienced sustained pain relief within 2 to 24 hours post-dose was 53.3% for meloxicam/rizatriptan, 33.5% for placebo, and 43.9% for rizatriptan (p <0.001, p ═ 0.006 relative to meloxicam/rizatriptan, respectively) (fig. 16B).

A statistically significantly greater proportion of meloxicam/rizatriptan patients (46.5%) also experienced sustained pain relief from 2 to 48 hours compared to placebo (31.1%) and rizatriptan (36.5%) patients (p <0.001, p ═ 0.003, relative to meloxicam/rizatriptan, respectively) (fig. 17B). A statistically significantly greater proportion of meloxicam/rizatriptan patients (15.4%) also experienced sustained analgesia of 2 to 48 hours compared to placebo (5.3%), rizatriptan (8.8%) and MoSEICTM meloxicam (8.1) patients (p <0.001, p ═ 0.003, p ═ 0.001, relative to meloxicam/rizatriptan, respectively) (fig. 17A). About 77% of patients receiving meloxicam/rizatriptan treatment achieve analgesia at 2 hours and remain indolent for 48 hours.

23.0% of patients receiving meloxicam/rizatriptan were on rescue medication, 43.5% of patients receiving placebo, and 34.7% of patients receiving rizatriptan (p <0.001 per group compared to meloxicam/rizatriptan) (fig. 18). About 77% of patients receiving meloxicam/rizatriptan do not require rescue medication. These results demonstrate that meloxicam/rizatriptan is superior to rizatriptan (an activity comparator) in treating migraine.

Meloxicam/rizatriptan is statistically significantly better than rizatriptan at several other secondary endpoints, including patient global impression change (PGI-C) (p ═ 0.022), and restoration of normal function at 24 hours (p ═ 0.027).

Some p-values for meloxicam/rizatriptan versus rizatriptan for various endpoints are listed in table 10 below, demonstrating that meloxicam/rizatriptan is statistically significantly superior to rizatriptan in treating migraine.

TABLE 10P values of meloxicam/rizatriptan relative to rizatriptan for different endpoints

Given that the active comparator rizatriptan in this trial is considered one of the fastest acting oral triptans and the most potent drugs currently available for acute migraine treatment, and that this trial recruits refractory migraine sufferers, the observed therapeutic effects of meloxicam/rizatriptan provide better and more sustained migraine relief than rizatriptan, is very significant. Many patients respond poorly to current acute migraine treatments, exposing them to the disabilities associated with headache and an increased risk of progressing to chronic migraine, factors associated with increased medical costs. The results of this study indicate that meloxicam/rizatriptan may provide an important treatment option for intractable migraine sufferers.

Meloxicam/rizatriptan is safe and well tolerated in patients studied in the trial. The most commonly reported adverse events for meloxicam/rizatriptan are nausea, dizziness and somnolence, none of which exceed placebo or exceed 3%. There was a serious adverse event in the meloxicam/rizatriptan group that the investigator considered unrelated to the study drug.

The results of this trial demonstrate the ability of meloxicam/rizatriptan to provide unique benefits to migraine sufferers in a tightly designed trial comprising patients with refractory migraine headaches with rapid, potent and long lasting migraine relief compared to the potent active comparator rizatriptan. These results are potentially of great importance to patient care based on a high rate of inadequate response to current treatments and patient dissatisfaction.

Meloxicam/rizatriptan combines multiple mechanisms of action to address various migraine processes with the goal of providing enhanced effectiveness. Meloxicam/rizatriptan is believed to act by inhibiting CGRP release, reversing CGRP mediated vasodilation, and inhibiting neuroinflammation, pain signaling, and central sensitization. The results of this trial demonstrate that this approach suggests that meloxicam/rizatriptan can provide significant benefits over currently available treatments, even for difficult to treat migraine patients. Meloxicam/rizatriptan is useful for the acute treatment of migraine in adults with or without aura.

Example 12

Meloxicam/rizatriptan was also evaluated in another phase 3 trial, a randomized, double-blind, placebo-controlled study, evaluating the early treatment of migraine with meloxicam/rizatriptan. In contrast to ongoing trials in which patients with a history of unresponsive therapy treated migraine attacks once moderate or severe migraine headache occurred, in another trial patients would be administered meloxicam/rizatriptan at the earliest signs of migraine.

Eligible patients received randomized treatment with meloxicam/rizatriptan (20mg meloxicam/10 mg rizatriptan with SBE β CD and sodium bicarbonate as described in example 4 above) or placebo at a ratio of 1: 1. Adult subjects who have been specifically diagnosed with or without aura migraine. The treatment of meloxicam/rizatriptan begins at the first sign of a migraine attack.

Compared to placebo, for meloxicam/rizatriptan, 2 hours after administration, the primary endpoint of synergy was no headache and no most disturbing migraine-related symptoms (nausea, photophobia or phonophobia).

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., amounts, percentages, etc.) used in the specification and claims are to be understood as being modified in all instances by the term "about" and the exact value indicated. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing embodiments (especially in the context of the following claims) are to be construed to cover 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 otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. For reasons of convenience and/or expedited review, it is contemplated that one or more members of a group may be included in or deleted from a group. When any such inclusion or deletion occurs, the specification is considered to encompass the modified group if used in the appended claims, thereby satisfying the written description of all markush groups.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of those described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

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

Claims

1. A method of treating migraine, the method comprising: selecting a human migraine patient having a history of inadequate response to prior migraine treatment and orally administering a dosage form to the migraine patient, wherein the dosage form comprises the following combination: 1) a complex of meloxicam with sulfobutyl ether beta-cyclodextrin (SBE β CD), 2) a bicarbonate salt, and 3) rizatriptan.

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

3. The method of claim 1 or 2, wherein the human migraine patient is free of migraine headache 2 hours after oral administration of the dosage form to the human migraine patient.

4. The method of claim 1, 2, or 3, wherein the migraine patient experiences a reduction in nausea as a result of oral administration of the dosage form to the migraine patient.

5. The method of claim 1, 2,3, or 4, wherein the human migraine patient is free of nausea 2 hours after oral administration of the dosage form to the human migraine patient.

6. The method of claim 1, 2,3, 4, or 5, wherein the migraine sufferer experiences a reduction in photophobia as a result of oral administration of the dosage form to the migraine sufferer.

7. The method of claim 1, 2,3, 4, 5, or 6, wherein the human migraine patient is not photophobic 2 hours after oral administration of the dosage form to the human migraine patient.

8. The method of claim 1, 2,3, 4, 5,6, or 7, wherein the migraine sufferer experiences a reduction in phonophobia as a result of oral administration of the dosage form to the migraine sufferer.

9. The method of claim 1, 2,3, 4, 5,6, 7, or 8, wherein the human migraine patient is not daunting with sound 2 hours after oral administration of the dosage form to the human migraine patient.

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

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

12. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, or 11, wherein the dosage form contains from about 50mg to about 200mg of SBE β CD.

13. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, 11, or 12, wherein the dosage form is meloxicam in vivo in humans_maxSolids shorter than reference dosage formsAn oral dosage form, the reference dosage form: 1) contains the same amount of meloxicam, 2) does not contain SBE beta CD, and 3) does not contain bicarbonate.

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

15. The method according to claim 14, wherein the rizatriptan is present in salt form in an amount of about 10mg of molar equivalents of rizatriptan in free base form.

16. The method according to claim 14 or 15, wherein the rizatriptan is present as rizatriptan benzoate.

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

18. The method of claim 17, wherein the oral dosage form contains about 20mg of meloxicam.

19. The method of claim 17, wherein the oral dosage form contains about 15mg of meloxicam.

20. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the SBE β CD has from about 6 to about 7 sulfobutyl ether groups per β -cyclodextrin molecule.

21. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the oral dosage form contains from about 50mg to about 150mg of SBE β CD.

22. The method of claim 21, wherein the oral dosage form contains about 100mg SBE β CD.

23. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the molar ratio of SBE β CD to meloxicam is about 0.5 to about 2.

24. The method of claim 23, wherein the molar ratio of SBE β CD to meloxicam is about 0.8 to about 1.2.

25. The method of claim 23, wherein the molar ratio of SBE β CD to meloxicam is about 1.

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

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

28. The method of claim 27, wherein the oral dosage form comprises SBE β CD at a weight ratio to rizatriptan of about 10.

29. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein the bicarbonate comprises sodium bicarbonate.

30. The method of claim 29, wherein the oral dosage form contains 500mg sodium bicarbonate.

31. The method of claim 1, 2,3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, wherein the oral dosage form has exhibited a median Tmax of meloxicam in fasted human subjects_maxLess than about 90 minutes.

32. The method of claim 31, wherein the oral dosage form has shown a median T of meloxicam in fasted human subjects_maxLess than about 2 hours.

33. The method of claim 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, wherein the oral dosage form has been shown to reach a therapeutic plasma concentration in a human more quickly than the reference dosage form.