AU2023202545A1

AU2023202545A1 - Pharmaceutical compositions comprising meloxicam

Info

Publication number: AU2023202545A1
Application number: AU2023202545A
Authority: AU
Inventors: Herriot TABUTEAU
Original assignee: Axsome Therapeutics Inc
Current assignee: Axsome Therapeutics Inc
Priority date: 2019-02-06
Filing date: 2023-04-27
Publication date: 2023-05-18
Also published as: MX2021009435A; EP3920909A4; MA54904A; WO2020163620A1; ECSP21060962A; CO2021010380A2; EP3920909A1; JP2023062144A; JP2022519670A; AU2020218253A1; CA3128940A1; SG11202107926XA; CR20210420A; JP2024026732A; AU2020218253B2; JP7237386B2; IL285389A; CN113423397A; BR112021015467A2; JP7420990B2

Abstract

The present invention relates to the use of an oral medicament for treating acute migraine comprising the steps of selecting a human migraine patient with a history of inadequate response to prior acute migraine treatments and an mTOQ-4 score of 7 or less, and orally administering the medicament to the human migraine patient; wherein the medicament comprises a combination of a meloxicam and a rizatriptan, Said composition may further comprise a bicarbonate (especially sodium carbonate) and sulfobutyl ether beta cyclodextrin (SBEpCD).

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING MELOXICAM

Inventor: Herriot Tabuteau

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Pat. App. Nos. 62/802,198, filed

February 6, 2019; 62/803,756, filed February 11, 2019; 62/835,613, filed April 18, 2019;

62/846,311, filed May 10, 2019; 62/860,705, filed June 12, 2019; 62/895,933, filed September 4,

2019; 62/895,956, filed September 4, 2019; 62/955,905, and filed December 31, 2019; all of

which are incorporated by reference in their entirety.

BACKGROUND

[0002] Meloxicam, which has the structure:

CH,

OH 0 S

N C H

is a nonsteroidal anti-inflammatory (NSAID) drug that exhibits anti-inflammatory, analgesic,

and antipyretic activities. The meloxicam mechanism of action may be related to

prostaglandin synthetase (cyclo-oxygenase, COX) inhibition which is involved in the initial

steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins,

thromboxanes and prostacylin.

SUMMARY

[0003] Meloxicam and some other NSAIDs have poor aqueous solubility which may

reduce bioavailability and slow the onset of pain relief resulting from their use. One means

of increasing the solubility and bioavailability of meloxicam is through the use of

cyclodextrins. Cyclodextrin (also known as cycloamyloses) are generally cyclic

polysaccharides which form a bucket-like shape. Cyclodextrins help to increase bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the inside which helps to facilitate the transport of molecules. The naturally occurring cyclodextrins include six, seven, and eight glucose units (a, P, and y-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or less glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (i.e., an inclusion complex) with drugs by incorporating the drug into the center/hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around a drug in a micelle-type structure. This ability of cyclodextrins may allow them to act as carriers to increase the bioavailability of less soluble drugs.

[0004] Some embodiments include a method of treating migraine comprising: selecting a

human migraine patient with a history of inadequate response to prior migraine treatments,

and orally administering a dosage form to the migraine patient, wherein the dosage form

comprises a combination of: 1) a complex of meloxicam with a sulfobutyl ether S-cyclodextrin

(SBESCD), 2) a bicarbonate, and 3) a rizatriptan.

[0005] Some embodiments include an inclusion complex of meloxicam in a cyclodextrin.

[0006] Some embodiments include a dosage form comprising: 1) an inclusion complex of

meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or a bicarbonate.

[0007] Some embodiments include a method of administering meloxicam orally,

comprising orally administering a dosage form described herein to a patient in need of

treatment.

[0008] Some embodiments include a method of administering meloxicam intravenously,

comprising intravenously administering a dosage form described herein to a patient in need

of treatment.

[0009] Disclosed herein are formulations for an inclusion complex of cyclodextrin and

meloxicam with bicarbonate and methods of use thereof.

[0010] Disclosed herein are formulations and methods for delivering meloxicam with

cyclodextrin to a subject by oral, enteral, intravenous, intramuscular, subcutaneous,

intranasal, or other parenteral means.

[0011] Disclosed also are methods for treating pain and pain associated with conditions

by delivering a dosage form with meloxicam, cyclodextrin, and bicarbonate by oral, enteral,

intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means to a subject.

[0012] A combination of rizatriptan and meloxicam (referred to herein for convenience

as a "subject combination") may be used to treat a variety of pain conditions.

Rizatriptan has the structure as shown below. H

N_ NN

Rizatriptan

[0013] Some embodiments include a subject combination comprising: 1) an inclusion

complex of meloxicam and a cyclodextrin, 2) rizatriptan, and 3) a bicarbonate for treating

migraine in a human being. The migraine may be treatment-resistant migraine. The human

being may have a history of inadequate response to prior treatments.

[0014] Some embodiments include a subject combination comprising rizatriptan and

meloxicam that has rapid, sustained, substantial and statistically significant efficacy as

compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients

with a history of inadequate response to prior acute treatments.

[0015] Some embodiments include a subject combination comprising rizatriptan and

meloxicam that requires significantly less use of rescue medication as compared to

rizatriptan, meloxicam, or placebo.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a depiction of the results described in Example 2 and contained in Table

6.

[0017] Figure 2 is another depiction of the results described in Example 2 and contained

in Table 6.

[0018] Figure 3 is another depiction of the results described in Example 2 and contained

in Table 6.

[0019] Figure 4 is another depiction of the results described in Example 2 and contained

in Table 6.

[0020] Figure 5 is another depiction of the results described in Example 2 and contained

in Table 6.

[0021] Figure 6 is another depiction of the results described in Example 2 and contained

in Table 6.

[0022] Figure 7 is another depiction of the results described in Example 2 and contained

in Table 6.

[0023] Figure 8 is another depiction of the results described in Example 2 and contained

in Table 6.

[0024] Figure 9 is another depiction of the results described in Example 2 and contained

in Table 6.

[0025] Figure 10 is another depiction of the results described in Example 2 and contained

in Table 6.

[0026] FIG. 11 is a plot of meloxicam plasma concentration at various time points over

the first 24 hours for an embodiment of a dosage form described herein and a commercially

available meloxicam dosage form.

[0027] FIG. 12 is a plot of meloxicam plasma concentration at various time points over

the first 24 hours for a dosage form of Meloxicam/Rizatriptan described in Example 6 and a

commercially available meloxicam dosage form.

[0028] FIG. 13 is a plot of rizatriptan plasma concentration at various time points over the

first 12 hours for a dosage form of Meloxicam/Rizatriptan described in Example 6 and a

commercially available meloxicam dosage form.

[0029] Fig. 14 shows plots of the percentages of subjects reporting pain relief at various

time points over the first 4 hours post dose of the dosage forms of Meloxicam/Rizatriptan,

rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.

[0030] Fig. 15 shows the percentages of subjects achieving pain freedom at 2 hours, 4

hours, 12 hours, and 16 hours post dose of the dosage forms of Meloxicam/Rizatriptan,

rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.

[0031] Fig. 16A shows the percentages of subjects achieving sustained pain freedom from

2 hours to 24 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan,

MoSEIC meloxicam, and placebo described in Example 11.

[0032] Fig. 16B shows the percentages of subjects achieving sustained pain relief from 2

hours to 24 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan,

MoSEIC meloxicam, and placebo described in Example 11.

[0033] Fig. 17A shows the percentages of subjects achieving sustained pain freedom from

2 hours to 48 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan,

MoSEIC meloxicam, and placebo described in Example 11.

[0034] Fig. 17B shows the percentages of subjects achieving sustained pain relief from 2

hours to 48 hours post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan,

MoSEIC meloxicam, and placebo described in Example 11.

[0035] Fig. 18 shows the percentages of subjects who took rescue medication through

hour 24 post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC

meloxicam, and placebo described in Example 11.

DETAILED DESCRIPTION

[0036] Provided herein are dosage forms with NSAIDs (such as meloxicam) and

cyclodextrin (optionally in an inclusion complex), and/or bicarbonate, and methods of

treatment using the dosage form.

[0037] A dosage form may be given enterally including, but not limited to, oral, sublingual,

or rectal delivery, or parenterally including, but not limited to, intravenous, intramuscular,

intranasal, or subcutaneous delivery.

[0038] Some methods include administration of a product that combines an NSAID that

is formulated with: a) a cyclodextrin and/or b) a buffering agent. In some embodiments, the

method involves treating a patient with a pharmaceutical formulation comprising meloxicam

and a cyclodextrin and/or a carbonate/bicarbonate. Method embodiments may also include

treating a patient to increase the bioavailability of meloxicam in the patient or increase the

rate at which the meloxicam becomes bioavailable.

[0039] The combination of meloxicam, a cyclodextrin (such as SBESCD), and a bicarbonate

(such as sodium bicarbonate) may substantially increase the solubility and rate of absorption

of meloxicam after oral administration, while maintaining its extended plasma concentration

half-life in mammals, such as humans after oral administration.

[0040] The combination of meloxicam, a cyclodextrin (such as SBESCD), and a

bicarbonate (such as sodium bicarbonate) may substantially increase the oral bioavailability

of meloxicam in mammals, such as humans, after oral administration.

[0041] Unless otherwise indicated, any reference to a compound herein, such as

meloxicam or rizatriptan, by structure, name, or any other means, includes pharmaceutically

acceptable salts, alternate solid forms, such as polymorphs, solvates, hydrates, enantiomers,

tautomers, deuterium-modified forms, or any other chemical species, such as precursors,

prodrugs, or any other chemical species that may rapidly convert to a compound described

herein under conditions in which the compounds are used as described herein.

[0042] A subject combination may be given 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.

[0043] Normally, the combination of meloxicam and rizatriptan is administered so that

the human being receives the meloxicam and rizatriptan within a short period of time with respect to one another. For example, the meloxicam and rizatriptan may 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, the meloxicam and rizatriptan are administered simultaneously, which for the purpose of this disclosure includes administration within about 5 minutes. In some embodiments, the meloxicam and rizatriptan are administered in a single dosage form.

[0044] The term "treating" or "treatment" broadly includes any kind of treatment activity,

including the diagnosis, cure, mitigation, or prevention of disease in man or other animals, or

any activity that otherwise affects the structure or any function of the body of man or other

animals.

[0045] The dosage form or the subject combination may be used to treat, or provide relief

of, 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 due to injury, pain due to illness

(e.g., fever), post-operative pain, etc. In some instances, pain relief may be palliative, or pain

relief may be provided independent of improvement of the disease or condition or the

underlying cause of the disease or condition. For example, although the underlying disease

may not improve, or may continue to progress, an individual suffering from the disease may

experience pain relief. In some embodiments, the pain affects a muscle, nerve, cartilage,

bone, ligament, tendon, tendon sheaths, bursae, or joint.

[0046] Migraine is a disabling neurological disorder characterized by recurrent attacks of

pulsating head pain accompanied by nausea and sensitivity to light and sound. This pain may

be moderate to severe, but is often severe and incapacitating, requiring bed rest. The

headaches may affect one half of the head, may be pulsating in nature, and may last from 2

to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light

(photophobia), sound (phonophobia), or smell. The pain can be made worse by physical

activity. Migraines may be associated with an aura, which may be a short period of visual

disturbance which signals that the headache will soon occur. Some migraine patients may

not have aura.

[0047] In some embodiments, the human being who is being treated for migraine pain

suffers from allodynia with their migraine attacks. Allodynia, which is pain from normally non

painful stimuli (such as brushing hair, wearing glasses, taking a shower, etc.). Patients having

allodynia are believed to be less likely to respond well to triptan medications.

[0048] Current treatments are suboptimal, with more than 70% of sufferers reporting

dissatisfaction with existing acute treatments. The most commonly reported reasons for

patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and recurrence of

pain during the same day. Suboptimal acute treatment is associated with a significantly

increased risk of new-onset chronic migraine, which may be prevented by improving acute

treatment outcomes.

[0049] Administering a subject combination to a human being suffering from migraine,

such as an acute attack of migraine pain oraura, may quickly result in a reduction in a migraine

symptom, such as pain, nausea, vomiting, photophobia, or phonophobia, such as at or within

about 5 minutes (intended as a shorthand for "at about 5 minutes, 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,

orat orwithin about 3 hours. In some embodiments, a human being experiences a reduction

of, or complete relief from, pain, such as headache pain or migraine pain, 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 relief experienced, is greaterthan would be experienced by receiving

the same amount of rizatriptan without meloxicam. In some embodiments, the relief

experienced, is greater than would be experienced by receiving the same amount of

meloxicam without rizatriptan.

[0050] The combination of meloxicam and rizatriptan may have distinct dual mechanisms

of action for the acute treatment of migraine. Meloxicam is a potent, COX-2 preferential

NSAID which is limited by slow absorption. Rizatriptan is a potent 5-HT1B/Dagonist believed

to have efficacy in migraine.

[0051] Observation of relief or reduction in a symptom at a specific period of time, such

as "at 2 hours," is useful because it allows the effectiveness of the treatment to be evaluated

at a specific or consistent time point, which facilitates comparison between patients.

Observation of relief or reduction in a symptom within a specific period of time, such as

"within about 2 hours," is useful because it is desirable for relief or reduction of a symptom

to occur as early as possible, and specifying that relief occur within a specified time sets a

guideline in which it is desirable that relief occur.

[0052] For some methods, administration of the subject combination may achieve a reduction in migraine pain, nausea, vomiting, photophobia, or phonophobia that lasts at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8-24 hours, about 24 hours, or more than 24 hours.

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

[0054] In some embodiments, the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0055] In some embodiments, the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.

[0056] In some embodiments, the meloxicam and the rizatriptan are administered simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty four hours after the meloxicam and the rizatriptan are administered, the human being experiences greater pain relief than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0057] In some embodiments, the meloxicam and the rizatriptan are administered

simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and two hours

after the meloxicam and the rizatriptan are administered, the human being experiences

greater relief from nausea than the human being would have experienced two hours after

receiving the same amount of meloxicam without the rizatriptan.

[0058] In some embodiments, the meloxicam and the rizatriptan are administered

simultaneously (e.g. in a single dosage form, such as a single oral dosage form), and twenty

four hours after the meloxicam and the rizatriptan are administered, the human being

experiences greater relief from nausea than the human being would have experienced

twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0059] In some embodiments, the meloxicam and the rizatriptan are administered

receiving the same amount of rizatriptan without the meloxicam.

[0060] In some embodiments, the meloxicam and the rizatriptan are administered

twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0061] In some embodiments, the meloxicam and the rizatriptan are administered

greater relief from vomiting than the human being would have experienced two hours after

receiving the same amount of meloxicam without the rizatriptan.

[0062] In some embodiments, the meloxicam and the rizatriptan are administered

experiences greater relief from vomiting than the human being would have experienced

[0063] In some embodiments, the meloxicam and the rizatriptan are administered

receiving the same amount of rizatriptan without the meloxicam.

[0064] In some embodiments, the meloxicam and the rizatriptan are administered

twenty-four hours after receiving the same amount of rizatriptan without the meloxicam. In

some embodiments, the meloxicam and the rizatriptan are administered simultaneously (e.g.

in a single dosage form, such as a single oral dosage form), and two hours afterthe meloxicam

and the rizatriptan are administered, the human being experiences greater relief from

photophobia than the human being would have experienced two hours after receiving the

same amount of meloxicam without the rizatriptan.

[0065] In some embodiments, the meloxicam and the rizatriptan are administered

experiences greater relief from photophobia than the human being would have experienced

[0066] In some embodiments, the meloxicam and the rizatriptan are administered

greater relief from photophobia than the human being would have experienced two hours

after receiving the same amount of rizatriptan without the meloxicam.

[0067] In some embodiments, the meloxicam and the rizatriptan are administered

[0068] In some embodiments, the meloxicam and the rizatriptan are administered

greater relief from phonophobia than the human being would have experienced two hours

after receiving the same amount of meloxicam without the rizatriptan.

[0069] In some embodiments, the meloxicam and the rizatriptan are administered

experiences greater relief from phonophobia than the human being would have experienced

[0070] In some embodiments, the meloxicam and the rizatriptan are administered

after receiving the same amount of rizatriptan without the meloxicam.

[0071] In some embodiments, the meloxicam and the rizatriptan are administered

[0072] In some embodiments, the human being receiving the subject combination has a

history of inadequate response to prior migraine treatments. For example, if the human

being is asked whether he or she was pain-free within two hours of treatment for most

attacks, and given the option of answering "never," "rarely," "less than half the time," or "half

the time or more;" and the human being answers "never," "rarely," or "less than half the

time," then the human being has had an inadequate response to the treatment. Similarly, if

the human being is asked whether one dose of medication usually relieved the human being's

headache and kept it away for at least 24 hours, and given the option of answering "never," "rarely," "less than half the time," or "half the time or more;" and the human being answers

"never," "rarely," or "less than half the time," then the human being has had an inadequate

response to the treatment.

[0073] In some embodiments, the human being receiving the subject combination has

indicated that he or she was "never" pain-free within two hours of treatment for most attacks.

In some embodiments, the human being receiving the subject combination has indicated that

he or she was "rarely" pain-free within two hours of treatment for most attacks. In some

embodiments, the human being receiving the subject combination has indicated that he or

she was pain-free within two hours of treatment for most attacks "less than half the time."

[0074] In some embodiments, the human being receiving the subject combination has

indicated that one dose of medication "never" relieved the respondent's headache and kept

it away for at least 24 hours. In some embodiments, the human being receiving the subject

combination has indicated that one dose of medication "rarely" relieved the respondent's

headache and kept it away for at least 24 hours. In some embodiments, the human being

receiving the subject combination has indicated that one dose of medication relieved the

respondent's headache and kept it away for at least 24 hours "less than half the time."

[0075] In some embodiments, the human being receiving the subject combination has a

history of inadequate response to prior migraine treatments as assessed by a total mean score

ofless than 7, less than 6, less than 5, less than 4, less than 3, less than 2,1-2, 2-3,3-4,4-5,5

6, or 6-7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4). In some

embodiments, the human being has had prior triptan use before receives the subject

combination, such as a combination comprising meloxicam and rizatriptan.

[0076] In some embodiments, the human being receiving the subject combination, such

as a combination comprising meloxicam and rizatriptan, has migraine, and may have a history

of inadequate response to prior migraine treatments. In some embodiments, the human

being having migraine does not have cluster headaches or other types of migraines. In some

embodiments, the human being having migraine does not have chronic daily headache. In

some embodiments, the human being having migraine does not have more than 15, 15-20,

-25, 25-28, 28-30, or 30-31 non-migraine headache days per month. In some

embodiments, the human being having migraine does not have a history of significant

cardiovascular disease. In some embodiments, the human being having migraine does not

have uncontrolled hypertension.

[0077] In some embodiments, the dosage form may also be administered to relieve

arthritis pain. In some embodiments the dosage form may be administered to relieve other signs and/or symptoms of arthritis. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (pauciarticular and polyarticular course), osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid), arthropathies, non articular rheumatism, peri-articular disorders, axial spondyloarthritis, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and neuropathic arthropathies including

Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

In other embodiments, the arthritis pain may be chronic or acute. In some embodiments the

dosage form may be administered to relief the signs and/orsymptoms of an arthritis including

but not limited osteoarthritis

[0078] For some methods, administration of the dosage form may achieve a reduction in

pain that lasts at least about one hour, two hours, three hours, four hours, six hours, at least

about eight hours, about eight to about 24 hours, or about 24 hours. In other embodiments,

administration of the dosage form may achieve a reduction in pain that is observed at about

minutes, at about 30 minutes, at about one hour, at about two hours, at about three hours,

at about four hours, at about five hours, at about six hours, at less than 15 minutes, at less

than 20 minutes, 30 minutes, at less than one hour, at less than two hours, at less than three

hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or othertime period bound

by these ranges, after administration of the dosage form.

[0079] In some embodiments, the dosage form may also be administered to relieve

neuropathic pain, including diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, 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-associated neuropathy, and radio-therapy or chemo

therapy associated neuropathy. The neuropathic pain treated may be chronic or acute.

[0080] In some methods, the dosage form may be administered to relieve inflammatory

pain including inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and

complex regional pain syndrome. In other embodiments, the inflammatory pain may be

chronic or acute.

[0081] Arthritis refers to inflammatory joint diseases that can be associated with pain.

Examples of arthritis pain include but are not limited to pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. The inflammatory joint disease treated may be chronic or acute.

[0082] For some methods, the 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, cramps, tendonitis, epidondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to injury, Tunnel syndromes, pain associated with bone fractures, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip. In other embodiments, the musculoskeletal pain may be chronic or acute.

[0083] For some methods, administration of the dosage form or the subject combination may achieve a reduction in pain that lasts at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8 to about 24 hours, or about 24 hours. In other embodiments, administration of the subject combination may achieve a reduction in pain that is observed at about 10 minutes, at about 30 minutes, at about one hour, at about two hours, at about three hours, at about four hours, at about five hours, at about six hours, at or within about 5 minutes, at or within about 10 minutes, at or within about 15 minutes, at or within about minutes, at or within about 25 minutes, at or within about 30 minutes, at or within about minutes, at or within about 40 minutes, at or within about 45 minutes, at or within about minutes, or at or within about 60 minutes, at two hours or less, at three hours or less, or other time period bound by these ranges, after administration of the subject combination.

[0084] A human being that is treated for a disease or condition with the dosage forms described herein may be of any age. For example the person may have an age of about 10 years to about 90 years, about 20 years to about 80 years, about 30 years to about 75 years, about 40 years to about 70 years, about 1 year to about 16 years, about 80 years to about 95 years, about 18 years or more, about 20 years or more, about 25 years or more, about 30 years or more, about 40 years or more, about 45 years or more, about 50 years or more, about 55 years or more, about 60 years or more, about 65 years or more, or any other age in a range bounded by, or between, these values.

[0085] In some embodiments, a human beingwho is treated for migraine with the dosage forms described herein, for example comprising meloxicam, rizatriptan, SBESCD, and a bicarbonate such as sodium bicarbonate, may be of 18 years to 65 years of age, about 18-20 years ofage, about 20-25 years ofage, about 25-30years ofage, about 30-40 years ofage, 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 in a range bounded by, or between, these values.

[0086] In some embodiments, a human being who is treated for migraine with a dosage forms described herein, such as a dosage form comprising meloxicam, rizatriptan, SBESCD, and a bicarbonate such as sodium bicarbonate, may be white, black or African American, or Asian.

[0087] In some embodiments, a human being that is treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has suffered from the pain or condition associated with the 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 1year, or any duration in a range bounded by, or between, these values.

[0088] In some embodiments, a human being that is treated for migraine with a dosage form comprising meloxicam and rizatriptan has been diagnosed of migraine with or without aura as defined by the ICHD-3 criteria for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years, or longer, or at least 1 year, or any duration in a range bounded by, or between, these values.

[0089] In some embodiments, a human being has an average 2 to 8, 2-3, 3-4, 4-5, 5-6, 6 7, or 7-8 moderate to severe migraines per month.

[0090] A cyclodextrin used in a dosage form with meloxicam could include a cyclodextrin, a cyclodextrin derivative, and/or a salt thereof. An inclusion complex of meloxicam and cyclodextrin may be more water-soluble relative to the non-complexed meloxicam. The cyclodextrin may be a naturally-occurring cyclodextrin (e.g., a, S, or y-cyclodextrins) or a synthetic cyclodextrin. In some embodiments, a-cyclodextrins, derivatives, or salts thereof may be used. a-Cyclodextrins may include, but are not limited to, (2,3,6-tri--acetyl)-a cyclodextrin, (2,3,6-tri-0-methyl)-a-cyclodextrin, (2,3,6-tri-O-octyl)-a-cyclodextrin, 6-bromo

6-deoxy-a-cyclodextrin, 6-iodo-6-deoxy-a-cyclodextrin, (6-0-tertbutyl-dimethylsilyl)-a

cyclodextrin, butyl-a-cyclodextrin, succinyl-a-cyclodextrin, (2-hydroxypropyl)-a-cyclodextrin,

or combinations thereof.

[0091] In some embodiments, S-cyclodextrins, derivatives, or salts thereof may be used.

S-cyclodextrins may include, but are not limited to, hydroxypropyl-S-cyclodextrin, 6

monodeoxy-6-monoamino-S-cyclodextrin, glucosyl-S-cyclodextrin, maltosyl-S-cyclodextrin,

6-0-a-D-glucosyl-S-cyclodextrin, 6-0-a-maltosyl-S-cyclodextrin, 6-azido-6-deoxy-S

cyclodextrin, (2,3-di-O-acetyl-6-0-sulfo)-S-cyclodextrin, methyl-S-cyclodextrin, dimethyl-S

cyclodextrin (DMSCD), trimethyl-S-cyclodextrin (TMSCD), (2,3-di-O-methyl-6-0-sulfo)-S

cyclodextrin, (2,6-di-0-methyl)-S-cyclodextrin, (2,6-di-O-ethyl)-S-cyclodextrin, (2,3,6-tri-0

methyl)-S-cyclodextrin, (2,3,6-tri-O-acetyl)-S-cyclodextrin, -(2,3,6-tri-O-benzoyl)-S

cyclodextrin, (2,3,6-tri-O-ethyl)-S-cyclodextrin, 6-iodo-6-deoxy-S-cyclodextrin, 6-(dimethyl

tert-butylsilyl)-6-deoxy-S-cyclodextrin, 6-bromo-6-deoxy-S-cyclodextrin, monoacetyl-S

cyclodextrin, diacetyl-S-cyclodextrin, triacetyl-S-cyclodextrin, (3-0-acetyl-2,6-di-0-methyl)-S

cyclodextrin, (6-0-maltosyl)-S-cyclodextrin, (6-0-sulfo)-S-cyclodextrin, (6-0-t

butyldimethylsilyl-2,3-di-O-acetyl)-S-cyclodextrin, succinyl-(2-hydroxypropyl)-S-cyclodextrin,

(2,6-di-O-)ethyl-S-cyclodextrin, (2-carboxyethyl)-S-cyclodextrin (CMESCD), hydroxyethyl-S

cyclodextrin (HESCD), (2-hydroxypropyl)-S-cyclodextrin, (2-hydroxypropyl)-S-cyclodextrin

(HPSCD), (3-hydroxypropyl)-S-cyclodextrin (3HPSCD), (2,3-hydroxypropyl)-S-cyclodextrin

(DHPSCD), butyl-S-cyclodextrin, methyl-S-cyclodextrin, silyl((6-0-tert-butyldimethyl)-2,3,-di

O-acetyl)-S-cyclodextrin, succinyl-S-cyclodextrin, (2-hydroxyisobutyl)- S-cyclodextrin, randomly methylated-S-cyclodextrin, branched-S-cyclodextrin, or combinations thereof.

[0092] In other embodiments, a S-cyclodextrin may be a sulfoalkyl ether cyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include,

but are not limited to, sulfobutyl ether-S-cyclodextrin (e.g., SBESCD, betadex, CAPTISOL*). In

some embodiments, a SBESCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about

6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0093] In some embodiments, y-cyclodextrins, derivatives, or salts thereof may be used.

y-cyclodextrins may include carboxymethyl-y-cyclodextrin, (2,3,6-tri-O-acetyl)-y-cyclodextrin,

(2,3,6-tri-0-methyl)-y-cyclodextrin, (2,6-di-0-pentyl)-y-cyclodextrin, 6-(dimethyl-tert butylsilyl)-6-deoxy-y-cyclodextrin, 6-bromo-6-deoxy-y-cyclodextrin, 6-iodo-6-deoxy-y cyclodextrin, (6-O-t-butyldimethylsilyl)-y-cyclodextrin, succinyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin (2-hydroxypropyl)-y-cyclodextrin, acetyl-y-cyclodextrin, butyl y-cyclodextrin, or combinations thereof.

[0094] In some embodiments, the dosage form may include a bicarbonate, such as

sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate,

ammonium bicarbonate, or a combination thereof. A bicarbonate may help to increase

bioavailability of the meloxicam.

[0095] In other embodiments, the dosage form may include a carbonate, derivatives, or

salts thereof. Examples of carbonates may include aluminum carbonate, ammonium

carbonate, barium carbonate, calcium carbonate, cobalt(II) carbonate, lanthanum carbonate,

lithium carbonate, magnesium carbonate, manganese(II) carbonate, potassium carbonate,

sodium carbonate, or combinations thereof.

[0096] 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 salt

form of the meloxicam, by creating an inclusion complex with meloxicam and cyclodextrin,

and/or by including a bicarbonate. This may allow a reduced molar amount of the meloxicam

to be used as compared to other meloxicam dosage forms.

[0097] Unless otherwise indicated, any reference to a compound herein, such as

meloxicam or a cyclodextrin, by structure, name, or any other means, includes

pharmaceutically acceptable salts, alternate solid forms, such as polymorphs, solvates,

hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species

that may rapidly convert to a compound described herein under conditions in which the

compounds are used as described herein.

[0098] In some embodiments, use of a cyclodextrin, a carbonate, or a bicarbonate may

improve the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at

least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about

%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any

amount in a range bounded by, or between, these values as compared to administration of

meloxicam alone.

[0099] Due to the improved bioavailability, the dosage form may contain, or a subject

may receive, on a molar basis, less of the meloxicam than would otherwise be administered.

For example, a dosage form may contain, or a mammal may receive, 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 up to about 90 mole% less,

mole% less, or any amount in a range bounded by, or between, these values as would

otherwise be administered of meloxicam.

[0100] In other embodiments, use of other NSAIDs, opioids, or other pain medications

may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about

%, 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 NSAIDs, opioids or

other pain medications without administration of meloxicam with cyclodextrin, carbonate,

and/or bicarbonate.

[0101] In some embodiments, a dosage form may contain meloxicam in an amount from

about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about 1-35 mg; about 1-25

mg; about 1-15 mg; about 5-20 mg; about 5-10 mg; about 5-15 mg; about 10-20 mg; about

-30 mg; about 30-40 mg; about 40-50 mg; about 5 mg; about 7.5 mg; about 10 mg; about

mg; about 30 mg; or any amount in a range bounded by, or between, any of these values.

These doses may be a safe dose for repeated administration, such as once hourly dosing to

once daily dosing, twice daily dosing, dosing one to 12 times daily, doing 3, 4, 5, or 6 times

daily, etc. In some embodiments, the meloxicam may be safely administered 2, 3, 4, 5, 6, 7,

8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times a day, once a day, or less

frequently, such as once a week, once every two weeks, once a month, etc.

[0102] For some dosage forms, meloxicam forms a complex with the substituted-S

cyclodextrin or other another cyclodextrin which may be formulated into a solid dosage form.

Such a dosage form may be suitable for oral administration. A meloxicam-cyclodextrin

inclusion complex may also be dissolved in water or another solvent to form a parenteral

formulation. However, physical mixtures of meloxicam and the substituted-S-cyclodextrin or

other cyclodextrins may also be used in oral or parenteral dosage forms.

[0103] Formation of an inclusion complex of meloxicam and a cyclodextrin may help to

improve the properties of a dosage form. For some inclusion complexes, the meloxicam and

the cyclodextrin (e.g., SBESCD) may have a molar ratio of about 0.5-2 (a molar ratio of 0.5 is

0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7

0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about

1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or

any ratio in a range bounded by any of these values.

[0104] For some dosage forms, a cyclodextrin (e.g., SBEISCD) may be employed in a weight

ratio to the meloxicam within the range from about 1-1000 (e.g. 1 g of cyclodextrin per 1 g of

meloxicam is a weight ratio of 1); about 1-20; about 1-10; about 1-15; about 2-4, about 3-5,

about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in a range bounded

by, or between, any of these values. For some dosage forms, a cyclodextrin (e.g., SBESCD)

may be employed in a weight ratio to the meloxicam within the range from about 0.001-1

(e.g. 0.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about 0.01-1; about

0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about

0.7-1, about 0.8-1, or any weight ratio in a range bounded by, or between, any of these values.

Each type of cyclodextrin employed may have a different ratio.

[0105] For some dosage forms, the cyclodextrin may be present in an amount from about

1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about 100-175

mg; a bout 20-80 mg; a bout 25-50 mg; a bout 60-100 mg; about 80-100 mg; about 80-120 mg;

about 100-120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90

mg; about 40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount in a

range bounded by, or between, any of these values.

[0106] For some methods, the inclusion complex of meloxicam and cyclodextrin such as

a substituted-S-cyclodextrin is delivered orally (for example by tablet, capsule, elixir, or the

like). Other potential routes of administration include intravenous, intramuscular, intranasal,

lyophilized parenteral, subcutaneous, transdermal, transmucosal, or through other

parenteral means. The meloxicam may also be delivered alone or non-complexed with

cyclodextrin.

[0107] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in amount

from about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about 200-800 mg; about 1

500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg; about 100

500 mg; about 100-300 mg; about 500-1000 mg; about 300-700 mg; about 400-600 mg; about

-250 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg;

about 400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about 440-540

mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about 480-580 mg; about 490

590 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about 800-900 mg; about

150-650 mg; about 350-850 mg; or any amount in a range bounded by, or between, any of

these values.

[0108] Some dosage forms contain a carbonate in amount from about 1-1000 mg; about

1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg; about

100-500 mg; about 100-300 mg; about 200-800 mg; about 500-1000 mg; about 300-700 mg;

about 400-600 mg; about 50-250 mg; about 250-750 mg; about 100-200 mg; about 200-300

mg; about 300-400 mg; about 400-500 mg; about 500-600 mg; about 600-700 mg; about 700

800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or any amount in a range

bounded by, or between, any of these values.

[0109] In some embodiments, the dailydose of meloxicam (e.g., an oral dose, a parenteral

dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about

2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about

2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about

2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about

2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about

-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount

in a range bounded by any of these values.

[0110] In some embodiments, the weekly dose of meloxicam (e.g., an oral dose) is about

1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg; about

-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about 30-70 mg; about 40

mg; about 50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about

100-150 mg; about 30-100 mg; or any amount in a range bounded by, or between, any of

these values. The weekly dose may be given as a single dose, given once during the week, or

may be given in 2, 3, 4, 5, 6, or 7 individual doses during the week.

[0111] In some embodiments, the monthly dose of meloxicam (e.g., an oral dose), or a

dose administered over a period of a month, is about 5000 mg or less; about 4000 mg or less;

about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700 mg or less;

about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000

mg; about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg; about 50-200

mg; about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg; about 360

400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about

100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg;

about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; or any monthly dose in a range

bounded by, or between, any of these values. A monthly dose may be given as a single dose,

or as two or more individual 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 in 56 to 62 daily doses or more. In some

embodiments,the monthlydose is administered in 5 to 15 individual dosesduringthe month.

The monthly dose may be administered for only 1 month, or may be repeatedly administered

for 2 or more months.

[0112] In other embodiments, the dosage form may be administered weekly for about

one, two, three, four, or more consecutive weeks, every other week or bi-weekly, or once

every three weeks. This regimen may be repeated once weekly, twice in a month, three times

in a month, once monthly, once every two months, once every three months, or as directed

by a medical professional.

[0113] In certain embodiments, the pharmaceutical composition results in increased

bioavailability (e.g., reduced Tmax, increased Cmax, increased AUC, etc.) of the meloxicam from

the dosage form as compared to a dosage form containing meloxicam but not containing a

cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate). In some

embodiments, the bioavailability of meloxicam will increase with multiple dosing. For

example, the bioavailability of meloxicam in the dosage form may increase after about 1-10

days of dosing; about 2-6 days of dosing; about 3-5 days of dosing; about 4-6 days of dosing;

about 5-8 days of dosing; about 5 days of dosing; about 6 days of dosing; about 7 days of

dosing; about 8 days of dosing; about 10 days of dosing; about 15 days of dosing; or time in any range bounded by, or between, any of these values; as compared to the bioavailability of meloxicam in a dosage form not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).

[0114] Some of the dosage forms may result in a desired range for an area under the

plasma concentration curve (AUC) of meloxicam. For example the dosage with meloxicam

may result in an AUC of meloxicam of about 1-150 pg-hr/mL; about 10-30 pg-hr/mL; about

-40 pg-hr/mL; about 30-50 pg-hr/mL; about 40-60 pg-hr/mL; about 50-70 pg-hr/mL; about

-80 pg-hr/mL; about 70-90 pg-hr/mL; about 80-100 pg-hr/mL; about 10-100 pg-hr/mL;

about 50-150 pg-hr/mL; about 25-125 pg-hr/mL; about 75-150 pg-hr/mL; about 20-50

pg-hr/mL; about 40-70 pg-hr/mL; about 60-90 pg-hr/mL; about 80-110 pg-hr/mL; about 100

130 pg-hr/mL; about 120-150 pg-hr/mL; or any AUC in a range bounded by, or between, any

of these values.

[0115] Unless otherwise indicated, the AUC refers to the AUC calculated to the last

measured concentration (AUCo-t), such as, over a period of 6 hours (AUCo-), over a period of

12 hours (AUCo-12), over a period of 24 hours (AUCo-2 4 ), or extrapolated to infinity (AUCo-if).

[0116] In Example 3 below, the AUCo-2 4 of meloxicam in human beings for an oral dosage

form containing sodium bicarbonate and sulfobutylether S-cyclodextrin (SBESCD) was about

27 pg-hr/mL. This dosage form contained 15 mg of meloxicam.

[0117] The 15 mg IV and intramuscular doses also provide an AUCO- 24 of meloxicam in

human beings that is about 27 ag-hr/mL. The AUC of meloxicam is believed to be

approximately dose proportional. So for this oral dosage form, or for an IV or intramuscular

dosage form, a meloxicam dose of, for example, approximately 17 mg to about 30 mg would

be expected to result in an AUCO- 2 4 of meloxicam of about 30-50 g-hr/mL.

[0118] For some acute pain conditions, such as migraine and other types of headache, the

AUC for a short period after oral administration, such as an AUC measured over 6 hours (or

AUCo-), may be of particular interest. For example, some dosage forms may result in an AUCo

6 of at least about 6 pg-hr/mL; at least about 7 pg-hr/mL; at least about 8 pg-hr/mL; at least about 9 pg-hr/mL; about 6-10 pg-hr/mL; about 7-11 pg-hr/mL; about 8-12 pg-hr/mL; about 9

13 pg-hr/mL; or any AUC in a range bounded by, or between, any of these values.

[0119] In some embodiments, the dosage form may result in a Cmax of meloxicam of about

-2500 ng/mL; about 100-2250 ng/mL; about 500-2000 ng/mL; about 1000-2500 ng/mL;

about 1000-2000 ng/mL; about 100-900 ng/mL; about 750-1500 ng/mL; about 1250-2000

ng/mL; about 1500-2300 ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about 50

500 ng/mL; about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200 ng/mL; about

1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100 ng/mL; about 1500-1900

ng/mL; about 1600-2100 ng/mL; about 1700-2000 ng/mL; about 1800-2000 ng/mL; about

1900-2500 ng/mL; about 150-1700 ng/mL; about 1600-1800 ng/mL; about 1700-1900 ng/mL;

about 1800-2000 ng/mL; about 1900-2100 ng/mL; about 2000-2200 ng/mL; about 2100-2300

ng/mL; about 2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or any

Cmax in a range bounded by, or between, any of these values.

[0120] For example, a method described herein may reduce the Tmaxof meloxicam. In

some embodiments, the method may include treating a patient to achieve the Tmax of

meloxicam in the patient within about 10 minutes; about 20 minutes; about 30 minutes;

about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes;

about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes; about 180

minutes; about 1-10 hr; about 2-9 hr; about 3-7 hr; about 4-6 hr; about 1-5 hr; about 2-7 hr;

about3-8 hr; about4-9 hr;about1-4 hr; about 2-5 hr;about 3-6 hr; about4-7 hr;about5-8

hr; about 6-9 hr; about 7-10 hr; after administration or any Tmax in a range bounded by, or

between, any of these values.

[0121] In some embodiments, an oral dosage form may have a Tmax of meloxicam that is

shorter than would be achieved by administering meloxicam by intramuscular injection. In

some embodiments, an oral dosage form may have a Tmax of meloxicam that is shorter, or

may increase meloxicam plasma levels at a faster rate, by a factor of at least about 1.5, about

2,about3,about4,about 5,about6,about7, about 8,about9,about10,about12, about

, about 20, or by a factor of about 1.5-1000, about 2-100, about 3-100, about 4-100, about

-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100,

about 15-100, about 20-100, or by a factor in a range bounded by any of these values.

[0122] In some embodiments, a dosage form comprising meloxicam may result in a

plasma concentration of meloxicam at 12 hours that is about 0.01-0.5 pg/mL; about 0.5-0.7

pig/mL; about 0.6-0.8 pg/mL; about 0.7-0.9 pg/mL; about 0.8-1 pg/mL; about 0.9-1.1 pg/mL; about 1-1.2 pg/mIL; about 1.1-1.3 pg/mIL; about 1.2-1.4 pg/mIL; about 1.3-1.5 pg/mIL; about 1.4-1.6 pg/mL; about 1.5-1.7 pg/mL; about 1.6-1.8 pg/mL; about 1.7-1.9 pg/mL; about 1.8-2 pg/mL; about 1.9-2.1 pg/mL; about 2-2.2 pg/mL; about 2.1-2.3 pg/mL; about 2.2-2.4 pg/mL; about 2.3-2.5 pg/mIL; about 2.4-2.6 pg/mL; about 2.5-2.7 pg/mIL; about 2.6-2.8 pg/mL; about 2.7-2.9 pg/mL; about 2.8-3 pg/mL; about 2.9-3.1 pg/mL; about 3-3.2 pg/mL; about 3.1-3.3 pg/m L; a bout 3.2-3.4 pg/m L; a bout 3.3-3.5 pg/m L; a bout 3.4-3.6 pg/m L; a bout 3.5-3.7 pg/m L; about 3.6-3.8 pg/mL; about 3.7-3.9 pg/mL; about 3.8-4 pg/mL; or any plasma concentration in a range bounded by, or between, any of these values.

[0123] In some embodiments, meloxicam is administered at a dose that results in a meloxicam plasma level (such as a Cavg, or average plasma level) of about 0.01-0.5 g/mL; about 0.5-0.7 pg/mL; about 0.6-0.8 pg/mL; about 0.7-0.9 pg/mL; about 0.8-1 pg/mL; about 0.9-1.1 pg/mL; about 1-1.2 pg/mL; about 1.1-1.3 pg/mL; about 1.2-1.4 pg/mL; about 1.3-1.5 pg/mIL; about 1.4-1.6 pg/mIL; about 1.5-1.7 pg/mIL; about 1.6-1.8 pg/mIL; about 1.7-1.9 pg/mIL; about 1.8-2 pg/mL; about 1.9-2.1 pg/mIL; about 2-2.2 pg/mL; about 2.1-2.3 pg/mIL; about 2.2 2.4 pg/mL; about 2.3-2.5 pg/mL; about 2.4-2.6 pg/mL; about 2.5-2.7 pg/mL; about 2.6-2.8 pg/mL; about 2.7-2.9 pg/mL; about 2.8-3 pg/mL; about 2.9-3.1 pg/mL; about 3-3.2 pg/mL; about 3.1-3.3 pg/mIL; about 3.2-3.4 pg/mL; about 3.3-3.5 pg/mIL; about 3.4-3.6 pg/mL; about 3.5-3.7 pg/mL; about 3.6-3.8 pg/mL; about 3.7-3.9 pg/mL; about 3.8-4 pg/mL; about 0.1-20 pg/mL; about 0.5-15 pg/mL; about 0.5-10 pg/mL; about 5-15 pg/mL; about 10-20 pg/mL; a bout 7.5-15 g/mL; a bout 2-10 pg/m L; a bout 1-8 pg/m L; a bout 1-6 pg/m L; a bout 1-2 pg/mL; about 0.5-3.5 pg/mL; about 0.5-7 pg/mL; about 12-20 pg/mL; about 8-12 pg/mL; about 1-4 pg/mL; about 4-7 pg/mL; about 7-11 pg/mL; about 11-15 pg/mL; about 15-19 pg/mL; about 16-20 pg/mL; or any amount of meloxicam plasma level in a range bounded by, or between, any of these values.

[0124] Administration of a dosage form described herein may result in a decreased time to therapeutic plasma concentration of meloxicam. The therapeutic plasma concentration is the Cavg for a 15 mg dose of Mobic© meloxicam. In some embodiments, the time to therapeutic plasma concentration of meloxicam (Tthera) is about 10-30 minutes, about 10-15 minutes, about 15-20 minutes, about 20-25 minutes, about 25-30 minutes, about 10-20 minutes, about 20-30 minutes, about 16-18 minutes, or about 17 minutes.

[0125] A method described herein may reduce the Tmax of rizatriptan. For example, the

method may achieve a Tmax of rizatriptan in the patient within about 50 minutes; within about

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 about 55-60 minutes after administration, or any Tmax in a range bounded by any

of these values.

[0126] In some embodiments, the meloxicam and the rizatriptan are administered

greater relief from allodynia than the human being would have experienced two hours after

receiving the same amount of meloxicam without the rizatriptan.

[0127] In some embodiments, the meloxicam and the rizatriptan are administered

experiences greater relief from allodynia than the human being would have experienced

[0128] In some embodiments, the meloxicam and the rizatriptan are administered

receiving the same amount of rizatriptan without the meloxicam.

[0129] In some embodiments, the meloxicam and the rizatriptan are administered

[0130] One embodiment is a method for reducing the risk of gastrointestinal side effects

in people taking NSAIDs for pain relief and for other conditions, particularly during chronic

treatment, and improving the bioavailability of the NSAID. In one embodiment, the method

involves the administration of a product that combines: a) an agent that actively raises intragastric pH; and b) an NSAID that is formulated with a cyclodextrin. In another embodiment, the method involves the administration of a product that combines: a) an agent that actively raises intragastric pH; b) an NSAID that is formulated with a cyclodextrin; and c) a buffering agent. Either short or long acting acid inhibitors can be effectively used in the dosage forms. This method has the added benefit of being able to protect patients from other gastrointestinal ulcerogens whose effect may otherwise be enhanced by the disruption of gastroprotective prostaglandins due to NSAID therapy.

[0131] The meloxicam formulation in an aqueous parenteral form may include a buffer to

adjust the pH of an aqueous formulation, within a range of about 2 to about 5; about 3.5 to

about5;about5 toabout11;about6toabout9;about6toabout8;about6toabout7;or

any other pH in a range bounded by, or between, any of these values. The meloxicam

formulation in an oral form may include a buffer to adjust the pH of stomach fluid within a

range of about 2 to about 5; about 3.5 to about 5; about 5 to about 11; about 6 to about 9;

about 6 to about 8; about 6 to about 7; or any other pH in a range bounded by, or between,

any of these values. Examples of buffers suitable for use herein include sulfate buffers,

phosphate buffers, borate buffers, carbonate buffers, citrate buffers, etc.

[0132] In some embodiments, the dosage form may be formulated for oral

administration, for example, with an inert diluent or with an edible carrier, or it may be

enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated

directly with the food of the diet. For oral therapeutic administration, the active compound

may be incorporated with an excipient and used in the form of ingestible tablets, buccal

tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups,

wafers, patches, and the like.

[0133] Tablets, troches, pills, capsules and the like may also contain one or more of the

following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient, such

as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid

and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose,

lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen or cherry

flavoring. 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 coating, for

instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts employed.

[0134] Some compositions or dosage forms may be a liquid, or may comprise a solid

phase dispersed in a liquid.

[0135] The dosage form may further comprise a second therapeutically active agent, such

as an acid inhibitor or an analgesic.

[0136] In some embodiments, the dosage form may further comprise an acid inhibitor

present in an amount effective to raise the gastric pH of a patient to at least 2, to at least 2.5,

to at least 3, to at least 3.5, to at least 4, and more to at least 5, when one or more unit dosage

forms are administered. The term "acid inhibitor" refers to agents that inhibit gastric acid

secretion and increase gastric pH. Specific H 2 blockers, also referred to as H 2 antagonists or

histamine H 2 blockers or antagonists, that may be used include but are not limited to

cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine, or

combinations thereof.

[0137] Other agents that may be effectively used as acid inhibitors are the proton pump

inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole,

rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments the daily

dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80 mg,

about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15

mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg or any other

amount in a range bounded by, or between, any of these values.

[0138] Examples of particular proton pump inhibitors include esomeprazole, present in

unit dosage forms in an amount of between 5 mg and 50 mg; omeprazole, present in unit

dosage forms in an amount of between 5 mg and 50 mg; lansoprazole, present in unit dosage

forms in an amount of between 5 mg and 150 mg (and preferably at between 5 mg and 30

mg); and pantoprazole, present in unit dosage forms in an amount of between 10 mg and 200

mg. In some embodiments, the proton pump inhibitor is present in the dosage form in an

amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newer class of acid inhibitor has been developed which competes with potassium at the acid pump. The compounds in this class have been referred to as "reversible proton pump inhibitors" or "acid pump antagonists" and may also be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see W09605177 and W09605199). Other compounds in this group are H-335/25 (AstraZeneca, Dialog file 128, accession number

020806); Sch-28080 (Schering Plough, Dialog file 128, accession number 009663); Sch-32651

(Schering Plough, Dialog file 128, accession number 006883) and SK&F-96067 (CAS Registry

no. 115607-61-9).

[0139] The second therapeutically active agent may include an analgesic such as a second

non-steroidal anti-inflammatory drug, an opioid, a steroid, a triptan, etc. In some

embodiments, the dosage form or treatment also 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

(considered to be an NSAID for the purposes of the present disclosure), ibuprofen,

flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen,

benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof. It will be understood that, for the purposes of the

present disclosure, reference to an acid inhibitor, NSAID, or analgesic agent will include all of

the common forms of these compounds and, in particular, their pharmaceutically acceptable

salts. The amounts of NSAIDs which are therapeutically effective may be lower in the current

embodiments than otherwise found in practice due to potential positive kinetic interaction

and NSAID absorption in the presence of an acid inhibitor, and or in the presence of a

buffering agent.

[0140] 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.

The opioid may include, but is not limited to, (dextro)propoxyphene, A-methylfentanyl,

alfentanil, allylprodine, bezitramide, buprenorphine, butorphanol, carfentanyl, desmethylprodine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, ohmefentanyl, oripavine, oxycodone, oxymorphone,

PEPAP, paramorphine, pentazocine, phenazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.

[0141] Useful triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan,

donitriptan, almotriptan, frovatriptan, alvitriptan, zolmatriptan, etc. In some embodiments,

the triptan comprises rizatriptan. In some embodiments, the dosage form may contain about

1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7

12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 15-20 mg, or about 20-30 mg,

of the triptan, such as rizatriptan, or any amount in a range bounded by any of these values.

[0142] In some embodiments; a dosage form comprising the subject combination may

contain rizatriptan in an amount of about 1-50 mg; about 1-10 mg; about 10-20 mg; about

-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; a bout 2.5 mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6

mg; a bout 7 mg; about 7.5 mg; about 8 mg, a bout 9 mg, about 10 mg; about 15 mg; about 20

mg, about 25 mg, about 30 mg; or any amount in a range bounded by, or between, any of

these values.

[0143] For acute migraines, the amount of meloxicam and/or rizatriptan in a single dose,

or the AUC of the meloxicam and/or rizatriptan associated with a single dose, is of particular

interest. For example, after a single dose, the symptoms may be relieved for an extended

period of time, such that, in the short term, repeated doses may not be needed. For more

continuous conditions, including more chronic, continuous, or frequent migraine symptoms,

daily, weekly, or monthly doses may be of particular interest.

[0144] For any amounts of rizatriptan described herein, salt forms of rizatriptan may be

present in the amounts recited above, or amounts that are molar equivalents to these

amounts for the rizatriptan free base. For example, assuming that the molecular weight of

rizatriptan free base is 269.3 g/mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Thus, a

molar equivalent of 10 mg of rizatriptan free base would be the mass of 37.1 mmol of that

saltform. For example, for the benzoate salt (mw = 391.2 g/mol), the molar equivalent of 10

mg of the free base (or 37.1 mmol), would be 14.5 mg. These doses may be safe for repeated

administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4

days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15

days,16 days,17 days,18 days,19 days, 20 days, 21days, 22 days, 23 days, 24 days, 25 days,

26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, about 1-2 months,

about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months,

about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11

months, about 11-12 months, etc.

[0145] A pharmaceutical composition may be in the form of a tablet or capsule that has:

(a) the acid inhibitor; and/or (b) a buffering agent; and (c) the non-steroidal anti-inflammatory

drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in a

patient upon administration of one or more of said unit dosage forms. The components of

the pharmaceutical composition may be in an immediate or extended release form

individually or in total.

[0146] The term "unit dosage form" as used herein refers to a single entity for drug

administration. For example, a single tablet or capsule combining both an acid inhibitor and

an NSAID would be a unit dosage form. A "unit dosage form" (or "unit dose form") may also

be referred to as a "fixed dosage form" (or "fixed dose form") or "fixed dosage combination"

(or "fixed dose combination") and are otherwise interchangeable. In one embodiment, the

unit dosage form is a multilayer tablet.

[0147] 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 still another

embodiment, the unit dosage form is a multilayer tablet comprising a single core and one or

more layers outside of the core.

[0148] Some dosage forms may comprise a first layer comprising meloxicam, an SBESCD,

and a bicarbonate; and a second layer comprising a second therapeutically active agent and

a bicarbonate.

[0149] The first layer may contain, for example, any amount of meloxicam in one of the

ranges recited above. For example, all of the meloxicam in the dosage form may be present

in the first layer. The second layer may contain all of the second therapeutically active agent,

such that any amount in the ranges recited above with respect to the second therapeutically

active agent may apply to the second layer.

[0150] In some embodiments, the first layer contains about 10-200 mg, about 50-150 mg,

about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of the bicarbonate,

such as sodium bicarbonate, or any amount of the bicarbonate in a range bounded by any of

these values.

[0151] In some embodiments, the second layer contains about 100-500 mg, about 200

500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of the

bicarbonate, such as sodium bicarbonate, or any amount of the bicarbonate in a range

bounded by any of these values.

[0152] In some embodiments, the pharmaceutical composition may have an effective

amount of meloxicam, a cyclodextrin, and a carbonate or bicarbonate to increase

bioavailability of meloxicam. In other embodiments, the pharmaceutical composition may

have an effective amount of meloxicam, sulfobutylether-S-cyclodextrin (SBESCD), and

sodium bicarbonate to increase bioavailability of meloxicam or reduce the Tmaxof meloxicam.

[0153] Some oral dosage forms may have enteric coatings or film coatings. In some

embodiments, a dosage form may comprise a tablet or a capsule having an enteric coating.

In some embodiments, a dosage form may comprise a tablet or a capsule having a film

coating.

[0154] An embodiment of the present disclosure is directed to a pharmaceutical

composition in unit dosage form suitable for administration to a patient, comprising:

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

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

(c) meloxicam, which may or may not be formulated with a cyclodextrin, and

which may or may not be surrounded by an enteric coating

[0155] An embodiment of the present disclosure is directed to a pharmaceutical

composition in unit dosage form suitable for administration to a patient for treat a disease, a

condition, or disorder, such as migraine, comprising:

(1) an inclusion complex of a meloxicam and a sulfobutyl ether S-cyclodextrin (SBEISCD);

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

(3) a triptan, such as rizatriptan.

[0156] In certain embodiments, the pharmaceutical composition results in faster release

or dissolution of the meloxicam from the dosage form as compared to a dosage form

containing meloxicam but not containing the acid inhibitor, or not containing the buffering

agent.

[0157] A dosage form comprising a combination of rizatriptan and meloxicam (a "subject

combination") may be used to treat migraine. The subject combination may be used for the

acute treatment of migraine. The subject combination may provide substantially greater and

more sustained migraine pain relief compared to rizatriptan, meloxicam, or placebo. The

subject combination may provide rapid relief of migraine pain. The subject combination may

significantly reduce the use of rescue medication compared to rizatriptan, meloxicam and

placebo. The migraine patients being treated with a combination of rizatriptan and

meloxicam described herein may have a history of inadequate response to prior acute

treatments. The migraine patients being treated with a combination of rizatriptan and

meloxicam described herein may have allodynia. The migraine patients being treated with a

combination of rizatriptan and meloxicam described herein may have severe pain intensity.

The migraine patients being treated with a combination of rizatriptan and meloxicam

described herein may have obesity. The migraine patients being treated with a combination

of rizatriptan and meloxicam described herein may have morning migraine. The migraine

patients being treated with a combination of rizatriptan and meloxicam described herein may

have a total mean score of the Migraine Treatment Optimization Questionnaire (mTOQ-4) of

less than 7, such as 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. The migraine patients being treated with a

combination of rizatriptan and meloxicam described herein may have allodynia, severe pain intensity, obesity, morning migraine, a total mean score of the mTOQ-4 of less than 7, and a history of inadequate response to prior acute treatments. A dosage form comprising a combination of rizatriptan and meloxicam described herein is safe and well tolerated in the migraine patients being treated.

[0158] A dosage form comprising a combination of rizatriptan and meloxicam described

herein may provide rapid relief of migraine pain in less than 15 minutes, about 15 minutes,

less than 30 minutes, 15-30 minutes, less than 1 hour, 0.5-0.75 hour, or 0.75-1 hour post dose.

The combination of rizatriptan and meloxicam described herein may provide relief of

migraine pain that is numerically greater than rizatriptan at less than 15 minutes, about 5

minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes,

about 30-45 minutes, about 45-60 minutes, about 1-1.5 hours, about 1.5-2 hours, about 2

2.5 hours, about 2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours, about 5

6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-24 hours, about 24

48 hours, or longer, post dose. The percentage of migraine patients reporting pain relief with

the treatment of a combination of rizatriptan and meloxicam described herein may be 1

100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60

%, 70-80%, 80-90%, 90-95%, or 95-100%.

[0159] The migraine patients receiving a dosage form comprising a combination of

rizatriptan and meloxicam described herein ("subject combination") may achieve pain

freedom at less than 2 hours, about 2 hours, about 2-3 hours, about 3-4 hours, about 4-6

hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16

hours,about20-24 hours,about 24-30hours,about30-36 hours,about36-40 hours,about

-44 hours, about 44-48 hours,or longer post dose.

[0160] The percentage of migraine patients achieving pain freedom increases over time

after receiving a dose of a combination of rizatriptan and meloxicam described herein. For

example, at 2 h post dose, the percentage of migraine patients achieving pain freedom may

be about 15-25%, about 15-20%, about 20%, about 20-25%. At 4 h post dose, the percentage

of migraine patients achieving pain freedom may be about 30-50%, about 30-40%, about 40%,

about 40-45%, about 45-47%, about 47-50%. At 12 h post dose, the percentage of migraine

patients achieving pain freedom may be about 45-70%, about 45-50%, about 50-55%, about

-60%, about 56-57%, about 60-65%, about 65-70%. At 16 h post dose, the percentage of migraine patients achieving pain freedom may be about 45-70%, about 45-50%, about 50

%, about 55-60%, about 58-59%, about 60-65%, about 65-70%. The combination of

rizatriptan and meloxicam described herein may provide significant improvement over

rizatriptan in pain freedom in the migraine patients. There may be about 2-10%, 2-3%, 3-5%,

-7%, 6-7%, 7-8%, 8-9%, or 9-10% more migraine patients receiving the combination of

rizatriptan and meloxicam described herein achieving pain freedom than the migraine

patients receiving rizatriptan at 2-16 hours post dose with an improvement of about 10-25%,

-15%, 14-15%, 15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25%. For

example, at 4 hours post dose, if about 40% migraine patients receiving the subject

combination achieve pain freedom, while 33% migraine patients receiving rizatriptan achieve

pain freedom, then the improvement of the subject combination is about 21% [((40

33)/33)x100%]. The improvement with the subject combination over meloxicam may be

bigger than over rizatriptan in migraine patients achieving pain freedom. For example, The

improvement with the subject combination over meloxicam in migraine patients achieving

pain freedom may be about 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55

%, 60-70%, 65-75%, or 70-75% at 2-16 hours post dose.

[0161] 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 receiving the combination of

rizatriptan and meloxicam described herein ("subject combination") achieving pain freedom

at 2 hours may maintain it through 24 hours post dose. The increase of the number of

migraine patients (or improvement) achieving sustained pain freedom from 2-24 hours post

dose of the subject combination may be about 35-55%, about 35-40%, about 40-45%, about

-50%, or about 50-55% as compared to administering rizatriptan. The increase of the

number of migraine patients (or improvement) achieving sustained pain freedom from 2-24

hours post dose of the subject combination may be about 100-165%, about 100-110%, about

110-120%, about 120-130%, about 130-140%, about 140-150%, about 150-160%, or about

160-165% as compared to administering meloxicam.

[0162] The increase of the number of migraine patients (or improvement) achieving

sustained pain relief from 2-24 hours post dose of the subject combination may be about 15

%, about 15-20%, about 20-25%, about 25-30%, about 20-22%, or about 21% as compared

to administering rizatriptan. The increase of the number of migraine patients (or improvement) achieving sustained pain relief from 2-24 hours post dose 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% as compared to

administering meloxicam.

[0163] 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 patients receiving the combination

of rizatriptan and meloxicam described herein ("subject combination") achieving pain

freedom at 2 hours may maintain it through 48 hours post dose. The increase of the number

of migraine patients (or improvement) achieving sustained pain freedom from 2-48 hours

post dose of the subject combination may be about 60-90%, about 60-70%, about 70-75%,

about 75-80%, about 80-90%, or about 75% as compared to administering rizatriptan. The

increase of the number of migraine patients (or improvement) achieving sustained pain

freedom from 2-48 hours post dose of the subject combination may be about 70-110%, about

-80%, about 80-90%, about 90-100%, about 100-110%, or about 90% as compared to

administering meloxicam.

[0164] The increase of the number of migraine patients (or improvement) achieving

sustained pain relief from 2-48 hours post dose of the subject combination may be about 20

%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27

28%, about 28-20%, or about 27% as compared to administering rizatriptan. The increase of

the number of migraine patients (or improvement) achieving sustained pain relief from 2-48

hours post dose of the subject combination may be about 15-30%, about 15-20%, about 20

%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%, about 24

%, or about 23% as compared to administering meloxicam.

[0165] There may be at least 50%, at least 60%, at least 70%, about 60-65%, about 65

%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or about

77% of migraine patients receiving the combination of rizatriptan and meloxicam described

herein ("subject combination") may not require rescue medication. The decrease of the

number of migraine patients who took rescue medication through 24 hours post dose 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% as compared to administering

placebo. The decrease of the number of migraine patients who took rescue medication through 24 hours post dose 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 administering meloxicam. The decrease of the number of migraine patients who took rescue medication through 24 hours post dose 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 administering rizatriptan.

[0166] The following embodiments are contemplated:

Embodiment 1. An inclusion complex of meloxicam in a cyclodextrin.

Embodiment 2. A dosage form comprising: 1) the inclusion complex of embodiment 1,

or 2) meloxicam and a carbonate or a bicarbonate.

Embodiment 3. The dosage form of embodiment 2 comprising the inclusion complex,

wherein the cyclodextrin comprises substituted S-cyclodextrin.

Embodiment 4. The dosage form of embodiment 3, wherein the substituted S cyclodextrin is a sulfobutyl ether S-cyclodextrin (SBESCD) or hydroxypropyl S-cyclodextrin (HPBCD).

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

SBESCD.

Embodiment 6. The dosage form of embodiment 5, wherein the SBESCD has about 6 to

about 7 sulfobutyl ether groups for each molecule of S-cyclodextrin.

Embodiment 7. The dosage form of embodiment 6, wherein the meloxicam and the

SBESCD have a molar ratio of about 0.8 to about 1.2.

Embodiment 8. The dosage form of embodiment 6, wherein the meloxicam and the

SBESCD have a molar ratio of about 1.

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

bicarbonate.

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

sodium bicarbonate.

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

oral dosage form.

Embodiment 12. The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein

about 50 mg to about 200 mg of SBESCD is present in the dosage form.

Embodiment 13. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,

wherein the carbonate or bicarbonate is present in an amount in a range of about 400 mg to

about 600 mg.

Embodiment 14. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13,

wherein the Tmax of meloxicam is decreased as compared to a dosage form not having a

carbonate, a bicarbonate, or a cyclodextrin.

Embodiment 15. The method of embodiment 14, wherein the Tmax of meloxicam is

achieved in the patient at a time in a range of about 10 minutes to about 180 minutes after

administration.

Embodiment 16. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,

or 15, having an oral bioavailability of meloxicam that is higher than a dosage form not having

a carbonate, a bicarbonate, or a cyclodextrin.

Embodiment 17. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,

, 16, 17, 18, 19, or 20, further comprising an acid inhibitor.

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

proton pump inhibitor.

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

inhibitor is esomeprazole.

Embodiment 20. The dosage form of embodiment 19, wherein about 30 mg to about 50

mg of esomeprazole is present in the dosage form.

Embodiment 21. A method of administering meloxicam orally, comprising orally

administering 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 to a patient in need of treatment.

Embodiment 22. The method of embodiment 21, wherein the dosage form is

administered to treat pain.

Embodiment 23. The method of embodiment 21, wherein the dosage form is

administered to treat inflammatory pain.

Embodiment 24. The method of embodiment 21, wherein the dosage form is

administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

Embodiment 25. A method of administering meloxicam intravenously, comprising

intravenously administering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14,

or 15, to a patient in need of treatment.

Embodiment 26. The method of embodiment 21, wherein the dosage form is

administered to treat migraine.

Embodiment 27. A dosage form comprising: 1) the inclusion complex of meloxicam in a

cyclodextrin, 2) a bicarbonate, and 3) a triptan.

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

sulfobutyl ether S-cyclodextrin (SBESCD).

Embodiment 31. The dosage form of embodiment 30, wherein the SBESCD has about 6

to about 7 sulfobutyl ether groups for each molecule of S-cyclodextrin.

Embodiment 32. The dosage form of embodiment 30, wherein the meloxicam and the

SBESCD have a molar ratio of about 0.8 to about 1.2.

Embodiment 33. The dosage form of embodiment 32, wherein the meloxicam and the

SBESCD have a molar ratio of about 1.

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

an oral dosage form.

Embodiment 35. The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34,

wherein about 50 mg to about 200 mg of SBESCD is present in the dosage form.

Embodiment 36. The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35,

wherein the bicarbonate is present in an amount of about 400 mg to about 1000 mg.

Embodiment 37. A method of treating migraine, comprising administering a dosage form

comprising meloxicam, at least 400 mg of a bicarbonate, and a rizatriptan to a human being

suffering from migraine; wherein the Tmax of rizatriptan in the dosage form is shorter than

that in a reference dosage form comprising a) same amount of rizatriptan; 2) no meloxicam;

and c) no bicarbonate.

Embodiment 38. A method of treating migraine, comprising administering meloxicam

and about 8 mg to about 13 mg of rizatriptan, based upon the weight of the rizatriptan in the

free base form, to a human being who is suffering from an acute attack of migraine pain or

migraine aura, wherein the meloxicam and the rizatriptan are administered within about 30

minutes of one another, wherein administering the meloxicam to the human being results in

a Tmax of meloxicam of 110 minutes or less, and an AUCo 24 of meloxicam of about 30 g-hr/mL

to about 50 pg-hr/mL.

Embodiment 39. A pharmaceutical dosage form comprising: 1) about 0.028 mmol to

about 0.085 mmol of meloxicam in a free acid or a salt form, 2) about 0.019 mmol to about

0.056 mmol of rizatriptan in a free base or a salt form, 3) about 100 mg to about 175 mg of a

sulfobutylether-S-cyclodextrin (SBESCD), and 4) about 400 mg to about 600 mg of sodium

bicarbonate.

Embodiment 40. A method of treating migraine comprising: selecting a human migraine

patient with a history of inadequate response to prior migraine treatments, and orally

administering a dosage form to the migraine patient, wherein the dosage form comprises a

combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether S-cyclodextrin (SBEISCD)), 2) a bicarbonate, and 3) a rizatriptan.

Embodiment 41. The method of embodiment 40, wherein the human migraine patient

experiences relief of the migraine pain as a result of orally administering the dosage form to

the migraine patient.

Embodiment 42. The method of embodiment 40 or 41, wherein the human migraine

patient is free of migraine pain two hours after the dosage form is orally administered to the

human migraine patient.

Embodiment 43. The method of embodiment 40, 41, or 42, wherein the migraine

patient experiences a reduction in nausea as a result of orally administering the dosage form

to the migraine patient.

Embodiment 44. The method of embodiment 40, 41, 42, or 43, wherein the human

migraine patient is free of nausea two hours after the dosage form is orally administered to

the human migraine patient.

Embodiment 45. The method of embodiment 40, 41, 42,43, or 44, wherein the migraine

patient experiences a reduction in photophobia as a result of orally administering the dosage

form to the migraine patient.

Embodiment 46. The method of embodiment 40, 41, 42, 43, 44, or 45, wherein the

human migraine patient is free of photophobia two hours after the dosage form is orally

administered to the human migraine patient.

Embodiment 47. The method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein the

migraine patient experiences a reduction in phonophobia as a result of orally administering

the dosage form to the migraine patient.

Embodiment 48. The method of embodiment 40, 41, 42, 43, 44, 45, 46, or 47, wherein

the human migraine patient is free of phonophobia two hours after the dosage form is orally

administered to the human migraine patient.

Embodiment 49. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, or 48,

wherein the dosage form contains 400 mg to 600 mg of the bicarbonate.

Embodiment 50. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49,

wherein the dosage form contains about 5 mg to about 50 mg of meloxicam.

Embodiment 51. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50,

wherein the dosage form contains about 50 mg to about 200 mg of the SBESCD.

Embodiment 52. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or

51, wherein the dosage form is a solid oral dosage form having a shorter Tmax of meloxicam

in the human being than a reference dosage form that: 1) contains the same amount of

meloxicam, 2) does not contain an SBESCD, and 3) does not contain a bicarbonate.

Embodiment 53. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, or 52, wherein about 1 mg to about 50 mg of the rizatriptan is present in the oral dosage

form based upon the weight of the rizatriptan in the free base form.

Embodiment 54. The method of embodiment 53, wherein the rizatriptan is present in a

salt form in an amount that is a molar equivalent of about 10 mg of the rizatriptan in the free

base form.

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

as rizatriptan benzoate.

Embodiment 56. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, or 55, wherein the oral dosage form contains about 10 mg to about 30 mg of

meloxicam.

Embodiment 57. The method of embodiment 56, wherein the oral dosage form contains

about 20 mg of meloxicam.

Embodiment 58. The method of embodiment 56, wherein the oral dosage form contains

about 15 mg of meloxicam.

Embodiment 59. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, or 58, wherein the SBESCD has about 6 to about 7 sulfobutyl ether

groups for each molecule of S-cyclodextrin.

Embodiment 60. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the oral dosage form contains about 50 mg to

about150mgofthe SBESCD.

Embodiment 61. The method of embodiment 60, wherein the oral dosage form contains

about100mgofthe SBESCD.

Embodiment 62. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61, wherein the molar ratio of the SBESCD to

meloxicam is about 0.5 to about 2.

Embodiment 63. The method of embodiment 62, wherein the molar ratio of the SBESCD

to meloxicam is about 0.8 to about 1.2.

Embodiment 64. The method of embodiment 62, wherein the molar ratio of the SBESCD

to meloxicam is about 1.

Embodiment 65. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64, wherein the oral dosage form contains

about 10 mg to about 40 mg of meloxicam, and about 5 mg to about 50 mg of rizatriptan.

Embodiment 66. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, wherein the oral dosage form

contains SBESCD that is in a weight ratio to rizatriptan that is within a range of about 1 to

about 100.

Embodiment 67. The method of embodiment 66, wherein the oral dosage form contains

SBESCD that is in a weight ratio to rizatriptan that is about 10.

Embodiment 68. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67, wherein the bicarbonate

comprises sodium bicarbonate.

Embodiment 69. The method of embodiment 68, wherein the oral dosage form contains

500 mg of sodium bicarbonate.

Embodiment 70. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69, wherein the oral

dosage form has been shown to have a median Tmax of meloxicam that is less than about 90

minutes in fasted human subjects.

Embodiment 71. The method of embodiment 70, wherein the oral dosage form has been

shown to have a median Tmax of meloxicam that is less than about 2 hours in fasted human

subjects.

Embodiment 72. The method of embodiment 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,

63, 64, 65, 66, 67, 68, 69, 70, or 71, wherein the oral dosage form has been shown to have

faster time to therapeutic plasma concentration in the human being as compared to the

reference dosage form.

Embodiment 73. A method of treating migraine comprising: selecting a human migraine

combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether S-cyclodextrin (SBESCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient

the migraine patient.

Embodiment 74. A method of treating migraine comprising: selecting a human migraine

combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether S-cyclodextrin (SBESCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free

of migraine pain two hours after the dosage form is orally administered to the human

migraine patient.

Embodiment 75. A method of treating migraine comprising: selecting a human migraine

combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether S-cyclodextrin (SBESCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine patient experiences a

reduction in nausea as a result of orally administering the dosage form to the migraine

patient.

Embodiment 76. A method of treating migraine comprising: selecting a human migraine

of nausea two hours after the dosage form is orally administered to the human migraine

patient.

Embodiment 77. A method of treating migraine comprising: selecting a human migraine

reduction in photophobia as a result of orally administering the dosage form to the migraine

patient.

Embodiment 78. A method of treating migraine comprising: selecting a human migraine

of photophobia two hours after the dosage form is orally administered to the human migraine

patient.

Embodiment 79. A method of treating migraine comprising: selecting a human migraine

reduction in phonophobia as a result of orally administering the dosage form to the migraine

patient.

Embodiment 80. A method of treating migraine comprising: selecting a human migraine

of phonophobia two hours after the dosage form is orally administered to the human

migraine patient.

Example 1

[0167] The effect of varying amounts of potassium carbonate (K 2CO 3 ) and sodium

bicarbonate (NaHCO3) on the pH of acidic media was tested. The acidic media was chosen to

simulate gastric conditions. K 2 CO3 or NaHCO3 was added to 50 mL of a 0.01 N HCI solution

(pH 2). The pH of the solution was measured afteraddition of the K 2 CO3 or NaHCO3. Deionized

water (240 mL) was then added to the mixture and pH was measured again. The results are

shown in Tables 1-4.

Table 1. Results with K2 CO 3 (0.01 N HCl)

K 2CO3 (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

Table 2. Results with K2 CO3 (0.01 N HCI + Water)

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

Table 3. Results with NaHCO 3 (0.01 N HCl)

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

Table 4. Results with NaHCO 3 (0.01 N HCI+ Water)

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

[0168] Tablets containing meloxicam and combinations of a sulfobutylether-S

cyclodextrin (SBESCD) (a cyclodextrin, containing about 6 to about 7 sulfobutyl ether groups

for each molecule of S-cyclodextrin), K 2 CO 3 , or NaHCO3 were manufactured and tested for

for dissolution. The tested tablets are listed in Table 5. Meloxicam in the form of meloxicam/

SBESCD inclusion complexes was used in the tablets containing meloxicam and SBESCD. The

inclusion complexes were formed by mixing meloxicam and SBESCD in an aqueous pH

adjusted solution. The pH of the solution was adjusted using buffering agents. The resulting

soluble meloxicam/ SBESCD inclusion complexes were then spray dried. This spray-dried

dispersion was used in the manufacture of the tablets containing SBESCD.

Table 5. Tablets

Tablet A 15 mg meloxicam + 25 mg K 2CO3 Tablet B 15 mg meloxicam + 50 mg K 2CO3 Tablet C 15 mg meloxicam + 100 mg K 2CO3 Tablet D 15 mg meloxicam + 150 mg K 2CO3 Tablet E 15 mg meloxicam + 500 mg NaHCO 3 Tablet F 15 mg meloxicam + 100 mg SBESCD Tablet G 15 mg meloxicam + 100 mg SBESCD + 25 mg K 2 CO3 Tablet H 15 mg meloxicam + 100 mg SBESCD + 50 mg K 2 CO3 Tablet I 15 mg meloxicam + 100 mg SBESCD + 100 mg K 2 CO3 Tablet J 15 mg meloxicam + 100 mg SBESCD + 150 mg K 2 CO3 Tablet K 15 mg meloxicam + 100 mg SBESCD + 500 mg NaHCO 3 Tablet L 15 mg meloxicam (MOBIC©)

[0169] Dissolution testing in acidic medium (chosen to simulate gastric conditions) was

performed by placing the tablets in a 0.01 N HCI solution, at an agitation rate of 75 RPM, and

vessel temperature of approximately 37 °C. The results are presented in Tables 6 and in

Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are

presented as percent (%) of meloxicam dissolved.

Table 6. Dissolution Results

15 30 45 60 90 120 0 mins mins mins mins mins mins mins 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 1 0% 32% 33% 27% 21% 16% 15% Tablet J 0% 26% 27% 19% 15% 12% 11% Tablet K 0% 85% 86% 86% 86% 86% 86% Tablet L 0% 2% 2% 2% 2% 2% 2%

[0170] Dissolution of meloxicam was greater with the tablets containing various

combinations of meloxicam and SBESCD, K 2 CO 3 , or NaHCO 3, as compared to tablets

containing meloxicam alone. For example, after 120 minutes, dissolution of meloxicam tablets containing NaHCO3 was 95% as compared to 2% for tablets containing meloxicam alone.

[0171] Dissolution of meloxicam increases with increasing amounts of K 2 CO3 in the absence of SBESCD. However, in the presence of SBESCD, increasing amounts of K 2 CO3 did not appear to increase meloxicam dissolution. At the highest dose of potassium carbonate tested, meloxicam dissolution in the presence of SBESCD was reduced by approximately 50% as compared to meloxicam dissolution in the absence of SBESCD at 120 minutes.

[0172] Dissolution of meloxicam with NaHCO3 was significantly greater than that observed with the highest dose of K 2CO3 at 15 minutes (50% versus 30%), and at 120 minutes (92% versus 23%). Meloxicam dissolution in the presence of SBESCD was also significantly greater with NaHCO3 as compared to the highest dose of K 2 CO3 at 15 minutes (85% versus 26%), and at 120 minutes (86% versus 12%). NaHCO 3 in the presence of SBESCD increased meloxicam dissolution more at 15 minutes as compared to potassium carbonate, which resulted in a reduction in dissolution.

Example 3

[0173] A bilayer tablet containing 1) an inclusion complex of SBESCD with meloxicam, prepared as described below, and 2) sodium bicarbonate was prepared (SBESCD Meloxicam/Bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam and 100 mg SBESCD, and 100 mg of sodium bicarbonate. The second layer contained 40 mg of esomeprazole and 400 mg of sodium bicarbonate.

[0174] A total of 20 human subjects were randomly assigned in a 1:1 ratio to treatment with the SBESCD-Meloxicam/Bicarbonate tablets described above or Mobic© tablets (15 mg meloxicam), once daily for 6 days under fasting conditions.

[0175] On the first day of dosing, plasma samples were collected for concentration analysis of meloxicam at several time points. Concentrations of meloxicam were determined using LC-MS/MS. Pharmacokinetic parameters were calculated. The results are depicted in FIG. 11.

[0176] The median Tmax for meloxicam, the trial's primary endpoint, was 9 times faster for

hours respectively, p<0.0001).

[0177] The SBESCD-Meloxicam/Bicarbonate tablets also demonstrated higher mean

maximum plasma concentration (Cmax) (p=0.0018), faster time to therapeutic plasma

concentration (p<0.0001), and faster time to half-maximal plasma concentration (p<0.0001)

[0178] Meloxicam in the form of meloxicam/SBEISCD inclusion complexes was used in the

tablets containing meloxicam and SBESCD. The inclusion complexes were formed by mixing

meloxicam and SBESCD in an aqueous pH-adjusted solution. The pH of the solution was

adjusted using buffering agents. The resulting soluble meloxicam/SBESCD inclusion

complexes were then spray dried. This spray-dried dispersion was used in the manufacture of

the tablets containing SBESCD.

Example 4

A monolayer tablet containing 1) the inclusion complex of SBESCD with meloxicam; 2)

rizatriptan; and 3) sodium bicarbonate was prepared (SBESCD

Meloxicam/rizatriptan/Bicarbonate). The monolayer tablet contained 20 mg of meloxicam,

mg of rizatriptan, and 500 mg of sodium bicarbonate. The inclusion complex was the same

as the inclusion complex of Example 3.

Dissolution testing of the tablets in acidic medium (chosen to simulate gastric

conditions) was performed by placing the tablets in a 0.01 N HCI solution, at an agitation rate

of 75 RPM, and vessel temperature of approximately 37°C. The results are presented in Table

7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as

percent (%) of meloxicam, and percent (%) of rizatriptan dissolved.

Table 7. Dissolution Results

Time-point (minutes) 0 min 15 min 30 min 45 min 60 min 90 min 120 min

Rizatriptan 0% 89% 102% 103% 103% 103% 103%

Meloxicam 0% 79% 92% 93% 93% 93% 94%

As shown in Table 7, the dissolution results of the tablets in Example 4 are very similar

to the dissolution result of Example 3. Therefore, we expected the pharmacokinetic

properties, including bioavailability, Tmax of meloxicam, etc., of the tablets in Example 4 to be

similar to those described in Example 3 and FIG. 11. This expectation turned out to be correct,

as shown in the examples below.

Example 5

[0179] The monolayer tablet of Example 4 was administered to six human subjects. On

the first day of dosing, plasma samples were collected for concentration analysis of rizatriptan

at several time points. Concentrations of rizatriptan and meloxicam were determined using

LC-MS/MS. Pharmacokinetic parameters were calculated. The results for meloxicam were

comparable to those reported for the bilayer dosage form of Example 3. The median Tmax of

rizatriptan was 0.75 hours and the mean Cmax of rizatriptan was 20.710 ng/mL By

comparison, the reported Tmax of the commercial rizatriptan dosage form, Maxalt*, is 1.0-1.5

hours.

Example 6

[0180] A Phase 1, randomized, single-dose, parallel-group clinical study was conducted to

evaluate the PK, safety and tolerability of 1) a combination of meloxicam (20 mg), rizatriptan

(10 mg), SBESCD, and sodium bicarbonate (meloxicam/rizatriptan), as compared to 2) and

fasted conditions. A total of 20 healthy, adult male or female volunteers were randomized in

[0181] Blood samples for PK analysis were collected pre dose and at multiple time points

post dose. The pre-specified primary endpoint was Tthera, the time to reach a therapeutic

plasma concentration of meloxicam, defined as the Cavg of meloxicam after administration of

the highest approved dose (15 mg) of standard meloxicam, which is approximately 1000

ng/mL. PK results for the rizatriptan component of meloxicam/rizatriptan were compared to

[0182] PK results for the meloxicam (20 mg) component of meloxicam/rizatriptan from

this trial were compared to PK results for Mobic (15 mg meloxicam) from Example 3.

Phase 1 Results

[0183] Meloxicam was rapidly absorbed after oral administration of

meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan), with a median time to

therapeutic plasma concentration (Tthera) of 17 minutes, the primary endpoint (Figure 12 and

Table 8). Median Tmax was 1 hour compared to 4.5 hours for 15 mg standard meloxicam

(Mobic). The very short Tmax suggests the potential for meloxicam/rizatriptan to have rapid

onset of action in treating migraine. Mean plasma elimination half-life (T 1/ 2 ) for meloxicam

was 18.2 hours after administration of meloxicam/rizatriptan, which compares to 21.5 hours

for standard meloxicam. The long elimination half-life suggests the potential for

meloxicam/rizatriptan to enhanced and sustained efficacy, and to reduce migraine pain

recurrence.

Table 8. Meloxicam Pharmacokinetic Parameters for Meloxicam/Rizatriptan

Statistic AUCO-inf T 1/2 e I(hr) Cmax (ng/mL) Tmax (hr)a Tthera (hr)a (ng-hr/mL) N 10 10 10 10 10

Geometric 46,865 17.5 2,532 1.0 0.29 Mean SD 11,965 5.25 607 0.5-2.5 0.20-0.61

aTmax and Tthera present the value as a median or a range.

[0184] Rizatriptan was rapidly absorbed after oral administration of

meloxicam/rizatriptan, with a Tmax of 0.64 hour (38 min), which compares to 0.88 hour for the

same dose of standard rizatriptan (Maxalt) (Figure 13 and Table 9). Systemic exposure

measured using Cmax and AUC were also numerically greater for rizatriptan after

administration of meloxicam/rizatriptan versus standard rizatriptan.

Table 9. Rizatriptan Pharmacokinetic Parameters for Meloxicam/Rizatriptan and Standard

Rizatriptan

Statistic AUCO-inf T1/2 el Cmax Tmax (hr)a (pg-hr/mL) (hr) (ng/mL)

N 10 10 10 10

Geometric 83,800 1.98 29,991 0.64 Mean

Statistic AUCo-nf T 1/2 el Cmax Tmax (hr)a (pg.hr/ML) (hr) (ng/mL)

Meloxicam/Rizatriptan SD 22,787 0.28 11,041 0.5-2.5

(20 mg meloxicam/10

mg rizatriptan)

Standard Rizatriptan N 10 10 10 10

aTmax presents the value as a median or a range.

[0185] Meloxicam/rizatriptan was well tolerated with no relevant differences in safety

profile between the two treatment arms. There were no serious adverse events in the study.

Example 7

[0186] A Phase 3, randomized, double-blind, multicenter, active- and placebo-controlled

trial is carried out to assess the efficacy and safety of meloxicam/rizatriptan in the acute

treatment of moderate and severe migraine, in patients with a history of inadequate response

to prior acute migraine treatments. Eligible patients are randomized in a 2:2:2:1 ratio to

treatment with meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, with SBESCD and

sodium bicarbonate as described in Example 4 above), rizatriptan (10 mg) (rizatriptan arm),

meloxicam (20 mg) with SBESCD and sodium bicarbonate (meloxicam arm), or placebo. Co

primary endpoints are freedom from headache pain, and freedom from the most bothersome

migraine-associated symptom (nausea, photophobia, or phonophobia), two hours after

dosing, for meloxicam/rizatriptan as compared to placebo.

[0187] Superiority of meloxicam/rizatriptan to the rizatriptan and the meloxicam arms

(component contribution) will be established based on sustained freedom from headache

pain from 2 hours to 24 hours after dosing (key secondary endpoint).

[0188] Eligible patients must have a history of inadequate response to prior acute

migraine treatments, assessed using the Migraine Treatment Optimization Questionnaire

(mTOQ-4). The mTOQ-4 is a validated questionnaire that assesses efficacy response to prior acute treatments based on four aspects (two-hour pain freedom, efficacy for at least 24 hours with one dose, ability to plan daily activities, and disruption of daily activities).

[0189] It is expected that meloxicam/rizatriptan will show significant improvement over placebo and superiority over the rizatriptan and the meloxicam arms because of the rapid absorption and distinct dual mechanisms of action of meloxicam/rizatriptan described herein.

Example 8

[0190] A female migraine sufferer visits her physician in the hope of having relief from her migraine pain. Her doctor gives her 10 mg rizatriptan (Maxalt*), which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On her next visit, her doctor gives her 20 mg of meloxicam in a tablet also containing SBESCD and 500 mg of sodium bicarbonate, which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On her nextvisit, herdoctorgives hera tablet described in Example4 above. She reports that at 2 hours and 24 hours after taking the tablet, she has about 10-30% improvement in pain, nausea, allodynia, photophobia, and/or phonophobia over what she experienced after taking meloxicam or rizatriptan alone.

Example 9

[0191] A male migraine sufferer visits his physician in the hope of having relief from his migraine pain. His doctor gives him 10 mg rizatriptan (Maxalt*), which he takes during his next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On his next visit, his doctorgives his 20 mg of meloxicam in a tablet also containing SBESCD and 500 mg of sodium bicarbonate, which he takes during his next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On his next visit, his doctor gives him a tablet described in Example 4 above. He reports that at 2 hours and 24 hours after taking the tablet, he has about 30-60% improvement in pain, nausea, allodynia, photophobia, and/or phonophobia over what he experienced after taking meloxicam or rizatriptan alone.

Example 10

[0192] A female migraine sufferer visits her physician in the hope of having relief from

her migraine pain. Her doctor gives her 10 mg rizatriptan (Maxalt*), which she takes during

her next acute migraine. It provides some relief of pain, nausea, allodynia, photophobia, and

phonophobia, but not complete relief from these symptoms. On her next visit, her doctor

gives her 20 mg of meloxicam in a tablet also containing SBESCD and 500 mg of sodium

bicarbonate, which she takes during her next acute migraine. It provides some relief of pain,

nausea, allodynia, photophobia, and phonophobia, but not complete relief from these

symptoms. On her nextvisit, herdoctorgives hera tablet described in Example4 above. She

reports that at 2 hours and 24 hours after taking the tablet, she has about 60-100%

improvement in pain, nausea, allodynia, photophobia, and/or phonophobia over what she

experienced after taking meloxicam or rizatriptan alone.

Example 11

[0193] Over 37 million Americans suffer from migraine according to the Centers for

Disease Control, and it is the leading cause of disability among neurological disorders in the

United States according to the American Migraine Foundation. Migraine is characterized by

recurrent attacks of pulsating, often severe and disabling head pain associated with nausea,

and sensitivity to light and or sound. It is estimated that migraine accounts for $78 billion in

direct (e.g. doctor visits, medications) and indirect (e.g. missed work, lost productivity) costs

each year in the United States [Gooch CL, Pracht E, Borenstein AR, The burden of neurological

disease in the United States: A summary report and call to action. Ann Neurol. 2017 Apr;

81(4):479-484]. Published surveys of migraine sufferers indicate that more than 70% are not

fully satisfied with their current treatment, that nearly 80% would try a new therapy, and that

they desire treatments that work faster, more consistently, and result in less symptom

recurrence [(1) Smelt AF, Louter MA, Kies DA, Blom JW, Terwindt GM, van der Heijden GJ, De

Gucht V, Ferrari MD, Assendelft WJ, What do patients consider to be the most important

outcomes for effectiveness studies on migraine treatment? Results of a Delphi study. PLoS

One. 2014 Jun 16;9(6):e98933, 6; and (2) Lipton RB, Stewart WF, Acute migraine therapy: do

doctors understand what patients with migraine want from therapy? Headache.

1999;39(suppl2):S20-S26].

[0194] The World Health Organization classifies severe migraine attacks as among the

most disabling illnesses, comparable to dementia, quadriplegia and active psychosis [(1)

Menken et al. Arch Neurol. 2000;57:418-420; and (2) Shapiro and Goadsby. Cephalalgia.

2007;27:991-4]. Debilitating pain, and the often-constant fear of the next migraine attack,

damage family life, social life, and employment [Global Burden of Disease Study. Lancet.

2017;390:1211-1259]. Depression and anxiety are twice as common in people with migraine

than in healthy individuals [Antonaci et al. J Headache Pain. 2011;12:115-125]. Widespread

misperception of the seriousness of migraine contributes to its under-recognition and under

treatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of

patients are not fully satisfied with their current treatment. Thus, there is an urgent need for

new treatments that provide improved efficacy for this serious neurological disease.

[0195] A Phase 3, randomized, double-blind, multicenter, placebo- and active-controlled

trial was conducted to assess the efficacy and safety of the combination of meloxicam and

rizatriptan (meloxicam/rizatriptan) in the acute treatment of moderate and severe migraine.

Eligible patients must have an age of 18 to 65 years, an established diagnosis (at least 1 year)

of migraine with or without aura as defined by ICHD-3 criteria, an average of 2 to 8 moderate

to severe migraines per month, had a history of inadequate response to prior acute migraine

treatments, assessed by a score of 7 using the Migraine Treatment Optimization

Questionnaire (mTOQ-4) (the average score was 3.6), correspondingto poor response to prior

acute treatments. Exclusion criteria included cluster headaches or other types of migraines,

chronic daily headache (> 15 non-migraine headache days per month), history of significant

cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate

response, enrolled patients exhibited a high rate of characteristics that are strongly

associated with poor treatment outcomes including cutaneous allodynia (75.4%), severe

migraine pain intensity (41.2%), obesity (43.7%), and morning migraine (36.6%). A total of

1,594 patients were randomized in a 2:2:2:1 ratio to the monolayer tablet of Example 4 (20

mg meloxicam/10 mg rizatriptan, with SBEISCD and sodium bicarbonate), rizatriptan (10 mg),

meloxicam (20 mg) with SBESCD (MoSEIC Meloxicam), or placebo, to treat a single migraine

attack of moderate or severe intensity. The two co-primary endpoints of the trial were the

proportion of patients who are free from headache pain two hours after dosing, and the

proportion of patients who no longer suffered from their most bothersome migraine associated symptom (nausea, photophobia, or phonophobia) two hours after dosing, for meloxicam/rizatriptan as compared to placebo. Superiority of meloxicam/rizatriptan to the rizatriptan and meloxicam arms (component contribution) was to be established based on sustained freedom from headache pain from two to 24 hours after dosing (key secondary endpoint). The study was conducted pursuant to an FDA Special Protocol Assessment (SPA).

Rizatriptan, an active comparator in the trial, is considered to be the fastest acting oral triptan

and one of the most effective medications currently available for the acute treatment of

migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D)

agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov

17;358(9294):1668-75.)

[0196] Meloxicam/rizatriptan provided rapid relief of migraine pain with the percentage

of patients achieving pain relief with meloxicam/rizatriptan being numerically greater than

with rizatriptan at every time point measured starting at 15 minutes, and statistically

significant by 60 minutes (p=0.04) (Fig. 14). The proportions of patients experiencing pain

relief 1.5 hours after dosing were 60.5% for meloxicam/rizatriptan compared to 52.5% for

rizatriptan and 48.3% for placebo (p=0.019, p=0.04, respectively versus

meloxicam/rizatriptan) (Fig. 14).

[0197] Meloxicam/rizatriptan met the two regulatory co-primary endpoints by

demonstrating, with high statistical significance, a greater percentage of patients as

compared to placebo achieving pain freedom (19.9% versus 6.7%, p<0.001, Fig. 15), and

absence of most bothersome symptom (36.9% versus 24.4%, p=0.002), 2 hours after dosing.

[0198] Superiority of meloxicam/rizatriptan to rizatriptan (active comparator and TM MoSEIC meloxicam (component contribution) was established as specified in the SPA, by

the demonstration of a greater percentage of patients receiving meloxicam/rizatriptan

achieving sustained pain freedom from 2 hours to 24 hours after dosing, compared to TM rizatriptan, MoSEIC meloxicam, and placebo (16.1%, 11.2%, 6.8% and 5.3%, respectively;

p=0.038, p=0.001, and p<0.001, respectively versus meloxicam/rizatriptan, Fig. 16A), the pre

specified key secondary endpoint to demonstrate component contribution. About 80% of the

patients treated with meloxicam/rizatriptan who achieved pain freedom at 2 hours

maintained pain freedom through 24 hours. These results demonstrated the significant improvement in pain freedom and superiority of meloxicam/rizatriptan to rizatriptan in treating migraine.

[0199] Meloxicam/rizatriptan provided substantially greater and more sustained

migraine pain relief compared to placebo and rizatriptan, which translated to a significant

reduction in rescue medication use for meloxicam/rizatriptan compared to placebo and

rizatriptan. The percentage of patients experiencing sustained pain relief from 2 hours to 24

hours after dosing was 53.3% for meloxicam/rizatriptan, compared to 33.5% for placebo and

43.9% for rizatriptan (p<0.001, p=0.006, respectively versus meloxicam/rizatriptan) (Fig.16B).

[0200] Sustained pain relief from 2 hours to 48 hours was also experienced by a

statistically significantly greater proportion of meloxicam/rizatriptan patients (46.5%),

compared to placebo (31.1%) and rizatriptan (36.5%) patients (p<0.001, p=0.003, respectively

versus meloxicam/rizatriptan) (Fig. 17B). The sustained pain freedom from 2 hours to 48

hours was also experienced by a statistically significantly greater proportion of

meloxicam/rizatriptan patients (15.4%), compared to placebo (5.3%), and rizatriptan (8.8%), TM and MoSEIC meloxicam (8.1%) patients (p<0.001, p=0.003, p=<0.001, respectively versus

meloxicam/rizatriptan) (Fig. 17A). About 77% of patients treated with meloxicam/rizatriptan

who achieved pain freedom at 2 hours maintained the pain freedom through 48 hours.

[0201] Rescue medication was used by 23.0% patients received meloxicam/rizatriptan,

compared to 43.5% patients received placebo and 34.7% patients received rizatriptan

(p<0.001 for each group versus meloxicam/rizatriptan) (Fig. 18). About 77% of patients

receiving meloxicam/rizatriptan did not require rescue medication. These results

demonstrated the superiority of meloxicam/rizatriptan to rizatriptan, an active comparator,

in treating migraine.

[0202] Meloxicam/rizatriptan was statistically significantly superior to rizatriptan on

several other secondary endpoints, including Patient Global Impression of Change (PGI-C)

(p=0.022), and return to normal functioning at 24 hours (p=0.027).

[0203] Some of the p-values for meloxicam/rizatriptan versus rizatriptan for various

endpoints are listed in Table 10 below, demonstrating the statistically significant superiority

of meloxicam/rizatriptan over rizatriptan in treating migraine.

Table 10. P-Values for Meloxicam/Rizatriptan vs Rizatriptan for Various Endpoints

Endpoint P-value Meloxicam/Rizatriptan vs Rizatriptan

1 hour Pain Relief 0.04

2-24 hour Sustained Pain Relief 0.006

2-48 hour Sustained Pain Relief 0.003

2-24 hour Sustained Pain Freedom 0.038

2-48 hour Sustained Pain Freedom 0.003

PGI-C 0.022

Functional Improvement at 24 hours 0.027

Use of Rescue Medication <0.001

[0204] Given that Rizatriptan, an active comparator in the trial, is considered to be the

fastest acting oral triptan and one of the most effective medications currently available for

the acute treatment of migraine, and that this trial enrolled patients with difficult-to-treat

migraine, the observed treatment effects with meloxicam/rizatriptan that provided greater

and more lasting migraine pain relief than rizatriptan, is highly significant. Many patients

experience a suboptimal response to their current acute migraine treatments, placing them

at increased risk of headache related disability and progression to chronic migraine, factors

associated with increased healthcare costs. The results of this study suggest that

meloxicam/rizatriptan may provide an important treatment option for people with difficult

to-treat migraine.

[0205] Meloxicam/rizatriptan was safe and well tolerated in the patients studied in the

trial. The most commonly reported adverse events with meloxicam/rizatriptan were nausea,

dizziness and somnolence, none of which occurred at a rate greater than placebo or greater

than 3%. There was one serious adverse event in the meloxicam/rizatriptan arm which was

deemed by the investigator not to be related to the study drug.

[0206] The results of this trial demonstrate the ability of meloxicam/rizatriptan to provide

unique benefits to migraine patients, with fast, strong, and durable relief of migraine pain as

compared to a potent active comparator, rizatriptan, in a stringently designed trial enriched

with patients with difficult-to-treat migraine. These results have potentially important

implications for patient care based on the high rate of inadequate response to and patient

dissatisfaction with current treatments.

[0207] Meloxicam/rizatriptan incorporates multiple mechanisms of action to address

various migraine processes with the goal of providing enhanced effectiveness.

Meloxicam/rizatriptan is thought to act by inhibiting CGRP release, reversing CGRP-mediated

vasodilation, and inhibiting neuro-inflammation, pain signal transmission, and central

sensitization. The results of this trial validate this approach, demonstrating that

meloxicam/rizatriptan can provide significant benefit that is greater than that of currently

available treatments, even in patients with difficult-to-treat migraine. Meloxicam/rizatriptan

may be used for the acute treatment of migraine in adults with or without aura effectively.

Example 12

[0208] Meloxicam/rizatriptan is also being evaluated in another Phase 3 trial which is a

randomized, double-blind, placebo-controlled study evaluating the early treatment of

migraine with meloxicam/rizatriptan. In contrast to this ongoing trial in which patients with

a history of inadequate response treated migraine attacks once they have developed

moderate or severe intensity of migraine, in the other trial, patients are to administer

meloxicam/rizatriptan at the earliest sign of migraine pain.

[0209] Eligible patients are randomized in a 1:1 ratio to treatment with

meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, with SBESCD and sodium

bicarbonate as described in Example 4 above), or placebo. Adult subjects with an established

diagnosis of migraine with or without aura. The treatment with meloxicam/rizatriptan is

initiated at the first sign of migraine pain onset.

[0210] Co-primary endpoints are freedom from headache pain, and freedom from the

most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia),

two hours after dosing, for meloxicam/rizatriptan as compared to placebo.

[0211] Unless otherwise indicated, all numbers expressing quantities of ingredients,

properties such as amounts, percentage, and so forth used in the specification and claims are

to be understood in all instances as indicating both the exact values as shown and as being

modified by the term "about." 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.

[0212] The terms "a," "an," "the" and similar referents used in the context of describing

the 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 the 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 essential to the practice of the claims.

[0213] Groupings of alternative elements or embodiments disclosed herein are not to be

construed as limitations. Each group member may be referred to and claimed individually or

in any combination with other members of the group or other elements found herein. It is

anticipated that one or more members of a group may be included in, or deleted from, a

group for reasons of convenience and/or to expedite prosecution. When any such inclusion

or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling

the written description of all Markush groups if used in the appended claims.

[0214] Certain embodiments are described herein, including the best mode known to the

inventors for carrying out the claimed embodiments. Of course, variations on these described

embodiments will become apparent to those of ordinary skill in the art upon reading the

foregoing description. The inventor expects skilled artisans to employ such variations as

appropriate, andthe inventors intend forthe claimed embodimentsto be practiced otherwise

than 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.

[0215] In closing, it is to 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, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

1. Use of an oral medicament for treating acute migraine comprising the steps of selecting

a human migraine patient with a history of inadequate response to prior acute migraine treatments and an mTOQ-4 score of 7 or less, and orally administering the medicament to the

human migraine patient; wherein the medicament comprises a combination of a meloxicam and

a rizatriptan.

2. The use of claim 1, wherein the mTOQ-4 score of the human migraine patient is about 3

to about 4, corresponding to poor response to prior acute treatments.

3. The use of claim 1 or 2, wherein the human migraine patient experiences a reduction in

migraine pain at about 10 minutes, about 30 minutes, or about 60 minutes after orally administration of the medicament.

4. The use of claim 1, 2 or 3, wherein the human migraine patient experiences faster relief of migraine pain upon orally administering the medicament to the human migraine patient as

compared to the rizatriptan alone, the meloxicam alone, or a placebo.

5. The use of claim 1, 2, 3 or 4, wherein the human migraine patient is free of migraine pain two hours after the medicament is orally administered to the human migraine patient.

6. The use of claim 5, wherein orally administering the medicament results in a higher chance of achieving pain freedom in the human migraine patient as compared to administering

a placebo.

7. The use of claim 1, 2, 3, 4, 5 or 6, wherein the human migraine patient experience

sustained pain freedom from 2 hours to 24 hours after the medicament is orally administered to the human migraine patient.

8. The use of claim 1, 2, 3, 4, 5, 6 or 7, wherein orally administering the medicament results

in a higher chance of achieving sustained pain freedom from 2 hours to 24 hours as compared to

orally administering the rizatriptan alone, the meloxicam alone, or a placebo.

9. The use of claim 8, wherein orally administering the medicament results in a higher

chance of achieving sustained pain freedom from 2 hours to 48 hours as compared to orally administering the rizatriptan alone, the meloxicam alone, or a placebo.

10. The use of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the human migraine patient has most bothersome symptom of nausea, photophobia, or phonophobia, or a combination thereof, and

wherein the migraine patient experiences a reduction in nausea, photophobia, phonophobia, or

a combination thereof as a result of orally administering the medicament to the human migraine patient.

11. The use of claim 10, wherein the human migraine patient is free of nausea, photophobia, phonophobia, or a combination thereof two hours after the medicament is orally administered

to the human migraine patient.

12. The use of claim 11, wherein orally administering the medicament results in a higher

chance of achieving absence of the most bothersome symptom of nausea, photophobia, or phonophobia, or a combination thereof, in the human migraine patient as compared to

administering a placebo.

13. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11or 12, wherein the oral medicament contains about 5 mg to about 50 mg of the meloxicam.

14. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein about 1 mg to about 50 mg of the rizatriptan is present in the oral medicament based upon the weight of rizatriptan in

the free base form.

15. The use of claim 14, wherein the rizatriptan is present in a salt form in an amount that is

a molar equivalent amount of about 10 mg of rizatriptan in the free base form.

16. The use of claim 14 or 15, wherein the rizatriptan is present as rizatriptan benzoate.

17. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the oral

medicament contains about 10 mg to about 30 mg of the meloxicam.

18. The use of claim 17, wherein the oral medicament contains about 20 mg of the meloxicam.

19. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the

oral medicament further comprises SBEICD, and wherein the SBECD has about 6 to about 7 sulfobutyl ether groups for each molecule of p-cyclodextrin.

20. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein the oral medicament contains about 50 mg to about 200 mg of the SBECD.

21. The use of claim 20, wherein the oral medicament contains about 100 mg of the SBECD.

22. The use of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein the oral medicament further comprises about 400 mg to about 600 mg of a bicarbonate.

23. The use of claim 22, wherein the combination contains about 500 mg of sodium carbonate.

24. The use of claim 23, wherein the oral medicament has been shown to have a median Tmax of meloxicam that is about 90 minutes or less in fasted human subjects.