USE OF A COMBINATION COMPRISING MELOXICAM

Description

1 / 84 USE OF A COMBINATION COMPRISING MELOXICAM Divided from BR 11 2021 015467 1, filed on 06.02.2020 CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of U.S. Provisional Patent Application 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, filed December 31, 2019; all of which are incorporated by reference in their entirety. BACKGROUND

[002] Meloxicam, which has the following structure: Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthetase (cyclooxygenase, COX), which is involved in the initial steps of the arachidonic acid cascade, resulting in reduced formation of prostaglandins, thromboxanes, and prostacyclin. SUMMARY

[003] Meloxicam and some other NSAIDs have low aqueous solubility, which may reduce bioavailability and delay the onset of pain relief. Petition 870260076164, dated 07 / 30 / 2026, page 13 / 117 2 / 84 resulting from its use. One way to increase the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cycloamyloses) are generally cyclic polysaccharides that have a bucket shape. Cyclodextrins help increase the bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the outside, which helps facilitate the transport of molecules. Naturally occurring cyclodextrins include six, seven, and eight glucose units (α, β, and γ-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are possible.In aqueous solutions, cyclodextrins can form complexes (i.e., an inclusion complex) with drugs by incorporating the drug into the central / hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around a drug in a micelle-like structure. This capability of cyclodextrins may allow them to act as vehicles to increase the bioavailability of less soluble drugs.

[004] Some embodiments include a method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous migraine treatments and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) a meloxicam complex with a β-cyclodextrin sulfobutyl ether (SBEeCD), 2) a bicarbonate, and 3) a rizatriptan.

[005] Some embodiments include a meloxicam inclusion complex in a cyclodextrin.

[006] Some embodiments include a dosage form comprising: 1) an inclusion complex of meloxicam and a cyclodextrin, Petition 870260076164, dated 07 / 30 / 2026, page 14 / 117 3 / 84 or 2) meloxicam and a carbonate or bicarbonate.

[007] Some embodiments include a method of oral administration of meloxicam, comprising orally administering a dosage form described in the present invention to a patient in need of treatment.

[008] Some embodiments include a method of administering meloxicam intravenously, comprising administering intravenously a dosage form described in the present invention to a patient in need of treatment.

[009] The present invention discloses formulations for a cyclodextrin and meloxicam inclusion complex with bicarbonate and methods of using them.

[010] Formulations and methods for delivering meloxicam with cyclodextrin to an individual via oral, enteral, intravenous, intramuscular, subcutaneous, intranasal or other parenteral routes are disclosed herein.

[011] Methods are also disclosed for treating pain and pain associated with conditions by delivering a dosage form containing meloxicam, cyclodextrin, and bicarbonate orally, enterally, intravenously, intramuscularly, subcutaneously, intranasally, or by other parenteral means to an individual.

[012] A combination of rizatriptan and meloxicam (referred to in the present invention for convenience as an “individual combination”) can be used to treat a variety of pain conditions.

[013] Rizatriptan has the structure shown below. Petition 870260076164, dated 07 / 30 / 2026, page 15 / 117 4 / 84 Rizatriptan

[014] Some modalities include an individual combination comprising: 1) a meloxicam and cyclodextrin inclusion complex, 2) rizatriptan, and 3) a bicarbonate to treat migraine in a human being. The migraine may be treatment-resistant. The human being may have a history of inadequate response to previous treatments.

[015] Some modalities include a combination in question comprising rizatriptan and meloxicam that has rapid, sustained, substantial, and statistically significant efficacy compared with placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of inadequate response to previous acute treatments.

[016] Some modalities include a combination in question comprising rizatriptan and meloxicam that requires significantly less use of emergency medication compared with rizatriptan, meloxicam, or placebo. BRIEF DESCRIPTION OF THE DRAWINGS

[017] Figure 1 is a representation of the results described in Example 2 and contained in Table 6.

[018] Figure 2 is another representation of the results described in Example 2 and contained in Table 6.

[019] Figure 3 is another representation of the results described in Example 2 and contained in Table 6.

[020] Figure 4 is another representation of the results described in Example 2 and contained in Table 6.

[021] Figure 5 is another representation of the results described in Example 2 and contained in Table 6.

[022] Figure 6 is another representation of the results described in Example Petition 870260076164, dated 07 / 30 / 2026, page 16 / 117 5 / 84 and contained in Table 6.

[023] Figure 7 is another representation of the results described in Example 2 and contained in Table 6.

[024] Figure 8 is another representation of the results described in Example 2 and contained in Table 6.

[025] Figure 9 is another representation of the results described in Example 2 and contained in Table 6.

[026] Figure 10 is another representation of the results described in Example 2 and contained in Table 6.

[027] FIG. 11 is a graph of plasma meloxicam concentration at various time points over the first 24 hours for one embodiment of a dosage form described in the present invention and a commercially available meloxicam dosage form.

[028] FIG. 12 is a graph of plasma meloxicam concentration at various time points over the first 24 hours for a Meloxicam / Rizatriptan dosage form described in Example 6 and a commercially available meloxicam dosage form.

[029] FIG. 13 is a graph of rizatriptan plasma concentration at various time points over the first 12 hours for a Meloxicam / Rizatriptan dosage form described in Example 6 and a commercially available meloxicam dosage form.

[030] Fig. 14 shows graphs of the percentages of individuals who reported pain relief at various time points during the first 4 hours post-dose of the Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC, and placebo dosage forms described in Example 11.

[031] Fig. 15 shows the percentages of individuals who achieved pain freedom at 2 hours, 4 hours, 12 hours, and 16 hours post-dose of the forms Petition 870260076164, dated 07 / 30 / 2026, page 17 / 117 6 / 84 dosage of Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC and placebo described in Example 11.

[032] Fig. 16A shows the percentages of individuals who achieved sustained pain freedom from 2 to 24 hours post-dose of the Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC, and placebo dosage forms described in Example 11.

[033] Fig. 16B shows the percentages of individuals who achieved sustained pain relief from 2 to 24 hours post-dose of the Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC, and placebo dosage forms described in Example 11.

[034] Fig. 17A shows the percentages of individuals who achieved sustained pain freedom from 2 hours to 48 hours post-dose of the Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC, and placebo dosage forms described in Example 11.

[035] Fig. 17B shows the percentages of individuals who achieved sustained pain relief from 2 hours to 48 hours post-dose of the Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC, and placebo dosage forms described in Example 11.

[036] Fig. 18 shows the percentages of individuals who took emergency medication up to 24 hours post-dose of the Meloxicam / Rizatriptan, rizatriptan, Meloxicam MoSEIC, and placebo dosage forms described in Example 11. DETAILED DESCRIPTION

[037] Dosage forms containing NSAIDs (such as meloxicam) and cyclodextrin (optionally in an inclusion complex) and / or bicarbonate and treatment methods using the dosage form are provided in the present invention. Petition 870260076164, dated 07 / 30 / 2026, page 18 / 117 7 / 84

[038] A dosage form may be given enterally, including but not limited to oral, sublingual or rectal administration, or parenterally, including but not limited to intravenous, intramuscular, intranasal or subcutaneous administration.

[039] Some methods involve administering a product that combines an NSAID 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. The embodiments of the method may also include treating a patient to increase the bioavailability of meloxicam in the patient or to increase the rate at which meloxicam becomes bioavailable.

[040] The combination of meloxicam, a cyclodextrin (such as SBEeCD) and a bicarbonate (such as sodium bicarbonate) can substantially increase the solubility and absorption rate of meloxicam after oral administration, while maintaining its extended plasma concentration half-life in mammals, such as humans after oral administration.

[041] The combination of meloxicam, a cyclodextrin (such as SBEeCD) and a bicarbonate (such as sodium bicarbonate) can substantially increase the oral bioavailability of meloxicam in mammals, such as humans, after oral administration.

[042] Unless otherwise indicated, any reference to a compound in the present invention, such as meloxicam or rizatriptan, by structure, name or otherwise, includes pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other species. Petition 870260076164, dated 07 / 30 / 2026, p. 19 / 117 8 / 84 chemical compounds, such as precursors, prodrugs, or any other chemical species that can rapidly convert into a compound described in the present invention under conditions in which the compounds are used as described in the present invention.

[043] A combination in question may be given enterally, including but not limited to oral, sublingual or rectal administration, or parenterally, including but not limited to intravenous, intramuscular, intranasal or subcutaneous administration. In some embodiments, 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.

[044] Typically, the combination of meloxicam and rizatriptan is administered so that the human receives meloxicam and rizatriptan within a short period of time relative to each other. For example, 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 each other. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which for the purpose of this invention includes administration within about 5 minutes. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form.

[045] The term treat or treatment includes broadly any type of treatment activity, including the diagnosis, cure, mitigation or prevention of diseases in humans or other animals, or any activity that affects the structure or any function of the body of humans or other animals. Petition 870260076164, dated 07 / 30 / 2026, p. 20 / 117 9 / 84

[046] The dosage form or combination in question may be used to treat or provide relief from 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), postoperative pain, etc. In some cases, pain relief may be palliative, or pain relief may be provided regardless of improvement in 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 modalities, the pain affects a muscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths, bursa, or joint.

[047] Migraine is a debilitating neurological disease characterized by recurrent attacks of throbbing headache accompanied by nausea and sensitivity to light and sound. This pain can be moderate to severe, but is usually severe and debilitating, requiring rest. Headaches can affect half of the head, may be throbbing in nature, and last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or smell. The pain may be aggravated by physical activity. Migraine may be associated with an aura, which may be a short period of visual disturbance that signals that a headache will occur soon. Some migraine patients may not have an aura.

[048] In some modalities, the human being who is being treated for migraine pain suffers from allodynia with their migraine attacks. Allodynia, which is pain caused by normally non-painful stimuli (such as Petition 870260076164, dated 07 / 30 / 2026, page 21 / 117 10 / 84 brushing hair, wearing glasses, showering, etc.). Patients with allodynia are believed to be less likely to respond well to triptan medications.

[049] Current treatments are suboptimal, with over 70% of patients reporting dissatisfaction with existing acute treatments. The most commonly reported reasons for patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and same-day pain recurrence. Suboptimal acute treatment is associated with a significantly increased risk of new onset of chronic migraine, which can be avoided by improving acute treatment outcomes.

[050] The administration of a combination in question to a human being suffering from migraine, such as an acute attack of aura or migraine pain, may result rapidly in the reduction of a migraine symptom, such as pain, nausea, vomiting, photophobia or phonophobia, such as in or within about 5 minutes (intended as an abbreviation for “in about 5 minutes, or within about 5 minutes”), in or within about 10 minutes, in or within about 30 minutes, in or within about 1 hour, or within about 90 minutes, in or within about 2 hours, in or within about 2.5 hours, or in or within about 3 hours.In some modalities, a human being experiences a reduction or complete relief of pain, such as headache or migraine pain, nausea, vomiting, photophobia and / or phonophobia, in or within about 1 hour, in or within about 90 minutes, in or within about 2 hours, in or within about 2.5 hours, or in or within about 3 hours. In some modalities, the relief experienced is greater than would be experienced by receiving the same amount of rizatriptan without meloxicam. In some modalities, the relief experienced is greater than would be experienced by receiving the same amount. Petition 870260076164, dated 07 / 30 / 2026, p. 22 / 117 11 / 84 amount of meloxicam without rizatriptan.

[051] 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 that is limited by slow absorption. Rizatriptan is a potent 5-HT1b / d agonist that is believed to be effective in migraine.

[052] Observing the relief or reduction of a symptom within a specific time period, such as “within 2 hours,” is useful because it allows the effectiveness of the treatment to be assessed at a specific or consistent point in time, which facilitates comparison between patients. Observing relief or reduction in a symptom within a specific time period, such as “within approximately 2 hours,” is useful because it is desirable for relief or reduction of a symptom to occur as soon as possible, and specifying that relief occurs within a specified time defines a guideline in which relief is desirable to occur.

[053] For some methods, administration of the combination in question 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.

[054] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form), and two hours after meloxicam and rizatriptan are administered, the human experiences greater pain relief than the human would have experienced two hours after receiving the same amount of meloxicam without rizatriptan. Petition 870260076164, dated 07 / 30 / 2026, page 23 / 117 12 / 84

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

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

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

[058] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from nausea than the human would have experienced two hours after receiving the same amount of meloxicam without rizatriptan.

[059] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours later Petition 870260076164, dated 07 / 30 / 2026, page 24 / 117 13 / 84 When meloxicam and rizatriptan are administered, the human experiences greater relief from nausea than the human would have experienced twenty-four hours after receiving the same amount of meloxicam without rizatriptan.

[060] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from nausea than the human would have experienced two hours after receiving the same amount of rizatriptan without meloxicam.

[061] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief from nausea than the human would have experienced twenty-four hours after receiving the same amount of rizatriptan without meloxicam.

[062] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form), and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from vomiting than the human would have experienced two hours after receiving the same amount of meloxicam without rizatriptan.

[063] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences Petition 870260076164, dated 07 / 30 / 2026, page 25 / 117 14 / 84 greater relief from vomiting than a human would have experienced twenty-four hours after receiving the same amount of meloxicam without rizatriptan.

[064] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form), and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from vomiting than the human would have experienced two hours after receiving the same amount of rizatriptan without meloxicam.

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

[066] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief from photophobia than the human would have experienced twenty-four hours after receiving the same amount of meloxicam without the Petition 870260076164, dated 07 / 30 / 2026, page 26 / 117 15 / 84 rizatriptan.

[067] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from photophobia than the human would have experienced two hours after receiving the same amount of rizatriptan without meloxicam.

[068] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief from photophobia than the human would have experienced twenty-four hours after receiving the same amount of rizatriptan without meloxicam.

[069] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from phonophobia than the human would have experienced two hours after receiving the same amount of meloxicam without rizatriptan.

[070] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief from phonophobia than the human would have experienced twenty-four hours after receiving the same amount of meloxicam without rizatriptan. Petition 870260076164, dated 07 / 30 / 2026, page 27 / 117 16 / 84

[071] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from phonophobia than the human would have experienced two hours after receiving the same amount of rizatriptan without meloxicam.

[072] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief from phonophobia than the human would have experienced twenty-four hours after receiving the same amount of rizatriptan without meloxicam.

[073] In some modalities, the human receiving the combination in question has a history of inadequate response to previous migraine treatments. For example, if the human is asked whether he or she was pain-free within two hours of treatment for most attacks and given the option of responding never, rarely, “less than half the time” or half the time or more; and the human responds never, rarely or less than half the time, then the human had an inadequate response to treatment. Similarly, if the human is asked whether a dose of medication generally relieves the human's headache and keeps it inactive for at least 24 hours, and is given the option of responding never, rarely, less than half the time, or half the time or more; and the human responds never, rarely or less than half the time, then the human had an inadequate response to treatment. Petition 870260076164, dated 07 / 30 / 2026, page 28 / 117 17 / 84

[074] In some modalities, the human receiving the combination in question indicated that he or she was never pain-free within two hours of treatment for most attacks. In some modalities, the human receiving the combination in question indicated that he or she was rarely pain-free within two hours of treatment for most attacks. In some modalities, the human receiving the combination in question indicated that he or she was pain-free within two hours of treatment for most attacks less than half the time.

[075] In some embodiments, the human receiving the combination in question indicated that a dose of medication never relieved the respondent's headache and kept it inactive for at least 24 hours. In some embodiments, the human receiving the combination in question indicated that a dose of medication rarely relieved the respondent's headache and kept it inactive for at least 24 hours. In some embodiments, the human receiving the combination in question indicated that a dose of medication relieved the respondent's headache and kept it inactive for at least 24 hours less than half the time.

[076] In some modalities, the human receiving the combination in question has a history of inadequate response to prior migraine treatments, as assessed by a mean total score of less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1-2, 2-3, 3-4, 45, 5-6, or 6-7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4). In some modalities, the human has had prior use of triptans before receiving the combination in question, such as a combination comprising meloxicam and rizatriptan.

[077] In some forms, the human being who receives the combination in question, such as a combination comprising meloxicam and Petition 870260076164, dated 07 / 30 / 2026, page 29 / 117 18 / 84 rizatriptan, has migraine and may have a history of inadequate response to previous migraine treatments. In some modalities, the person with migraine does not have cluster headaches or other types of migraine. In some modalities, the person with migraine does not have chronic daily headache. In some modalities, the person with migraine does not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 migraine-free days per month. In some modalities, the person with migraine does not have a history of significant cardiovascular disease. In some modalities, the person with migraine does not have uncontrolled hypertension.

[078] In some modalities, the dosage form may also be administered to relieve arthritis pain. In some modalities, 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 type), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) osteoarthritis, arthropathies, non-articular rheumatism, periarticular disorders, axial spondyloarthritis, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and neuropathic arthropathies including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. In other modalities, arthritis pain may be chronic or acute. In some modalities, the dosage form may be administered to relieve the signs and / or symptoms of arthritis, including, but not limited to, osteoarthritis.

[079] 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 modalities, administration of the dosage form may achieve a reduction in pain that is Petition 870260076164, dated 07 / 30 / 2026, page 30 / 117 19 / 84 observed in about 10 minutes, in about 30 minutes, in about one hour, in about two hours, in about three hours, in about four hours, in about five hours, in about six hours, in less than 15 minutes, in less than 20 minutes, 30 minutes, in less than one hour, in less than two hours, in less than three hours, in about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 60 minutes, or another period of time limited by these ranges, after administration of the dosage form.

[080] In some modalities, the dosage form may also be administered to relieve neuropathic pain, including diabetic peripheral neuropathy, postherpetic 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 radiation or chemotherapy-associated neuropathy. Treated neuropathic pain may be chronic or acute.

[081] In some methods, the dosage form can be administered to relieve inflammatory pain, including inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndrome. In other modalities, inflammatory pain can be chronic or acute.

[082] Arthritis refers to inflammatory diseases of the joints that may 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, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism, periarticular disorders, neuropathic arthropathies, including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. Treated inflammatory joint disease may Petition 870260076164, dated 07 / 30 / 2026, p. 31 / 117 20 / 84 can be chronic or acute.

[083] For some methods, meloxicam may be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain may include, but are not limited to, back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, cramps, tendinitis, epidural epidural pain, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to injury, carpal 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 modalities, musculoskeletal pain may be chronic or acute.

[084] For some methods, administration of the dosage form or combination in question 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 modalities, administration of the combination in question may achieve a reduction in pain that is observed in approximately 10 minutes, in approximately 30 minutes, in approximately one hour, in approximately two hours, in approximately three hours, in approximately four hours, within approximately five hours, in approximately six hours, in or within approximately 5 minutes, in or within approximately 10 minutes, in or within approximately 15 minutes, in or within approximately 20 minutes, in or within approximately 25 minutes, in or within approximately 30 minutes, in or within approximately 35 minutes, in or within approximately 40 minutes, in or within approximately 45 minutes, in or within approximately 50 minutes, or in or within approximately 60 minutes, in two hours or less, in three hours or less, or another period of time limited by these ranges, after administration of the combination in question. Petition 870260076164, dated 07 / 30 / 2026, page 32 / 117 21 / 84

[085] A human being who is treated for a disease or condition with the dosage forms described in this invention may be of any age. For example, the person may be aged from 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 1 year 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.

[086] In some embodiments, a human being who is treated for migraine with the dosage forms described in the present invention, for example, comprising meloxicam, rizatriptan, SBEeCD and a bicarbonate, such as sodium bicarbonate, may be from 18 to 65 years of age, about 18-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-40 years of age, about 40-45 years of age, about 40-50 years of age, about 50-60 years of age, about 60-65 years of age, or any other age in a range delimited by, or between, these values.

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

[088] In some embodiments, a human being who is treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has suffered from pain or a pain-related condition for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least Petition 870260076164, dated 07 / 30 / 2026, page 33 / 117 22 / 84 weeks, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or any duration within a range defined by, or between, these values.

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

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

[091] A cyclodextrin used in a dosage form with meloxicam may include a cyclodextrin, a cyclodextrin derivative, and / or a salt thereof. A meloxicam-cyclodextrin inclusion complex may be more water-soluble than uncomplexed meloxicam. The cyclodextrin may be a naturally occurring cyclodextrin (e.g., α, β, or γcyclodextrins) or a synthetic cyclodextrin. In some embodiments, αcyclodextrins, derivatives, or salts thereof may be used. α-cyclodextrins may include, but are not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O-tert-butyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, suciei-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[092] In some embodiments, β-cyclodextrins, derivatives or salts thereof may be used. β-cyclodextrins may include, but are not Petition 870260076164, dated 07 / 30 / 2026, p. 34 / 117 23 / 84 limited to hydroxypropyl-e-cyclodextrin, 6-monodeoxy-6-monoamino-ecyclodextrin, glucosyl-e-cyclodextrin, maltosyl-e-cyclodextrin, 6-OaD-glucosylβ-cyclodextrin, 6-Oa-maltosyl-e-cyclodextrin, 6-azido-6-deoxy-ecyclodextrin, (2,3-di-O-acetyl-6-O-sulfo)-e-cyclodextrin, methyl-e-cyclodextrin, dimethyl-e-cyclodextrin (DMeCD), trimethyl-e-cyclodextrin (TMeCD), (2,3-di-Omethyl-6-O-sulfo)-e-cyclodextrin, (2,6-di-O-methyl)-e-cyclodextrin, (2,6-di-O-ethyl)β-cyclodextrin, (2,3,6-tri-O-methyl)-e-cyclodextrin, (2,3,6-tri-O-acetyl)-ecyclodextrin, -(2,3,6-tri-O-benzoyl)-e-cyclodextrin, (2,3,6-tri-O-ethyl)-ecyclodextrin, 6-iodo-6-deoxy-e-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6deoxy-e-cyclodextrin, 6-bromo-6-deoxy-e-cyclodextrin, monoacetyl-βcyclodextrin, diacetyl-e-cyclodextrin, triacetyl-e-cyclodextrin, (3-O-acetyl-2,6di-O-methyl)-e-cyclodextrin, (6-O-maltosyl)-e-cyclodextrin, (6-O-sulfo)-ecyclodextrin, (6-Ot-butyldimethylsilyl-2,3-di-O-acetyl)-e-cyclodextrin,succinyl-(2hydroxypropyl)-e-cyclodextrin, (2,6-di-O-)ethyl-e-cyclodextrin, (2-carboxyethyl)-ecyclodextrin (CMEeCD), hydroxyethyl-e-cyclodextrin (HEeCD), (2-hydroxypropyl)-ecyclodextrin, (2-hydroxypropyl)-e-cyclodextrin (HPeCD), (3-hydroxypropyl)-ecyclodextrin (3HPeCD), (2,3-hydroxypropyl)-e-cyclodextrin (DHPeCD), butyl-βcyclodextrin, methyl-e-cyclodextrin, silyl((6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)β-cyclodextrin, succinyl-e-cyclodextrin, (2-hydroxyisobutyl)-e-cyclodextrin, methylated βcyclodextrin randomly, branched β-cyclodextrin or combinations thereof.

[093] In other embodiments, a β-cyclodextrin may be a sulfoalkyl ether cyclodextrin, a derivative thereof, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-β-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In some embodiments, an SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per Petition 870260076164, dated 07 / 30 / 2026, page 35 / 117 24 / 84 cyclodextrin molecule.

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

[095] 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 the bioavailability of meloxicam.

[096] 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.

[097] In some embodiments, enhanced bioavailability of the dosage form can be achieved when treating one of these conditions by administering a dosage form comprising a salt form of meloxicam, creating an inclusion complex with meloxicam and cyclodextrin and / or including a bicarbonate. This may allow a reduced molar amount of meloxicam to be used compared to other forms of Petition 870260076164, dated 07 / 30 / 2026, page 36 / 117 25 / 84 meloxicam dosage.

[098] Unless otherwise indicated, any reference to a compound in the present invention, such as meloxicam or a cyclodextrin, by structure, name or otherwise, includes pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, enantiomers, tautomers, modified forms of deuterium, or any other chemical species that can rapidly convert into a compound described in the present invention under conditions in which the compounds are used as described in the present invention.

[099] In some embodiments, the use of a cyclodextrin, carbonate or 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 70%, 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 ​​compared with administration of meloxicam alone.

[100] Due to improved bioavailability, the dosage form may contain, or an individual may receive, on a molar basis, less meloxicam than would otherwise be administered. For example, a dosage form may contain, or a mammal may receive, at least about 10% less by mol, at least about 20% less by mol, at least about 30% less by mol, at least about 40% less by mol, at least about 50% less by mol, at least about 60% less by mol, at least about 70% less by mol, at least about 80% less by mol, at least about 85% less by mol and / or up to about 90% less by mol, 95% less by mol, or any amount in a range bounded by, or between, Petition 870260076164, dated 07 / 30 / 2026, p. 37 / 117 26 / 84 these values ​​as would be administered with meloxicam.

[101] In other modalities, the 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 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, up to about 100%, compared with the use of other NSAIDs, opioids or other pain medications without administration of meloxicam with cyclodextrin, carbonate and / or bicarbonate.

[102] In some embodiments, a dosage form may contain meloxicam in an amount of about 1-50mg; about 1-10mg; about 1-5mg; about 10-40mg; about 1-35mg; about 1-25mg; about 1-15mg; about 5-20mg; about 5-10mg; about 5-15mg; about 10-20mg; about 20-30mg; about 30-40mg; about 40-50mg; about 5mg; about 7.5mg; about 10mg; about 15mg; about 30mg; 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 a one-hour dose for a daily dose, a twice-daily dose, a dose from one to twelve times a day, taking it 3, 4, 5, or 6 times a day, etc.In some modalities, meloxicam can 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.

[103] For some dosage forms, meloxicam forms a complex with substituted β-cyclodextrin or another cyclodextrin that can be formulated into a solid dosage form. This dosage form may be suitable Petition 870260076164, dated 07 / 30 / 2026, p. 38 / 117 27 / 84 for oral administration. A meloxicam-cyclodextrin inclusion complex can also be dissolved in water or another solvent to form a parenteral formulation. However, physical mixtures of meloxicam and substituted β-cyclodextrin or other cyclodextrins can also be used in oral or parenteral dosage forms.

[104] The formation of a meloxicam and cyclodextrin inclusion complex may help to improve the properties of a dosage form. For some inclusion complexes, meloxicam and cyclodextrin (e.g., SBEeCD) 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.

[105] For some dosage forms, a cyclodextrin (e.g., SBEeCD) may be employed at a weight ratio to meloxicam within the range of about 1-1000 (e.g., 1g of cyclodextrin per 1g of meloxicam is a weight ratio of 1); about 1-20; about 1-10; about 115; 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., SBEeCD) may be employed in a weight ratio to meloxicam within the range of approximately 0.001-1 (e.g., 0.1g of cyclodextrin per 1g of meloxicam is a weight ratio of 0.1); approximately 0.01-1; approximately 0.05-1; approximately 0.1-1; approximately 0.2-1; approximately 0.3-1, approximately 0.4-1, approximately 0.5-1, approximately 0.6-1, approximately 0.7-1, approximately 0.8-1 or any Petition 870260076164, dated 07 / 30 / 2026, p. 39 / 117 28 / 84 ratio by weight within a range defined by, or between, any of these values. Each type of cyclodextrin used may have a different ratio.

[106] For some dosage forms, cyclodextrin may be present in an amount of approximately 1-200mg; 25-175mg; approximately 50-150mg; approximately 25-100mg; approximately 75-150mg; approximately 100-175mg; approximately 20-80mg; approximately 25-50mg; approximately 60-100mg; approximately 80-100mg; approximately 80-120mg; approximately 100-120mg; approximately 100-140mg; approximately 120-160mg; approximately 140-180mg; approximately 30-90mg; approximately 40-80mg; approximately 50-70mg, approximately 55-65mg, approximately 60-62mg, or any amount within a range defined by, or between, any of these values.

[107] For some methods, the meloxicam and cyclodextrin inclusion complex, such as a substituted β-cyclodextrin, is delivered orally (e.g., by tablet, capsule, elixir or similar). Other potential routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal or by other parenteral means. Meloxicam may also be delivered alone or not complexed with cyclodextrin.

[108] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in an amount of about 1-2000mg; about 11000mg; about 100-1000mg; about 200-800mg; about 1-500mg; about 1-200mg; about 1-100mg; about 50-750mg; about 500-1000mg; about 100-500mg; about 100-300mg; about 500-1000mg; about 300-700mg; about 400-600mg; about 50-250mg; about 250-750mg; about 100-200mg; about 200-300mg; about 300-400mg; approximately 400-500mg; approximately 410-510mg; approximately 420-520mg; approximately 430-530mg; approximately 440-540mg; approximately 450-550mg; approximately 460-560mg; approximately 470-570mg; approximately 480-580mg; approximately 490-590mg; approximately 500-600mg; approximately 600-700mg; approximately Petition 870260076164, dated 07 / 30 / 2026, page 40 / 117 29 / 84 of 700-800mg; approximately 800-900mg; approximately 150-650mg; approximately 350-850mg; or any amount within a range delimited by, or between, any of these values.

[109] Some dosage forms contain a carbonate in amounts of approximately 1-1000mg; approximately 1-500mg; approximately 1-200mg; approximately 1-100mg; approximately 50-750mg; approximately 500-1000mg; approximately 100-500mg; approximately 100-300mg; approximately 200-800mg; approximately 500-1000mg; approximately 300-700mg; approximately 400-600mg; approximately 50-250mg; approximately 250-750mg; approximately 100-200mg; approximately 200-300mg; approximately 300-400mg; approximately 400-500mg; approximately 500-600mg; approximately 600-700mg; approximately 700-800mg; approximately 800-900mg; approximately 150-650mg; approximately 350-850mg; or any amount within a range defined by, or between, any of these values.

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

[111] In some embodiments, the weekly dose of meloxicam (e.g., an oral dose) is approximately 1-1000 mg; approximately 1-500 mg; approximately 10-250 mg; approximately 100-300 mg; approximately 10-100 mg; approximately 10-150 mg; approximately 10-300 mg; approximately 20-150 mg; approximately 20-60 mg; approximately 30-70 mg; approximately Petition 870260076164, dated 07 / 30 / 2026, page 41 / 117 30 / 84 of 40-60mg; approximately 50-70mg; approximately 70-90mg; approximately 90-110mg; approximately 50mg; approximately 55mg; approximately 100-150mg; approximately 30-100mg; or any amount within a range delimited 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.

[112] In some embodiments, the monthly dose of meloxicam (e.g., an oral dose), or a dose administered over a period of one month, is approximately 5000 mg or less; approximately 4000 mg or less; approximately 3000 mg or less; approximately 2000 mg or less; approximately 1000 mg or less; approximately 700 mg or less; approximately 600 mg or less; approximately 1-4000 mg; approximately 11000 mg; approximately 10-1000 mg; approximately 50-1000 mg; approximately 10-600 mg; approximately 40-600 mg; approximately 50-600 mg; approximately 40-400 mg; approximately 50-200 mg; approximately 200-240 mg; approximately 240-280 mg; approximately 280-320mg; approximately 320-360mg; approximately 360-400mg; approximately 400-450mg; approximately 450-500mg; approximately 500-600mg; approximately 250-350mg; approximately 100-600mg; approximately 40-2000mg; approximately 40-800mg; approximately 100-900mg; approximately 100-800mg; approximately 40-1000mg; approximately 50-1000mg; approximately 100-1000mg; or any monthly dose within a range delimited by, or between, any of these values.A monthly dose may be administered 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 biweekly 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 monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose may be administered for only 1 month, or it may be administered repeatedly. Petition 870260076164, dated 07 / 30 / 2026, p. 42 / 117 31 / 84 for 2 or more months.

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

[114] In certain embodiments, the pharmaceutical composition results in increased bioavailability (e.g., reduced Tmax, increased Cmax, increased AUC, etc.) of meloxicam from the dosage form 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 approximately 1 to 10 days of dosing; approximately 2 to 6 days of dosing; approximately 3 to 5 days after administration; approximately 4 to 6 days of dosing; approximately 5 to 8 days of dosing; approximately 5 days of dosing; approximately 6 days of dosing; approximately 7 days of dosing; approximately 8 days of dosing; approximately 10 days of dosing; approximately 15 days after administration; or time within any range delimited by, or between, any of these values; compared with the bioavailability of meloxicam in a dosage form that does not contain a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).

[115] Some dosage forms may result in a desired range for an area under the plasma concentration curve (AUC) of meloxicam. For example, dosing with meloxicam may result in an AUC of meloxicam of approximately 1-150 pg h / mL; approximately 10-30 pg h / mL; approximately 20- Petition 870260076164, dated 07 / 30 / 2026, p. 43 / 117 32 / 84 pg h / mL; about 30-50 pg h / mL; about 40-60 pg h / mL; about 50-70 pg h / mL; about 60-80 pg h / mL; about 70-90 pg h mL; about 80-100 pg h / mL; about 10-100 pg h / mL; about 50-150 pg h / mL; about 25-125 pg h / mL; about 75-150 pg h / mL; about 20-50 pg h / mL; about 40-70 pg h / mL; about 60-90 pg h / mL; about 80-110 pg h / mL; about 100-130 pg h / mL; approximately 120-150 pg h / mL; or any AUC within a range bounded by, or between, any of these values.

[116] Unless otherwise indicated, AUC refers to the AUC calculated for the last measured concentration (AUC0-t), such as over a period of 6 hours (AUC0-6), over a period of 12 hours (AUC0-12), over a period of 24 hours (AUC0-24), or extrapolated to infinity (AUC0-inf).

[117] In Example 3 below, the AUC0-24 of meloxicam in humans for an oral dosage form containing sodium bicarbonate and β-cyclodextrin sulfobutyl ether (SBEeCD) was approximately 27 μg hr / mL. This dosage form contained 15 mg of meloxicam.

[118] The 15 mg IV and intramuscular doses also provide an AUC0-24 of meloxicam in humans that is approximately 27 pg hr / mL. The AUC of meloxicam is believed to be approximately proportional to the dose. So, for this oral dosage form, or for an IV or intramuscular dosage form, a dose of meloxicam of, for example, approximately 17 mg to approximately 30 mg, would be expected to result in an AUC0-24 of meloxicam of approximately 30-50 pg hr / mL.

[119] For some acute pain conditions, such as migraine and other types of headache, the AUC over a short period after oral administration, such as an AUC measured over 6 hours (or AUC0-6), may be of particular interest. For example, some dosage forms may result in an AUC0-6 of at least about 6 pg h / mL; at least about 7 pg h / mL; by Petition 870260076164, dated 07 / 30 / 2026, p. 44 / 117 33 / 84 less than about 8 pg h / mL; at least about 9 pg h / mL; about 6-10 pg h / mL; about 7-11 pg h / mL; about 8-12 pg h / mL; about 9-13 pg h / mL; or any AUC in a range bounded by, or between, any of these values.

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

[121] For example, a method described in the present invention may reduce the Tmax of meloxicam. In some embodiments, the method may include treating a patient to achieve the patient's Tmax of meloxicam within about 10 minutes; about 20 minutes; only 30 minutes; about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes; about 180 minutes; about 1-10 hours; about 2-9 hours; about 3-7 hours; about 4-6 hours; about 1-5 hours; about 2-7 hours; about 3-8 hours; about 4-9 hours; about 1-4 hours; about Petition 870260076164, dated 07 / 30 / 2026, p. 45 / 117 34 / 84 2-5 hours; approximately 3-6 hours; approximately 4-7 hours; approximately 5-8 hours; approximately 6-9 hours; approximately 7-10 hours; after administration or any Tmax within a range delimited by, or between, any of these values.

[122] 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 shorter Tmax of meloxicam or may increase plasma levels of meloxicam at a more accelerated rate, by a factor of at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20, or by a factor of about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100, or by a factor within a range defined by either of these values.

[123] In some embodiments, a dosage form comprising meloxicam may result in a 12-hour plasma concentration of meloxicam that is approximately 0.01-0.5 pg / mL; approximately 0.5-0.7 pg / mL; approximately 0.6-0.8 pg / mL; approximately 0.7-0.9 pg / mL; approximately 0.8-1 pg / mL; approximately 0.9-1.1 pg / mL; approximately 1-1.2 pg / mL; approximately 1.1-1.3 pg / mL; approximately 1.2-1.4 pg / mL; approximately 1.3-1.5 pg / mL; approximately 1.4-1.6 pg / mL; approximately 1.5-1.7 pg / mL; approximately 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 / 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 / mL; about 3.2-3.4 pg / mL; about 3.3-3.5 pg / mL; about 3.4-3.6 pg / mL; about 3.5-3.7 pg / mL; about 3.6-3.8 Petition 870260076164, dated 07 / 30 / 2026, page 46 / 117 35 / 84 pg / mL; approximately 3.7-3.9 pg / mL; approximately 3.8-4 pg / mL; or any plasma concentration within or between any of these values.

[124] In some embodiments, meloxicam is administered at a dose that results in a plasma level of meloxicam (such as a Cmean, or mean plasma level) of approximately 0.01-0.5 pg / mL; approximately 0.5-0.7 pg / mL; approximately 0.6-0.8 pg / mL; approximately 0.7-0.9 pg / mL; approximately 0.8-1 pg / mL; approximately 0.9-1.1 pg / mL; approximately 1-1.2 pg / mL; approximately 1.1-1.3 pg / mL; approximately 1.2-1.4 pg / mL; approximately 1.3-1.5 pg / mL; approximately 1.4-1.6 pg / mL; approximately 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 / 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 / mL; about 3.2-3.4 pg / mL; about 3.3-3.5 pg / mL; 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; about 7.5-15 pg / mL; about 2-10 pg / mL; about 18 pg / mL; about 1-6 pg / mL; about 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; approximately 15-19 pg / mL; approximately 16-20 μg / mL; or any plasma level of meloxicam within a range defined by, or between, any of these values.

[125] Administration of a dosage form described in the present invention may result in a decrease in the time to therapeutic plasma concentration of meloxicam. The therapeutic plasma concentration is the average Cmax for a 15 mg dose of meloxicam Mobic®. In some embodiments, the time to therapeutic plasma concentration of Petition 870260076164, dated 07 / 30 / 2026, p. 47 / 117 36 / 84 meloxicam (Ttera) 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.

[126] A method described in the present invention can reduce the Tmax of rizatriptan. For example, the method can achieve a Tmax of rizatriptan in the patient within about 50 minutes; within about 60 minutes; within about 70 minutes; within about 80 minutes; or within about 90 minutes; in about 40-60 minutes, in about 40-45 minutes, in about 45-50 minutes, in about 50-55 minutes, or about 55-60 minutes after administration, or any Tmax within a range bounded by any of these values.

[127] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form), and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from allodynia than the human would have experienced two hours after receiving the same amount of meloxicam without rizatriptan.

[128] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief of allodynia than the human would have experienced twenty-four hours after receiving the same amount of meloxicam without rizatriptan.

[129] In some modalities, meloxicam and rizatriptan are administered simultaneously (e.g., in a dosage form Petition 870260076164, dated 07 / 30 / 2026, page 48 / 117 37 / 84 single dose (such as a single oral dosage form), and two hours after meloxicam and rizatriptan are administered, the human experiences greater relief from allodynia than the human would have experienced two hours after receiving the same amount of rizatriptan without meloxicam.

[130] In some embodiments, meloxicam and rizatriptan are administered simultaneously (for example, in a single-dose form, such as a single oral dose form) and twenty-four hours after meloxicam and rizatriptan are administered, the human experiences greater relief of allodynia than the human would have experienced twenty-four hours after receiving the same amount of rizatriptan without meloxicam.

[131] One embodiment is a method for reducing the risk of gastrointestinal side effects in people taking NSAIDs for pain relief and other conditions, particularly during chronic treatment, and for improving the bioavailability of the NSAID. In one embodiment, the method involves administering 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 administering 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. Short- or long-acting acid inhibitors can be used effectively in 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 interruption of gastroprotective prostaglandins due to NSAID therapy.

[132] The formulation of meloxicam in an aqueous parenteral form may include a buffer to adjust the pH of an aqueous formulation, within a Petition 870260076164, dated 07 / 30 / 2026, page 49 / 117 38 / 84 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. The formulation of meloxicam in an oral form may include a buffer to adjust the pH of the gastric 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 in the present invention include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, etc.

[133] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or with an edible vehicle, or it may be contained in hard or soft gelatin capsules, compressed into tablets or incorporated directly with food in 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, turmeric tablets, capsules, elixirs, dispersions, suspensions, solutions, syrups, lozenges, patches and the like.

[134] Tablets, tablets, pills, capsules and the like may also contain one or more of the following: a binder such as tragacanth gum, acacia gum, 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 sweetener such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, wintergreen oil or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to the materials of Petition 870260076164, dated 07 / 30 / 2026, p. 50 / 117 39 / 84 type above, a liquid vehicle. Various other materials may be present as a coating, for example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a colorant and flavoring, such as cherry or orange. It may be desirable that the material in a dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the quantities employed.

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

[136] The dosage form may additionally comprise a second therapeutically active agent, such as an acid inhibitor or an analgesic.

[137] In some embodiments, the dosage form may additionally comprise an acid inhibitor present in an amount effective to raise a patient’s gastric pH to at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and further 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 raise gastric pH. Specific H2 blockers, also referred to as H2 antagonists or histamine H2 blockers or antagonists, that may be used include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine, or combinations thereof.

[138] Other agents that can be effectively used as acid inhibitors are proton pump inhibitors, such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole, and tenatoprazole. In some embodiments, the daily dose of the acid inhibitor is approximately 1-200 mg, approximately 1-100 mg, approximately 1-50 mg, approximately 40 mg. Petition 870260076164, dated 07 / 30 / 2026, p. 51 / 117 40 / 84 80mg, approximately 5-50mg, approximately 20-40mg, approximately 10-50mg, approximately 10-20mg, approximately 20-40mg, approximately 15-50mg, approximately 30-60mg, approximately 10mg, approximately 20mg, approximately 30mg, approximately 40mg, or any other amount within a range delimited by, or between, any of these values.

[139] Examples of particular proton pump inhibitors include esomeprazole, available in single-dose forms in amounts between 5 mg and 50 mg; omeprazole, available in single-dose forms in amounts between 5 mg and 50 mg; lansoprazole, available in single-dose forms in amounts between 5 mg and 150 mg (and preferably between 5 mg and 30 mg); and pantoprazole, available in single-dose forms in amounts between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is available in single-dose forms in amounts of approximately 10-30 mg, approximately 20-40 mg, approximately 30-50 mg, approximately 40-60 mg, approximately 50-70 mg, approximately 60-80 mg, approximately 70-90 mg, or approximately 80-100 mg. Recently, a new class of acid inhibitors has been developed that competes with potassium in the acid pump. Compounds in this class have been referred to as "reversible proton pump inhibitors" or "acid pump antagonists" and can also be used.Examples include AZD0865, AR-H047108, CS-526, pumaprazole, revaprazine, and soraprazine (see WO9605177 and WO9605199). 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 number 115607-61-9).

[140] The second therapeutically active agent may include an analgesic, such as a second nonsteroidal anti-inflammatory drug, an opioid, a steroid, a triptan, etc. In some embodiments, the form of Petition 870260076164, dated 07 / 30 / 2026, page 52 / 117 41 / 84 dosage or treatment also additionally includes the administration of a second non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. NSAIDs may include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID for the purposes of the present invention), 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 invention, reference to an acid inhibitor, NSAID, or analgesic agent will include all common forms of these compounds and, in particular, their pharmaceutically acceptable salts. The amounts of NSAIDs that are therapeutically effective may be lower in current embodiments than those encountered in practice due to the potential positive kinetic interaction and absorption of NSAIDs in the presence of an acid inhibitor and / or in the presence of a buffering agent.

[141] In other modalities, the dosage or treatment regimen may additionally comprise the administration of an opioid in an amount effective to reduce or eliminate pain or inflammation. The opioid may include, but is not limited to, dextropropoxyphene, α-methylfentanyl, alfentanil, allylprodine, bezitramide, buprenorphine, butorphanol, carfentanil, desmethylprodine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan, levorphanol, loperamide, Petition 870260076164, dated 07 / 30 / 2026, page 53 / 117 42 / 84 meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, ohmefentanil or oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol or combinations thereof.

[142] 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 within a range bounded by any of these values.

[143] In some embodiments; a dosage form comprising the combination in question may contain rizatriptan in an amount of about 1-50mg; about 1-10mg; about 10-20mg; about 20-30mg; about 30-40mg; or about 40-50mg; about 10-40mg; about 1-35mg; about 125mg; about 1-15mg; about 1-10mg; about 5-20mg; about 1-5mg; about 2-6mg; about 3-7mg; about 4-8mg; about 5-10mg; about 6-11mg; about 7-12mg; about 8-13mg; about 9-11mg; about 9-14mg; about 10-15mg; approximately 11-16mg; approximately 12-17mg; approximately 13-18mg; approximately 14-19mg; approximately 15-20mg; approximately 5-15mg; approximately 0.5mg; approximately 1mg; approximately 1.5mg; approximately 2mg; approximately 2.5mg; approximately 3mg; approximately 3.5mg; approximately 4mg; approximately 4.5mg; approximately 5mg; approximately 6mg; approximately 7mg; approximately 7.5mg; approximately 8mg; approximately 9mg; approximately 10mg; approximately 15mg; approximately 20mg; approximately 25mg; approximately 30mg; or any amount in a Petition 870260076164, dated 07 / 30 / 2026, p. 54 / 117 43 / 84 range delimited by, or between, any of these values.

[144] For acute migraines, the amount of meloxicam and / or rizatriptan in a single dose, or the AUC of meloxicam and / or rizatriptan associated with a single dose, is of particular interest. For example, after a single dose, symptoms may be relieved for a long period of time, so that, in the short term, repeated doses may not be necessary. For more continuous conditions, including more chronic, continuous or frequent migraine symptoms, daily, weekly or monthly doses may be of particular interest.

[145] For any quantities of rizatriptan described in the present invention, the salt forms of rizatriptan may be present in the quantities cited above, or in quantities that are molar equivalents to these quantities for the free base of rizatriptan. For example, assuming that the molecular weight of the free base of rizatriptan is 269.3 g / mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Thus, a molar equivalent of 10 mg of free base of rizatriptan would be the mass of 37.1 mmol of that salt form. 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 intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4 to 6 weeks, approximately 1 to 2 months, approximately 6 weeks, approximately 2 to 3 months, approximately 3 to 4 months, approximately 4 to 5 months, approximately 5 to 6 months, approximately 6 to 7 months. about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months etc.

[146] A pharmaceutical composition may be in the form of a Petition 870260076164, dated 07 / 30 / 2026, p. 55 / 117 44 / 84 tablet or capsule containing: (a) an acid inhibitor; and / or (b) a buffering agent; and (c) a nonsteroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in a patient after administration of one or more of the aforementioned unit dosage forms. The components of the pharmaceutical composition may be in an immediate-release or extended-release form, individually or in total.

[147] The term “unit dosage form”, as used in the present invention, refers to a single entity for drug administration. For example, a single tablet or capsule combining 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.

[148] In another embodiment, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In yet another embodiment, the unit dosage form is a multilayer tablet comprising a single core and one or more layers outside the core.

[149] Some dosage forms may comprise a first layer comprising meloxicam, an SBEeCD and a bicarbonate; and a second layer comprising a second therapeutically active agent and a bicarbonate.

[150] The first layer may contain, for example, any amount of meloxicam in one of the ranges mentioned above. For example, all the meloxicam in dosage form may be present in the first layer. The second Petition 870260076164, dated 07 / 30 / 2026, page 56 / 117 The 45 / 84 layer may contain all of the second therapeutically active agent, just as any amount within the ranges mentioned above in relation to the second therapeutically active agent may be applied to the second layer.

[151] In some embodiments, the first layer contains about 10200mg, about 50-150mg, about 50-100mg, about 70-120mg, about 90140mg or about 100mg of bicarbonate, such as sodium bicarbonate or any amount of bicarbonate in a range delimited by any of these values.

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

[153] In some embodiments, the pharmaceutical composition may have an effective amount of meloxicam, a cyclodextrin, and a carbonate or bicarbonate to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition may have an effective amount of meloxicam, β-cyclodextrin sulfobutyl ether (SBEeCD), and sodium bicarbonate to increase the bioavailability of meloxicam or reduce the Tmax of meloxicam.

[154] 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.

[155] One embodiment of the present invention is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: Petition 870260076164, dated 07 / 30 / 2026, p. 57 / 117 46 / 84 (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.

[156] One embodiment of the present invention is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient to treat a disease, condition or disorder, such as migraine, comprising: (1) an inclusion complex of a meloxicam and a β-cyclodextrin sulfobutyl ether (SBEeCD); (2) a bicarbonate, such as sodium bicarbonate or potassium bicarbonate; and (3) a triptan, such as rizatriptan.

[157] In certain embodiments, the pharmaceutical composition results in more accelerated release or dissolution of meloxicam from the dosage form compared with a dosage form containing meloxicam but not containing the acid inhibitor or not containing the buffering agent.

[158] A dosage form comprising a combination of rizatriptan and meloxicam (a “combination in question”) may be used to treat migraine. The combination in question may be used for the acute treatment of migraine. The combination in question may provide substantially superior and more sustained migraine pain relief compared with rizatriptan, meloxicam, or placebo. The combination in question may provide rapid migraine pain relief. The combination in question may significantly reduce the use of emergency medication compared with Petition 870260076164, dated 07 / 30 / 2026, page 58 / 117 47 / 84 rizatriptan, meloxicam, and placebo. Migraine patients being treated with a combination of rizatriptan and meloxicam described in the present invention may have a history of inadequate response to previous acute treatments. Migraine patients being treated with a combination of rizatriptan and meloxicam described in the present invention may have allodynia. Migraine patients being treated with a combination of rizatriptan and meloxicam described in the present invention may have severe pain intensity. Migraine patients being treated with a combination of rizatriptan and meloxicam described in the present invention may have obesity. Migraine patients being treated with a combination of rizatriptan and meloxicam described in the present invention may have morning migraine.Patients with migraine being treated with a combination of rizatriptan and meloxicam described in the present invention may have a mean total score on 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. Patients with migraine being treated with a combination of rizatriptan and meloxicam described in the present invention may have allodynia, severe pain intensity, obesity, morning migraine, a mean total mTOQ-4 score of less than 7, and a history of inadequate response to previous acute treatments. A dosage form comprising a combination of rizatriptan and meloxicam described in the present invention is safe and well tolerated in patients with migraine being treated.

[159] A dosage form comprising a combination of rizatriptan and meloxicam described in the present invention can provide rapid relief from 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 hours or 0.75-1 hour post-dose. The combination of rizatriptan and meloxicam described in the present Petition 870260076164, dated 07 / 30 / 2026, page 59 / 117 The invention 48 / 84 can provide migraine pain relief that is numerically superior to rizatriptan in less than 15 minutes, approximately 5 minutes, approximately 5-10 minutes, approximately 10-15 minutes, approximately 15 minutes, approximately 15-30 minutes, approximately 30-45 minutes, approximately 45-60 minutes, approximately 1-1.5 hours, approximately 1.5-2 hours, approximately 2-2.5 hours, approximately 2.5-3 hours, approximately 3-3.5 hours, approximately 3.5-4 hours, approximately 4-5 hours, approximately 5-6 hours, approximately 6-8 hours, approximately 8-10 hours, approximately 10-12 hours, approximately 12-24 hours, approximately 24-48 hours or longer post-dose. The percentage of migraine patients reporting pain relief with treatment using a combination of rizatriptan and meloxicam described in the present invention may be 1-100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, or 95-100%.

[160] Migraine patients receiving a dosage form comprising a combination of rizatriptan and meloxicam described in the present invention (“combination in question”) may achieve pain freedom in less than 2 hours, about 2 hours, about 2-3 hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about 20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40 hours, about 40-44 hours, about 44-48 hours or longer post-dose.

[161] The percentage of migraine patients achieving pain freedom increases with time after receiving a dose of a rizatriptan and meloxicam combination described in the present invention. For example, at 2 hours 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 hours post-dose, the percentage of migraine patients achieving pain freedom may be about 30-50%, about 30-40%, about Petition 870260076164, dated 07 / 30 / 2026, page 60 / 117 49 / 84 of 40%, approximately 40-45%, approximately 45-47%, approximately 47-50%. In the 12-hour post-dose period, the percentage of migraine patients achieving pain freedom may be approximately 45-70%, approximately 45-50%, approximately 50-55%, approximately 55-60%, approximately 56-57%, approximately 60-65%, approximately 65-70%. In the 16-hour post-dose period, the percentage of migraine patients achieving pain freedom may be approximately 45-70%, approximately 45-50%, approximately 50-55%, approximately 55-60%, approximately 58-59%, approximately 60-65%, approximately 65-70%. The combination of rizatriptan and meloxicam described in the present invention may provide significant improvement over rizatriptan in pain freedom in patients with migraine.There may be approximately 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8%, 8-9%, or 9-10% more migraine patients receiving the rizatriptan and meloxicam combination described in the present invention achieving pain freedom than migraine patients receiving rizatriptan in the 2-16 hour post-dose period, with an improvement of approximately 10-25%, 10-15%, 14-15%, 15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25%. For example, in the 4-hour post-dose period, if approximately 40% of migraine patients receiving the combination in question achieve pain freedom, while 33% of migraine patients receiving rizatriptan achieve pain freedom, then the improvement with the combination in question is approximately 21% [((40-33) / 33)x100%]. The improvement with the combination in question over meloxicam may be greater than over rizatriptan in migraine patients achieving pain freedom.For example, the improvement with the combination in question over meloxicam in migraine patients achieving pain freedom can be around 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75% or 70-75% 2-16 hours post-dose.

[162] 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% Petition 870260076164, dated 07 / 30 / 2026, page 61 / 117 50 / 84 of migraine patients receiving the rizatriptan and meloxicam combination described in the present invention (“combination in question”) achieving pain freedom within 2 hours may maintain it for 24 hours post-dose. The increase in the number of migraine patients (or improvement) achieving sustained pain freedom 2-24 hours post-dose of the combination in question may be approximately 35-55%, approximately 35-40%, approximately 40-45%, approximately 45-50%, or approximately 50-55% compared with rizatriptan administration. The increase in the number of migraine patients (or improvement) achieving sustained pain freedom 2-24 hours post-dose of the combination in question may be approximately 100-165%, approximately 100-110%, approximately 110-120%, approximately 120-130%, approximately 130-140%, approximately 140-150%, approximately 150-160%, or approximately 160-165% compared with meloxicam administration.

[163] The increase in the number of migraine patients (or improvement) achieving sustained pain relief 2-24 hours post-dose of the combination in question may be approximately 15-30%, approximately 15-20%, approximately 20-25%, approximately 25-30%, approximately 20-22% or approximately 21% compared with rizatriptan administration. The increase in the number of migraine patients (or improvement) achieving sustained pain relief 2-24 hours post-dose of the combination in question may be approximately 20-35%, approximately 20-25%, approximately 25-30%, approximately 30-35%, approximately 25-26%, approximately 26-27%, approximately 27-28%, approximately 28-30%, or approximately 27% compared to meloxicam administration.

[164] 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 rizatriptan and meloxicam combination described in the present invention (combination in question) Petition 870260076164, dated 07 / 30 / 2026, page 62 / 117 51 / 84 achieving pain freedom within 2 hours, and maintaining it for 48 hours post-dose. The increase in the number of migraine patients (or improvement) achieving sustained pain freedom 2-48 hours post-dose of the combination in question may be approximately 60-90%, approximately 60-70%, approximately 70-75%, approximately 75-80%, approximately 80-90%, or approximately 75% compared to rizatriptan administration. The increase in the number of migraine patients (or improvement) achieving sustained pain freedom 2-48 hours post-dose of the combination in question may be approximately 70-110%, approximately 70-80%, approximately 80-90%, approximately 90-100%, approximately 100-110%, or approximately 90% compared to meloxicam administration.

[165] The increase in the number of migraine patients (or improvement) achieving sustained pain relief 2-48 hours post-dose of the combination in question may be approximately 20-35%, approximately 20-25%, approximately 25-30%, approximately 30-35%, approximately 25-26%, approximately 26-27%, approximately 27-28%, approximately 28-20% or approximately 27% compared with rizatriptan administration. The increase in the number of migraine patients (or improvement) achieving sustained pain relief 2-48 hours post-dose of the combination in question may be approximately 15-30%, approximately 15-20%, approximately 20-25%, approximately 25-30%, approximately 20-21%, approximately 21-22%, approximately 22-23%, approximately 23-24%, approximately 24-25%, or approximately 23% compared to meloxicam administration.

[166] There may be at least 50%, at least 60%, at least 70%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95% or about 77% of migraine patients receiving the rizatriptan and meloxicam combination described in the present invention (“combination in question”) who may not require emergency medication. The decrease in the number of migraine patients who took emergency medication for 24 hours post-dose of the combination Petition 870260076164, dated 07 / 30 / 2026, page 63 / 117 The 52 / 84 response rate in question may be approximately 35-60%, approximately 35-40%, approximately 40-45%, approximately 45-50%, approximately 50-55%, approximately 55-60%, approximately 47-48%, or approximately 47% compared to placebo administration. The decrease in the number of migraine patients who took emergency medication within 24 hours post-dose of the combination in question may be approximately 25-45%, approximately 25-30%, approximately 30-35%, approximately 35-40%, approximately 40-45%, approximately 34-36%, or approximately 35% compared to meloxicam administration. The decrease in the number of migraine patients who took emergency medication within 24 hours post-dose of the combination in question may be approximately 25-40%, approximately 25-30%, approximately 30-35%, approximately 35-40%, approximately 33-35%, or approximately 34% compared with rizatriptan administration.

[167] The following modalities are contemplated:

[168] Embodiment 1. A meloxicam inclusion complex in a cyclodextrin.

[169] Modality 2. A dosage form comprising: 1) the inclusion complex of modality 1 or 2) meloxicam and a carbonate or a bicarbonate.

[170] Modality 3. The dosage form of modality 2 comprising the inclusion complex, wherein the cyclodextrin comprises substituted βcyclodextrin.

[171] Embodiment 4. The dosage form of embodiment 3, in which the substituted β-cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPBCD).

[172] Modality 5. The dosage form of modality 4, where cyclodextrin is SBEβCD.

[173] Modality 6. The dosage form of embodiment 5, in which SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule Petition 870260076164, dated 07 / 30 / 2026, p. 64 / 117 53 / 84 of β-cyclodextrin.

[174] Modality 7. The dosage form of modality 6, in which meloxicam and SBEeCD have a molar ratio of about 0.8 to about 1.2.

[175] Modality 8. The dosage form of modality 6, in which meloxicam and SBEβCD have a molar ratio of approximately 1.

[176] Modality 9. The dosage form of modality 2, 3, 4, 5, 6, 7 or 8, comprising a bicarbonate.

[177] Modality 10. The dosage form of modality 9, in which bicarbonate comprises sodium bicarbonate.

[178] Modality 11. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9 or 10, which is an oral dosage form.

[179] Modality 12. The dosage form of modality 2, 3, 4, 5, 6, 9, 10 or 11, in which approximately 50 mg to approximately 200 mg of SBEβCD is present in the dosage form.

[180] Modality 13. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, in which carbonate or bicarbonate is present in an amount in a range of about 400 mg to about 600 mg.

[181] Modality 14. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, in which the Tmax of meloxicam is reduced compared with a dosage form not having a carbonate, a bicarbonate or a cyclodextrin.

[182] Modality 15. The method of modality 14, in which the Tmax of meloxicam is reached in the patient at a time in a range of about 10 minutes to about 180 minutes after administration.

[183] ​​Modality 16. The dosage form of modality 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 Petition 870260076164, dated 07 / 30 / 2026, page 65 / 117 54 / 84 bicarbonate or cyclodextrin.

[184] Modality 17. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, additionally comprising an acid inhibitor.

[185] Modality 18. The dosage form of modality 17, in which the acid inhibitor is a proton pump inhibitor.

[186] Modality 19. The dosage form of modality 18, in which the proton pump inhibitor is esomeprazole.

[187] Modality 20. The dosage form of modality 19, in which approximately 30 mg to approximately 50 mg of esomeprazole is present in the dosage form.

[188] Modality 21. A method of administering meloxicam orally, comprising administering orally a dosage form of modality 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.

[189] Modality 22. The method of modality 21, in which the dosage form is administered to treat pain.

[190] Modality 23. The method of modality 21, in which the dosage form is administered to treat inflammatory pain.

[191] Modality 24. The method of modality 21, in which the dosage form is administered to treat osteoarthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.

[192] Modality 25. A method of administering meloxicam intravenously, comprising administering intravenously a dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 or 15 to a patient in need of treatment.

[193] Modality 26. The method of modality 21, in which the form of Petition 870260076164, dated 07 / 30 / 2026, page 66 / 117 The 55 / 84 dosage is administered to treat migraine.

[194] Modality 27. A dosage form comprising: 1) the meloxicam inclusion complex in a cyclodextrin, 2) a bicarbonate and 3) a triptan.

[195] Modality 28. The dosage form of modality 27, in which the triptan is rizatriptan.

[196] Modality 29. The dosage form of modality 27, in which bicarbonate comprises sodium bicarbonate.

[197] Modality 30. The dosage form of embodiment 27, in which the cyclodextrin is a β-cyclodextrin sulfobutyl ether (SBEeCD).

[198] Modality 31. The dosage form of embodiment 30, in which SBEeCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[199] Modality 32. The dosage form of modality 30, in which meloxicam and SBEeCD have a molar ratio of about 0.8 to about 1.2.

[200] Modality 33. The dosage form of modality 32, in which meloxicam and SBEβCD have a molar ratio of approximately 1.

[201] Modality 34. The dosage form of modality 27, 28, 29, 30, 31, 32 or 33, which is an oral dosage form.

[202] Modality 35. The dosage form of modality 27, 28, 29, 30, 31, 32, 33 or 34, in which approximately 50 mg to approximately 200 mg of SBEβCD is present in the dosage form.

[203] Modality 36. The dosage form of modality 27, 28, 29, 30, 31, 32, 33, 34 or 35, in which bicarbonate is present in an amount of about 400mg to about 1000mg.

[204] Modality 37. A method of treating migraine, comprising administering a dosage form comprising Petition 870260076164, dated 07 / 30 / 2026, page 67 / 117 56 / 84 meloxicam, at least 400 mg of bicarbonate and 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) the same amount of rizatriptan; 2) without meloxicam; and c) without bicarbonate.

[205] Modality 38. A method of treating migraine, comprising administering meloxicam and about 8 mg to about 13 mg of rizatriptan, based on the weight of rizatriptan in free base form, to a human suffering from an acute migraine pain attack or migraine aura, wherein meloxicam and rizatriptan are administered within about 30 minutes of each other, wherein administering meloxicam to the human results in a meloxicam Tmax of 110 minutes or less and a meloxicam AUCo-24 of about 30 pg h / mL to about 50 pg h / mL.

[206] Possibility 39. A pharmaceutical dosage form comprising: 1) about 0.028 mmol to about 0.085 mmol of meloxicam in a free acid or salt form, 2) about 0.019 mmol to about 0.056 mmol of rizatriptan in a free base or salt form, 3) about 100 mg to about 175 mg of a β-cyclodextrin sulfobutyl ether (SBEeCD), and 4) about 400 mg to about 600 mg of sodium bicarbonate.

[207] Modality 40. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous 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 β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan.

[208] Modality 41. The method of modality 40, in which the patient Petition 870260076164, dated 07 / 30 / 2026, pp. 68 / 117 57 / 84 humans with migraine experience relief from migraine pain as a result of administering the dosage form orally to the migraine patient.

[209] Modality 42. The method of modality 40 or 41, in which the human patient with migraine is free from migraine pain two hours after the dosage form is orally administered to the human patient with migraine.

[210] Modality 43. The method of modality 40, 41 or 42, in which the migraine patient experiences a reduction in nausea as a result of administering the dosage form orally to the migraine patient.

[211] Modality 44. The method of modality 40, 41, 42 or 43, in which the human patient with migraine is free of nausea two hours after the dosage form is orally administered to the human patient with migraine.

[212] Modality 45. The method of modality 40, 41, 42, 43 or 44, in which the migraine patient experiences a reduction in photophobia as a result of orally administering the dosage form to the migraine patient.

[213] Modality 46. The method of modality 40, 41, 42, 43, 44 or 45, in which the human patient with migraine is free of photophobia two hours after the dosage form is orally administered to the human patient with migraine.

[214] Modality 47. The method of modality 40, 41, 42, 43, 44, 45 or 46, in which the migraine patient experiences a reduction in phonophobia as a result of orally administering the dosage form to the migraine patient.

[215] Modality 48. The method of modality 40, 41, 42, 43, 44, 45, 46 Petition 870260076164, dated 07 / 30 / 2026, page 69 / 117 58 / 84 or 47, in which the human patient with migraine is free of phonophobia two hours after the dosage form is orally administered to the human patient with migraine.

[216] Modality 49. The method of modality 40, 41, 42, 43, 44, 45, 46, 47 or 48, in which the dosage form contains from 400mg to 600mg of bicarbonate.

[217] Modality 50. The method of modality 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, in which the dosage form contains about 5 mg to about 50 mg of meloxicam.

[218] Modality 51. The method of modality 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50, in which the dosage form contains about 50 mg to about 200 mg of SBEeCD.

[219] Modality 52. ​​The method of modality 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 humans than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain an SBEeCD and 3) does not contain a bicarbonate.

[220] Modality 53. The method of modality 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52, in which about 1 mg to about 50 mg of rizatriptan is present in the oral dosage form based on the weight of rizatriptan in free base form.

[221] Modality 54. The method of embodiment 53, in which rizatriptan is present in salt form in an amount that is a molar equivalent of about 10 mg of rizatriptan in free base form.

[222] Modality 55. The method of modality 53 or 54, in which rizatriptan is present as rizatriptan benzoate.

[223] Modality 56. The method of modality 40, 41, 42, 43, 44, 45, 46, Petition 870260076164, dated 07 / 30 / 2026, pp. 70 / 117 59 / 84 47, 48, 49, 50, 51, 52, 53, 54 or 55, where the oral dosage form contains approximately 10mg to approximately 30mg of meloxicam.

[224] Modality 57. The method of modality 56, in which the oral dosage form contains approximately 20 mg of meloxicam.

[225] Modality 58. The method of modality 56, in which the oral dosage form contains approximately 15 mg of meloxicam.

[226] 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 SBEeCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[227] Modality 60. The method of modality 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59 in which the oral dosage form contains about 50 mg to about 150 mg of SBEβCD.

[228] Modality 61. The method of modality 60, in which the oral dosage form contains approximately 100 mg of SBEβCD.

[229] Modality 62. The method of modality 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61, wherein the molar ratio of SBEβCD to meloxicam is about 0.5 to about 2.

[230] Modality 63. The method of modality 62, where the molar ratio of SBEβCD to meloxicam is about 0.8 to about 1.2.

[231] Modality 64. The method of modality 62, where the molar ratio of SBEβCD to meloxicam is about 1.

[232] Modality 65. The method of modality 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.

[233] Modality 66. The method of modality 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, in which Petition 870260076164, dated 07 / 30 / 2026, pp. 71 / 117 The 60 / 84 oral dosage form contains SBEeCD which is in a weight ratio to rizatriptan that is within a range of about 1 to about 100.

[234] Modality 67. The method of modality 66, in which the oral dosage form contains SBEeCD which is in a weight ratio to rizatriptan which is approximately 10.

[235] Modality 68. The method of modality 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 bicarbonate comprises sodium bicarbonate.

[236] Modality 69. The method of modality 68, in which the oral dosage form contains 500 mg of sodium bicarbonate.

[237] Modality 70. The modality method 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 or 69, in which the oral dosage form was shown to have a median Tmax of meloxicam that is less than about 90 minutes in fasting human subjects.

[238] Modality 71. The modality 70 method, in which the oral dosage form was shown to have a median Tmax of meloxicam that is less than about 2 hours in fasting human subjects.

[239] Modality 72. The method of modality 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71, in which the oral dosage form has been shown to have a faster time to therapeutic plasma concentration in humans compared with the reference dosage form.

[240] Modality 73. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous migraine treatments and orally administering a dosage form to the migraine patient, in Petition 870260076164, dated 07 / 30 / 2026, page 72 / 117 61 / 84 that the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the human patient with migraine experiences relief from migraine pain as a result of orally administering the dosage form to the migraine patient.

[241] Modality 74. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous 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 β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the human patient with migraine is free from migraine pain two hours after the dosage form is orally administered to the human patient with migraine.

[242] Modality 75. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous 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 β-cyclodextrin sulfobutyl ether (SBEeCD)), 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.

[243] Modality 76. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous migraine treatments and orally administering a dosage form to the migraine patient, in Petition 870260076164, dated 07 / 30 / 2026, pp. 73 / 117 62 / 84 that the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the human migraine patient is free of nausea two hours after the dosage form is orally administered to the human migraine patient.

[244] Modality 77. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous 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 β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the migraine patient experiences a reduction in photophobia as a result of orally administering the dosage form to the migraine patient.

[245] Modality 78. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous 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 β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the human patient with migraine is free of photophobia two hours after the dosage form is orally administered to the human patient with migraine.

[246] Modality 79. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous migraine treatments and orally administering a dosage form to the migraine patient, in Petition 870260076164, dated 07 / 30 / 2026, pp. 74 / 117 63 / 84 that the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the migraine patient experiences a reduction in phonophobia as a result of orally administering the dosage form to the migraine patient.

[247] Modality 80. A method of treating migraine comprising: selecting a human patient with migraine with a history of inadequate response to previous 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 β-cyclodextrin sulfobutyl ether (SBEeCD)), 2) a bicarbonate and 3) a rizatriptan, wherein the human patient with migraine is free of phonophobia two hours after the dosage form is orally administered to the human patient with migraine. EXAMPLE 1

[248] The effect of varying amounts of potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) on the pH of an acidic medium was tested. The acidic medium was chosen to simulate gastric conditions. K2CO3 or NaHCO3 was added to 50 mL of a 0.01 N HCl solution (pH 2). The pH of the solution was measured after the addition of K2CO3 or NaHCO3. Deionized water (240 mL) was then added to the mixture and the pH was measured again. The results are shown in Table 1-4. Table 1. Results with K2CO3 (0.01 N HCl) K2CO3 (mg) PH 25 2.84 35 6.29 45 8.05 Petition 870260076164, dated 07 / 30 / 2026, pp. 75 / 117 64 / 84 K2CO3 (mg) pH 50 8.29 100 9.43 200 10.14 300 10.39 400 10.55 450 10.58 Table 2. Results with K2CO3 (0.01 N HCl + Water) K2CO3 (mg) PH 200 10.27 300 10.46 400 10.57 450 10.63 Table 3. Results with NaHCO3 (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 NaHCO3 (0.01 N HCl + Water) NaHCO3 (mg) PH 200 5.41 300 5.89 400 6.11 450 6.46 500 8.33 750 8.54 Petition 870260076164, dated 07 / 30 / 2026, pp. 76 / 117 65 / 84 1000 8.60 EXAMPLE 2

[249] Tablets containing meloxicam and combinations of a β-cyclodextrin sulfobutyl ether (SBEeCD) (a cyclodextrin containing about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin), K2CO3 or NaHCO3 were manufactured and tested for dissolution. Tablets containing only meloxicam (MOBIC®) were acquired and also tested for dissolution. The tested tablets are listed in Table 5. Meloxicam in the form of meloxicam / SBEβCD inclusion complexes was used in the tablets containing meloxicam and SBEβCD. The inclusion complexes were formed by mixing meloxicam and SBEβCD in an aqueous solution of adjusted pH. The pH of the solution was adjusted using buffering agents. The resulting soluble meloxicam / SBEβCD inclusion complexes were then spray-dried. This spray-dried dispersion was used in the manufacture of tablets containing SBEβCD. Table 5. Tablets Tablet A 15mg meloxicam + 25mg K2CO3 Tablet B 15mg meloxicam + 50mg K2CO3 Tablet C 15mg meloxicam + 100mg K2CO3 Tablet D 15mg meloxicam + 150mg K2CO3 Tablet E 15mg meloxicam + 500mg NaHCO3 Tablet F 15mg meloxicam + 100mg SBEPCD Tablet G 15mg meloxicam + 100mg SBEPCD + 25mg K2CO3 Tablet H 15mg meloxicam + 100mg SBEPCD + 50mg K2CO3 Tablet I 15mg meloxicam + 100mg SBEPCD + 100mg K2CO3 Tablet J 15mg meloxicam + 100mg SBEPCD + 150mg K2CO3 Tablet K 15mg meloxicam + 100mg SBEPCD + 500mg NaHCO3 Tablet L 15mg meloxicam (MOBIC®)

[250] The acid dissolution test (chosen to simulate the Petition 870260076164, dated 07 / 30 / 2026, pp. 77 / 117 The experiment (66 / 84 gastric conditions) was performed by placing the tablets in a 0.01 N HCl solution, at a stirring rate of 75 RPM and a container temperature of approximately 37°C. The results are presented in Table 6 and Figures 1-10. The results at various time points (0, 15, 30, 45, 60, 90 and 120 minutes) are presented as a percentage (%) of meloxicam dissolved. Table 6. Dissolution Results 0 minute 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Tablet A 0% 23% 17% 15% 13% 12% 11% Tablet B 0% 27% 20% 17% 16% 17% 15% Tablet C 0% 31% 26% 25% 24% 23% 21% Tablet D 0% 30% 26% 25% 24% 23% 22% Tablet E 0% 50% 66% 77% 84% 92% 95% Tablet F 0% 26% 17% 14% 12% 11% 10% Tablet G 0% 48% 39% 26% 20% 16% 14% Tablet H 0% 44% 30% 22% 17% 16% 13% Tablet I 0% 32% 33% 27% 21% 16% 15% Tablet J 0% 26% 27% 19% 15% 12% 11% Tablet K 0% 85% 86% 86% 86% 86% 86% Tablet L 0% 2% 2% 2% 2% 2% 2%

[251] Meloxicam dissolution was superior with tablets containing various combinations of meloxicam and SBEeCD, K2CO3 or NaHCOs, compared with tablets containing only meloxicam. For example, after 120 minutes, the dissolution of meloxicam tablets containing NaHCOs was 95% compared with 2% for tablets containing only meloxicam.

[252] The dissolution of meloxicam increases with increasing amounts of K2CO3 in the absence of SBEeCD. However, in the presence of SBEeCD, the Petition 870260076164, dated 07 / 30 / 2026, pp. 78 / 117 67 / 84 increasing the amount of K2CO3 did not appear to increase meloxicam dissolution. At the highest dose of potassium carbonate tested, meloxicam dissolution in the presence of SBEeCD was reduced by approximately 50% compared to meloxicam dissolution in the absence of SBEβCD at 120 minutes.

[253] Meloxicam dissolution with NaHCO3 was significantly higher than that observed with the highest dose of K2CO3 at 15 minutes (50% versus 30%) and at 120 minutes (92% versus 23%). Meloxicam dissolution in the presence of SBEβCD was also significantly higher with NaHCO3 compared to the highest dose of K2CO3 at 15 minutes (85% versus 26%) and at 120 minutes (86% versus 12%). NaHCO3 in the presence of SBEβCD increased meloxicam dissolution more at 15 minutes compared to potassium carbonate, which resulted in reduced dissolution. EXAMPLE 3

[254] A bilayer tablet was prepared containing 1) an inclusion complex of SBEβCD with meloxicam, prepared as described below and 2) sodium bicarbonate (SBEβCD-Meloxicam / Bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam and 100 mg SBEβCD and 100 mg sodium bicarbonate. The second layer contained 40 mg esomeprazole and 400 mg sodium bicarbonate.

[255] A total of 20 human subjects were randomly assigned at a 1:1 ratio to treatment with the SBEβCDMeloxicam / Bicarbonate tablets described above or Mobic® tablets (15 mg meloxicam), once daily for 6 days under fasting conditions.

[256] On the first day of dosing, plasma samples were collected for analysis of meloxicam concentration at various time points. Meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. The results are Petition 870260076164, dated 07 / 30 / 2026, pp. 79 / 117 68 / 84 represented in FIG. 11.

[257] The median Tmax for meloxicam, the primary outcome of the trial, was 9 times faster for SBEeCD-Meloxicam / Bicarbonate tablets compared with Mobic® (0.5 hours versus 4.5 hours, respectively, p<0.0001).

[258] SBEeCD-Meloxicam / Bicarbonate tablets also demonstrated a higher mean peak plasma concentration (Cmax) (p=0.0018), faster time to therapeutic plasma concentration (p<0.0001) and faster time to half peak plasma concentration (p<0.0001) compared with Mobic®.

[259] Meloxicam in the form of meloxicam / SBEeCD inclusion complexes was used in tablets containing meloxicam and SBEeCD. The inclusion complexes were formed by mixing meloxicam and SBEeCD in an aqueous solution of adjusted pH. The pH of the solution was adjusted using buffering agents. The resulting soluble meloxicam / SBEβCD inclusion complexes were then spray-dried. This spray-dried dispersion was used in the manufacture of tablets containing SBEβCD. EXAMPLE 4

[260] A monolayer tablet containing 1) the SBEβCD inclusion complex with meloxicam; 2) rizatriptan; and 3) sodium bicarbonate, was prepared (SBEβCD-Meloxicam / rizatriptan / Bicarbonate). The monolayer tablet contained 20 mg of meloxicam, 10 mg of rizatriptan, and 500 mg of sodium bicarbonate. The inclusion complex was the same as the inclusion complex in Example 3.

[261] The tablet dissolution test in an acidic medium (chosen to simulate gastric conditions) was performed by placing the tablets in a 0.01 N HCl solution at a stirring rate of 75 RPM. Petition 870260076164, dated 07 / 30 / 2026, pp. 80 / 117 69 / 84 and a container temperature of approximately 37°C. The results are presented in Table 7. The results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percentage (%) of meloxicam and percentage (%) 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%

[262] 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 that the pharmacokinetic properties, including bioavailability, Tmax of meloxicam, etc., of the tablets in Example 4 would be similar to those described in Example 3 and FIG. 11. This expectation turned out to be correct, as shown in the following examples. EXAMPLE 5

[263] The monolayer tablet of Example 4 was administered to six human subjects. On the first day of dosing, plasma samples were collected for analysis of rizatriptan concentration at various time points. Rizatriptan and meloxicam concentrations 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 dosage form of rizatriptan, Maxalt®, is 1.0-1.5 hours. EXAMPLE 6

[264] A Phase 1, randomized, single-dose, group clinical study Petition 870260076164, dated 07 / 30 / 2026, pp. 81 / 117 A 70 / 84 parallel trial was conducted to evaluate the PK, safety, and tolerability of 1) a combination of meloxicam (20 mg), rizatriptan (10 mg), SBEeCD, and sodium bicarbonate (meloxicam / rizatriptan), compared with 2) Maxalt® (10 mg rizatriptan), in healthy human volunteers after oral administration under fasting conditions. A total of 20 healthy adult male or female volunteers were randomized in a 1:1 ratio to receive a single dose of meloxicam / rizatriptan or Maxalt® (10 mg rizatriptan).

[265] Blood samples for PK analysis were collected pre-dose and at multiple post-dose time points. The pre-specified primary outcome was Ttera, the time to reach a therapeutic plasma concentration of meloxicam, defined as the mean Cmax 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 those of Maxalt® (rizatriptan).

[266] The PK results for the meloxicam (20 mg) component of meloxicam / rizatriptan from this assay were compared to the PK results for Mobic® (15 mg meloxicam) from Example 3. Phase 1 Results

[267] Meloxicam was rapidly absorbed after oral administration of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan), with a median time to therapeutic plasma concentration (Ttera) of 17 minutes, the primary endpoint (Figure 12 and Table 8). The 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 a rapid onset of action in the treatment of migraine. The mean plasma elimination half-life (T1 / 2) for meloxicam was 18.2 hours after administration of meloxicam / rizatriptan, which compares to 21.5 hours for standard meloxicam. Petition 870260076164, dated 07 / 30 / 2026, page 82 / 117 71 / 84 The long elimination half-life suggests the potential of meloxicam / rizatriptan to enhance and sustain efficacy and to reduce the recurrence of migraine pain. Table 8. Pharmacokinetic Parameters of Meloxicam for Meloxicam / Rizatriptan Statistics AUCo-inf (ng^h / mL) T1 / 2 el (h) Cmax(ng / mL) Tmax (h)a Ttera (h)a N 10 10 10 10 10 Geometric Mean 46.865 17.5 2.532 1.0 0.29 SD 11.965 5.25 607 0.5-2.5 0.20-0.61 aTmax and Ttera present the value as a median or a range.

[268] Rizatriptan was rapidly absorbed after oral administration of meloxicam / rizatriptan, with a Tmax of 0.64 hours (38 minutes), which compares to 0.88 hours for the same dose of standard rizatriptan (Maxalt®) (Figure 13 and Table 9). Systemic exposure measured using Cmax and AUC was also numerically higher for rizatriptan after administration of meloxicam / rizatriptan versus standard rizatriptan. Table 9. Pharmacokinetic parameters of rizatriptan for Meloxicam / Rizatriptan and Standard Rizatriptan Statistics AUC0-inf (pg^h / mL) T1 / 2 el (h) Cmax (ng / mL) Tmax (h)a Meloxicam / Rizatriptan (20mg meloxicam / 10mg rizatriptan) N 10 10 10 10 Geometric Mean 83,800 1.98 29,991 0.64 SD 22,787 0.28 11,041 0.5 -2.5 Rizatriptan Standard (Maxalt®) (10mg rizatriptan) N 10 10 10 10 Geometric Mean 71,811 1.81 23,236 0.88 SD 24,287 0.11 9,476 0.5 -2 aTmax presents the value as a median or a range. Petition 870260076164, dated 07 / 30 / 2026, page 83 / 117 72 / 84

[269] Meloxicam / rizatriptan was well tolerated, with no relevant differences in the safety profile between the two treatment arms. There were no serious adverse events in the study. EXAMPLE 7

[270] A Phase 3, randomized, double-blind, multicenter, active- and placebo-controlled trial is conducted to verify the efficacy and safety of meloxicam / rizatriptan in the acute treatment of moderate to severe migraine in patients with a history of inadequate response to previous 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 SBEeCD and sodium bicarbonate as described in Example 4 above), rizatriptan (10 mg) (rizatriptan arm), meloxicam (20 mg) with SBEeCD and sodium bicarbonate (meloxicam arm), or placebo. The co-primary endpoints are freedom from headache and freedom from the most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia) two hours after dosing for meloxicam / rizatriptan compared with placebo.

[271] The superiority of meloxicam / rizatriptan to rizatriptan and meloxicam arms (contributing component) will be established based on freedom from sustained headache from 2 to 24 hours after dosing (key secondary endpoint).

[272] Eligible patients must have a history of inadequate response to previous acute migraine treatments, verified using the Migraine Treatment Optimization Questionnaire (mTOQ-4). The mTOQ-4 is a validated questionnaire that verifies the efficacy response to previous acute treatments based on four aspects (freedom from pain for two hours, efficacy for at least 24 hours with one dose, ability to plan Petition 870260076164, dated 07 / 30 / 2026, page 84 / 117 73 / 84 daily activities and interruption of daily activities).

[273] Meloxicam / rizatriptan is expected to show significant improvement over placebo and superiority over rizatriptan and meloxicam arms due to the rapid absorption and distinct dual mechanisms of action of meloxicam / rizatriptan described in the present invention. EXAMPLE 8

[274] A woman suffering from migraine visits her doctor hoping to find relief from her migraine pain. Her doctor gives her 10 mg of rizatriptan (Maxalt®), which she takes during her next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. At her next visit, her doctor gives her 20 mg of meloxicam in a tablet also containing SBEeCD and 500 mg of sodium bicarbonate, which she takes during her next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. At her next visit, her doctor gives her a tablet described in Example 4 above. She reports that 2 hours and 24 hours after taking the tablet, she experienced approximately a 10-30% improvement in pain, nausea, allodynia, photophobia, and / or phonophobia compared to what she experienced after taking only meloxicam or rizatriptan. EXAMPLE 9

[275] A man suffering from migraine visits his doctor hoping to find relief from his migraine pain. His doctor gives him 10 mg of rizatriptan (Maxalt®), which he takes during his next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On his next visit, his doctor gives him 20 mg of meloxicam in a tablet also containing SBEeCD and 500 mg of sodium bicarbonate, which he takes during his next acute migraine. He Petition 870260076164, dated 07 / 30 / 2026, pp. 85 / 117 74 / 84 provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. At 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 experienced approximately a 30-60% improvement in pain, nausea, allodynia, photophobia, and / or phonophobia compared to what he experienced after taking only meloxicam or rizatriptan. EXAMPLE 10

[276] A woman suffering from migraine visits her doctor hoping to find relief from her migraine pain. Her doctor gives her 10 mg of rizatriptan (Maxalt®), which she takes during her next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. At her next visit, her doctor gives her 20 mg of meloxicam in a tablet also containing SBEeCD and 500 mg of sodium bicarbonate, which she takes during her next acute migraine. It provides some relief from pain, nausea, allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. At her next visit, her doctor gives her a tablet described in Example 4 above. She reports that 2 hours and 24 hours after taking the tablet, she experienced approximately a 60-100% improvement in pain, nausea, allodynia, photophobia, and / or phonophobia compared to what she experienced after taking only meloxicam or rizatriptan. EXAMPLE 11

[277] More than 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 recurring attacks of throbbing headache, often severe and debilitating, associated with nausea and sensitivity to light and / or sound. Migraine is estimated to be Petition 870260076164, dated 07 / 30 / 2026, p. 86 / 117 75 / 84 responsible for $78 billion in direct costs (e.g., medical visits, medications) and indirect costs (e.g., absenteeism, lost productivity) 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. April 2017; 81(4):479-484]. Published research with people who suffer from migraine indicates that more than 70% are not fully satisfied with their current treatment, that almost 80% would try a new therapy, and that they want treatments that work faster, more consistently, and result in less recurrence of symptoms [(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.16 de junho de 2014; 9(6):e98933, 6; e (2) Lipton RB, Stewart WF, Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999; 39(suppl 2):S20-S26].

[278] The World Health Organization classifies severe migraine attacks as one of the most disabling diseases, comparable to dementia, tetraplegia, 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]. Most patients are not Petition 870260076164, dated 07 / 30 / 2026, page 87 / 117 76 / 84 completely satisfied with their current treatment. Thus, there is an urgent need for new treatments that provide improved effectiveness for this serious neurological disease.

[279] A Phase 3, randomized, double-blind, multicenter, placebo- and active-controlled trial was conducted to verify the efficacy and safety of the combination of meloxicam and rizatriptan (meloxicam / rizatriptan) in the acute treatment of moderate to severe migraine. Eligible patients had to be 18 to 65 years old, have an established diagnosis (of at least 1 year) of migraine with or without aura, as defined by the ICHD-3 criteria, an average of 2 to 8 moderate to severe migraines per month, and a history of inadequate response to previous treatments for acute migraine, verified by a score of 7 using the Migraine Treatment Optimization Questionnaire (mTOQ-4) (the average score was 3.6), corresponding to a poor response to previous acute treatments.Exclusion criteria included cluster headaches or other types of migraine, chronic daily headache (> 15 headache days without migraine per month), a history of significant cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, the patients involved exhibited a high rate of characteristics that are strongly associated with poor treatment outcomes, including cutaneous allodynia (75.4%), severe migraine intensity (41.2%), obesity (43.7%), and morning migraine (36.6%). A total of 1,594 patients were randomized in a 2:2:2:1 ratio to the Example 4 monolayer tablet (20 mg meloxicam / 10 mg rizatriptan, with SBEeCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg) with SBEeCD (Meloxicam MoSEIC), or placebo, to treat a single attack of moderate or severe migraine intensity. The two co-primary outcomes of the trial were the proportion of... Petition 870260076164, dated 07 / 30 / 2026, pp. 88 / 117 77 / 84 patients without headache 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 compared with placebo. The superiority of meloxicam / rizatriptan to the rizatriptan and meloxicam arms (contributing component) would be established based on freedom from sustained headache two to 24 hours after dosing (key secondary outcome). The study was conducted in accordance with an FDA Special Protocol Verification (SPA). Rizatriptan, a comparator active in the trial, is considered 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.November 17, 2001; 358(9294):1668-75).

[280] Meloxicam / rizatriptan provided rapid migraine pain relief, with the percentage of patients achieving pain relief with meloxicam / rizatriptan being numerically higher than with rizatriptan at each measured time point 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).

[281] Meloxicam / rizatriptan met both co-primary regulatory endpoints, demonstrating, with high statistical significance, a higher percentage of patients compared with placebo achieving pain freedom (19.9% ​​versus 6.7%, p <0.001, Fig. 15) and absence of the symptom. Petition 870260076164, dated 07 / 30 / 2026, pp. 89 / 117 78 / 84 more bothersome (36.9% versus 24.4%, p=0.002), 2 hours after dosing.

[282] The superiority of meloxicam / rizatriptan to rizatriptan (comparator active) and meloxicam MoSEIC™ (contributing component) was established as specified in the SPA, by demonstrating a higher percentage of patients receiving meloxicam / rizatriptan achieving sustained pain freedom from 2 to 24 hours post-dosing, compared with rizatriptan, meloxicam MoSEIC™, 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 key secondary endpoint pre-specified to demonstrate the contributing component. Approximately 80% of patients treated with meloxicam / rizatriptan who achieved pain freedom at 2 hours maintained pain freedom for 24 hours. These results demonstrated the significant improvement in pain freedom and superiority from meloxicam / rizatriptan to rizatriptan in the treatment of migraine.

[283] Meloxicam / rizatriptan provided substantially superior and more sustained relief of migraine pain compared with placebo and rizatriptan, which translated into a significant reduction in emergency medication use for meloxicam / rizatriptan compared with placebo and rizatriptan. The percentage of patients who experienced sustained pain relief from 2 hours to 24 hours after dosing was 53.3% for meloxicam / rizatriptan, compared with 33.5% for placebo and 43.9% for rizatriptan (p <0.001, p=0.006, respectively versus meloxicam / rizatriptan) (Fig. 16B).

[284] Sustained pain relief from 2 hours to 48 hours was also experienced by a statistically significantly higher proportion of patients with meloxicam / rizatriptan (46.5%) compared with patients with placebo (31.1%) and rizatriptan (36.5%) (p<0.001, p=0.003, Petition 870260076164, dated 07 / 30 / 2026, pp. 90 / 117 79 / 84 respectively versus meloxicam / rizatriptan) (Fig. 17B). Sustained pain freedom from 2 hours to 48 hours was also experienced by a statistically significantly higher proportion of patients with meloxicam / rizatriptan (15.4%) compared with patients on placebo (5.3%) and rizatriptan (8.8%) and meloxicam MoSEIC™ (8.1%) (p<0.001, p=0.003, p=<0.001, respectively versus meloxicam / rizatriptan) (Fig. 17A). Approximately 77% of patients treated with meloxicam / rizatriptan who achieved pain freedom at 2 hours maintained pain freedom for 48 hours.

[285] Emergency medication was used by 23.0% of patients who received meloxicam / rizatriptan, compared with 43.5% of patients who received placebo and 34.7% of patients who received rizatriptan (p<0.001 for each group versus meloxicam / rizatriptan) (Fig. 18). Approximately 77% of patients who received meloxicam / rizatriptan did not require emergency medication. These results demonstrated the superiority of meloxicam / rizatriptan to rizatriptan, an active comparator, in the treatment of migraine.

[286] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan in several other secondary outcomes, including Patient Global Impression of Change (PGI-C) (p=0.022) and return to normal functioning at 24 hours (p=0.027).

[287] Some of the p-values ​​for meloxicam / rizatriptan versus rizatriptan for various outcomes are listed in Table 10 below, demonstrating the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in the treatment of migraine. Table 10. p-values ​​for Meloxicam / Rizatriptan vs. Rizatriptan for Various Outcomes Petition 870260076164, dated 07 / 30 / 2026, pp. 91 / 117 80 / 84 Outcome p-value Meloxicam / Rizatriptan vs Rizatriptan 1 hour Pain Relief 0.04 Sustained Pain Relief for 2-24 hours 0.006 Sustained Pain Relief for 2-48 hours 0.003 Sustained Pain Freedom for 2-24 hours 0.038 Sustained Pain Freedom for 2-48 hours 0.003 PGI-C 0.022 Functional Improvement at 24 hours 0.027 Emergency Medication Use <0.001

[288] Given that rizatriptan, a comparator active in the trial, is considered the fastest-acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine, and that this trial involved patients with difficult-to-treat migraine, the observed effects of treatment with meloxicam / rizatriptan, which provided superior and longer-lasting migraine pain relief than rizatriptan, are 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.

[289] 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 higher than placebo or greater than 3%. There was one serious adverse event in the meloxicam / rizatriptan arm that was considered Petition 870260076164, dated 07 / 30 / 2026, pp. 92 / 117 81 / 84 by the investigator as unrelated to the study drug.

[290] The results of this trial demonstrate the ability of meloxicam / rizatriptan to provide unique benefits for migraine patients, with accelerated, strong and durable relief of migraine pain compared to a potent comparator active, rizatriptan, in a rigorously 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 and patient dissatisfaction with current treatments.

[291] Meloxicam / rizatriptan incorporates multiple mechanisms of action targeting various migraine processes with the aim of providing enhanced efficacy. Meloxicam / rizatriptan is believed to act by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and inhibiting neuroinflammation, pain signal transmission, and central sensitization. The results of this trial validate this approach, demonstrating that meloxicam / rizatriptan can provide significant benefit that is superior to currently available treatments, even in patients with difficult-to-treat migraine. Meloxicam / rizatriptan can be used for the acute treatment of migraine in adults with or without aura effectively. EXAMPLE 12

[292] Meloxicam / rizatriptan is also being evaluated in another Phase 3 trial, which is a randomized, double-blind, placebo-controlled study evaluating early migraine treatment with meloxicam / rizatriptan. In contrast to this ongoing trial in which patients with a history of inadequate response were treated for migraine attacks once they developed moderate or severe migraine, in the other trial, patients must administer meloxicam / rizatriptan Petition 870260076164, dated 07 / 30 / 2026, pp. 93 / 117 82 / 84 at the earliest sign of migraine pain.

[293] Eligible patients are randomized in a 1:1 ratio to treatment with meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with SBEeCD and sodium bicarbonate as described in Example 4 above) or placebo. Adult individuals with an established diagnosis of migraine with or without aura. Treatment with meloxicam / rizatriptan is initiated at the first sign of migraine pain onset.

[294] The co-primary endpoints are freedom from headache and freedom from the most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia), two hours after dosing, for meloxicam / rizatriptan compared with placebo.

[295] Unless otherwise indicated, all numbers expressing ingredient quantities, properties such as amounts, percentages, and so forth, used in the specification and claims shall be understood in all cases as indicating the exact values, as shown, and as being modified by the term “about.” Therefore, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the desired properties sought to be obtained. At a minimum, 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 interpreted in light of the number of significant digits reported and applying common rounding techniques.

[296] The terms “a”, “an”, “the” and similar referents used in the context of describing the embodiments (especially in the context of the following claims) should be interpreted to cover both the singular and the plural, unless otherwise indicated in the present invention or clearly stated. Petition 870260076164, dated 07 / 30 / 2026, pp. 94 / 117 83 / 84 contradicted by the context. All methods described in this invention can be performed in any appropriate order, unless otherwise indicated in this invention or otherwise clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., “such as”) provided in the present invention is intended merely to better illuminate embodiments and does not represent a limitation on the scope of any claim. No language in the specification should be interpreted as indicating any unclaimed element essential to the performance of claims.

[297] The alternative groupings of elements or embodiments disclosed in the present invention should not be interpreted as limitations. Each member of the group may be referred to and claimed individually or in any combination with other members of the group or other elements found in the present invention. It is foreseen that one or more members of a group may be included or deleted from a group for reasons of convenience and / or to expedite the process. When any such inclusion or deletion occurs, the specification is considered as containing the modified group, thus fulfilling the written description of all Markush groups if used in the appended claims.

[298] Certain embodiments are described in the present invention, including the best known mode of carrying out the claimed embodiments. Certainly, variations in these described embodiments will become apparent to those skilled in the art by reading the preceding description. The inventor expects those skilled in the art to employ such variations as appropriate, and the inventors intend that the claimed embodiments be carried out in a manner other than that specifically described in the present invention. Therefore, the claims include all of the Petition 870260076164, dated 07 / 30 / 2026, pp. 95 / 117 84 / 84 modifications and equivalents of the material cited in the claims, as permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations thereof is contemplated, unless otherwise indicated in the present invention or otherwise clearly contradicted by the context.

[299] In closing, it should be understood that the embodiments disclosed in the present invention are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not limitation, alternative embodiments may be used in accordance with the teachings of the present invention. Therefore, the claims are not limited to embodiments precisely as shown and described. Petition 870260076164, dated 07 / 30 / 2026, pp. 96 / 117

Claims

1 / 3 CLAIMS 1. Use of a combination, characterized in that it is for the manufacture of a medicament to treat migraine in a human patient with migraine with a history of inadequate response to previous migraine treatments, wherein the medicament is formulated to be orally administered to the migraine patient, and wherein the medicament comprises a combination of meloxicam and rizatriptan.

2. Use according to claim 1, characterized in that the human patient with migraine experiences relief from migraine pain as a result of oral administration of the medication to the migraine patient.

3. Use according to claim 1 or 2, characterized in that the human patient with migraine is free from migraine pain two hours after the medication is orally administered to the human patient with migraine.

4. Use in accordance with any of claims 1 to 3, characterized in that the patient has nausea, photophobia or phonophobia, or a combination thereof, and in that the migraine patient experiences a reduction in nausea, photophobia or phonophobia as a result of oral administration of the medication to the migraine patient.

5. Use according to claim 4, characterized in that the human patient with migraine is free from nausea, photophobia or phonophobia two hours after the medication is orally administered to the human patient with migraine.

6. Use in accordance with any of claims 1 to 5, characterized in that the combination contains from about 5 mg to about 50 mg of meloxicam. Petition 870260076164, dated 07 / 30 / 2026, p. 97 / 117 2 / 3 7. Use according to any of claims 1 to 6, characterized in that the medicine is a solid oral medicine comprising a combination of: 1) a meloxicam complex with a β-cyclodextrin sulfobutyl ether (SBEeCD), 2) a bicarbonate, and 3) rizatriptan, wherein the medicine has a shorter Tmax of meloxicam in humans than a reference medicine that: 1) contains the same amount of meloxicam, 2) does not contain an SBEeCD, 3) does not contain a rizatriptan, and 4) does not contain a bicarbonate.

8. Use in accordance with any of claims 1 to 7, characterized in that about 1 mg to about 50 mg of rizatriptan is present in the oral medication based on the weight of rizatriptan in free base form.

9. Use according to claim 8, characterized in that rizatriptan is present in salt form in an amount that is a molar equivalent of about 10 mg of rizatriptan in free base form.

10. Use according to claim 8 or 9, characterized in that rizatriptan is present as rizatriptan benzoate.

11. Use in accordance with any of claims 1 to 10, characterized in that the oral medication contains from about 10 mg to about 30 mg of meloxicam.

12. Use according to claim 11, characterized in that the oral medication contains approximately 20 mg of meloxicam.

13. Use in accordance with any of claims 7 to 12, characterized in that SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

14. Use in accordance with any of claims 7 to 13, characterized in that the oral medication contains approximately 50 mg to approximately 200 mg of SBEβCD. Petition 870260076164, dated 07 / 30 / 2026, pp. 98 / 117 3 / 3 15. Use according to claim 14, characterized in that the oral medication contains approximately 100 mg of SBEeCD.

16. Use in accordance with any of claims 1 to 15, characterized in that the oral medication contains approximately 10 mg to approximately 40 mg of meloxicam and approximately 5 mg to approximately 50 mg of rizatriptan.

17. Use in accordance with any one of claims 7 to 16, characterized in that the bicarbonate comprises 500 mg of sodium bicarbonate.

18. Use according to claim 17, characterized in that the oral medication has been shown to have a mean Tmax of meloxicam that is less than about 2 hours in fasting human subjects.

19. Use in accordance with any of claims 7 to 18, characterized in that the oral medication has been shown to have a faster time to therapeutic plasma concentration in humans compared to the reference medication.

20. Use in accordance with any of claims 7 to 19, characterized in that the combination contains 400 mg to 600 mg of bicarbonate. Petition 870260076164, dated 07 / 30 / 2026, pp. 99 / 117

Images