Pharmaceutical composition comprising meloxicam

Abstract

Disclosed herein are compositions comprising an NSAID, e.g., meloxicam and / or rizatriptan, in combination with a cyclodextrin and / or a carbonate or bicarbonate salt. These compositions can be administered orally, e.g., to improve the bioavailability or pharmacokinetics of an NSAID for the treatment of pain, e.g., migraine, arthritis, and other conditions. Also disclosed herein are methods of treating pain, e.g., migraine, comprising administering meloxicam and rizatriptan to a person suffering from pain, e.g., migraine. For migraine, these methods can be particularly useful when meloxicam and rizatriptan are administered during an acute attack of migraine or migraine aura in a human. In some embodiments, the combination of meloxicam and rizatriptan can be administered in a manner that results in a T max of 3 hours or less.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180094890.5 (filed on December 29, 2021, entitled "Pharmaceutical Composition Containing Meloxicam").

[0002] Cross-reference of related applications

[0003] This application claims priority to U.S. Provisional Patent Application 63 / 133,125, filed December 31, 2020, the entire contents of which are expressly incorporated herein by reference. Background Technology

[0004] Meloxicam, its structure is as follows:

[0005]

[0006] Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities. Its mechanism of action may involve inhibition of prostaglandin synthase (cyclooxygenase, COX), which is involved in the initial steps of the arachidonic acid cascade reaction, leading to a reduction in the formation of prostaglandins, thromboxanes, and prostacyclin. Summary of the Invention

[0007] Meloxicam and some other NSAIDs have poor water solubility, which may reduce bioavailability and slow down pain relief from their use. One way to increase meloxicam dissolution and bioavailability is through the use of cyclodextrins. Cyclodextrins (also known as cyclic amylose) are typically barrel-shaped cyclic polysaccharides. Cyclodextrins help improve the bioavailability of other molecules because the interior of a cyclodextrin is hydrophobic while the exterior is hydrophilic, which facilitates molecule transport. Naturally occurring cyclodextrins contain six, seven, and eight glucose units (α, β, and γ-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (i.e., inclusion complexes) with drugs by incorporating the drug into the central / hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around drugs in a micellar structure. This ability of cyclodextrins allows them to act as carriers to increase the bioavailability of poorly soluble drugs.

[0008] Some implementations include a method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate and 3) rizatriptan.

[0009] Some implementations include meloxicam inclusion complexes in cyclodextrin.

[0010] Some implementations include a dosage form comprising: 1) an inclusion complex of meloxicam and cyclodextrin, or 2) meloxicam and a carbonate or bicarbonate.

[0011] Some implementations include a method of oral administration of meloxicam, the method comprising orally administering the dosage form described herein to a patient requiring treatment.

[0012] Some implementations include a method of intravenous administration of meloxicam, the method comprising administering the dosage form described herein intravenously to a patient requiring treatment.

[0013] This article discloses the formulations and methods of use of inclusion complexes of cyclodextrin and meloxicam with bicarbonate.

[0014] This article discloses formulations and methods for delivering meloxicam and cyclodextrin to subjects via oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral routes.

[0015] It also discloses methods for treating pain and pain-related conditions by delivering dosage forms containing meloxicam, cyclodextrin, and bicarbonate to subjects orally, enterally, intravenously, intramuscularly, subcutaneously, intranasally, or otherwise parenterally.

[0016] The combination of rizatriptan and meloxicam (referred to as the “topic combination” in this article for convenience) can be used to treat a variety of pain conditions.

[0017] Rizatritan has the structure shown below.

[0018]

[0019] Rizatrotan

[0020] Some implementations include a combination of ingredients for treating human migraines, the combination comprising: 1) an inclusion complex of meloxicam and cyclodextrin, 2) rizatriptan, and 3) a bicarbonate. Migraines can be treatment-resistant migraines. Humans may have a history of inadequate response to previous treatments.

[0021] Some implementations include a combination of rizatriptan and meloxicam, which has rapid, sustained, substantial, and statistically significant efficacy in the acute treatment of migraine in patients with a history of inadequate response to prior acute treatment, compared to placebo, rizatriptan, or meloxicam.

[0022] Some implementations include a combination of rizatriptan and meloxicam, which requires significantly less rescue medication compared to rizatriptan, meloxicam, or placebo. Attached Figure Description

[0023] Figure 1 This is a description of the results described in Example 2 and included in Table 6.

[0024] Figure 2 This is another description of the results described in Example 2 and included in Table 6.

[0025] Figure 3 This is another description of the results described in Example 2 and included in Table 6.

[0026] Figure 4 This is another description of the results described in Example 2 and included in Table 6.

[0027] Figure 5 This is another description of the results described in Example 2 and included in Table 6.

[0028] Figure 6 This is another description of the results described in Example 2 and included in Table 6.

[0029] Figure 7 This is another description of the results described in Example 2 and included in Table 6.

[0030] Figure 8 This is another description of the results described in Example 2 and included in Table 6.

[0031] Figure 9 This is another description of the results described in Example 2 and included in Table 6.

[0032] Figure 10 This is another description of the results described in Example 2 and included in Table 6.

[0033] Figure 11 This is a graph showing the implementation of the dosage form described in this article and the plasma concentration of meloxicam at different time points within the first 24 hours for commercially available meloxicam dosage forms.

[0034] Figure 12 This is a graph showing the plasma concentrations of meloxicam at different time points within the first 24 hours for the meloxicam / rizatriptan formulation and the commercially available meloxicam formulation described in Example 6.

[0035] Figure 13 This is a graph showing the plasma concentrations of rizatriptan at different time points within the first 12 hours for the meloxicam / rizatriptan formulation described in Example 6 and the commercially available meloxicam formulation.

[0036] Figure 14A graph showing the percentage of subjects reporting pain relief at different time points within the first 4 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 11.

[0037] Figure 14A The percentage of subjects who reported pain relief with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo at 1.0 and 1.5 hours is shown.

[0038] Figure 15 The percentage of subjects who achieved pain relief at 2, 4, 12, and 16 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo dosage forms described in Example 11 is shown.

[0039] Figure 16A This shows the percentage of subjects who achieved sustained pain relief 2 to 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo dosage forms described in Example 11.

[0040] Figure 16B This shows the percentage of subjects who achieved sustained pain relief 2 to 24 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 11.

[0041] Figure 17A This shows the percentage of subjects who achieved sustained pain relief 2 to 48 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo dosage forms described in Example 11.

[0042] Figure 17B This shows the percentage of subjects who achieved sustained pain relief 2 to 48 hours after administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo formulations described in Example 11.

[0043] Figure 17C The percentage of subjects who achieved sustained pain relief from 2 to 48 hours with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo is shown.

[0044] Figure 17D The percentage of subjects who achieved sustained pain relief from 2 to 48 hours with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo is shown.

[0045] Figure 18This shows the percentage of subjects who took the rescue medication within 24 hours of administration of the meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo dosage forms described in Example 11.

[0046] Figure 19A and Figure 19B This shows the percentage of subjects in Example 12 who received meloxicam / rizatriptan and placebo whose most painful and bothersome symptoms were resolved.

[0047] Figure 20 This shows the percentage of subjects who achieved pain relief over time in Example 12 who took meloxicam / rizatriptan and placebo.

[0048] Figure 21 This shows the percentage of subjects who, over time, experienced relief from their most bothersome symptoms in the subjects taking meloxicam / rizatriptan and placebo in Example 12.

[0049] Figure 22A and Figure 22B The percentage of subjects who achieved pain relief during hours 2–24 and 2–48 was shown for those who took meloxicam / rizatriptan and placebo in Example 12.

[0050] Figure 23 This shows the percentage of subjects who achieved pain relief within 2–24 hours in Example 12 who took meloxicam / rizatriptan and placebo.

[0051] Figure 24 The percentage of subjects who received the rescue medication was shown among those who received meloxicam / rizatriptan and placebo in Example 12.

[0052] Figure 25 The percentage of subjects who did not have functional disability in Example 12, including those taking meloxicam / rizatriptan and placebo, is shown.

[0053] Figure 26 This shows the percentage of subjects who had “significant improvement” or “great improvement” in overall patient impression (PGI-C) at hour 2 in Example 12, for those taking meloxicam / rizatriptan and placebo.

[0054] Figure 27 This demonstrates the probability of experiencing pain relief at different time points after administration for subjects taking meloxicam / rizatriptan, rizatriptan, MoSEIC meloxicam, and placebo in Example 11.

[0055] Figure 28 This shows the percentage of subjects who experienced pain recurrence within 48 hours of administration in Example 11 who took meloxicam / rizatriptan and rizatriptan. Detailed Implementation

[0056] This article provides dosage forms containing an NSAID (e.g., meloxicam) and cyclodextrin (optionally in an inclusion complex) and / or bicarbonate, as well as treatment methods using such dosage forms.

[0057] Dosage forms can be administered via the intestines, including but not limited to oral, sublingual or rectal delivery, or via parenteral delivery, including but not limited to intravenous, intramuscular, intranasal or subcutaneous delivery.

[0058] Some methods involve administering a product containing a combination of NSAIDs, said NSAIDs being formulated with a) cyclodextrin and / or b) a buffer. In some embodiments, the method includes treating a patient with a pharmaceutical formulation comprising meloxicam and cyclodextrin and / or carbonate / bicarbonate. Method embodiments may also include treating the patient to increase the bioavailability of meloxicam in the patient or to increase the rate at which meloxicam becomes bioavailable.

[0059] The combination of meloxicam, cyclodextrin (such as SBEβCD), and bicarbonate (such as sodium bicarbonate) can significantly increase the dissolution and absorption of meloxicam after oral administration, while maintaining its prolonged plasma concentration half-life in mammals (such as humans) after oral administration.

[0060] Combinations of meloxicam, cyclodextrins (e.g., SBEβCD), and bicarbonates (e.g., sodium bicarbonate) can significantly increase the oral bioavailability of meloxicam in mammals (e.g., humans) after oral administration.

[0061] Unless otherwise stated, any reference to the compounds described herein by structure, name or any other means, such as meloxicam or rizatriptan, including pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterated forms, or any other chemical substance such as a prodrug, prodrug or any other chemical substance that can be rapidly converted into the compounds described herein under the conditions under which the compounds are used as described herein, is considered a reference to the compounds described herein.

[0062] The combination of ingredients can be administered enterally, including but not limited to oral, sublingual, or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal, or subcutaneous delivery. In some embodiments, both meloxicam and rizatriptan are administered orally. In some embodiments, meloxicam is administered intravenously, while rizatriptan is administered orally. In some embodiments, meloxicam is administered intramuscularly, while rizatriptan is administered orally.

[0063] Typically, administration of the combination of meloxicam and rizatriptan allows a human to receive meloxicam and rizatriptan within a short period of time relative to each other. For example, meloxicam and rizatriptan may be administered within approximately 2 hours, approximately 1 hour, approximately 30 minutes, approximately 20 minutes, approximately 15 minutes, approximately 10 minutes, approximately 5 minutes, or approximately 1 minute of the other. In some embodiments, meloxicam and rizatriptan are administered simultaneously, which, for the purposes of this disclosure, includes administration within approximately 5 minutes. In some embodiments, meloxicam and rizatriptan are administered in a single dosage form.

[0064] The term “treating” or “treatment” in a broad sense includes any kind of therapeutic activity, including diagnosing, curing, alleviating or preventing disease in humans or other animals, or any activity that otherwise affects the structure or any function of the body of a human or other animal.

[0065] Dosage forms or combinations of therapies may be used to treat or relieve any type of pain, including but not limited to migraines and other types of headaches, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, generalized pain, cancer-related pain, acute pain, pain caused by injury, pain caused by illness (such as fever), postoperative pain, etc. In some cases, pain relief may be palliative or may be provided independently of the improvement of the disease or condition or the underlying cause of the disease or condition. For example, an individual with an underlying disease may experience pain relief even though the disease may not improve or may continue to develop. In some implementations, the pain affects muscles, nerves, cartilage, bone, ligaments, tendons, tendon sheaths, bursae, or joints.

[0066] Migraine is a disabling neurological disorder characterized by recurrent episodes of throbbing headache accompanied by nausea and sensitivity to light and sound. The pain can be moderate to severe, but is often intense and immobile, requiring bed rest. The headache may affect one half of the head, may be throbbing in nature, and can last from 2 to 72 hours. Related symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or odors. Migraines may be accompanied by visual disturbances. Migraine pain can be exacerbated by physical activity. Migraines may be associated with an aura, which may be a brief visual disturbance indicating that the headache will soon follow. Some migraine sufferers may not have an aura.

[0067] In some implementations, a person receiving migraine treatment suffers from atypical pain accompanying migraine attacks, such as atypical skin pain. Atypical pain (e.g., atypical skin pain) is typically triggered by non-painful stimuli (such as combing hair, wearing glasses, bathing, etc.). Patients with atypical pain (e.g., atypical skin pain) are considered less likely to respond well to triptans.

[0068] Current treatment is inadequate, with over 70% of patients reporting dissatisfaction with their existing acute care. The most common reasons for patient dissatisfaction are slow pain relief, inconsistent pain relief, and recurrence of pain on the same day. Inadequate acute care is associated with a significantly increased risk of developing new-onset chronic migraines, which can be prevented by improving acute care outcomes.

[0069] Administering the combination of the themes to a person suffering from an acute attack of migraine, such as a migraine or one with aura, can rapidly induce relief of migraine symptoms, such as pain, nausea, vomiting, photophobia, or phonophobia, for example, within about 5 minutes (an abbreviation of "within about 5 minutes"), within about 10 minutes, within about 30 minutes, within about 1 hour, within about 90 minutes, within about 2 hours, within about 2.5 hours, or within about 3 hours. In some embodiments, the person experiences pain relief or complete remission, such as headache or migraine, nausea, vomiting, photophobia, and / or phonophobia, within about 1 hour, within about 90 minutes, within about 2 hours, within about 2.5 hours, or within about 3 hours. In some embodiments, the relief experienced is greater than that experienced with the same amount of rizatriptan in the absence of meloxicam. In some implementations, the remission experienced is greater than that experienced with the same amount of meloxicam without rizatriptan.

[0070] Thematic combinations can be applied at the earliest signs of migraine, or shortly after, for example, within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, or within about 1 hour. In this early stage, the pain may still be mild, or it may later develop into moderate or severe intensity. For some methods, thematic combinations can be applied when the migraine has already reached moderate or severe intensity.

[0071] In some implementations, the combination of meloxicam and rizatriptan is administered to human migraine patients who have or are selected to have a functional disability. In some implementations, the treatment enables human migraine patients to resume normal activities within 24 hours of receiving treatment.

[0072] The combination of meloxicam and rizatriptan offers a unique dual mechanism of action for the acute treatment of migraines. Meloxicam is a potent COX-2-preferred nonsteroidal anti-inflammatory drug (NSAID) but is slowly absorbed. Rizatriptan is a potent 5-HT1 inhibitor believed to be effective against migraines. B / D Receptor agonists.

[0073] Observing symptom relief or reduction within a specific time period (e.g., "2 hours") is useful because it allows for assessment of treatment effectiveness at specific or consistent time points, which facilitates comparisons between patients. Observing symptom relief or reduction within a specific time period (e.g., "approximately 2 hours") is useful because it is expected that symptom relief or reduction will occur as early as possible, and specifying that relief occurs within a specific timeframe sets guidelines in which relief is expected.

[0074] For some methods, the application of thematic combinations can achieve relief of migraine, nausea, vomiting, photophobia, or phonophobia for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8-24 hours, about 24 hours, or more than 24 hours.

[0075] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the pain relief experienced by humans is greater than the pain relief experienced by humans 2 hours after receiving the same amount of meloxicam without rizatriptan.

[0076] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the pain relief experienced by humans is greater than the pain relief experienced by humans 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0077] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the pain relief experienced by humans is greater than the pain relief experienced by humans 2 hours after receiving the same amount of rizatriptan without meloxicam.

[0078] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the pain relief experienced by humans is greater than the pain relief experienced by humans 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0079] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the nausea relief experienced by humans is greater than the nausea relief experienced by humans 2 hours after receiving the same amount of meloxicam without rizatriptan.

[0080] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the nausea relief experienced by humans is greater than the nausea relief experienced by humans 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0081] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the nausea relief experienced by humans is greater than the nausea relief experienced by humans 2 hours after receiving the same amount of rizatriptan without meloxicam.

[0082] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the nausea relief experienced by humans is greater than the nausea relief experienced by humans 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0083] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the vomiting relief experienced by humans is greater than the vomiting relief experienced by humans 2 hours after receiving the same amount of meloxicam without rizatriptan.

[0084] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and vomiting relief experienced by humans 24 hours after administration of meloxicam and rizatriptan is greater than vomiting relief experienced by humans 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0085] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the vomiting relief experienced by humans is greater than the vomiting relief experienced by humans 2 hours after receiving the same amount of rizatriptan without meloxicam.

[0086] In some embodiments, concurrent administration of meloxicam and rizatriptan (e.g., in a single dosage form, such as a single oral dosage form) resulted in greater relief of vomiting in humans 24 hours after administration of meloxicam and rizatriptan compared to the relief experienced 24 hours after administration of the same amount of rizatriptan without meloxicam. In some embodiments, concurrent administration of meloxicam and rizatriptan (e.g., in a single dosage form, such as a single oral dosage form) resulted in greater relief of photophobia in humans 2 hours after administration of meloxicam and rizatriptan compared to the relief experienced 2 hours after administration of the same amount of meloxicam without rizatriptan.

[0087] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the photophobia relief experienced by humans is greater than the photophobia relief experienced by humans 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0088] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the photophobia relief experienced by humans is greater than the photophobia relief experienced by humans 2 hours after receiving the same amount of rizatriptan without meloxicam.

[0089] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the photophobia relief experienced by humans is greater than the photophobia relief experienced by humans 24 hours after receiving the same amount of rizatriptan without meloxicam.

[0090] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human experience of voice phobia relief is greater than the human experience of voice phobia relief 2 hours after receiving the same amount of meloxicam without rizatriptan.

[0091] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experience of voice phobia relief is greater than that experienced 24 hours after the human receives the same amount of meloxicam without rizatriptan.

[0092] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the human experience of voice phobia relief is greater than the voice phobia relief experienced 2 hours after the human receives the same amount of rizatriptan without meloxicam.

[0093] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 24 hours after administration of meloxicam and rizatriptan, the human experience of voice phobia relief is greater than that experienced 24 hours after the human receives the same amount of rizatriptan without meloxicam.

[0094] In some implementations, the person receiving the combination of therapies has a history of inadequate response to previous migraine treatments. For example, if the person is asked whether he or she is pain-free for two hours during most attacks, and given options of “never,” “rarely,” “less than half the time,” or “more than half the time,” and the person answers “never,” “rarely,” or “less than half the time,” then the person has an inadequate response to treatment. Similarly, if the person is asked whether a dose of medication typically relieves their headache and keeps it for at least 24 hours, and given options of “never,” “rarely,” “less than half the time,” or “more than half the time,” and the person answers “never,” “rarely,” or “less than half the time,” then the person has an inadequate response to treatment.

[0095] In some implementations, the person receiving the subject combination has indicated that he or she "never" experienced pain-free periods for most of the two hours of treatment. In some implementations, the person receiving the subject combination has indicated that he or she experienced "rarely" pain-free periods for most of the two hours of treatment. In some implementations, the person receiving the subject combination has indicated that he or she experienced pain-free periods for most of the two hours of treatment "less than half the time."

[0096] In some embodiments, recipients of the subject combination have indicated that a dose of the medication "never" relieved the recipient's headache and kept it away from the headache for at least 24 hours. In some embodiments, recipients of the subject combination have indicated that a dose of the medication "rarely" relieved the recipient's headache and kept it away from the headache for at least 24 hours. In some embodiments, recipients of the subject combination have indicated that a dose of the medication relieved the subject's headache and kept it away from the headache for at least 24 hours "less than half the time."

[0097] In some implementations, the recipient of the topic combination has a history of inadequate response to previous migraine treatment, as indicated by a total mean score of less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7 as assessed by the migraine treatment optimization questionnaire-4. In some implementations, the recipient has previously used triptan prior to receiving the topic combination, for example, a combination containing meloxicam and rizatriptan.

[0098] In some embodiments, the person receiving the combination of therapies, such as a combination containing meloxicam and rizatriptan, suffers from migraines and may have a history of inadequate response to previous migraine treatments. In some embodiments, the person suffering from migraines does not experience cluster headaches or other types of migraines. In some embodiments, the person suffering from migraines does not experience chronic daily headaches. In some embodiments, the person suffering from migraines has no more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 non-migraine days per month. In some embodiments, the person suffering from migraines does not have a history of major cardiovascular disease. In some embodiments, the person suffering from migraines does not have uncontrolled hypertension.

[0099] In some embodiments, the dosage form may also be administered to relieve arthritis pain. In some embodiments, the dosage form may be administered to relieve other signs and / or symptoms of arthritis. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (oligoarticular and polyarticular courses), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthritis, arthropathy, non-articular rheumatoid diseases, periarticular diseases, axial spondyloarthritis, transient hip osteoarthritis, vertebral compression fractures, osteoporosis and neurogenic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome. In other embodiments, arthritis pain may be chronic or acute. In some embodiments, the dosage form may be administered to relieve signs and / or symptoms of arthritis (including, but not limited to, osteoarthritis).

[0100] For some methods, administration of the dosage form can achieve pain relief lasting for at least about 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least about 8 hours, about 8 to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form can achieve pain relief observed at about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, less than 15 minutes, less than 20 minutes, 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or at other time periods limited by these ranges.

[0101] In some embodiments, the dosage form can also be administered to relieve neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, sciatica, pudendal neuralgia, and central pain. Other causes of neuropathic pain may include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation or chemotherapy-related neuropathy. The neuropathic pain being treated can be chronic or acute.

[0102] In some methods, dosage forms can be administered to relieve inflammatory pain, including inflammatory musculoskeletal pain, injury-related pain, arthritis pain, and complex regional pain syndromes. In other embodiments, the inflammatory pain can be chronic or acute.

[0103] Arthritis refers to inflammatory joint diseases 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) arthropathy, non-articular rheumatoid diseases, periarticular diseases, neurogenic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome. The inflammatory joint diseases treated can be chronic or acute.

[0104] In some methods, meloxicam can be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain may include, but are not limited to, back pain, low back pain (e.g., lumbosacral pain), neck pain, infection, spasm, tendinitis, epididymitis, carpal tunnel syndrome, arthralgia, fibromyalgia, pain due to injury, tubular syndrome, fracture-related pain, sprain, fibrous dysplasia, osteogenesis imperfecta, Paget's disease, transient osteoporosis, and transient hip osteoporosis. In other embodiments, musculoskeletal pain may be chronic or acute.

[0105] For some methods, the administration of dosage forms or combination of therapies can achieve pain relief lasting for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, about 8 to about 24 hours, or about 24 hours. In other embodiments, the application of the theme combination can achieve pain relief observed at approximately 10 minutes, approximately 30 minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 5 minutes or less, approximately 10 minutes or less, approximately 15 minutes or less, approximately 20 minutes or less, approximately 25 minutes or less, approximately 30 minutes or less, approximately 35 minutes or less, approximately 40 minutes or less, approximately 45 minutes or less, approximately 50 minutes or less, or approximately 60 minutes or less, at 2 hours or less, at 3 hours or less, or other time periods limited by these ranges.

[0106] The person treating a disease or condition with the dosage form described herein can be of any age. For example, the person's age can be approximately 10 to approximately 90 years, approximately 20 to approximately 80 years, approximately 30 to approximately 75 years, approximately 40 to approximately 70 years, approximately 1 to approximately 16 years, approximately 80 to approximately 95 years, approximately 18 years or older, approximately 20 years or older, approximately 25 years or older, approximately 30 years or older, approximately 40 years or older, approximately 45 years or older, approximately 50 years or older, approximately 55 years or older, approximately 60 years or older, approximately 65 years or older, or any other age range that is above or between these values.

[0107] In some embodiments, the person treated with migraines using the dosage forms described herein, such as those containing meloxicam, rizatriptan, SBEβCD, and bicarbonates such as sodium bicarbonate, may be 18–65 years of age, approximately 18–20 years of age, approximately 20–25 years of age, approximately 25–30 years of age, approximately 30–40 years of age, approximately 40–45 years of age, approximately 40–50 years of age, approximately 50–60 years of age, approximately 60–65 years of age, or any other age range defined by or between these values.

[0108] In some implementations, the person treating migraines with the dosage forms described herein, such as those containing meloxicam, rizatriptan, SBEβCD, and bicarbonates such as sodium bicarbonate, can be white, black, African American, or Asian.

[0109] In some implementations, a person treating a disease or condition with a dosage form containing meloxicam or another NSAID suffers from pain or pain-related symptoms for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or any duration within or above these values.

[0110] In some implementations, the person treated with a formulation containing meloxicam and rizatriptan has been diagnosed with migraine with or without aura for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years or longer, or at least 1 year, or any duration within or between these values, as defined by the ICHD-3 criteria.

[0111] In some implementations, humans experience an average of 2-8, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 moderate to severe migraines per month.

[0112] Cyclodextrins used in dosage forms with meloxicam may include cyclodextrins, cyclodextrin derivatives, and / or salts thereof. The inclusion complex of meloxicam and cyclodextrin may be more soluble in water than unreintegrated meloxicam. The cyclodextrin may be a naturally occurring cyclodextrin (e.g., α, β, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, its derivatives, or salts 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, succinoyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0113] In some embodiments, β-cyclodextrin, its derivatives, or salts may be used. β-cyclodextrin may include, but is not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl-6-O-sulfonyl)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), and (2,3-di-O-methyl-β-cyclodextrin. (6-O-sulfonyl)-β-cyclodextrin, (2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3,6-tri-O-methyl)-β-cyclodextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, (2,3,6-tri-O-benzoyl)-β-cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin, 6-bromo-6-deoxy-β-cyclodextrin Monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin, (6-O-maltose)-β-cyclodextrin, (6-O-sulfonyl)-β-cyclodextrin, (6-Ot-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinoyl-(2-hydroxypropyl)-β-cyclodextrin, (2,6-di-O-)ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (CMEβCD) HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl-(6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin, succinoyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, random methylated-β-cyclodextrin, branched-chain-β-cyclodextrin or combinations thereof.

[0114] In other embodiments, the β-cyclodextrin can be a sulfonyl ether cyclodextrin, its derivatives, or a salt. Examples of sulfonyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-β-cyclodextrin (e.g., SBEβCD, beta-cyclodextrin (betadex), CAPTISOL®). In some embodiments, for each cyclodextrin molecule, SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups.

[0115] In some embodiments, γ-cyclodextrin, its derivatives, or salts may be used. γ-cyclodextrin may include carboxymethyl-γ-cyclodextrin, (2,3,6-tri-O-acetyl)-γ-cyclodextrin, (2,3,6-tri-O-methyl)-γ-cyclodextrin, (2,6-di-O-pentyl)-γ-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin, 6-bromo-6-deoxy-γ-cyclodextrin, 6-iodo-6-deoxy-γ-cyclodextrin, (6-O-tert-butyldimethylsilyl)-γ-cyclodextrin, succinoyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

[0116] In some embodiments, the dosage form may include bicarbonates, such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or combinations thereof. Bicarbonates may help improve the bioavailability of meloxicam.

[0117] In other embodiments, the dosage form may include carbonates, derivatives, or salts. 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.

[0118] In some embodiments, enhanced bioavailability of the dosage form can be achieved in treating one of these conditions by administering a dosage form containing a meloxicam salt, by forming an inclusion complex with meloxicam and cyclodextrin, and / or by containing a bicarbonate. This allows for the use of a reduced molar amount of meloxicam compared to other meloxicam dosage forms.

[0119] Unless otherwise stated, any reference to the compounds described herein by structure, name or any other means, such as meloxicam or cyclodextrin, includes pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterated forms, or any other chemical substance that can be rapidly converted into the compounds described herein under the conditions under which the compounds are used.

[0120] In some implementations, the use of cyclodextrin, carbonate, or bicarbonate may increase the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at most about 100%, at most about 200%, or any amount within or above these values, compared to the use of meloxicam alone.

[0121] Due to improved bioavailability, the dosage form may contain, or be acceptable to a subject, less meloxicam, in moles than when otherwise administered. For example, the dosage form may contain, or be acceptable to a mammal, at least about 10 mol%, at least about 20 mol%, at least about 30 mol%, at least about 40 mol%, at least about 50 mol%, at least about 60 mol%, at least about 70 mol%, at least about 80 mol%, at least about 85 mol%, and / or at most about 90 mol%, 95 mol%, or any amount of meloxicam defined by or within the range of these values.

[0122] In other embodiments, the use of other NSAIDs, opioids, or other analgesics may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, up to about 100%, compared to the use of other nonsteroidal anti-inflammatory drugs, opioids, or other analgesics without the administration of meloxicam and cyclodextrin, carbonates, and / or bicarbonates.

[0123] In some embodiments, the dosage form may contain meloxicam in an amount of about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 5-20 mg; about 5-10 mg; about 5-15 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; about 40-50 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30 mg; or any amount defined by or within a range of any of these values. These doses may be safe doses for repeated administration, such as once-hourly to once-daily, twice-daily, 1 to 12 times daily, 3, 4, 5, or 6 times daily, etc. In some implementations, 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.

[0124] For some dosage forms, meloxicam forms a complex with substituted β-cyclodextrin or other cyclodextrins that can be formulated into solid dosage forms. This dosage form may be suitable for oral administration. Meloxicam-cyclodextrin inclusion complexes can also be dissolved in water or another solvent to form parenteral dosage forms. However, physical mixtures of meloxicam and substituted β-cyclodextrin or other cyclodextrins can also be used in oral or parenteral dosage forms.

[0125] The formation of inclusion complexes of meloxicam and cyclodextrin may help improve the properties of the dosage form. For some inclusion complexes, the molar ratio of meloxicam to cyclodextrin (e.g., SBEβCD) can be about 0.5–2 (0.5 molar ratio 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 within the range defined by any of these values.

[0126] For some dosage forms, cyclodextrin (e.g., SBEβCD) may be used with meloxicam in the following weight ratios: about 1-1000 (e.g., a weight ratio of 1 g cyclodextrin to 1 g meloxicam); about 1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio defined by or within the range of any of these values. For some dosage forms, cyclodextrins (e.g., SBEβCD) can be used with meloxicam in the following weight ratios: about 0.001-1 (e.g., a weight ratio of 0.1 g cyclodextrin to 1 g meloxicam is 0.1); about 0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weight ratio defined by or within a range of these values. Different ratios can be used for each type of cyclodextrin.

[0127] For some dosage forms, cyclodextrin may be present in the following amounts: about 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about 40-80 mg; about 50-70 mg; about 55-65 mg; about 60-62 mg; or any amount defined by or within the range of any of these values.

[0128] For some methods, meloxicam and cyclodextrins, such as substituted β-cyclodextrins, inclusion complexes are delivered orally (e.g., via tablets, capsules, elixirs, etc.). Other possible routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal, or other parenteral routes. Meloxicam can also be delivered alone or without conjugation with cyclodextrin.

[0129] Some dosage forms contain the following amounts of bicarbonate (e.g., sodium bicarbonate): approximately 1-2000 mg; approximately 1-1000 mg; approximately 100-1000 mg; approximately 200-800 mg; approximately 1-500 mg; approximately 1-200 mg; approximately 1-100 mg; approximately 50-750 mg; approximately 500-1000 mg; approximately 100-500 mg; approximately 100-300 mg; approximately 500-1000 mg; approximately 300-700 mg; approximately 400-600 mg; approximately 50-250 mg; approximately 250-750 mg; approximately 100-200 mg; approximately 200-300 mg; approximately 300-400 mg; approximately 400-500 mg; approximately 410-510 mg; approximately 420-520 mg; approximately 430-530 mg. mg; about 440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about 480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or any amount defined by or within the range of any of these values.

[0130] Some dosage forms contain the following amounts of carbonate: approximately 1-1000 mg; approximately 1-500 mg; approximately 1-200 mg; approximately 1-100 mg; approximately 50-750 mg; approximately 500-1000 mg; approximately 100-500 mg; approximately 100-300 mg; approximately 200-800 mg; approximately 500-1000 mg; approximately 300-700 mg; approximately 400-600 mg; approximately 50-250 mg; approximately 250-750 mg; approximately 100-200 mg; approximately 200-300 mg; approximately 300-400 mg; approximately 400-500 mg; approximately 500-600 mg; approximately 600-700 mg; approximately 700-800 mg; approximately 800-900 mg; approximately 150-650 mg; approximately 350-850 mg. mg; or any quantity defined by or within the range of any of these values.

[0131] In some embodiments, the daily dose of meloxicam (e.g., oral dose, parenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg. mg, approximately 25-30 mg, approximately 30-35 mg, or any amount within the range defined by any of these values.

[0132] In some embodiments, the weekly dose of meloxicam (e.g., oral dose) is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100-150 mg; about 30-100 mg; or any amount defined by or within a range of any of these values. The weekly dose may be administered as a single dose once a week, or may be administered as 2, 3, 4, 5, 6 or 7 separate doses during a week.

[0133] In some embodiments, the monthly dose (e.g., oral dose) of meloxicam or the dose administered over a month is less than about 5000 mg; less than about 4000 mg; less than about 3000 mg; less than about 2000 mg; less than about 1000 mg; less than about 700 mg; less than about 600 mg; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg; about 50-200 mg; about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg. mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; or any monthly dose defined by or within the range of any of these values. The 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 as two or three bi-weekly doses. In some embodiments, the monthly dose is administered as four or five weekly doses. In some embodiments, the monthly dose is administered as 28 to 31 daily doses, or 56 to 62 or more daily doses. In some embodiments, the monthly dose is administered as five to 15 individual doses during the month. The monthly dose may be administered for one month only, or may be repeated for two months or longer.

[0134] For the treatment of migraines, a combination of meloxicam and rizatriptan can be used to treat migraine attacks of at least 2, 3, 4, 5, 6, 8, 10, or up to 10, 20, 30, 2-5, 5-10, 10-15, 15-20, or 20-30 per month. Treatment may last for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, at least 24 months and / or up to 6 months, up to 12 months, up to 18 months, up to 2 years, up to 5 years, up to 10 years, up to 20 years, up to 50 years, up to 80 years, up to 100 years or longer.

[0135] In other embodiments, the dosage form can be administered for approximately one, two, three, four, or more consecutive weeks, once every week or every two weeks, or once every three weeks. This regimen can be repeated weekly, 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.

[0136] In some embodiments, the pharmaceutical composition results in increased bioavailability of meloxicam from the dosage form compared to dosage forms containing meloxicam but without cyclodextrin, acid inhibitors, or buffers (such as bicarbonates) (e.g., decreased T). max The increase of C max (Increased AUC, etc.). In some embodiments, the bioavailability of meloxicam will increase with repeated dosing. For example, compared to the bioavailability of meloxicam in a dosage form that does not contain cyclodextrin, acid inhibitors, or buffers (such as bicarbonate), the bioavailability of meloxicam in the dosage form may increase after a period of time defined by or within any of these values, such as about 1-10 days of dosing, about 2-6 days of dosing, about 3-5 days of dosing, about 4-6 days of dosing, about 5-8 days of dosing, about 5 days of dosing, about 6 days of dosing, about 7 days of dosing, about 8 days of dosing, about 10 days of dosing, about 15 days of dosing, or any time range defined by or within any of these values.

[0137] Some dosage forms may result in meloxicam achieving the desired area under the plasma concentration curve (AUC). For example, meloxicam dosages can result in AUCs of approximately 1-150 µg•hr / mL, approximately 10-30 µg•hr / mL, approximately 20-40 µg•hr / mL, approximately 30-50 µg•hr / mL, approximately 40-60 µg•hr / mL, approximately 50-70 µg•hr / mL, approximately 60-80 µg•hr / mL, approximately 70-90 µg•hr / mL, approximately 80-100 µg•hr / mL, approximately 10-100 µg•hr / mL, approximately 50-150 µg•hr / mL, approximately 25-125 µg•hr / mL, approximately 75-150 µg•hr / mL, approximately 20-50 µg•hr / mL, approximately 40-70 µg•hr / mL, approximately 60-90 µg•hr / mL, and approximately 80-110 µg•hr / mL. µg•hr / mL, about 100-130 µg•hr / mL, about 120-150 µg•hr / mL, or any AUC defined by or within the range of any of these values.

[0138] Unless otherwise stated, AUC refers to the AUC calculated based on the last measured concentration. 0-t For example, within 6 hours (AUC) 0-6 ), within 12 hours (AUC) 0-12 ), exceeding 24 hours (AUC) 0-24 ) or extrapolated to an infinite time interval (AUC) 0-inf ).

[0139] In Example 3 below, the AUC of meloxicam in humans was measured for an oral dosage form containing sodium bicarbonate and sulfobutyl ether β-cyclodextrin (SBEβCD). 0-24 It is approximately 27 µg·hr / mL. This dosage form contains 15 mg of meloxicam.

[0140] The 15 mg intravenous and intramuscular dose also provides the AUC of meloxicam in humans. 0-24 The AUC of meloxicam is approximately 27 µg·hr / mL. The AUC of meloxicam is considered to be dose-dependent. Therefore, for this oral dosage form, or for intravenous or intramuscular dosage forms, doses of meloxicam, such as approximately 17 mg to approximately 30 mg, are expected to result in an AUC of approximately 30–50 µg·hr / mL. 0-24 .

[0141] For some acute pain conditions, such as migraines and other types of headaches, the AUC within a short period of time after oral administration (e.g., AUC measured within 6 hours) is important. 0-6This may be of particular interest. For example, some dosage forms may produce AUCs of at least about 6 µg•hr / mL, at least about 7 µg•hr / mL, at least about 8 µg•hr / mL, at least about 9 µg•hr / mL, about 6–10 µg•hr / mL, about 7–11 µg•hr / mL, about 8–12 µg•hr / mL, and about 9–13 µg•hr / mL. 0-6 Or any AUC defined by or within the range of any of these values.

[0142] In some implementations, the dosage form can lead to C of meloxicam. max 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 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 ng / mL or any C value defined by or within the range of any of these values. max .

[0143] For example, the method described in this paper can reduce meloxicam's T... maxIn some embodiments, the method may include treating the patient to achieve the T value of meloxicam within approximately 10 minutes, approximately 20 minutes, approximately 30 minutes, approximately 40 minutes, approximately 50 minutes, approximately 60 minutes, approximately 70 minutes, approximately 80 minutes, approximately 90 minutes, approximately 100 minutes, approximately 110 minutes, approximately 120 minutes, approximately 180 minutes, approximately 1-10 hours, approximately 2-9 hours, approximately 3-7 hours, approximately 4-6 hours, approximately 1-5 hours, approximately 2-7 hours, approximately 3-8 hours, approximately 4-9 hours, approximately 1-4 hours, approximately 2-5 hours, approximately 3-6 hours, approximately 4-7 hours, approximately 5-8 hours, approximately 6-9 hours, or approximately 7-10 hours after administration. max Or any T defined by any of these values ​​or falling within the range of any of these values. max .

[0144] In some implementations, the oral formulation of meloxicam's T max It can achieve T than when meloxicam is administered via intramuscular injection. max Shorter. In some implementations, the oral dosage form may have a shorter To of meloxicam. max It may increase meloxicam plasma levels at a rate 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 times, or about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100 times, or multiples within the range defined by any of these values.

[0145] The oral dosage form in Example 3 below provides a T-wave response of meloxicam for approximately 30 minutes. max The report mentions intravenous meloxicam T... max For infusion, it takes approximately 30 minutes; for bolus, it takes approximately 3 minutes. The reported intramuscular injection of meloxicam T... max It takes approximately 60-84 minutes.

[0146] In some embodiments, the meloxicam-containing formulation may result in plasma concentrations of meloxicam at 12 hours of approximately 0.01-0.5 µg / mL, approximately 0.5-0.7 µg / mL, approximately 0.6-0.8 µg / mL, approximately 0.7-0.9 µg / mL, approximately 0.8-1 µg / mL, approximately 0.9-1.1 µg / mL, approximately 1-1.2 µg / mL, approximately 1.1-1.3 µg / mL, approximately 1.2-1.4 µg / mL, approximately 1.3-1.5 µg / mL, approximately 1.4-1.6 µg / mL, approximately 1.5-1.7 µg / mL, approximately 1.6-1.8 µg / mL, approximately 1.7-1.9 µg / mL, approximately 1.8-2 µg / mL, approximately 1.9-2.1 µg / mL, and approximately 2-2.2 µg / mL. µg / mL, approximately 2.1-2.3 µg / mL, approximately 2.2-2.4 µg / mL, approximately 2.3-2.5 µg / mL, approximately 2.4-2.6 µg / mL, approximately 2.5-2.7 µg / mL, approximately 2.6-2.8 µg / mL, approximately 2.7-2.9 µg / mL, approximately 2.8-3 µg / mL, approximately 2.9-3.1 µg / mL, approximately 3-3.2 µg / mL, approximately 3.1-3.3 µg / mL, approximately 3.2-3.4 µg / mL, approximately 3.3-3.5 µg / mL, approximately 3.4-3.6 µg / mL, approximately 3.5-3.7 µg / mL, approximately 3.6-3.8 µg / mL, approximately 3.7-3.9 µg / mL µg / mL, approximately 3.8–4 µg / mL, or any plasma concentration defined by or within the range of any of these values.

[0147] In some implementations, meloxicam is used to achieve meloxicam plasma levels (e.g., C). avgThe mean plasma concentrations (or average plasma levels) were approximately 0.01–0.5 µg / mL; approximately 0.5–0.7 µg / mL; approximately 0.6–0.8 µg / mL; approximately 0.7–0.9 µg / mL; approximately 0.8–1 µg / mL; approximately 0.9–1.1 µg / mL; approximately 1–1.2 µg / mL; approximately 1.1–1.3 µg / mL; approximately 1.2–1.4 µg / mL; approximately 1.3–1.5 µg / mL; approximately 1.4–1.6 µg / mL; approximately 1.5–1.7 µg / mL; approximately 1.6–1.8 µg / mL; approximately 1.7–1.9 µg / mL; approximately 1.8–2 µg / mL; approximately 1.9–2.1 µg / mL; approximately 2–2.2 µg / mL; approximately 2.1–2.3 µg / mL; approximately 2.2–2.4 µg / mL. µg / mL; approx. 2.3-2.5 µg / mL; approx. 2.4-2.6 µg / mL; approx. 2.5-2.7 µg / mL; approx. 2.6-2.8 µg / mL; approx. 2.7-2.9 µg / mL; approx. 2.8-3 µg / mL; approx. 2.9-3.1 µg / mL; approx. 3-3.2 µg / mL; approx. 3.1-3.3 µg / mL; approx. 3.2-3.4 µg / mL; approx. 3.3-3.5 µg / mL; approx. 3.4-3.6 µg / mL; approx. 3.5-3.7 µg / mL; approx. 3.6-3.8 µg / mL; approx. 3.7-3.9 µg / mL; approx. 3.8-4 µg / mL; approx. 0.1-20 µg / mL; approx. 0.5-15 µg / mL; approx. 0.5-10 µg / mL μg / mL; about 5-15 μg / mL; about 10-20 μg / mL; about 7.5-15 μg / mL; about 2-10 μg / mL; about 1-8 μg / mL; about 1-6 μg / mL; about 1-2 μg / mL; about 0.5-3.5 μg / mL; about 0.5-7 μg / mL; about 12-20 μg / mL; about 8-12 μg / mL; about 1-4 μg / mL; about 4-7 μg / mL; about 7-11 μg / mL; about 11-15 μg / mL; about 15-19 μg / mL; about 16-20 μg / mL; or any amount of meloxicam plasma level defined by or within the range of any of these values.

[0148] Administration of the dosage form described herein may result in a reduced time to reach therapeutic plasma concentrations of meloxicam. Therapeutic plasma concentrations are the C60% of 15 mg Mobic® meloxicam. avg In some implementations, the time (T0) for meloxicam to reach therapeutic plasma concentrations is... theraThe time intervals are approximately 10-30 minutes, 10-15 minutes, 15-20 minutes, 20-25 minutes, 25-30 minutes, 10-20 minutes, 20-30 minutes, 16-18 minutes, or 17 minutes.

[0149] The method described in this article can reduce T levels of rizatriptan. max For example, this method can achieve rizatriptan's T-value in the patient within approximately 50 minutes, approximately 60 minutes, approximately 70 minutes, approximately 80 minutes, or approximately 90 minutes, approximately 40-60 minutes, approximately 40-45 minutes, approximately 45-50 minutes, approximately 50-55 minutes, or approximately 55-60 minutes after administration. max Or any T within the range defined by any of these values. max .

[0150] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the reduction in abnormal pain (e.g., skin abnormal pain) experienced by a person is greater than the reduction in abnormal pain (e.g., skin abnormal pain) experienced by a person 2 hours after receiving the same amount of meloxicam without rizatriptan.

[0151] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the reduction in abnormal pain (e.g., skin abnormal pain) experienced by humans is greater than the reduction in abnormal pain (e.g., skin abnormal pain) experienced by humans within 24 hours after receiving the same amount of meloxicam without rizatriptan.

[0152] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and 2 hours after administration of meloxicam and rizatriptan, the reduction in abnormal pain (e.g., skin abnormal pain) experienced by humans is greater than the reduction in abnormal pain (e.g., skin abnormal pain) experienced by humans 2 hours after receiving the same amount of rizatriptan without meloxicam.

[0153] In some implementations, meloxicam and rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and within 24 hours after administration of meloxicam and rizatriptan, the reduction in abnormal pain (e.g., skin abnormal pain) experienced by humans is greater than the reduction in abnormal pain (e.g., skin abnormal pain) experienced by humans within 24 hours after administration of the same amount of rizatriptan without meloxicam.

[0154] One implementation is a method for reducing the risk of gastrointestinal side effects and improving the bioavailability of NSAIDs, particularly during chronic treatment, for individuals taking NSAIDs to relieve pain and other conditions. In one implementation, the method includes administering a product in combination with: a) an agent that actively raises gastric pH; and b) an NSAID formulated with cyclodextrin. In another implementation, the method includes administering a product in combination with: a) an agent that actively raises gastric pH; b) an NSAID formulated with cyclodextrin; and c) a buffer. Both short-acting and long-acting acid inhibitors can be effectively used in the dosage form. This method has the added benefit of protecting patients from other gastrointestinal ulcerogens whose effects might otherwise be enhanced by the destruction of gastric protective prostaglandins induced by NSAID treatment.

[0155] Aqueous parenteral meloxicam formulations may contain buffers to adjust the pH of the aqueous formulation to 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 defined by or within a range of these values. Oral meloxicam formulations may contain buffers to adjust the pH of gastric juice to 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 defined by or within a range of these values. Examples of buffers suitable for use herein include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, etc.

[0156] In some embodiments, the dosage form can be formulated for oral administration, for example, together with an inert diluent or an edible carrier, or it can be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into dietary foods. For oral therapeutic administration, the active compound can be combined with excipients and used in the form of ingestible tablets, sublingual tablets, coated tablets, lozenges, capsules, elixirs, dispersants, suspensions, solutions, syrups, wafers, patches, etc.

[0157] Tablets, lozenges, pills, capsules, etc., may also contain one or more of the following: binders, such as gum arabic, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, or saccharin; or flavorings, such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, it may also contain a liquid carrier in addition to the materials of the types mentioned above. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain active compounds, sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings, such as cherry or orange flavoring. It may be necessary that the materials in the dosage form or pharmaceutical composition are pharmaceutically pure and substantially non-toxic at the amounts used.

[0158] Some compositions or dosage forms may be liquids, or may contain a solid phase dispersed in a liquid.

[0159] The dosage form may also contain a secondary therapeutic agent, such as an acid inhibitor or analgesic.

[0160] In some embodiments, when one or more unit dosage forms are administered, the dosage forms may further comprise an acid inhibitor present in an amount that effectively raises the 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. The term "acid inhibitor" refers to an agent that inhibits gastric acid secretion and increases gastric pH. Specific H2 blockers that may be used, also known as H2 antagonists or histamine H2 blockers or antagonists, include, but are not limited to, cimetidine, ranitidine, ibrutidine, prabutidine, lavtidine, loxitidine, famotidine, or combinations thereof.

[0161] Other agents that can be effectively used as acid inhibitors are proton pump inhibitors, such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, paliprazole, lemminoprazole, and tenaprazole. In some embodiments, the daily dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or any other amount defined by or within a range of any of these values.

[0162] Specific examples of proton pump inhibitors include esomeprazole, present in unit dosage forms of 5 mg to 50 mg; omeprazole, present in unit dosage forms of 5 mg to 50 mg; lansoprazole, present in unit dosage forms of 5 mg to 150 mg (and preferably 5 mg to 30 mg); and pantoprazole, present in unit dosage forms of 10 mg to 200 mg. In some embodiments, the proton pump inhibitor is present in dosage forms of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newer acid inhibitor that can compete with potassium in the acid pump has been developed. These compounds are referred to as “reversible proton pump inhibitors” or “acid pump antagonists” and are also used. Examples include AZD-0865, AR-H047108, CS-526, promalazine, renvarazan, and soralazan (see WO9605177 and WO9605199). Other compounds in this group are H-335 / 25 (AstraZeneca, conversation document 128, accession number 020806); Sch-28080 (Schering Plough, conversation document 128, accession number 009663); Sch-32651 (Schering Plough, conversation document 128, accession number 006883) and SK&F-96067 (CAS registry number 115607-61-9).

[0163] The second therapeutic agent may include analgesics, such as a second nonsteroidal anti-inflammatory drug (NSAID), opioids, steroids, triptans, etc. In some embodiments, the dosage form or treatment further includes administering the second NSAID in an amount that effectively reduces or eliminates pain or inflammation. NSAIDs may include, but are not limited to, celecoxib, rofecoxib, romecoxib, vardicoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID for the purposes of this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxapazine, etodoxacin, indomethacin, ketoprofen, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamic acid, diflunisal, sulfen, tometidine, fenprofen, sulfen, phenoxprofen, acetylclofenac, tofenamic acid, hydroxybutanol, azaprocone, phenylbutazone, or combinations thereof. It should be understood that, for the purposes of this disclosure, references to acid inhibitors, NSAIDs, or analgesics will include all common forms of these compounds, particularly their pharmaceutically acceptable salts. Due to potential positive kinetic interactions and NSAID absorption in the presence of acid inhibitors and / or buffers, the amount of therapeutically effective nonsteroidal anti-inflammatory drug in the current embodiments may be lower than found in practice.

[0164] In other embodiments, the dosage form or treatment may also include administration of an opioid substance in an amount that effectively reduces or eliminates pain or inflammation. Opioid substances may include, but are not limited to, (dextral)propoxyphene, alpha-methylfentanyl, alfentanyl, allylrodine, benzoylmide, buprenorphine, butorphanol, carfentanil, norprodine, dextromorphine, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, hydromorphone, diphenoxylate, dipipirone, etofen, fentanyl, ketobemidone, lephendamine, levonorgestrel, and levomethadone. Safenoxate, levonorgestrel, loperamide, meperidine, mepitafen, methadone, methylmorphine, morphine, nalbuphine, nalmefenoxate, naloxone, naltrexone, nicormorphine, hydroxymethylfentanil, papaverine, oxycodone, hydroxymorphone, PEPAP, paramorphine, tebuconazole, oxazol, piperazine, prodine, remifentanil, sufentanil, tapentadol, telidazole, tramadol, or combinations thereof.

[0165] Useful triptans may include sumatriptan, rizatriptan, nalatriptan, itraptan, donitriptan, amotriptan, frotriptan, avitriptan, zomatriptan, etc. In some embodiments, the triptan includes 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 a triptan, such as rizatriptan, or any amount within the range defined by any of these values.

[0166] In some embodiments, the dosage form containing the subject combination may contain about 1-50 mg; about 1-10 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; or about 40-50 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 1-10 mg; about 5-20 mg; about 1-5 mg; about 2-6 mg; about 3-7 mg; about 4-8 mg; about 5-10 mg; about 6-11 mg; about 7-12 mg; about 8-13 mg; about 9-11 mg; about 9-14 mg; about 10-15 mg; about 11-16 mg; about 12-17 mg; about 13-18 mg; about 14-19 mg; about 15-20 mg; about 5-15 mg; about 0.5 mg; about 1 mg; about 1.5 mg. mg; about 2 mg; about 2.5 mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6 mg; about 7 mg; about 7.5 mg; about 8 mg; about 9 mg; about 10 mg; about 15 mg; about 20 mg; about 25 mg; about 30 mg or any amount of rizatriptan defined by or within the range of any of these values.

[0167] For acute migraines, the amount of a single dose of meloxicam and / or rizatriptan, or the AUC of meloxicam and / or rizatriptan associated with a single dose, is of particular interest. For example, symptoms may be relieved for a longer period after a single dose, thus potentially eliminating the need for repeated dosing in the short term. For more continuous symptoms, including more chronic, continuous, or frequent migraine symptoms, daily, weekly, or monthly doses may be of particular interest.

[0168] For any amount of rizatriptan described herein, the salt form of rizatriptan may be present in the amounts described above, or in an amount that is a molar equivalent to these amounts of the free base of rizatriptan. For example, assuming the molecular weight of the free base of rizatriptan is 269.3 g / mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Therefore, the molar equivalent of 10 mg of the free base of rizatriptan will be 37.1 mmol of the mass of this salt form. For example, for benzoate (mw = 391.2 g / mol), the molar equivalent of 10 mg of the free base (or 37.1 mmol) will be 14.5 mg. These doses may be safe for repeated administration, for example, once, twice, three or four times daily, or at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, approximately 1-2 months, approximately 6 weeks, approximately 2-3 months, approximately 3-4 months, approximately 4-5 months, approximately 5-6 months, approximately 6-7 months, approximately 7-8 months, approximately 8-9 months, approximately 9-10 months, approximately 10-11 months, approximately 11-12 months, etc.

[0169] The pharmaceutical composition may be in the form of tablets or capsules, having: (a) an acid inhibitor; and / or (b) a buffer; and (c) a nonsteroidal anti-inflammatory drug (NSAID) present in an amount that effectively reduces or eliminates pain or inflammation in a patient after administration of one or more of the said unit dosage forms. The components of the pharmaceutical composition may be individually or collectively in an immediate-release or sustained-release form.

[0170] As used herein, the term "unit dosage form" refers to a single entity intended for drug administration. For example, a single tablet or capsule combining both an acid inhibitor and a nonsteroidal anti-inflammatory drug would be a unit dosage form. "Unit dosage form" may also be referred to as "fixed dosage form" or "fixed dosage combination," and these terms are interchangeable. In one embodiment, the unit dosage form is a multilayer tablet.

[0171] In another embodiment, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In still another embodiment, the unit dosage form is a multilayer tablet comprising a single core and one or more outer layers.

[0172] Some dosage forms may contain a first layer containing meloxicam, SBEβCD and bicarbonate; and a second layer containing a second therapeutic agent and bicarbonate.

[0173] The first layer may contain any amount of meloxicam, for example, within one of the ranges described above. For instance, all meloxicams in the dosage form may be present in the first layer. The second layer may contain all the second therapeutic agents, such that any amount within the range of the second therapeutic agents described above may be applied to the second layer.

[0174] In some embodiments, the first layer contains about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of bicarbonate, such as sodium bicarbonate, or any amount of bicarbonate within the range defined by any of these values.

[0175] In some embodiments, the second layer contains about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of bicarbonate, such as sodium bicarbonate, or any amount of bicarbonate within the range defined by any of these values.

[0176] In some embodiments, the pharmaceutical composition may contain effective amounts of meloxicam, cyclodextrin, and carbonate or bicarbonate to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition may contain effective amounts of meloxicam, sulfobutyl ether-β-cyclodextrin (SBEβCD), and sodium bicarbonate to increase the bioavailability of meloxicam or decrease the Tg of meloxicam. max .

[0177] Some oral dosage forms may have an enteric coating or a film coating. In some embodiments, the dosage form may include tablets or capsules with an enteric coating. In some embodiments, the dosage form may include tablets or capsules with a film coating.

[0178] One embodiment of this disclosure relates to a pharmaceutical composition in a unit dosage form suitable for administration to a patient, the pharmaceutical composition comprising:

[0179] (a) Esomeprazole, which may or may not be surrounded by an enteric coating;

[0180] (b) Sodium bicarbonate or potassium bicarbonate and / or sodium carbonate or potassium carbonate; and

[0181] (c) Meloxicam, which may or may not be formulated with cyclodextrin and may or may not be coated with an enteric coating.

[0182] One embodiment of this disclosure relates to a pharmaceutical composition in a unit dosage form suitable for administration to a patient to treat a disease, condition, or disorder such as migraine, said pharmaceutical composition comprising:

[0183] (1) Inclusion complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD);

[0184] (2) Bicarbonates, such as sodium bicarbonate or potassium bicarbonate; and

[0185] (3) Triptans, such as rizatriptan.

[0186] In some embodiments, the pharmaceutical composition results in a faster release or dissolution of meloxicam from the dosage form compared to dosage forms containing meloxicam but without an acid inhibitor or a buffer.

[0187] A dosage form containing a combination of rizatriptan and meloxicam (the “Theme Combination”) is available for the treatment of migraine. The Theme Combination can be used for the acute treatment of migraine. The Theme Combination provides significantly greater and more sustained migraine relief compared to rizatriptan, meloxicam, or placebo. The Theme Combination provides rapid relief of migraine. The Theme Combination significantly reduces the use of rescue medication compared to rizatriptan, meloxicam, and placebo. Patients with migraine treated with the rizatriptan and meloxicam combination described herein may have a history of inadequate response to prior acute treatment. Patients with migraine treated with the rizatriptan and meloxicam combination described herein may have atypical pain (e.g., atypical skin pain). Patients with migraine treated with the rizatriptan and meloxicam combination described herein may have severe pain intensity. Patients with migraine treated with the rizatriptan and meloxicam combination described herein may be obese. Patients with migraine treated with the rizatriptan and meloxicam combination described herein may have morning migraines. Migraine patients treated with the rizatriptan and meloxicam combination described herein may have a mean total Migraine Treatment Optimization Questionnaire (mTOQ-4) score of less than 7, for example, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. Migraine patients treated with the rizatriptan and meloxicam combination described herein may have atypical pain (e.g., atypical skin pain), severe pain intensity, obesity, morning migraines, a mean total mTOQ-4 score of less than 7, and a history of inadequate response to prior acute treatment. Formulations containing the rizatriptan and meloxicam combination described herein are safe and well-tolerated in the treated migraine patients.

[0188] Dosage forms containing the combination of rizatriptan and meloxicam described herein can provide rapid relief of migraine 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 after administration. The combination of rizatriptan and meloxicam described in this article can provide migraine relief numerically greater than that of rizatriptan within 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 after administration. The percentage of migraine patients who experienced pain relief when treated with the combination of rizatriptan and meloxicam described in this article can be 1-100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, or 95-100%.

[0189] Migraine patients receiving a formulation containing the combination of rizatriptan and meloxicam described herein (the “Subject Combination”) may experience pain relief in less than 2 hours, approximately 2 hours, approximately 2–3 hours, approximately 3–4 hours, approximately 4–6 hours, approximately 6–8 hours, approximately 8–10 hours, approximately 10–12 hours, approximately 12–16 hours, approximately 16–20 hours, approximately 20–24 hours, approximately 24–30 hours, approximately 30–36 hours, approximately 36–40 hours, approximately 40–44 hours, approximately 44–48 hours or longer after administration.

[0190] Following a single dose of the combination of rizatriptan and meloxicam described herein, the percentage of migraine sufferers achieving pain relief increases over time. For example, at 2 hours post-administration, the percentage of migraine sufferers achieving pain relief may be approximately 15-25%, approximately 15-20%, approximately 20%, and approximately 20-25%. At 4 hours post-administration, the percentage of migraine sufferers achieving pain relief may be approximately 30-50%, approximately 30-40%, approximately 40%, approximately 40-45%, approximately 45-47%, and approximately 47-50%. At 12 hours post-administration, the percentage of migraine sufferers achieving pain relief may be approximately 45-70%, approximately 45-50%, approximately 50-55%, approximately 55-60%, approximately 56-57%, approximately 60-65%, and approximately 65-70%. At 16 hours post-administration, the percentage of migraine patients achieving pain relief was approximately 45-70%, 45-50%, 50-55%, 55-60%, 58-59%, 60-65%, or 65-70%. The combination of rizatriptan and meloxicam described in this article provides a significant improvement in pain relief compared to rizatriptan alone in migraine patients. Migraine patients receiving the combination of rizatriptan and meloxicam described in this article may achieve pain relief by approximately 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8%, 8-9%, or 9-10% more than migraine patients receiving rizatriptan 2-16 hours post-administration, with improvements 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, if approximately 40% of migraine patients receiving the theme combination achieve pain relief compared to 33% of those receiving rizatriptan 4 hours after administration, the improvement from the theme combination would be approximately 21% [((40-33) / 33)×100%]. Among migraine patients who achieve pain relief, the theme combination may show greater improvement over meloxicam than rizatriptan. For instance, at 2-16 hours after administration, the improvement from meloxicam in migraine patients who achieve pain relief could be approximately 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75%.

[0191] It is possible that at least 50%, at least 60%, at least 70%, at least 80%, approximately 70-80%, approximately 80-90%, approximately 90-95%, or approximately 80% of migraine patients who achieve pain relief at 2 hours after administration of the combination of rizatriptan and meloxicam described herein (the “Subject Combination”) can maintain this relief for up to 24 hours after administration. The increase (or improvement) in the number of migraine patients achieving sustained pain relief 2–24 hours after administration of the Subject Combination compared to rizatriptan administration could be approximately 35-55%, approximately 35-40%, approximately 40-45%, approximately 45-50%, or approximately 50-55%. Compared with meloxicam administration, the increase (or improvement) in the number of migraine patients achieving sustained pain relief 2–24 hours after administration of the subject combination can 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%.

[0192] Compared with rizatriptan administration, the increase in the number of migraine patients achieving sustained pain relief (or improvement) 2–24 hours after administration of the subject combination may be approximately 15–30%, approximately 15–20%, approximately 20–25%, approximately 25–30%, approximately 20–22%, or approximately 21%. Compared with meloxicam administration, the increase in the number of migraine patients achieving sustained pain relief (or improvement) 2–24 hours after administration of the subject combination 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%.

[0193] It is possible that at least 50%, at least 60%, at least 70%, at least 80%, approximately 70-80%, approximately 80-90%, approximately 90-95%, or approximately 77% of migraine patients who achieve pain relief at 2 hours after administration of the combination of rizatriptan and meloxicam described herein (the “Subject Combination”) can maintain this effect for up to 48 hours after administration. The increase (or improvement) in the number of migraine patients achieving sustained pain relief 2-48 hours after administration of the Subject Combination compared to rizatriptan administration can be approximately 60-90%, approximately 60-70%, approximately 70-75%, approximately 75-80%, approximately 80-90%, or approximately 75%. The increase (or improvement) in the number of migraine patients achieving sustained pain relief 2-48 hours after administration of the Subject Combination compared to meloxicam administration can be approximately 70-110%, approximately 70-80%, approximately 80-90%, approximately 90-100%, approximately 100-110%, or approximately 90%.

[0194] Compared with rizatriptan administration, the increase (or improvement) in the number of migraine patients achieving sustained pain relief 2–48 hours after administration of the subject combination could 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 meloxicam administration, the increase (or improvement) in the number of migraine patients achieving sustained pain relief 2–48 hours after administration of the subject combination could 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%.

[0195] At least 50%, at least 60%, at least 70%, approximately 60-65%, approximately 65-70%, approximately 70-75%, approximately 75-80%, approximately 80-85%, approximately 85-90%, approximately 90-95%, or approximately 77% of migraine patients receiving the combination of rizatriptan and meloxicam described herein (the “Subject Combination”) may not require rescue medication. The reduction in the number of migraine patients requiring rescue medication within 24 hours of receiving the Subject Combination compared to placebo administration 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 meloxicam administration, the reduction in the number of migraine patients taking rescue medication within 24 hours of administration of the theme combination 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 rizatriptan administration, the reduction in the number of migraine patients taking rescue medication within 24 hours of administration of the theme combination may be approximately 25-40%, approximately 25-30%, approximately 30-35%, approximately 35-40%, approximately 33-35%, or approximately 34%. In some implementations, migraine patients do not take rescue medication within 24 hours of administration of the theme combination.

[0196] The following implementation methods are envisioned:

[0197] Implementation Method 1. Meloxicam inclusion complex in cyclodextrin.

[0198] Implementation Method 2. A dosage form comprising: 1) the inclusion complex of Implementation Method 1, or 2) meloxicam and a carbonate or bicarbonate.

[0199] Implementation Method 3. The dosage form of Implementation Method 2, wherein the dosage form comprises an inclusion complex, wherein the cyclodextrin comprises a substituted β-cyclodextrin.

[0200] Implementation Method 4. The dosage form of Implementation Method 3, wherein the substituted β-cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPβCD).

[0201] Implementation Method 5. Dosage Form of Implementation Method 4, wherein the cyclodextrin is SBEβCD.

[0202] Implementation Method 6. The dosage form of Implementation Method 5, wherein for each β-cyclodextrin molecule, SBEβCD has about 6 to about 7 sulfobutyl ether groups.

[0203] Implementation method 7. The dosage form of implementation method 6, wherein the molar ratio of meloxicam to SBEβCD is about 0.8 to about 1.2.

[0204] Implementation method 8. Dosage form of implementation method 6, wherein the molar ratio of meloxicam to SBEβCD is about 1.

[0205] Implementation method 9. Dosage form of implementation method 2, 3, 4, 5, 6, 7 or 8, wherein the dosage form comprises a bicarbonate.

[0206] Implementation method 10. Dosage form of implementation method 9, wherein the bicarbonate salt includes sodium bicarbonate.

[0207] Implementation method 11. Dosage form of implementation method 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the dosage form is an oral dosage form.

[0208] Implementation method 12. Dosage forms of implementation methods 2, 3, 4, 5, 6, 9, 10 or 11, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form.

[0209] Implementation method 13. Dosage form of implementation method 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the carbonate or bicarbonate is present in an amount ranging from about 400 mg to about 600 mg.

[0210] Implementation method 14. Dosage forms of implementation methods 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein the T-type of meloxicam... max It is lower than that of formulations that do not contain carbonates, bicarbonates or cyclodextrins.

[0211] Implementation Method 15. The method of Implementation Method 14, wherein meloxicam T is achieved in the patient within a time range of approximately 10 minutes to approximately 180 minutes after administration. max .

[0212] Implementation method 16. The dosage forms of implementation methods 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 have higher oral bioavailability of meloxicam than dosage forms that do not contain carbonate, bicarbonate or cyclodextrin.

[0213] Implementation method 17. Dosage forms of implementation methods 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the dosage form further comprises an acid inhibitor.

[0214] Implementation method 18. Dosage form of implementation method 17, wherein the acid inhibitor is a proton pump inhibitor.

[0215] Implementation Method 19. Dosage form of Implementation Method 18, wherein the proton pump inhibitor is esomeprazole.

[0216] Implementation Method 20. The dosage form of Implementation Method 19, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form.

[0217] Implementation Method 21. A method of oral administration of meloxicam, the method comprising orally administering to a patient requiring treatment a dosage form of implementation method 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0218] Implementation Method 22. The method of Implementation Method 21, wherein the dosage form is administered to treat pain.

[0219] Implementation Method 23. The method of Implementation Method 21, wherein the dosage form is administered to treat inflammatory pain.

[0220] Implementation Method 24. The method of Implementation Method 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[0221] Implementation Method 25. A method of intravenous administration of meloxicam, the method comprising administering intravenous administration of a dosage form of Implementation Method 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 or 15 to a patient requiring treatment.

[0222] Implementation Method 26. The method of Implementation Method 21, wherein the dosage form is administered to treat migraine.

[0223] Implementation Method 27. A dosage form comprising: 1) a meloxicam inclusion complex in cyclodextrin, 2) a bicarbonate, and 3) a triptan.

[0224] Implementation method 28. Dosage form of implementation method 27, wherein the triptan drug is rizatriptan.

[0225] Implementation Method 29. Dosage form of Implementation Method 27, wherein the bicarbonate salt includes sodium bicarbonate.

[0226] Implementation Method 30. Dosage Form of Implementation Method 27, wherein the cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD).

[0227] Implementation Method 31. The dosage form of Implementation Method 30, wherein for each β-cyclodextrin molecule, SBEβCD has about 6 to about 7 sulfobutyl ether groups.

[0228] Implementation Method 32. The dosage form of Implementation Method 30, wherein the molar ratio of meloxicam to SBEβCD is about 0.8 to about 1.2.

[0229] Implementation method 33. Dosage form of implementation method 32, wherein the molar ratio of meloxicam to SBEβCD is about 1.

[0230] Implementation method 34. Dosage form of implementation methods 27, 28, 29, 30, 31, 32 or 33, wherein the dosage form is an oral dosage form.

[0231] Implementation method 35. Dosage forms of implementation methods 27, 28, 29, 30, 31, 32, 33 or 34, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form.

[0232] Implementation method 36. Dosage forms of implementation methods 27, 28, 29, 30, 31, 32, 33, 34 or 35, wherein the bicarbonate is present in an amount of about 400 mg to about 1000 mg.

[0233] Implementation Method 37. A method for treating migraine, the method comprising administering to a person suffering from migraine a dosage form comprising meloxicam, at least 400 mg of bicarbonate, and rizatriptan; wherein the rizatriptan in the dosage form has a T... max Shorter than the Tmax of the reference dosage form containing a) the same amount of rizatriptan, 2) meloxicam-free and c) bicarbonate-free.

[0234] Implementation Method 38. A method for treating migraine, the method comprising administering meloxicam and rizatriptan in a free base form, weighing about 8 mg to about 13 mg, to a person suffering from migraine or an acute attack of migraine aura, wherein the meloxicam and rizatriptan are administered approximately 30 minutes apart, wherein administration of meloxicam to the person results in a T-cell effect of meloxicam. max For 110 minutes or less, and meloxicam's AUC 0-24 It is approximately 30 mg·hr / mL to approximately 50 mg·hr / mL.

[0235] Implementation Method 39. A pharmaceutical dosage form comprising: 1) meloxicam in the form of about 0.028 mmol to about 0.085 mmol of free acid or salt, 2) rizatriptan in the form of about 0.019 mmol to about 0.056 mmol of free base or salt, 3) sulfobutyl ether-β-cyclodextrin (SBEβCD) in the form of about 100 mg to about 175 mg, and 4) sodium bicarbonate in the form of about 400 mg to about 600 mg.

[0236] Implementation 40. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate and 3) rizatriptan.

[0237] Implementation 41. The method of Implementation 40, wherein the human migraine patient experiences migraine relief by orally administering the dosage form to the migraine patient.

[0238] Implementation 42. The method of Implementation 40 or 41, wherein 2 hours after oral administration of the dosage form to a human migraine patient, the human migraine patient does not have a migraine.

[0239] Implementation method 43. The method of implementation method 40, 41 or 42, wherein the migraine patient experiences a reduction in nausea due to oral administration of the dosage form to the migraine patient.

[0240] Implementation method 44. The method of implementation method 40, 41, 42 or 43, wherein the human migraine patient does not experience nausea 2 hours after oral administration of the dosage form to the human migraine patient.

[0241] Implementation method 45. The method of implementation method 40, 41, 42, 43 or 44, wherein the migraine patient experiences a reduction in photophobia due to oral administration of the dosage form to the migraine patient.

[0242] Implementation method 46. The method of implementation method 40, 41, 42, 43, 44 or 45, wherein 2 hours after oral administration of the dosage form to a human migraine patient, the human migraine patient does not have photophobia.

[0243] Implementation method 47. The method of implementation method 40, 41, 42, 43, 44, 45 or 46, wherein the migraine patient experiences a reduction in phonophobia due to oral administration of the dosage form to the migraine patient.

[0244] Implementation method 48. The method of implementation methods 40, 41, 42, 43, 44, 45, 46 or 47, wherein 2 hours after oral administration of the dosage form to a human migraine patient, the human migraine patient does not have phonophobia.

[0245] Implementation method 49. The method of implementation methods 40, 41, 42, 43, 44, 45, 46, 47 or 48, wherein the dosage form contains 400 mg to 600 mg of bicarbonate.

[0246] Implementation method 50. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, wherein the dosage form contains about 5 mg to about 50 mg of meloxicam.

[0247] Implementation method 51. The method of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50, wherein the dosage form contains about 50 mg to about 200 mg of SBEβCD.

[0248] Implementation method 52. The method of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51, wherein the dosage form is meloxicam T in the human body. max A shorter solid oral dosage form than a reference dosage form, wherein the reference dosage form: 1) contains the same amount of meloxicam, 2) is free of SBEβCD, and 3) is free of bicarbonate.

[0249] Implementation method 53. The method of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52, wherein rizatriptan in the form of free base is present in an oral dosage form at a weight of about 1 mg to about 50 mg.

[0250] Implementation Method 54. The method of Implementation Method 53, wherein rizatriptan is present in the form of a salt in an amount of about 10 mg of the molar equivalent of rizatriptan in the form of a free base.

[0251] Implementation method 55. The method of implementation method 53 or 54, wherein rizatriptan is present in the form of rizatriptan benzoate.

[0252] Implementation method 56. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55, wherein the oral dosage form contains about 10 mg to about 30 mg of meloxicam.

[0253] Implementation Method 57. The method of Implementation Method 56, wherein the oral dosage form contains about 20 mg of meloxicam.

[0254] Implementation Method 57. The method of Implementation Method 56, wherein the oral dosage form contains about 15 mg of meloxicam.

[0255] Implementation method 59. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 or 58, wherein for each β-cyclodextrin molecule, SBEβCD has about 6 to about 7 sulfobutyl ether groups.

[0256] Implementation method 60. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59, wherein the oral dosage form contains about 50 mg to about 150 mg of SBEβCD.

[0257] Implementation Method 61. The method of Implementation Method 60, wherein the oral dosage form contains about 100 mg of SBEβCD.

[0258] Implementation method 62. The methods of implementation methods 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.

[0259] Implementation method 63. The method of implementation method 62, wherein the molar ratio of SBEβCD to meloxicam is about 0.8 to about 1.2.

[0260] Implementation method 64. The method of implementation method 62, wherein the molar ratio of SBEβCD to meloxicam is about 1.

[0261] Implementation method 65. The method of implementation methods 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.

[0262] Implementation method 66. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65, wherein the oral dosage form comprises SBEβCD in a weight ratio to rizatriptan in the range of about 1 to about 100.

[0263] Embodiment 67. The method of Embodiment 66, wherein the oral dosage form comprises SBEβCD in a weight ratio of about 10 to rizatriptan.

[0264] Implementation method 68. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 or 67, wherein the bicarbonate includes sodium bicarbonate.

[0265] Implementation Method 69. The method of Implementation Method 68, wherein the oral dosage form contains 500 mg of sodium bicarbonate.

[0266] Implementation method 70. The methods of implementation methods 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 or 69, wherein the oral dosage form has been shown to have a median Tmax of less than about 90 minutes in fasted human subjects.

[0267] Implementation Method 71. The method of Implementation Method 70, wherein the oral dosage form has been shown to have a median Tmax of less than about 2 hours in fasted human subjects with meloxicam.

[0268] Implementation method 72. The method of implementation methods 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71, wherein the oral dosage form has been shown to reach therapeutic plasma concentrations in the human body more quickly than a reference dosage form.

[0269] Implementation 73. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan, wherein the human migraine patient experiences migraine relief due to the oral administration of the dosage form to the migraine patient.

[0270] Implementation 74. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate and 3) rizatriptan, wherein 2 hours after orally administering the dosage form to the human migraine patient, the human migraine patient is free of migraine.

[0271] Implementation 75. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan, wherein the migraine patient experiences relief from nausea due to oral administration of the dosage form to the migraine patient.

[0272] Implementation 76. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate and 3) rizatriptan, wherein the human migraine patient does not experience nausea 2 hours after oral administration of the dosage form to the human migraine patient.

[0273] Implementation 77. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan, wherein the migraine patient experiences a reduction in photophobia due to the oral administration of the dosage form to the migraine patient.

[0274] Implementation 78. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate and 3) rizatriptan, wherein, 2 hours after oral administration of the dosage form to the human migraine patient, the human migraine patient does not have photophobia.

[0275] Implementation 79. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate, and 3) rizatriptan, wherein the migraine patient experiences a reduction in phonophobia due to the oral administration of the dosage form to the migraine patient.

[0276] Implementation 80. A method for treating migraine, the method comprising: selecting a human migraine patient with a history of inadequate response to previous migraine treatment, 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 sulfobutyl ether β-cyclodextrin (SBEβCD), 2) bicarbonate and 3) rizatriptan, wherein, 2 hours after oral administration of the dosage form to the human migraine patient, the human migraine patient does not experience phonophobia.

[0277] Implementation Method 81. A method for more rapidly improving migraine relief associated with rizatriptan therapy, comprising: orally administering to a person in need a combination of: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) bicarbonate, 3) rizatriptan, wherein the migraine relief experienced one hour after administration of said combination is greater than the migraine relief experienced by a person one hour after administration of the same amount of rizatriptan alone.

[0278] Implementation 82. A method for relieving migraine, comprising: orally administering to a person in need a combination of the following substances: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan, wherein the combination is orally administered to a person suffering from moderate to severe migraine of acute migraine, wherein the person experiences greater relief from the most distressing symptoms two hours after administration of the combination compared to the person experiencing relief from the most distressing symptoms two hours after administration of the same amount of rizatriptan alone.

[0279] Implementation 83. A method for relieving migraine, comprising: orally administering to a person in need a combination of the following substances: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan, wherein the combination is orally administered when the person suffers from moderate to severe migraine of acute migraine, wherein the person suffers from migraine accompanied by abnormal skin pain, and wherein the person who orally administers the combination experiences greater migraine relief two hours after administration compared to the person who experiences migraine relief two hours after administration of the same amount of meloxicam alone.

[0280] Implementation 84. A method for relieving migraine, comprising: orally administering to a person in need a combination of the following substances: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan, wherein the combination is orally administered when the person is suffering from severe migraine of acute migraine, wherein the person who orally administers the combination experiences greater migraine relief two hours after administration compared to the person who experienced migraine relief two hours after administration of the same amount of meloxicam alone.

[0281] Implementation 85. A method for relieving migraine, comprising: orally administering to a person in need a combination of the following substances: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan, wherein the combination is orally administered when the person is suffering from moderate to severe migraine of acute migraine, wherein the person is obese, and wherein the person who orally administers the combination two hours after the administration experiences greater migraine relief than the person who experiences migraine relief two hours after administering the same amount of meloxicam alone.

[0282] Implementation 86. A method for relieving migraine, comprising: orally administering to a person in need a combination of the following substances: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) a bicarbonate, and 3) rizatriptan, wherein the combination is orally administered when the person suffers from moderate to severe migraine of acute migraine, wherein the person suffers from morning migraine, and wherein the person who orally administers the combination experiences greater migraine relief two hours after administration compared to the person who experiences migraine relief two hours after administration of the same amount of meloxicam alone.

[0283] Implementation 87. A method for relieving migraine, comprising: orally administering to a person in need a combination of the following substances: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin, 2) bicarbonate, and 3) rizatriptan, wherein the combination is orally administered when the person has a moderate to severe migraine of acute migraine, wherein the person has been diagnosed with migraine with or without aura as defined in the International Classification of Headache Disorders, Third Edition (ICHD-3), for at least one year prior to the oral administration of the combination, and wherein the person experiences greater migraine relief two hours after oral administration of the combination compared to the person experiencing migraine relief two hours after administration of the same amount of meloxicam alone.

[0284] Implementation 88. A method of treating migraine, comprising: orally administering a dosage form to a human migraine patient, wherein the oral dosage form comprises a combination of: 1) a complex of meloxicam and sulfobutyl ether-β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) rizatriptan, wherein, at the time of administration of the dosage form, the human migraine patient suffers from migraine with abnormal skin pain, and wherein, 2 hours after oral administration of the dosage form to the human migraine patient, the human migraine patient does not have migraine.

[0285] Implementation method 89. The method of implementation methods 81, 82, 83, 84, 85, 86, 87 or 88, wherein the migraine is accompanied by visual disturbances.

[0286] Implementation 90. The method of Implementation 89, wherein 2 hours after oral administration of the combination, the person achieved the absence of visual disturbance.

[0287] Example 1

[0288] The effects of different amounts of potassium carbonate (K₂CO₃) and sodium bicarbonate (NaHCO₃) on the pH of an acidic medium were tested. An acidic medium was chosen to simulate gastric conditions. K₂CO₃ or NaHCO₃ was added to 50 mL of 0.01 N HCl solution (pH 2). The pH of the solution was measured after adding K₂CO₃ or NaHCO₃. Then, 240 mL of deionized water was added to the mixture, and the pH was measured again. The results are shown in Tables 1-4.

[0289] Table 1. Results using K2CO3 (0.01 N HCl)

[0290]

[0291] Table 2. Results using K2CO3 (0.01 N HCl + water)

[0292]

[0293] Table 3. Results using NaHCO3 (0.01 N HCl)

[0294]

[0295] Table 4. Results using NaHCO3 (0.01 N HCl + water)

[0296]

[0297] Example 2

[0298] Tablets containing a combination of meloxicam and sulfobutyl ether-β-cyclodextrin (SBEβCD) (a cyclodextrin containing about 6 to about 7 sulfobutyl ether groups per β-cyclodextrin molecule), K2CO3, or NaHCO3 were manufactured and their dissolution was tested. Tablets containing only meloxicam (MOBIC®) were purchased and their dissolution was tested. The tablets tested are listed in Table 5. Meloxicam in the form of a meloxicam / SBEβCD inclusion complex was used in tablets containing both meloxicam and SBEβCD. The inclusion complex was formed by mixing meloxicam and SBEβCD in a pH-adjusted aqueous solution. The pH of the solution was adjusted using a buffer. The resulting soluble meloxicam / SBEβCD inclusion complex was then spray-dried. This spray-dried dispersion was used to manufacture tablets containing SBEβCD.

[0299] Table 5. Tablets

[0300]

[0301] Dissolution was tested in an acidic medium (selecting conditions simulating the stomach) by placing tablets in a 0.01 N HCl solution with a stirring rate of 75 RPM and a container temperature of approximately 37 °C. The results are shown in Table 6 and... Figure 1-10 The results are presented in the table. Results at different time points (0, 15, 30, 45, 60, 90 and 120 minutes) are expressed as the percentage of meloxicam dissolved (%).

[0302] Table 6. Dissolution Results

[0303]

[0304] Compared to tablets containing meloxicam alone, tablets containing various combinations of meloxicam and SBEβCD, K2CO3, or NaHCO3 exhibit higher meloxicam dissolution rates. For example, after 120 minutes, meloxicam tablets containing NaHCO3 showed a dissolution rate of 95%, while tablets containing meloxicam alone showed a dissolution rate of 2%.

[0305] In the absence of SBEβCD, meloxicam dissolution increased with increasing K₂CO₃ concentration. However, in the presence of SBEβCD, increasing the amount of K₂CO₃ did not appear to increase meloxicam dissolution. At the highest tested dose of potassium carbonate, meloxicam dissolution was approximately 50% lower in the presence of SBEβCD at 120 minutes compared to the dissolution in the absence of SBEβCD.

[0306] Meloxicam with NaHCO3 showed significantly higher dissolution rates than those observed with the highest dose of K2CO3 at 15 minutes (50% vs. 30%) and 120 minutes (92% vs. 23%). In the presence of SBEβCD, the dissolution rate of meloxicam with NaHCO3 was also significantly increased compared to that with the highest dose of K2CO3 at 15 minutes (85% vs. 26%) and 120 minutes (86% vs. 12%). In the presence of SBEβCD, NaHCO3 increased meloxicam dissolution more significantly at 15 minutes than potassium carbonate, which resulted in a decrease in overall dissolution rate.

[0307] Example 3

[0308] The preparation comprises 1) an inclusion complex of SBEβCD and meloxicam prepared as described below, and 2) a bilayer tablet of sodium bicarbonate (SBEβCD-meloxicam / bicarbonate). The first layer contains an inclusion complex of 15 mg meloxicam, 100 mg SBEβCD, and 100 mg sodium bicarbonate. The second layer contains 40 mg esomeprazole and 400 mg sodium bicarbonate.

[0309] A total of 20 human subjects were randomly assigned in a 1:1 ratio to receive either the above-mentioned SBEβCD-meloxicam / bicarbonate tablets or Mobic® tablets (15 mg meloxicam) once daily for 6 days while fasting.

[0310] Plasma samples were collected at several time points on the first day of administration for meloxicam concentration analysis. Meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. Results are presented in... Figure 11 As shown in the image.

[0311] For SBEβCD-meloxicam / bicarbonate tablets, the median T value for meloxicam is... max That is, the primary endpoint of the test was 9 times faster than that of Mobic® (0.5 hours and 4.5 hours, respectively, p<0.0001).

[0312] SBEβCD-Meloxicam / Bicarbonate tablets also exhibited a higher mean maximum plasma concentration (C) compared to Mobic®. max (p=0.0018), faster time to reach therapeutic plasma concentration (p<0.0001), and faster time to reach half maximum plasma concentration (p<0.0001).

[0313] Meloxicam / SBEβCD inclusion complex is used in tablets containing meloxicam and SBEβCD. The inclusion complex is formed by mixing meloxicam and SBEβCD in a pH-adjusted aqueous solution. The pH of the solution is adjusted using a buffer. The resulting soluble meloxicam / SBEβCD inclusion complex is then spray-dried. This spray-dried dispersion is used to manufacture tablets containing SBEβCD.

[0314] Example 4

[0315] A single-layer tablet (SBEβCD-Meloxicam / Rizatriptan / Bicarbonate) was prepared containing 1) an inclusion complex of SBEβCD and meloxicam; 2) rizatriptan; and 3) sodium bicarbonate. The single-layer tablet contained 20 mg meloxicam, 10 mg rizatriptan, and 500 mg sodium bicarbonate. The inclusion complex was identical to that of Example 3.

[0316] Dissolution tests were conducted in an acidic medium (selecting conditions simulating the stomach) by placing tablets in a 0.01 N HCl solution with a stirring rate of 75 RPM and a container temperature of approximately 37°C. The results are listed in Table 7. Results at different time points (0, 15, 30, 45, 60, 90, and 120 minutes) are expressed as the percentage of meloxicam (%) and the percentage of rizatriptan dissolved (%).

[0317] Table 7. Dissolution Results

[0318]

[0319] As shown in Table 7, the dissolution results of the tablets in Example 4 are very similar to those in Example 3. Therefore, we anticipate that the pharmacokinetic characteristics of the tablets in Example 4, including the bioavailability of meloxicam and T0, will be similar. max Equal to Example 3 and Figure 11 Similar to what is described in [the text]. This expectation has proven correct, as illustrated in the following examples.

[0320] Example 5

[0321] The monolayer tablets of Example 4 were administered to six human subjects. Plasma samples were collected at several time points on day 1 for rizatriptan concentration analysis. The concentrations of rizatriptan and meloxicam were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. The results for meloxicam were comparable to those reported for the bilayer formulation of Example 3. The median T for rizatriptan was... max The duration was 0.75 hours, and the average C of rizatriptan was... max It was 20.710 ng / mL. In comparison, the commercial rizatriptan formulation Maxalt... ® The report Tmax It takes 1.0-1.5 hours.

[0322] Example 6

[0323] With 2) and Maxalt ® A randomized, single-dose, parallel-group phase 1 clinical trial was conducted in healthy human volunteers following oral administration of meloxicam (20 mg), rizatriptan (10 mg), SBEβCD, and sodium bicarbonate (meloxicam / rizatriptan) in comparison to a fasting condition to evaluate the pharmacokinetics, safety, and tolerability of the combination. A total of 20 healthy adult male or female volunteers were randomized in a 1:1 ratio to receive either a single dose of meloxicam / rizatriptan or Maxalt. ® (10 mg rizatriptan).

[0324] Blood samples were collected for pharmacokinetic analysis at multiple time points before and after drug administration. The pre-specified primary endpoint was T. thera The time to reach therapeutic plasma concentrations of meloxicam is defined as the time to reach the C60 concentration of meloxicam after administration of the highest approved dose (15 mg) of standard meloxicam. avg The concentration was approximately 1000 ng / mL. The pharmacokinetic (PK) results of the rizatriptan component of the meloxicam / rizatriptan mixture were compared with those of Maxalt. ® Comparison of PK results for (rizatritan).

[0325] The pharmacokinetic results of the meloxicam (20 mg) fraction of the meloxicam / rizatriptan from this trial were compared with those of the Mobic fraction from Example 3. ® The pharmacokinetic (PK) results of (15 mg meloxicam) were compared.

[0326] Results of Phase 1

[0327] Following oral administration of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan), meloxicam is rapidly absorbed, reaching the median time (T0) of therapeutic plasma concentration. thera ), that is, the primary endpoint ( Figure 12 (and Table 8) is 17 minutes. Median T max The time is 1 hour, while 15 mg of standard meloxicam (Mobic) ® The duration is 4.5 hours. (Very short T) max This indicates that meloxicam / rizatriptan has the potential for rapid onset of action in the treatment of migraine. Following administration of meloxicam / rizatriptan, the mean plasma elimination half-life (T0) of meloxicam was [not specified]. 1 / 2 The elimination half-life was 18.2 hours, compared to 21.5 hours for standard meloxicam. This longer elimination half-life suggests that meloxicam / rizatriptan has the potential for enhanced and sustained efficacy, as well as reduced migraine recurrence.

[0328] Table 8. Pharmacokinetic parameters of meloxicam / rizatriptan

[0329]

[0330] a T max and T thera Represent the value as a median or range.

[0331] Following oral administration of meloxicam / rizatriptan, rizatriptan is rapidly absorbed, T max The time was 0.64 hours (38 minutes), while the same dose of standard rizatriptan (Maxalt) took longer. ® ) is 0.88 hours ( Figure 13 (and Table 9). Compared with standard rizatriptan, for patients using C after meloxicam / rizatriptan administration... max The systemic exposure to rizatriptan, as measured by AUC, was also numerically higher.

[0332] Table 9. Pharmacokinetic parameters of rizatriptan in meloxicam / rizatriptan and standard rizatriptan

[0333]

[0334] a T max Represent the value as a median or range.

[0335] Meloxicam / rizatriptan was well tolerated, and there were no significant differences in safety between the two treatment groups. No serious adverse events occurred in the study.

[0336] Example 7

[0337] A phase 3, randomized, double-blind, multicenter, active- and placebo-controlled trial was conducted to evaluate the efficacy and safety of meloxicam / rizatriptan in the acute treatment of moderate and severe migraine in patients with a history of inadequate response to prior acute migraine treatment. Eligible patients were randomized in a 2:2:2:1 ratio to receive meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan with SBEβCD and sodium bicarbonate as described in Example 4 above), rizatriptan (10 mg) (rizatriptan group), meloxicam (20 mg) with SBEβCD and sodium bicarbonate (moloxicam group), or placebo. Compared with placebo, for meloxicam / rizatriptan, the synergistic primary endpoint of no headache and no most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) was observed 2 hours after administration.

[0338] The superiority of meloxicam / rizatriptan over the rizatriptan group and the meloxicam group (component contribution) will be determined based on the absence of headache for 2 to 24 hours after administration (key secondary endpoint).

[0339] Eligible patients must have a history of inadequate response to previous acute migraine treatment and be assessed using the migraine treatment optimization questionnaire (mTOQ-4). The mTOQ-4 is a validated questionnaire that assesses the response to previous acute treatment based on four dimensions: pain relief for 2 hours, efficacy of a single dose for at least 24 hours, ability to plan daily activities, and interruption of daily activities.

[0340] Due to the rapid absorption and unique dual mechanism of action of meloxicam / rizatriptan described in this article, it is expected that meloxicam / rizatriptan will show significant improvement over placebo and advantages over both the rizatriptan and meloxicam groups.

[0341] Example 8

[0342] A female migraine sufferer went to her doctor hoping to relieve her migraines. Her doctor prescribed 10 mg rizatriptan (Maxalt®) to take during her next acute migraine. It provided some relief from pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and phonophobia, but not complete relief from these symptoms. At her next visit, her doctor prescribed 20 mg meloxicam tablets, which also contain SBEβCD and 500 mg sodium bicarbonate, to take during her next acute migraine. It provided some relief from pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and phonophobia, but not complete relief from these symptoms. At her next visit, her doctor prescribed the tablets described in Example 4 above. She reported an approximately 10-30% improvement in her pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and / or phonophobia at 2 hours and 24 hours after taking the tablets, compared to what she experienced after taking meloxicam or rizatriptan alone.

[0343] Example 9

[0344] A male migraine sufferer visited his doctor hoping to relieve his migraines. His doctor prescribed 10 mg rizatriptan (Maxalt®) to take during his next acute migraine attack. It provided some relief from pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and phonophobia, but not complete relief from these symptoms. At his next visit, his doctor prescribed 20 mg meloxicam tablets, which also contain SBEβCD and 500 mg sodium bicarbonate, to take during his next acute migraine attack. It provided some relief from pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and phonophobia, but not complete relief from these symptoms. At his next visit, his doctor prescribed the tablets described in Example 4 above. He reported an approximately 30-60% improvement in his pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and / or phonophobia at 2 hours and 24 hours after taking the tablets, compared to what he experienced after taking meloxicam or rizatriptan alone.

[0345] Example 10

[0346] A woman suffering from migraines went to see her doctor hoping to relieve her migraines. Her doctor prescribed her 10 mg of rizatriptan (Maxalt). ® She took it during her next acute migraine. It provided some relief from pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and phonophobia, but not complete relief from these symptoms. At her next appointment, her doctor gave her 20 mg meloxicam tablets, which also contain SBEβCD and 500 mg sodium bicarbonate, to take during her next acute migraine. It provided some relief from pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and phonophobia, but not complete relief from these symptoms. At her next appointment, her doctor gave her the tablets described in Example 4 above. She reported that at 2 hours and 24 hours after taking the tablets, her pain, nausea, abnormal pain (such as dermatophyte pain), photophobia, and / or phonophobia were improved by approximately 60-100% compared to what she experienced after taking meloxicam or rizatriptan alone.

[0347] Example 11

[0348] According to the Centers for Disease Control and Prevention, more than 37 million Americans suffer from migraines, and according to the American Migraine Foundation, it is a leading cause of disability among neurological disorders in the United States. Migraines are characterized by recurrent, throbbing, often severe and disabling nausea-related headaches, and sensitivity to light and / or sound. It is estimated that migraines cause up to $78 billion annually in direct (e.g., medical visits, medication) and indirect (e.g., lost work, reduced productivity) losses 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 surveys of migraine patients indicate that over 70% are not entirely satisfied with their current treatment, nearly 80% would try new therapies, and they want treatment to be faster, more consistent, and result in fewer symptom relapses [(1) SmeltAF, 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 Delphistudy. PLoS One. 2014 Jun 16;9(6):e98933, 6; and (2) Lipton RB, Stewart WF, Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache.1999;39(suppl 2):S20-S26].

[0349] The World Health Organization classifies severe migraine attacks as one of the most disabling diseases, comparable to dementia, quadriplegia, and active psychosis [(1) Menken et al., Arch Neurol. 2000;57:418-420; and (2) Shapiro and Goadsby. Cephalalgia. 2007;27:991-4]. The debilitating pain, along with the persistent fear of the next migraine attack, impairs family life, social life, and employment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. People with migraines are twice as likely to experience depression and anxiety as healthy individuals [Antonaci et al., J Headache Pain. 2011;12:115–125]. Widespread misunderstandings about the severity of migraines contribute to under-awareness and undertreatment [Global Burden of Disease Study. Lancet. Most patients are not entirely satisfied with their current treatment]. Therefore, there is an urgent need for new therapies that offer improved treatment outcomes for this serious neurological disease.

[0350] A phase 3, randomized, double-blind, multicenter, placebo- and active-drug controlled trial was conducted to evaluate the efficacy and safety of meloxicam and rizatriptan (meloxicam / rizatriptan) in combination for the acute treatment of moderate and severe migraine. Eligible patients must be between 18 and 65 years of age, have a confirmed diagnosis of migraine with or without aura as defined by ICHD-3 criteria (for at least 1 year), experience 2 to 8 moderate to severe migraine episodes per month on average, have a history of inadequate response to previous acute migraine treatment, and be assessed on the migraine treatment optimization questionnaire-4 with a score of 7 (mean score 3.6), corresponding to poor response to previous acute treatment. Exclusion criteria included cluster headache or other types of migraine, chronic daily headache (more than 15 non-migraine days per month), history of severe cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, recruited patients also exhibited a high rate of characteristics closely associated with poor treatment outcomes, including skin abnormal pain (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 receive one of the following: a single-layer tablet (20 mg meloxicam / 10 mg rizatriptan with SBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam with SBEβCD (20 mg) (MoSEIC meloxicam), or placebo for the treatment of a moderate or severe single migraine attack. The two co-primary endpoints of this trial were the proportion of patients without headache 2 hours after administration of meloxicam / rizatriptan, compared to placebo, and the proportion of patients who no longer had the most bothersome migraine-related symptoms (nausea, photophobia, or phonophobia) 2 hours after administration. The superiority of meloxicam / rizatriptan compared to the rizatriptan group and the meloxicam group (component contribution) was determined based on the absence of headache for 2 to 24 hours post-dose (key secondary endpoint). This study was conducted under a Special Protocol Assessment (SPA) by the FDA. Rizatriptan, an active comparator in the trial, is considered the fastest-acting oral triptan and one of the most effective drugs currently available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B / 1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov 17;358(9294):1668-75.)

[0351] Meloxicam / rizatriptan provides rapid relief from migraines. At every time point measured starting from 15 minutes, the percentage of patients achieving pain relief using meloxicam / rizatriptan was numerically higher than those using rizatriptan, and this was statistically significant at 60 minutes (p=0.04). Figure 14 For meloxicam / rizatriptan, the proportion of patients experiencing pain relief 1.5 hours after administration was 60.5%, compared to 52.5% for rizatriptan and 48.3% for placebo (e.g., meloxicam / rizatriptan, p=0.019, p=0.04, respectively). Figure 14 ). Figure 14A The percentage of subjects who reported pain relief with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo at 1.0 and 1.5 hours is shown.

[0352] Meloxicam / rizatriptan demonstrated with high statistical significance that a higher percentage of patients achieved pain relief at 2 hours post-dose compared to placebo (19.9% ​​vs. 6.7%, p<0.001). Figure 15 The incidence rate was 36.9% (compared to 24.4%, p=0.002), and the number of patients with the most bothersome symptoms met both regulatory primary endpoints.

[0353] The superiority of meloxicam / rizatriptan over rizatriptan (activity comparison) and MoSEIC™ meloxicam (component contribution) was determined according to the provisions of the SPA, by the percentage of patients receiving meloxicam / rizatriptan who achieved sustained pain relief within 2 hours to 24 hours after administration being higher than that of rizatriptan, MoSEIC™ meloxicam, and placebo (16.1%, 11.2%, 6.8%, and 5.3%, respectively; p = 0.038, p = 0.001, and p < 0.001, respectively, relative to meloxicam / rizatriptan). Figure 16A To demonstrate this, key secondary endpoints were pre-specified to demonstrate component contribution. Approximately 80% of patients receiving meloxicam / rizatriptan achieved pain relief within 2 hours and remained pain-free for 24 hours. These results indicate that meloxicam / rizatriptan significantly improves pain relief in migraine treatment and is superior to rizatriptan.

[0354] Compared with placebo and rizatriptan, meloxicam / rizatriptan provided substantially greater and longer-lasting migraine relief, implying a significant reduction in rescue medication use compared to placebo and rizatriptan. The percentage of patients experiencing sustained pain relief within 2 to 24 hours after administration of meloxicam / rizatriptan was 53.3%, compared to 33.5% for placebo and 43.9% for rizatriptan (relative to meloxicam / rizatriptan, p<0.001, p=0.006, respectively). Figure 16B).

[0355] Compared with placebo (31.1%) and rizatriptan (36.5%) patients (relative to meloxicam / rizatriptan, p<0.001, p=0.003), a statistically significantly larger proportion of meloxicam / rizatriptan patients (46.5%) also experienced sustained pain relief for 2 to 48 hours. Figure 17B ). 17D shows the percentage of subjects who achieved sustained pain relief from 2 hours to 48 hours with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo. A statistically significantly larger proportion of meloxicam / rizatriptan patients (15.4%) also experienced sustained pain relief from 2 hours to 48 hours compared to placebo (5.3%), rizatriptan (8.8%), and MoSEIC™ meloxicam (8.1%) patients (p<0.001, p=0.003, p<0.001, respectively, compared to meloxicam / rizatriptan). Figure 17A ). Figure 17C The percentage of subjects who achieved sustained pain relief from 2 hours to 48 hours with meloxicam, rizatriptan, and meloxicam / rizatriptan compared to placebo is shown. Approximately 77% of patients receiving meloxicam / rizatriptan achieved pain relief at 2 hours and remained pain-free for 48 hours.

[0356] Among patients receiving meloxicam / rizatriptan, 23.0% used rescue medication, compared to 43.5% in those receiving placebo and 34.7% in those receiving rizatriptan (p<0.001 for each group compared to meloxicam / rizatriptan). Figure 18 Approximately 77% of patients receiving meloxicam / rizatriptan did not require rescue medication. These results demonstrate that meloxicam / rizatriptan is superior to rizatriptan (an active comparison drug) in the treatment of migraines.

[0357] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan on several other secondary endpoints, including changes in patient overall impression (PGI-C) (p=0.022) and recovery of normal function at 24 hours (p=0.027).

[0358] Table 10 below lists some p-values ​​for meloxicam / rizatriptan relative to rizatriptan for various endpoints, demonstrating that meloxicam / rizatriptan is statistically significantly superior to rizatriptan in the treatment of migraine.

[0359] Table 10. P-values ​​of meloxicam / rizatriptan relative to rizatriptan for different endpoints

[0360]

[0361] Furthermore, meloxicam / rizatriptan showed a greater probability of pain relief within 24 hours of administration; approximately 70% of patients taking meloxicam / rizatriptan experienced pain relief within 24 hours, compared to approximately 60% of patients taking rizatriptan or MoSEIC meloxicam, and approximately 50% of patients receiving placebo. Figure 27 As shown, meloxicam / rizatriptan was more likely to achieve pain relief within 30 minutes of administration than rizatriptan, resulting in a median time to pain relief that was nearly three times faster with meloxicam / rizatriptan than with rizatriptan, at 1.5 hours and 4 hours, respectively.

[0362] Furthermore, patients taking meloxicam / rizatriptan had a lower likelihood of pain recurrence compared to those taking rizatriptan; within 48 hours of administration, meloxicam / rizatriptan reduced pain recurrence by more than 50% compared to rizatripten, with 45.2% of patients experiencing pain recurrence after taking rizatriptan, compared to only 21.2% of patients taking meloxicam / rizatriptan. Figure 28 As shown.

[0363] Given that rizatriptan, the activity comparison drug in this trial, is considered one of the fastest-acting oral triptans and one of the most effective drugs currently available for the treatment of acute migraines, and considering that the trial enrolled patients with refractory migraines, the observed therapeutic effect of meloxicam / rizatriptan providing better and more durable migraine relief than rizatriptan is significant. Many patients respond poorly to current acute migraine treatments, increasing their risk of headache-related disability and progression to chronic migraines, factors associated with increased healthcare costs. The results of this study suggest that meloxicam / rizatriptan may offer an important treatment option for patients with refractory migraines.

[0364] Meloxicam / rizatriptan was generally safe and well-tolerated in the MOMENTUM Phase 3 trial, with adverse events occurring in 1% to 3% of patients. 11.1% of patients experienced any form of post-treatment adverse event after taking meloxicam / rizatriptan, while 2.7%, 1.6%, and 1.4% of patients experienced nausea, dizziness, and somnolence, respectively (Table 12). The rate of post-treatment adverse events was substantially similar to that of any other tested treatment after taking meloxicam / rizatriptan (Table 12).

[0365] Table 12.

[0366]

[0367] Data is presented in the form of the number of participants (% of participants).

[0368] The results of this trial demonstrate the ability of meloxicam / rizatriptan to provide unique benefit to migraine sufferers in a rigorously designed trial that included patients with refractory migraines, offering rapid, potent, and sustained migraine relief compared to the potent active ingredient rizatriptan. These results have potentially significant implications for patient care, given the high rates of inadequate response to current treatments and patient dissatisfaction.

[0369] Meloxicam / rizatriptan combines multiple mechanisms of action to address various migraine processes, aiming to provide enhanced effectiveness. Meloxicam / rizatriptan is believed to work by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and suppressing neuroinflammation, pain signaling, and central sensitization. The results of this trial validate this approach, demonstrating that meloxicam / rizatriptan can provide significant benefits beyond currently available treatments, even for patients with difficult-to-treat migraines. Meloxicam / rizatriptan is effective for the acute treatment of migraines in adults with or without aura.

[0370] Example 12

[0371] A phase 3, randomized, double-blind, multicenter, placebo-controlled trial was conducted to evaluate meloxicam / rizatriptan for early treatment of migraine. A total of 302 patients were randomized 1:1 to receive either a single dose of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan with SBEβCD and sodium bicarbonate as described in Example 4 above) or placebo at the earliest onset of a migraine attack, where the pain was mild before developing into moderate or severe intensity.

[0372] This clinical trial differs from the clinical trial in Example 11. The clinical trial in Example 11 recruited only patients with a history of inadequate response to prior acute treatment, and patients only waited for treatment of their attacks when the migraine reached moderate or severe intensity. In contrast, this clinical trial recruited all participants, and patients were instructed to administer meloxicam / rizatriptan at the earliest signs of migraine, while the pain was mild before developing into moderate or severe intensity.

[0373] The patients were adult subjects who had been diagnosed with migraine with or without aura.

[0374] Compared with placebo, for meloxicam / rizatriptan, the co-primary endpoint of no headache and no most bothersome migraine-related symptoms (nausea, photophobia or phonophobia) was observed 2 hours after administration.

[0375] Secondary endpoints included sustained pain relief, absence of migraine pain, changes in functional disability, and use of rescue medications.

[0376] Inclusion criteria included men or women aged 18–65 years (inclusive), a definitive diagnosis of migraine with or without aura as defined by ICHD-3 criteria (for at least 1 year), and an average of 2 to 8 migraines per month. Exclusion criteria included cluster headache, tension headache or other types of migraine, chronic daily headache (more than 15 non-migraine days per month), history of severe cardiovascular disease, and uncontrolled hypertension.

[0377] In this phase 3 trial of meloxicam / rizatriptan for early treatment of migraine, meloxicam / rizatriptan substantially significantly eliminated migraine and substantially significantly prevented the progression of migraine intensity. In the trial, compared with placebo, meloxicam / rizatriptan met the co-primary endpoints of no migraine and no most bothersome symptoms.

[0378] 2 hours after administration ( Figure 19A and Figure 19B Compared with placebo, meloxicam / rizatriptan showed statistically significant improvements in both co-primary endpoints: no pain (32.6% vs 16.3%, p=0.002) and no most bothersome symptoms (43.9% vs 26.7%, p=0.003). The most bothersome symptoms were nausea, photophobia, or phonophobia.

[0379] Meloxicam / rizatriptan provided no migraine pain within 30 minutes. Figure 20 ) and without the most bothersome symptoms ( Figure 21 In terms of the absence of migraine pain, it was numerically superior to placebo, achieving statistical significance at 90 minutes and every hour thereafter (p=0.003). Figure 20 At 12 hours, 64% of patients receiving meloxicam / rizatriptan were no longer experiencing pain, compared to 42% of those receiving a placebo. At 24 hours, 69% of patients receiving meloxicam / rizatriptan were no longer experiencing pain, compared to 47% of those receiving a placebo.

[0380] Compared with placebo, meloxicam / rizatriptan provided durable relief from migraine, with a statistically significantly higher proportion of patients achieving sustained pain-free status at 2 to 24 hours post-dose (22.7% vs 12.6%, p=0.030) and 2 to 48 hours post-dose (20.5% vs 9.6%, p=0.013). Figure 22A and Figure 22B ).

[0381] Within 2 to 24 hours, meloxicam / rizatriptan prevented migraine intensity greater than mild in 73.5% of patients, compared to 47.4% in patients taking placebo (p<0.001). Figure 23 A single dose of meloxicam / rizatriptan prevented migraines from developing beyond the mild stage.

[0382] The effect on pain progression translated into a significant reduction in rescue medication use; only 15.3% of patients taking meloxicam / rizatriptan required rescue medication within 24 hours of administration, compared to 42.2% of patients taking placebo (p<0.001). Figure 24 ).

[0383] Meloxicam / rizatriptan substantially reduced functional disability and demonstrated overall disease improvement. At 24 hours, 73.5% of patients taking meloxicam / rizatriptan were able to perform normal activities, compared to 47.4% of patients taking placebo (p<0.001). Figure 25 ).

[0384] On the Patient General Impression Change-C (PGI-C) scale, at hour 2, 52.4% of patients taking meloxicam / rizatriptan showed significant or substantial improvement, compared to 27.7% of patients taking placebo (p<0.001). Figure 26 ).

[0385] Meloxicam / rizatriptan was generally safe and well-tolerated in the trial. The most frequently reported adverse events were somnolence, dizziness, and paresthesia, all of which occurred in less than 5% of cases. No serious adverse events were reported in the trial.

[0386] Table 11.

[0387]

[0388] Data is presented in the form of the number of participants (% of participants).

[0389] Dr. Stewart Tepper, Professor of Neurology at Dartmouth Geisel School of Medicine, said, “[This] study demonstrates a high rate of migraine-free migraine treatment with meloxicam / rizatriptan and utilizes an innovative design to assess migraine progression. Notably, early treatment with meloxicam / rizatriptan prevented migraine progression in the vast majority of patients and restored normal function to an equally high proportion.” He added, “The multiple mechanisms of meloxicam / rizatriptan address many disordered physiological processes associated with migraine attacks. These results, combined with previous clinical data showing the superiority of meloxicam / rizatriptan over the active control, provide clinical evidence that this synergistic, multi-mechanism approach and the rapid absorption of meloxicam / rizatriptan can offer significant benefits to a wide range of patients. As clinicians continue to seek more effective options than existing therapies for their patients, meloxicam / rizatriptan could provide an important new treatment for this disabling disease.”

[0390] This Phase 3 trial confirmed the superior and durable efficacy of meloxicam / rizatriptan. The demonstrated prevention of migraine progression and significantly improved pain-free rates with early treatment with meloxicam / rizatriptan expands and enhances its differentiating effect in the acute treatment of migraine. Through this Phase 3 trial and the Phase 3 trial described in Example 11 in patients with a history of inadequate response to prior acute treatment, meloxicam / rizatriptan has now been evaluated in two well-controlled trials. These trials demonstrated the efficacy of meloxicam / rizatriptan compared to potent active drugs and placebo in a range of migraine attack scenarios, regardless of duration of migraine treatment, disease severity, or baseline pain intensity.

[0391] “Migraine is one of the most disabling diseases, causing patients to lose their ability to function and severely impairing their family life, social activities, and work capacity,” said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs at Axsome. “Published surveys have highlighted that patients remain dissatisfied with the effectiveness of currently available therapies.” “[This] trial results are the first to demonstrate that meloxicam / rizatriptan can prevent the progression of migraines before they reach moderate or severe intensity. These data provide substantial clinical evidence supporting the potential of meloxicam / rizatriptan as a multi-mechanism treatment for migraines that outperforms current standards of care and provides rapid, powerful, and sustained symptom relief, enabling patients to return to normal daily activities.”

[0392] Example 13

[0393] A long-term, open-label phase 3 trial of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan with SBEβCD and sodium bicarbonate as described in Example 4 above) was conducted. In this trial, meloxicam / rizatriptan treatment provided rapid, significant, and durable relief of migraine and related symptoms. Meloxicam / rizatriptan was well tolerated in long-term treatment, and its safety profile was consistent with results observed in previously reported controlled trials.

[0394] This clinical trial evaluated the long-term safety of meloxicam / rizatriptan (20 mg MoSEIC™ meloxicam / 10 mg rizatriptan) for up to 12 months in patients experiencing migraine attacks. The study enrolled patients who had completed the clinical trials described in Example 11 or Example 12. During the 12-month period, enrolled patients were treated for up to 10 migraine attacks per month, with one dose of meloxicam / rizatriptan for each migraine attack. The safety and efficacy of meloxicam / rizatriptan were evaluated during the trial. A total of 706 patients were enrolled. The trial was terminated according to pre-defined protocols once at least 300 patients had been treated for at least 2 migraine attacks per month for 6 months and approximately 100 patients had been treated for at least 2 migraine attacks per month for 12 months. By the end of the study, 515 patients had reached at least 6 months of treatment and 155 patients had reached at least 12 months of treatment. During the trial, more than 21,000 migraine patients received meloxicam / rizatriptan. Efficacy measures include relief of migraine and most bothersome symptoms (photophobia, phonophobia, nausea) as well as the use of rescue medications.

[0395] In this clinical trial, meloxicam / rizatriptan provided rapid and significant relief from migraines and related symptoms. Within one hour of administration, migraine relief was observed in 39% (range: 37-41%) of patients, indicating rapid onset of action of meloxicam / rizatriptan. Two hours after administration, migraine relief was observed in 68% (range: 65-71%) of patients, and pain relief was observed in 38% (range: 37-40%). 47% (range: 46-49%) of patients experienced relief from their most bothersome symptoms (photophobia, phonophobia, nausea) within two hours of administration.

[0396] Meloxicam / rizatriptan provides sustained relief from migraines. Following a single dose of meloxicam / rizatriptan, 85% (range: 84-86%) of patients did not require rescue medication within 24 hours, and 83% (range: 82-85%) did not require rescue medication within 48 hours. The rates of sustained pain relief for 2-24 hours and 2-48 hours were 60% (range: 59-62%) and 59% (range: 58-60%), respectively. The rates of sustained pain relief for 2-24 hours and 2-48 hours were 33% (range: 33-35%) and 32% (range: 32-34%), respectively.

[0397] Meloxicam / rizatriptan was well tolerated with long-term administration. The safety profile of meloxicam / rizatriptan during the 12-month treatment period was consistent with previous short-term controlled trials. The most common adverse events (≥3%) were nausea, dizziness, and vomiting. In the 12-month trial, 1.6% of patients discontinued treatment due to adverse events.

[0398] Unless otherwise stated, all figures used in the specification and claims to indicate the quantity or nature of an ingredient (e.g., quantity, percentage, etc.) should in all cases be understood to represent the exact value shown and modified by the term "approximately". Therefore, unless stated to the contrary, the numerical parameters specified in the specification and appended claims are approximate values ​​and may vary depending on the desired characteristics sought. At least, and rather than attempting to limit the application of the equivalence doctrine to the scope of the claims, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying ordinary rounding techniques.

[0399] Unless otherwise stated herein or clearly contradicted by the context, the terms “a,” “an,” “the,” and similar designations used in the context of describing embodiments (especially in the context of the claims) should be interpreted to cover both the singular and the plural. Unless otherwise stated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., “for example”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of any claim. No language in the specification should be construed as indicating any unclaimed element essential to the practice of the claims.

[0400] The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of the group or other elements discovered herein. For convenience and / or to expedite examination, it is conceivable that one or more members of a group may be included in or removed from that group. When any such inclusion or removal occurs, this specification is deemed to include the modified group if used in the appended claims, thereby satisfying the written description of all Markush groups.

[0401] This document describes certain implementations, including the best modes known to the inventors for carrying out the claimed implementations. Of course, variations of these described implementations will become apparent to those skilled in the art after reading the foregoing description. The inventors expect those skilled in the art to appropriately adopt such variations, and the inventors intend to practice the claimed implementations in ways different from those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Furthermore, unless otherwise stated herein or otherwise clearly contradicted by the context, any combination of the foregoing elements in all their possible variations is contemplated.

[0402] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications may be made within the scope of the claims. Therefore, alternative embodiments may be used in accordance with the teachings of this document, as examples rather than limitations. Consequently, the claims are not limited to the embodiments shown and described precisely as illustrated herein.

[0403] This disclosure relates to the following implementation plan:

[0404] 1. A method of treating migraine, comprising: orally administering a dosage form to a migraine patient during a migraine attack at least twice a month for at least six months, wherein said dosage form comprises a combination of meloxicam and rizatriptan.

[0405] 2. Use of the combination of meloxicam and rizatriptan in the preparation of a medicine for the treatment of migraine, for use at least twice a month for at least six months, wherein said medicine is a dosage form containing meloxicam and rizatriptan.

[0406] 3. The method or use according to item 1 or 2, wherein a human migraine patient experiences migraine relief due to oral administration of the dosage form to a migraine patient.

[0407] 4. The method or use according to item 1, 2 or 3, wherein the migraine patient suffers from migraine-related nausea, photophobia or phonophobia.

[0408] 5. The method or use according to item 4, wherein the migraine patient experiences a reduction in nausea due to oral administration of the dosage form to the migraine patient.

[0409] 6. The method or use according to item 4, wherein the migraine patient experiences a reduction in photophobia due to oral administration of the dosage form to the migraine patient.

[0410] 7. The method or use according to item 4, wherein the migraine patient experiences a reduction in phonophobia due to oral administration of the dosage form to the migraine patient.

[0411] 8. The method or use according to item 1, 2, 3, 4, 5, 6 or 7, wherein the dosage form further comprises 400 mg to 600 mg of bicarbonate.

[0412] 9. The method or use according to item 1, 2, 3, 4, 5, 6, 7 or 8, wherein the dosage form further comprises about 5 mg to about 50 mg of meloxicam.

[0413] 10. The method or use according to any of the following items 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the dosage form further comprises about 50 mg to about 200 mg of SBEβCD.

[0414] 11. The method or use according to item 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the dosage form is meloxicam T in the human body. max A shorter solid oral dosage form than a reference dosage form, wherein the reference dosage form: 1) contains the same amount of meloxicam, 2) is free of SBEβCD, and 3) is free of bicarbonate.

[0415] 12. The method or use according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein about 1 mg to about 50 mg of rizatriptan is present in the oral dosage form based on the weight of the free base form of rizatriptan.

[0416] 13. The method or use according to item 12, wherein the rizatriptan is present in the form of a salt in an amount of about 10 mg of the molar equivalent of rizatriptan in the form of a free base.

[0417] 14. The method or use according to item 12 or 13, wherein the rizatriptan is present in the form of rizatriptan benzoate.

[0418] 15. The method or use according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the oral dosage form comprises about 10 mg to about 30 mg of meloxicam.

[0419] 16. The method or use according to item 15, wherein the oral dosage form comprises about 20 mg of meloxicam.

[0420] 17. The method or use according to item 10, 11, 12, 13, 14, 15 or 16, wherein for each β-cyclodextrin molecule, the SBEβCD has about 6 to about 7 sulfobutyl ether groups.

[0421] 18. The method or use according to any of the following items 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein the oral dosage form comprises about 50 mg to about 150 mg of SBEβCD.

[0422] 19. The method or use according to item 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the oral dosage form comprises about 400 mg to about 600 mg of sodium bicarbonate.

[0423] 20. The method or use according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein a human migraine patient is able to resume normal activity within 24 hours after receiving treatment.

Claims

1. A method for treating migraines, comprising: During a migraine attack, the patient is given an oral dosage form at least twice a month for at least six months, wherein the dosage form contains a combination of meloxicam and rizatriptan.

2. Use of the combination of meloxicam and rizatriptan in the preparation of a medicine for the treatment of migraine, for use at least twice a month for at least six months, wherein said medicine is a dosage form containing meloxicam and rizatriptan.

3. The method or use according to claim 1 or 2, wherein the human migraine patient experiences migraine relief due to oral administration of the dosage form to the migraine patient.

4. The method or use according to claim 1, 2 or 3, wherein the migraine patient suffers from migraine-related nausea, photophobia or phonophobia.

5. The method or use according to claim 4, wherein the migraine patient experiences a reduction in nausea due to oral administration of the dosage form to the migraine patient.

6. The method or use according to claim 4, wherein the migraine patient experiences a reduction in photophobia due to oral administration of the dosage form to the migraine patient.

7. The method or use according to claim 4, wherein the migraine patient experiences a reduction in phonophobia due to oral administration of the dosage form to the migraine patient.

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

9. The method or use according to claim 8, wherein the rizatriptan is present in the form of a salt in an amount of about 10 mg of the molar equivalent of rizatriptan in the form of a free base.

10. The method or use according to claim 8 or 9, wherein the rizatriptan is present in the form of rizatriptan benzoate.

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