BR112019013901B1 - SOLID DOSAGE FORM - Google Patents

Abstract

Described herein are compositions comprising a drug such as a triptan (e.g., rizatriptan) and/or an NSAID (e.g., meloxicam) in combination with a cyclodextrin and/or a carbonate or bicarbonate. Such compositions can be administered orally, for example, to improve the bioavailability or pharmacokinetics of the drug for the treatment of illnesses such as pain.

Description

CROSS REFERENCE TO RELATED ORDERS

[001] This application claims the benefit of US provisional patent applications numbers 62/442,136, filed on January 4, 2017; 62/504,105, filed May 10, 2017; and 62/536,466, filed on July 25, 2017, which are all incorporated herein by reference in their entirety.

FUNDAMENTALS

[002] There continues to be a need for therapies with improved efficacy in the treatment of pain, inflammation and related illnesses. SUMMARY

[003] The description refers to the use of a bicarbonate and/or a cyclodextrin, such as sulfobutylether β-cyclodextrin (SBEβCD), to improve the pharmacokinetics or bioavailability of a drug, such as a non-steroidal anti-inflammatory drug (NSAID). ), for example, meloxicam, a triptan, for example, rizatriptan, or a combination thereof.

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

[005] Some embodiments include a dosage form comprising: meloxicam; a sulfobutyl ether β-cyclodextrin (SBEβCD); a bicarbonate; and a triptan, wherein the dosage form is an oral dosage form that has a shorter Tmax of meloxicam than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain an SBEβCD, and 3) it does not contain a bicarbonate.

[006] Some modalities include a complex including a triptan such as rizatriptan or frovatriptan in a cyclodextrin.

[007] Some embodiments include a dosage form comprising: 1) an inclusion complex of a triptan, such as rizatriptan or frovatriptan, and a cyclodextrin, or 2) a triptan, such as rizatriptan or frovatriptan, and a carbonate or bicarbonate .

[008] Some methods include administering a product that contains a combination of a triptan with: 1) a cyclodextrin and/or 2) a buffering agent. In some embodiments, the method involves treating a patient with a pharmaceutical formulation comprising a triptan, such as rizatriptan or frovatriptan, and a cyclodextrin and/or a carbonate/bicarbonate. Some embodiments may also include increasing the bioavailability of a triptan, such as rizatriptan or frovatriptan, or increasing the rate at which the triptan becomes bioavailable in a subject in need thereof compared to a formulation without a cyclodextrin or carbonate/bicarbonate.

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

[0010] The method of treating pain, comprising orally administering a dosage form described herein to a mammal or human in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is a representation of the results described in Example 2 and contained in Table 6.

[0012] Figure 2 is another representation of the results described in Example 2 and contained in Table 6.

[0013] Figure 3 is another representation of the results described in Example 2 and contained in Table 6.

[0014] Figure 4 is another representation of the results described in Example 2 and contained in Table 6.

[0015] Figure 5 is another representation of the results described in Example 2 and contained in Table 6.

[0016] Figure 6 is another representation of the results described in Example 2 and contained in Table 6.

[0017] Figure 7 is another representation of the results described in Example 2 and contained in Table 6.

[0018] Figure 8 is another representation of the results described in Example 2 and contained in Table 6.

[0019] Figure 9 is another representation of the results described in Example 2 and contained in Table 6.

[0020] Figure 10 is another representation of the results described in Example 2 and contained in Table 6.

[0021] FIG. 11 is a graph of meloxicam plasma concentration at various points in time for the first 24 hours for one embodiment of a dosage form described herein and a commercially available dosage form of meloxicam.

DETAILED DESCRIPTION

[0022] Meloxicam and some other NSAIDs have poor aqueous solubility that can reduce bioavailability and slow the onset of pain relief. One method to increase the solubility and bioavailability of meloxicam is through the use of cyclodextrins in combination with meloxicam.

[0023] In general, this can be accomplished using a dosage form, such as an oral dosage form, containing a triptan (such as rizatriptan), optionally in combination with an NSAID (such as meloxicam), and 1) a cyclodextrin (optionally in an inclusion complex), and/or 2) a buffering agent, such as a bicarbonate. Administering this type of dosage form to a patient may increase the bioavailability of the triptan (e.g., rizatriptan) or the NSAID (e.g., meloxicam) in the patient or increase the rate at which the triptan (e.g., rizatriptan) or the NSAID (e.g., meloxicam) becomes bioavailable, or increase the rate at which the plasma concentration of the triptan or NSAID increases. For example, the triptan or NSAID may have a shorter Tmax, or may have an increased Cmax or area under the plasma concentration curve (AUC) as a result of administration of this type of dosage form.

[0024] Any suitable triptan can be used, such as sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan, zolmatriptan, etc., including combinations or salts thereof. In some embodiments, the triptan comprises rizatriptan, which has the structure as shown below.

[0025] The NSAID may include, but is not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID for the purposes of present description), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen , aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof.

[0026] In some embodiments, the NSAID is meloxicam, which has the structure:

[0027] Meloxicam exhibits anti-inflammatory, analgesic and antipyretic activities. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthetase (cyclooxygenase, COX) which is involved in the initial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacyclin.

[0028] A dosage form may be supplied enterally including, but not limited to, oral, sublingual, or rectal dispensing, or parenterally including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous dispensing.

[0029] The term “treat” or “treatment” broadly includes any kind of treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or any function of the body of humans or other animals.

[0030] The dosage form can be used to treat, or provide relief from, any type of pain including, but not limited to, migraine and other types of headache, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute, localized pain, systemic pain, cancer-related pain, acute pain, pain due to injury, pain due to condition (e.g. fever), post-operative pain, etc. In some examples, pain relief may be palliative, or pain relief may be provided regardless of improvement in the disease or illness or the underlying cause of the disease or illness. For example, although the underlying disease may not improve, or may continue to progress, an individual suffering from the disease may experience pain relief. In some embodiments, the pain affects a muscle, nerve, cartilage, bone, ligament, tendon, tendon sheath, bursa, or joint.

[0031] Migraine is a headache disorder distinguished by recurrent headaches that can be moderate to severe. Headaches may affect one half of the head, may be pulsing in nature, and may last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or smell. The pain may be worsened by physical activity. Migraines may be associated with an aura, which may be a short period of visual disturbance that signals that the headache will occur soon.

[0032] In some methods, the dosage form can be administered to relieve inflammatory pain including inflammatory musculoskeletal pain, pain due to injury, arthritis pain and complex regional pain syndrome. In other embodiments, inflammatory pain may be chronic or acute.

[0033] In some embodiments, the dosage form (e.g., a dosage form containing a triptan such as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam) may also be administered to relieve arthritis pain. In some embodiments, the dosage form may be administered to alleviate other signs and/or symptoms of arthritis. Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (pauciarticular and polyarticular course), osteoarthritis, erosive, sero-negative (non-rheumatoid) osteoarthritis, arthropathies, non-articular rheumatism, periarticular disorders, axial spondyloarthritis, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis and neuropathic arthropathies including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. In other embodiments, arthritis pain may be chronic or acute.

[0034] In some embodiments, the dosage form (e.g., a dosage form containing a triptan such as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam) may also be administered to alleviate neuropathic pain, including diabetic peripheral neuropathy. , post herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, sciatica, pudendal neuralgia and central pain. Other causes of neuropathic pain may include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, neuropathy associated with HIV, and radiation therapy or associated neuropathy. with chemotherapy. Neuropathic pain can be chronic or acute.

[0035] For some methods, the dosage form (e.g., a dosage form containing a triptan such as rizatriptan or frovatriptan, and/or an NSAID such as 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, cramps, tendonitis, epidodylitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to injury, tunnel syndromes, pain associated with bone fractures, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip. In other modalities, musculoskeletal pain can be chronic or acute.

[0036] For some methods, administration of the dosage form (e.g., a dosage form containing a triptan such as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam) can achieve a reduction in pain that lasts at least about from one hour, two hours, three hours, four hours, six hours, at least about eight hours, about 8 to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form can achieve a reduction in pain that is observed in about 10 minutes, in about 30 minutes, in about one hour, in about two hours, in about three hours, in in about four hours, in about five hours, in about six hours, in or less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, in two hours or less, within three hours or less, or other period limited by these ranges, after administration of the dosage form.

[0037] A human being who is treated for an illness or disease with any of the dosage forms described herein (e.g., a dosage form containing a triptan such as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam ) can be of any age. For example, the person may have an age of about 10-90 years, about 20-80 years, about 30-75 years, about 40-70 years, about 1-16 years, about 80-95 years, about 18 years or more, about 20 years or more, about 25 years or more, about 30 years or more, about 40 years or more, about 45 years or more, about 50 years or more , about 55 years and over, about 60 years and over, about 65 years and over, or any other age in a range limited by, or between, any of these values.

[0038] In some embodiments, a human being who is treated for an illness or disease with a dosage form (e.g., a dosage form containing a triptan such as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam) has suffered of pain or illness associated with pain for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years, or any duration in a range limited by, or between , any of these values.

[0039] A cyclodextrin used in a dosage form with a drug (including meloxicam or another NSAID, rizatriptan, frovatriptan, or other triptan) may include a cyclodextrin, a cyclodextrin derivative, and/or a salt thereof. Cyclodextrins (also known as cycloamyloses) are generally cyclic polysaccharides that form a bucket-like shape. Cyclodextrins help increase the bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the outside, which helps facilitate the transport of hydrophobic molecules into a hydrophobic medium. Naturally occurring cyclodextrins include six, seven, and eight glucose units (α, β, and Y-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (i.e., an inclusion complex) with drugs, incorporating the drug into the central/hydrophobic portion of the cyclodextrin ring; although cyclodextrins are also known to aggregate around a drug in a micelle-like structure. This ability of cyclodextrins may allow them to act as carriers of less soluble drugs to increase the bioavailability of drugs.

[0040] An inclusion complex of drug (including meloxicam or another NSAID, rizatriptan, frovatriptan, or other triptan) and cyclodextrin may be more soluble in water compared to the drug without complexes. The cyclodextrin can be a naturally occurring cyclodextrin (e.g., α, β, or Y-cyclodextrins) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrins, derivatives, or salts thereof can be used. The 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, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0041] In some embodiments, β-cyclodextrins, derivatives, or salts thereof can be used. The β-cyclodextrins may include, but are not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glycosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glycosyl -β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin , methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin, (2, 6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3,6-tri-O-methyl)-β-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-maltosyl)-β-cyclodextrin, (6-O -sulfo)-β-cyclodextrin, (6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,6-di-O -)ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin ( HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl((6-O- tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin, succinyl-β-cyclodextrin, (2-hydroxy-isobutyl)-β-cyclodextrin, randomly methylated β-cyclodextrin, branched β-cyclodextrin, or combinations thereof.

[0042] In other embodiments, a β-cyclodextrin may be a sulfoalkyl ether cyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-e-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In some embodiments, an SBEβCD may have about 48, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0043] In some embodiments, Y-cyclodextrins, derivatives, or salts thereof can be used. Y-cyclodextrins may include carboxymethyl-Y-cyclodextrin, (2,3,6-tri-O-acetyl)-Y-cyclodextrin, (2,3,6-tri-O-methyl)-Y-cyclodextrin, (2 ,6-di-O-pentyl)-Y-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-Y-cyclodextrin, 6-bromo-6-deoxy-Y-cyclodextrin, 6-iodo-6- deoxy-Y-cyclodextrin, (6-O-t-butyldimethylsilyl)-Y-cyclodextrin, succinyl-Y-cyclodextrin, hydroxypropyl-Y-cyclodextrin, (2-hydroxypropyl)-Y-cyclodextrin, acetyl-Y-cyclodextrin, butyl-Y- cyclodextrin, or combinations thereof.

[0044] In some embodiments, the dosage form may include a bicarbonate, such as sodium bicarbonate, potassium bicarbonate, etc. A bicarbonate may help increase the pharmacokinetics or bioavailability of meloxicam or another drug such as rizatriptan.

[0045] In some embodiments, enhanced bioavailability of a drug, such as meloxicam or a triptan (e.g., rizatriptan), in dosage form can be achieved by administering a dosage form comprising a salt form of the drug, generating an inclusion complex of the drug with cyclodextrin, and/or including a bicarbonate. This may allow a reduced molar amount of the drug to be used compared to other dosage forms containing the drug in the treatment of diseases or disorders.

[0046] Unless otherwise indicated, any reference to a compound herein, such as meloxicam, an NSAID, a triptan, rizatriptan, or a cyclodextrin, by structure, name, or otherwise, includes pharmaceutically acceptable salts , alternative solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species, such as precursors, prodrugs that can rapidly convert to a compound described herein under conditions wherein the compounds are used as described herein.

[0047] In some embodiments, the use of a cyclodextrin or a bicarbonate can improve the oral bioavailability of meloxicam in a subject (human or animal) by at least about 10%, at least about 20%, at least about 30%. %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any amount in a range limited by, or between, any such values compared to administration of meloxicam alone.

[0048] In some embodiments, the use of a cyclodextrin or a bicarbonate can improve the oral bioavailability of a triptan, such as rizatriptan or frovatriptan, in a subject (human or animal) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90 %, up to about 100%, up to about 200%, or any amount in a range limited by, or between, any such values compared to administration of the triptan alone.

[0049] Due to the improved bioavailability as described above, the dosage form may contain, or a subject may receive, in terms of molarity, less of the drug, such as a triptan (e.g., rizatriptan or frovatriptan) or an NSAID (e.g., example, meloxicam) than would otherwise be administered of the drug alone. For example, a dosage form may contain, or a mammal may receive, at least about 10 mol% less, at least about 20 mol% less, at least about 30 mol% less, at least about at least about 40 mol% less, at least about 50 mol% less, at least about 60 mol% less, at least about 70 mol% less, at least about 80 mol% less less mol, at least about 85 less mol%, and/or up to about 90 less mol%, 95 less mol%, 98 less mol%, or any amount in a range limited by , or between, any such meloxicam values than would otherwise be administered meloxicam alone.

[0050] In other embodiments, the use of other NSAIDs, opioids, or other pain medications can 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%, or any amount in a range limited by, or between, any such values when administered with a drug, such as a triptan (e.g., rizatriptan) or an NSAID (e.g., meloxicam), with a cyclodextrin and/or a bicarbonate, compared to administering the NSAID, opioid, or other pain medication alone.

[0051] In some embodiments, a dosage form may contain an NSAID, such as celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered as being an NSAID for the purposes of the present description), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyfenbutazone, azapropazone, phenylbutazone, in an amount of about 1-1000 mg, about 1-500 mg, about 1-400 mg, about 1-300 mg, about of 1-200 mg, about 1-100 mg, about 1-50 mg, about 1-10 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 7-12 mg, about 5-15 mg, about 10-20 mg, about 15-25 mg, about 20-30 mg, about 25 -35 mg, about 30-40 mg, about 35-45 mg, about 40-50 mg, about 50-150 mg, about 50-100 mg, about 100-200 mg, about 150250 mg , about 200-300 mg, about 250-350 mg, about 300-400 mg, about 350-450 mg, about 400-500 mg, about 100 mg, about 200 mg, about 325 mg , or any quantity in a range limited by, or between, any such values. These doses may be a safe dose for repeated administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days , 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 1 week, about 4 weeks, about 6 weeks, about 1-2 months, about 6 weeks, about 2 -3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9- 10 months, about 10-11 months, about 11-12 months, about 2 years, etc.

[0052] In some embodiments, a 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 2-6 mg, about 37 mg, about 4-8 mg, about 5-10 mg, about 7-12 mg, about 5-15 mg, about 10-20 mg, about 15 -25 mg, about 20-30 mg, about 2535 mg, about 30-40 mg, about 35-45 mg, about 40-50 mg, about 125 mg; about 1-15 mg; about 5-20 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30 mg; or any quantity in a range limited by, or between, any such values. These doses may be a safe dose for repeated administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days , 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 1-2 months, about 4 weeks, about 6 weeks, about 2-3 months, about 3-4 months , about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 1112 months, about 2 years, etc.

[0053] For some dosage forms, a drug (such as meloxicam, frovatriptan or rizatriptan) forms a complex with substituted β-cyclodextrin or another cyclodextrin that can be formulated into a solid dosage form. Such a dosage form may be suitable for oral administration. A drug-cyclodextrin inclusion complex can also be dissolved in water or other solvent to form a parenteral formulation. However, physical mixtures of drug and substituted β-cyclodextrin or other cyclodextrins that are not inclusion complexes can also be used in oral or parenteral dosage forms.

[0054] The formation of an inclusion complex of a drug (such as meloxicam, frovatriptan or rizatriptan) and a cyclodextrin can help improve the properties of a dosage form. For some inclusion complexes, the drug and cyclodextrin (e.g., SBEβCD) may have a molar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 mol of drug to 1 mol 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 1.9-2.1, about 2- 2.2, about 0.8-1.2, about 1, or any ratio in a range limited by any of these values.

[0055] In some embodiments, an inclusion complex is formed by (1) mixing a homogeneous solution of a drug, such as meloxicam or a triptan, with a homogeneous solution of the cyclodextrin to form a homogeneous solution of the drug and the cyclodextrin, and (2) evaporating the solvent from the homogeneous solution of the drug and the cyclodextrin to form the complex comprising the drug inclusion complex in a cyclodextrin. In some embodiments, the solutions may be pH-adjusted aqueous solutions. The pH can be adjusted using a buffering agent. In some embodiments, evaporation comprises freeze-drying. In other embodiments, evaporation comprises spray drying. In some embodiments, evaporation comprises vacuum drying.

[0056] For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed at a weight ratio to meloxicam within the range of about 1-1000 (e.g., 1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about 1500, about 1-5, about 1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 810, 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 whatever weight ratio in a range limited by, or between, any such values. Each type of cyclodextrin employed may have a different weight ratio to meloxicam in the dosage form.

[0057] For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed in a weight ratio to the triptan, e.g., rizatriptan or frovatriptan, within the range of about 1-1000 (e.g., 10 g of cyclodextrin per 1 g of rizatriptan or frovatriptan is a weight ratio of 10); about 1-500; about 1-100; about 1-50; about 1-20; about 1-10; about 1-15; about 1-5, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 0.01-1; about 0.05-1; 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 ratio by weight in a range limited by, or between, any such values. Each type of cyclodextrin employed may have a different weight ratio to the triptan in the dosage form.

[0058] For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed at a weight ratio to rizatriptan within the range of about 1-1000 (e.g., 10 g of cyclodextrin per 1 g of rizatriptan is a weight ratio of 10); about 1500; about 1-100; about 1-50; about 1-20; about 1-10; about 115; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 9-11, about 10-12, about 11-13, about 12-14, about 13-15, about 14-16, about 15-17, about 16-18, about 17-19, about 18- 20, about 19-21, about 0.001-1; about 0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or whatever weight ratio in a range limited by, or between, any such values. Each type of cyclodextrin employed may have a different weight ratio to rizatriptan in the dosage form.

[0059] In some embodiments; a dosage form may contain rizatriptan in an amount of about 1-50 mg; about 1-10 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 1-50 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 712 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 1419 mg; about 15-20 mg; about 5-15 mg; about 10-20 mg; about 2030 mg; about 30-40 mg; about 40-50 mg; about 0.5 mg; about 1 mg; about 1.5 mg; about 2 mg; about 2.5 mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6 mg; about 7 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30 mg; or any quantity in a range limited by, or between, any such values. These doses may be a safe dose for repeated administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days , 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3 -4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10- 11 months, about 11-12 months, etc.

[0060] The other triptans can be administered to patients in any dosages effective in relieving pain. In some embodiments, the dosage form may contain the triptan in any amount within a range limited by any of the values described above.

[0061] In some embodiments, a dosage form may contain frovatriptan or another triptan in an amount of about 1-50 mg; about 1-10 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 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 813 mg; about 9-11 mg; about 9-14 mg; about 10-15 mg; about 1116 mg; about 12-17 mg; about 13-18 mg; about 14-19 mg; about 15-20 mg; about 5-15 mg; about 10-20 mg; about 0.5 mg; about 1 mg; about 1.5 mg; about 2 mg; about 2.5 mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6 mg; about 7 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30 mg; or any quantity in a range limited by, or between, any such values. These doses may be a safe dose for repeated administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days. , 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 4 weeks, about 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months , about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 2 years, etc.

[0062] For some dosage forms, cyclodextrin may be present in an amount of about 1-200 mg; about 1-100 mg; 25175 mg; about 50-150 mg; about 50-100 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 100120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 150-200 mg, about 100-150 mg; about 30-90 mg; about 4060 mg; about 40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount in a range limited by, or between, any of these values.

[0063] For some dosage forms, an inclusion complex of a drug (such as meloxicam or another NSAID, or rizatriptan, frovatriptan or other triptan) and cyclodextrin is about 1-10%, 5-20%, 5-15 %, 6-16%, 7-17%, 8-18%, 9-19%, 10-20%, 15-30%, 30-40%, 40-50%, 50-70%, or 70- 90% of the total weight of the dosage form, or any percentage within a range limited by any such values.

[0064] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in an amount of about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about 200-800 mg; about 1500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about 500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about 50-100 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about 400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about 440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about 480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about 800-900 mg; about 900-1000 mg; about 150-650 mg; about 350-850 mg; about 400 mg; about 450 mg; about 500 mg, about 550 mg; about 600 mg; or any quantity in a range limited by, or between, any such values. A bicarbonate, such as sodium bicarbonate, may be at least about 10%, at least about 15%, at least about 20%, about 20-40%, about 30-50%, about 40- 60%, about 50-70%, about 60-80%, or about 70-90%, or any percentage in a range limited by any of these values, of the total weight of the dosage form.

[0065] In some embodiments, the daily dose of meloxicam, or the amount of meloxicam administered in a single day (or in one administration, or by more than one divided dose arriving at the daily dose) is about 2-5 mg, about of 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 2-45 mg, about 2-50 mg, about 2-55 mg, about 2-60 mg, about 2-65 mg, about 2-70 mg, about 2-75 mg, about 3-8 mg, about 4-9 mg , about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 16-21 mg, about 17-22 mg, about 18-23 mg, about of 19-24 mg, about 20-25 mg, about 21-26 mg, about 22-27 mg, about 23-28 mg, about 24-29 mg, about 25-30 mg, about 26-31 mg, about 27-32 mg, about 2833 mg, about 29-34 mg, about 30-35 mg, about 31-36 mg, about 32-37 mg, about 33-38 mg, about 34-39 mg, about 35-40 mg, about 36-41 mg, about 37-42 mg, about 38-43 mg, about 39-44 mg, about 40-45 mg , about 41-46 mg, about 42-47 mg, about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg, about 4752 mg, about 48-53 mg, about 49-54 mg, about 50-55 mg, about 51-56 mg, about 52-57 mg, about 53-58 mg, about 54-59 mg, about 55 -60 mg, about 56-61 mg, about 57-62 mg, about 58-63 mg, about 59-64 mg, about 60-65 mg, about 61-66 mg, about 62- 67 mg, about 63-68 mg, about 64-69 mg, about 65-70 mg, about 6671 mg, about 67-72 mg, about 68-73 mg, about 69-74 mg, about 70-75 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any quantity in a range limited by any such values. The daily dose may be given as a single dose, given once daily, or may be given in 2, 3, 4, or more divided doses during one day.

[0066] In some embodiments, the weekly dose of meloxicam or the amount of meloxicam administered in a week (or in one administration, or by more than one divided dose reaching the weekly dose) is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100300 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 80-450 mg; about 80-100 mg; about 90-110 mg; about 100-120 mg; about 110-130 mg; about 120-140 mg; about 130-150 mg; about 140-160 mg; about 150-170 mg; about 160-180 mg; about 170-190 mg; about 180-200 mg; about 190-210 mg; about 200-220 mg; about 210-230 mg; about 220-240 mg; about 230-250 mg; about 240-260 mg; about 250-270 mg; about 260-280 mg; about 270-290 mg; about 280-300 mg; about 290-310 mg; about 300-320 mg; about 310-330 mg; about 340-360 mg; about 350-370 mg; about 360-380 mg; about 370-390 mg; about 380-400 mg; about 390-410 mg; about 400-420 mg; about 410-430 mg; about 420-440 mg; about 430-450 mg; about 50 mg; about 55 mg; about 100-150 mg; about 30-100 mg; or any quantity in a range limited by, or between, any such values. The weekly dose may be given as a single dose given once a week, or it may be given in 2, 3, 4, 5, 6 or 7 individual doses over a week.

[0067] In some embodiments, the monthly dose of meloxicam (e.g., an oral dose), or a dose administered over a period of one month, is about 5000 mg or less; about 4000 mg or less; about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700 mg or less; about 600 mg or less; about 300-2400 mg; about 300-350 mg; about 310-360 mg; about 320-370 mg; about 330-380 mg; about 340-390 mg; about 350-400 mg; about 360-410 mg; about 370-420 mg; about 380-430 mg; about 390-440 mg; about 400-450 mg; about 410-460 mg; about 420-470 mg; about 430-480 mg; about 440-490 mg; about 450-500 mg; about 460-510 mg; about 470-520 mg; about 480-530 mg; about 490-540 mg; about 500550 mg; about 510-560 mg; about 520-570 mg; about 530-580 mg; about 540-590 mg; about 550-600 mg; about 560-610 mg; about 570-620 mg; about 580-630 mg; about 590-640 mg; about 600-650 mg; about 610-660 mg; about 620-670 mg; about 630-680 mg; about 640-690 mg; about 650-700 mg; about 660-710 mg; about 670-720 mg; about 680-730 mg; about 690-740 mg; about 700-750 mg; about 710-760 mg; about 720-770 mg; about 730-780 mg; about 740-790 mg; about 750-800 mg; about 760-810 mg; about 770-820 mg; about 780-830 mg; about 790-840 mg; about 800-850 mg; about 810-860 mg; about 820-870 mg; about 830-880 mg; about 840-890 mg; about 850-900 mg; about 860-910 mg; about 870-920 mg; about 880-930 mg; about 890-940 mg; about 900-950 mg; about 910-960 mg; about 920-970 mg; about 930-980 mg; about 940-990 mg; about 9501000 mg; about 960-1010 mg; about 970-1020 mg; about 980-1030 mg; about 990-1040 mg; about 1000-1050 mg; about 1010-1060 mg; from 1230-1280 mg; about 1240-1290 mg; about 1250-1300 mg; from 1260-1310 mg; about 1270-1320 mg; about 1280-1330 mg; from 1290-1340 mg; about 1300-1350 mg; about 1310-1360 mg; from 1320-1370 mg; about 1330-1380 mg; about 1340-1390 mg; from 1350-1400 mg; about 1360-1410 mg; about 1370-1420 mg; from 1380-1430 mg; about 1390-1440 mg; about 1400-1450 mg; from 1410-1460 mg; about 1420-1470 mg; about 1430-1480 mg; from 1440-1490 mg; about 1450-1500 mg; about 1460-1510 mg; from 1470-1520 mg; about 1480-1530 mg; about 1490-1540 mg; from 1500-1550 mg; about 1510-1560 mg; about 1520-1570 mg; from 1530-1580 mg; about 1540-1590 mg; about 1550-1600 mg; from 1560-1610 mg; about 1570-1620 mg; about 1580-1630 mg; from 1590-1640 mg; about 1600-1650 mg; about 1610-1660 mg; from 1620-1670 mg; about 1630-1680 mg; about 1640-1690 mg; from 1650-1700 mg; about 1660-1710 mg; about 1670-1720 mg; from 1680-1730 mg; about 1690-1740 mg; about 1700-1750 mg; from 1710-1760 mg; about 1720-1770 mg; about 1730-1780 mg; from 1740-1790 mg; about 1750-1800 mg; about 1760-1810 mg; from 1770-1820 mg; about 1780-1830 mg; about 1790-1840 mg; from 1800-1850 mg; about 1810-1860 mg; about 1820-1870 mg; from 1830-1880 mg; about 1840-1890 mg; about 1850-1900 mg; from 1860-1910 mg; about 1870-1920 mg; about 1880-1930 mg; from 1890-1940 mg; about 1900-1950 mg; about 1910-1960 mg; from 1920-1970 mg; about 1930-1980 mg; about 1940-1990 mg; from 1950-2000 mg; about 1960-2010 mg; about 1970-2020 mg; from 1980-2030 mg; about 1990-2040 mg; about 2000-2050 mg; from 2010-2060 mg; about 2020-2070 mg; about 2030-2080 mg; from 2040-2090 mg; about 2050-2100 mg; about 2060-2110 mg; from 2070-2120 mg; about 2080-2130 mg; about 2090-2140 mg; about 2100-2150 mg; about 2110-2160 mg; about 2120-2170 mg; about 2130-2180 mg; about 2140-2190 mg; about 2150-2200 mg; about 2160-2210 mg; about 2170-2220 mg; about 2180-2230 mg; about 2190-2240 mg; about 2200-2250 mg; about 2210-2260 mg; about 2220-2270 mg; about 2230-2280 mg; about 2240-2290 mg; about 2250-2300 mg; about 2260-2310 mg; about 2270-2320 mg; about 2280-2330 mg; about 2290-2340 mg; about 2300-2350 mg; about 2310-2360 mg; about 2320-2370 mg; about 2330-2380 mg; about 2340-2390 mg; about 2350-2400 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; 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 1001000 mg; or any monthly dose in a range limited by, or between, any such values. A monthly dose may be given as a single dose, or as two or more individual doses administered during the month. In some embodiments, the monthly dose is administered biweekly in 2 or 3 divided doses. In some embodiments, the monthly dose is administered weekly in 4 or 5 divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses or more. In some embodiments, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose may be administered for only 1 month, or may be administered repeatedly for 2, 3, 4, 5, 6 or more months.

[0068] In some embodiments, the daily dose of frovatriptan or another triptan (e.g., an oral dose, a parenteral dose, etc.) is about 0.5-1 mg, about 1-2 mg, about 2 -3 mg, about 3-4 mg, about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2- 10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg , about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any quantity in a range limited by any such values.

[0069] In some embodiments, the daily dose of rizatriptan is about 0.5-100 mg, about 5-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 1-5 mg, about 1-6 mg, about 2-7 mg, about 3-8 mg, about 4-9 mg, about of 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 16-21 mg, about 1722 mg, about 18-23 mg, about 19-24 mg, about 20-25 mg, about 21-26 mg, about 22-27 mg, about 23-28 mg, about 24-29 mg, about 25-30 mg, about 26-31 mg , about 27-32 mg, about 28-33 mg, about 29-34 mg, about 30-35 mg, about 31-36 mg, about 32-37 mg, about 33-38 mg, about 34-39 mg, about 35-40 mg, about 3641 mg, about 37-42 mg, about 38-43 mg, about 39-44 mg, about 40-45 mg, about 41 -46 mg, about 42-47 mg, about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg, about 47-52 mg, the 48-53 mg, about 49-54 mg, about 50-55 mg, or any amount in a range limited by any of these values. The daily dose may be given as a single dose, given once daily, or may be given in 2, 3, 4, or more divided doses during one day.

[0070] In some embodiments, the weekly dose of frovatriptan or another triptan (e.g., an oral dose) is about 1-1000 mg; about 1500 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 7090 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100150 mg; about 30-100 mg; about 1-20 mg; about 1-10 mg; about 210 mg; about 2-5 mg; about 5-10 mg; about 2.5 mg; about 5 mg; about 7.5 mg; or any quantity in a range limited by, or between, any such values. The weekly dose may be given as a single dose given once a week, or it may be given in 2, 3, 4, 5, 6 or 7 individual doses over a week.

[0071] In some embodiments, the weekly dose of rizatriptan is about 1-1000 mg; about 10-400 mg, about 50-250 mg, about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100-150 mg; about 30-100 mg; about 1-20 mg; about 1-10 mg; about 2-10 mg; about 2-5 mg; about 5-10 mg; about 1-50 mg; about 10-60 mg; about 20-70 mg; about 30-80 mg; about 40-90 mg; about 50-100 mg; about 60-110 mg; about 70-120 mg; about 80-130 mg; about 90-140 mg; about 100-150 mg; about 110-160 mg; about 120-170 mg; about 130-180 mg; about 140-190 mg; about 150-200 mg; about 160-210 mg; about 170-220 mg; about 180-230 mg; about 190-240 mg; about 200-250 mg; about 210-260 mg; about 220-270 mg; about 230-280 mg; about 240-290 mg; about 250-300 mg; about 260-310 mg; about 270-320 mg; about 280-330 mg; about 290-340 mg; about 300-350 mg; about 310-360 mg; about 320-370 mg; about 330-380 mg; about 340-390 mg; about 350-400 mg; about 2.5 mg; about 5 mg; about 7.5 mg; or any quantity in a range limited by, or between, any such values. The weekly dose may be given as a single dose given once a week, or it may be given in 2, 3, 4, 5, 6 or 7 individual doses over a week.

[0072] In some embodiments, the monthly dose of frovatriptan or another triptan (e.g., an oral dose), or a dose administered over a period of one month, is about 5000 mg or less; about 4000 mg or less; about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700 mg or less; about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 501000 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 240280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; about 10-80 mg; about 10-40 mg; about 20-30 mg; or any monthly dose in a range limited by, or between, any such values. A monthly dose may be given as a single dose, or as two or more individual doses administered during the month. In some embodiments, the monthly dose is administered biweekly in 2 or 3 divided doses. In some embodiments, the monthly dose is administered weekly in 4 or 5 divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses or more. In some embodiments, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose may be administered for only 1 month, or may be administered repeatedly for 2, 3, 4, 5, 6 or more months.

[0073] In some embodiments, the monthly dose of rizatriptan, or a total dose administered within a period of one month, is about 5000 mg or less; about 4000 mg or less; about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700 mg or less; about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about 10-600 mg; about 40600 mg; about 50-600 mg; about 150-2400 mg, about 150-200 mg; about 160-210 mg; about 170-220 mg; about 180-230 mg; about 190-240 mg; about 200-250 mg; about 210-260 mg; about 220-270 mg; about 230-280 mg; about 240-290 mg; about 250-300 mg; about 260-310 mg; about 270-320 mg; about 280-330 mg; about 290-340 mg; about 300-350 mg; about 310-360 mg; about 320-370 mg; about 330-380 mg; about 340-390 mg; about 350-400 mg; about 360-410 mg; about 370-420 mg; about 380-430 mg; about 390-440 mg; about 400-450 mg; about 410-460 mg; about 420-470 mg; about 430-480 mg; about 440-490 mg; about 450-500 mg; about 460-510 mg; about 470-520 mg; about 480-530 mg; about 490-540 mg; about 500550 mg; about 510-560 mg; about 520-570 mg; about 530-580 mg; about 540-590 mg; about 550-600 mg; about 560-610 mg; about 570-620 mg; about 580-630 mg; about 590-640 mg; about 600-650 mg; about 610-660 mg; about 620-670 mg; about 630-680 mg; about 640-690 mg; about 650-700 mg; about 660-710 mg; about 670-720 mg; about 680-730 mg; about 690-740 mg; about 700-750 mg; about 710-760 mg; about 720-770 mg; about 730-780 mg; about 740-790 mg; about 750-800 mg; about 760-810 mg; about 770-820 mg; about 780-830 mg; about 790-840 mg; about 800-850 mg; about 810-860 mg; about 820-870 mg; about 830-880 mg; about 840-890 mg; about 850-900 mg; about 860-910 mg; about 870-920 mg; about 880-930 mg; about 890-940 mg; about 900-950 mg; about 910-960 mg; about 920-970 mg; about 930-980 mg; about 940-990 mg; about 9501000 mg; about 960-1010 mg; about 970-1020 mg; about 980-1030 mg; about 990-1040 mg; about 1000-1050 mg; about 1010-1060 mg; about 1020-1070 mg; about 1030-1080 mg; about 1040-1090 mg; about 1050-1100 mg; about 1060-1110 mg; about 1070-1120 mg; about 1080-1130 mg; about 1090-1140 mg; about 1100-1150 mg; about 1110-1160 mg; about 1120-1170 mg; about 1130-1180 mg; about 1140-1190 mg; about 1150-1200 mg; about 1160-1210 mg; about 1170-1220 mg; about 1180-1230 mg; about 1190-1240 mg; about 1200-1250 mg; about 1210-1260 mg; about 1220-1270 mg; about 1230-1280 mg; about 1240-1290 mg; about 1250-1300 mg; about 1260-1310 mg; about 1270-1320 mg; about 1280-1330 mg; about 1290-1340 mg; about 1300-1350 mg; about 1310-1360 mg; about 1320-1370 mg; about 1330-1380 mg; about 1340-1390 mg; about 1350-1400 mg; about 1360-1410 mg; about 1370-1420 mg; about 1380-1430 mg; about 1390-1440 mg; about 1400-1450 mg; about 1410-1460 mg; about 1420-1470 mg; about 1430-1480 mg; about 1440-1490 mg; about 1450-1500 mg; about 1460-1510 mg; about 1470-1520 mg; about 1480-1530 mg; about 1490-1540 mg; about 1500-1550 mg; about 1510-1560 mg; about 1520-1570 mg; about 1530-1580 mg; about 1540-1590 mg; about 1550-1600 mg; about 1560-1610 mg; about 1570-1620 mg; about 1580-1630 mg; about 1590-1640 mg; about 1600-1650 mg; about 1610-1660 mg; about 1620-1670 mg; about 1630-1680 mg; about 1640-1690 mg; about 1650-1700 mg; about 1660-1710 mg; about 1670-1720 mg; about 1680-1730 mg; about 1690-1740 mg; about 1700-1750 mg; about 1710-1760 mg; about 1720-1770 mg; about 1730-1780 mg; about 1740-1790 mg; about 1750-1800 mg; about 1760-1810 mg; about 2340-2390 mg; about 2350-2400 mg; about 40-400 mg; about 50-200 mg; about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg; about 1001000 mg; about 10-80 mg; about 10-40 mg; about 20-30 mg; or any monthly dose in a range limited by, or between, any such values. A monthly dose may be given as a single dose, or as two or more individual doses administered during the month. In some embodiments, the monthly dose is administered biweekly in 2 or 3 divided doses. In some embodiments, the monthly dose is administered weekly in 4 or 5 divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses or more. In some embodiments, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose may be administered for only 1 month, or may be administered repeatedly for 2, 3, 4, 5, 6 or more months.

[0074] In other embodiments, the dosage form may be administered weekly for about one, two, three, four, or more consecutive weeks, every two weeks or biweekly, or once every three weeks. This regimen can be repeated once a week, twice in a month, three times in a month, once a month, once every two months, once every three months, or as directed by a medical professional.

[0075] In certain embodiments, administering the pharmaceutical composition results in improved pharmacokinetics, such as increased bioavailability (e.g., reduced Tmax, increased Cmax, increased AUC, etc.) of a drug, such as meloxicam or another NSAID, rizatriptan, frovatriptan, or another triptan, in the dosage form compared to a dosage form containing the drug but not containing a cyclodextrin, an acid quencher, or a buffering agent (such as a bicarbonate). In some embodiments, the bioavailability of the drug increases with repeated dosing. For example, the bioavailability of the drug (such as meloxicam or another NSAID, rizatriptan, frovatriptan, or other triptan) in the dosage form may increase after about 1-10 days of repeated dosing; about 2-6 days of repeated dosing; about 3-5 days of repeated dosing; about 4-6 days of repeated dosing; about 5-8 days of repeated dosing; about 5 days of repeated dosing; about 6 days of repeated dosing; about 7 days of repeated dosing; about 8 days of repeated dosing; about 10 days of repeated dosing; about 15 days of repeated dosing; or a period in any range limited by, or between, any such values; compared to the bioavailability of the drug in a dosage form not containing a cyclodextrin, an acid quencher, or a buffering agent (such as a bicarbonate).

[0076] Administering some of the dosage forms to a human may result in a desired range for an area under the plasma concentration curve (AUC) of meloxicam. For example, meloxicam dosage forms can result in a meloxicam AUC of about 1-150 μg-h/rnL; about 10-30 μg-h/rnL; about 20-40 μgdi/niL; about 30-50 μg-h/rnL; about 40-60 μg-h/rnL; about 50-70 μgdi/niL; about 60-80 μg-h/niL; about 70-90 μg-h/niL; about 80-100 μg-h/niL; about 10-100 μg-h/niL; about 50-150 μgdi/niL; about 25-125 μgdi/niL; about 75-150 μg^h/rnL; about 20-50 μgdi/niL; about 40-70 μg-h/rnL; about 60-90 μg^li/niL about 80-110 μg-h/niL; about 100-130 μg^h/niL about 120-150 μgdi/niL; about 100-150 μg-h/rnL; or any AUC in a range limited by, or between, any such values.

[0077] Administering some of the dosage forms to a human being may result in a desired range for an area under the plasma concentration curve (AUC) of frovatriptan. For example, dosage forms with frovatriptan or another triptan may result in a frovatriptan or other triptan AUC of about 1-150 μg^li/niL about 10-30 μg^h/niL about 20-40 μgdi/niL niL about 30-50 μg^li/niL about 40-60 μg^h/niL about 50-70 μgdi/niL about 60-80 μg^li/niL about 70-90 μg^h/niL about 80-100 μg^li/niL about 10-100 μg^li/niL about 50150 μg^li/niL about 25-125 μg^li/niL about 75-150 μg^li/niL about 20 -50 μg^li/niL about 40-70 μg^li/niL about 60-90 μg^li/niL about 80-110 μg^li/niL about 100-130 μg^li/niL about 120 -150 μg^li/niL or any AUC within a range limited by, or between, any such values.

[0078] Unless otherwise indicated, AUC refers to the AUC calculated relative to the last measured concentration (AUC0-t), over a period of 24 hours (AUC0-24), or extrapolated to infinity (AUC0 -inf).

[0079] For some acute pain illnesses, such as migraine and other types of headache, the AUC for a short period after oral administration, such as an AUC measured over 6 hours (or AUC0-6), may be particular interest, for example, for rapid pain relief. For example, some dosage forms may result in a meloxicam AUC0-6 of at least about 6 μg^h/mL; at least about 7 μg^h/mL; at least about 8 μg-h/mL; at least about 9 μg-h/mL; about 610 μg-h/mL; about 7-11 μg-h/mL; about 8-12 μg-h/mL; about 9-13 μg-h/mL; or any AUC0-6 in a range limited by, or between, any such values.

[0080] In some embodiments, the dosage form can result in a meloxicam Cmax of about 10-2500 ng/mL; about 100-2250 ng/mL; about 500-2000 ng/mL; about 1000-2500 ng/mL; about 10002000 ng/mL; about 100-900 ng/mL; about 750-1500 ng/mL; about 1250-2000 ng/mL; about 1500-2300 ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about 50-500 ng/mL; about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200 ng/mL; about 1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100 ng/mL; about 1500-1900 ng/mL; about 1600-2100 ng/mL; about 1700-2000 ng/mL; about 1800-2000 ng/mL; about 1900-2500 ng/mL; about 150-1700 ng/mL; about 1600-1800 ng/mL; about 1700-1900 ng/mL; about 1800-2000 ng/mL; about 1900-2100 ng/mL; about 2000-2200 ng/mL; about 2100-2300 ng/mL; about 2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or any Cmax in a range limited by, or between, any such values.

[0081] In some embodiments, the dosage form can result in a frovatriptan Cmax of about 10-2500 ng/mL; about 100-2250 ng/mL; about 500-2000 ng/mL; about 1000-2500 ng/mL; about 10002000 ng/mL; about 100-900 ng/mL; about 750-1500 ng/mL; about 1250-2000 ng/mL; about 1500-2300 ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about 50-500 ng/mL; about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200 ng/mL; about 1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100 ng/mL; about 1500-1900 ng/mL; about 1600-2100 ng/mL; about 1700-2000 ng/mL; about 1800-2000 ng/mL; about 1900-2500 ng/mL; about 150-1700 ng/mL; about 1600-1800 ng/mL; about 1700-1900 ng/mL; about 1800-2000 ng/mL; about 1900-2100 ng/mL; about 2000-2200 ng/mL; about 2100-2300 ng/mL; about 2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or any Cmax in a range limited by, or between, any such values.

[0082] For example, a method described herein can reduce the Tmax of meloxicam. In some embodiments, the method may include treating a patient to achieve Tmax of meloxicam in the patient within about 10 minutes; about 20 minutes; about 30 minutes; about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes; about 180 minutes; about 10-30 minutes; about 20-40 minutes, about 30-50 minutes, about 4060 minutes; about 50-70 minutes; about 60-90 minutes; about 70-100 minutes; about 80-110 minutes; about 90-120 minutes; about 1-10h; about 2-9 hours; about 3-7 hours; about 4-6 hours; about 1-5 hours; about 2-7 hours; about 3-8 hours; about 4-9 hours; about 1-4 hours; about 2-5 hours; about 3-6 hours; about 4-7 hours; about 5-8 hours; about 6-9 h; about 7-10 h; or any Tmax in a range limited by, or between, any such values; after administration of the dosage forms described above.

[0083] In some embodiments, an oral dosage form may have a Tmax of meloxicam that is shorter than would be achieved by administering meloxicam by intramuscular injection. In some embodiments, an oral dosage form may have a meloxicam Tmax that is shorter, or may increase meloxicam plasma levels at a more rapid rate, by a factor of at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20, or by a factor of about from 1.12, about 1.5-3, about 2-4, about 3-5, about 4-6, about 1.5-1000, about 2-100, about 3-100 , about 4-100, about 5-100, about 6100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15 -100, about 20-100, or by a factor in a range limited by any such values, compared to that observed by intramuscular injection.

[0084] For example, a method described herein can reduce the Tmax of frovatriptan. In some embodiments, the method may include treating a patient to achieve the Tmax of frovatriptan in the patient within about 10 minutes; about 20 minutes; about 30 minutes; about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes; about 180 minutes; about 10-30 minutes; about 20-40 minutes; about 30-50 minutes; about 4060 minutes; about 50-70 minutes; about 60-80 minutes; about 70-90 minutes; about 0.1-1 hour; about 0.1-0.5 hour; about 0.5-1 hour; about 1-10h; about 2-9 hours; about 3-7 hours; about 4-6 hours; about 1-5 hours; about 2-7 hours; about 3-8 hours; about 4-9 hours; about 1-4 hours; about 2-5 hours; about 3-6 hours; about 4-7 hours; about 5-8 hours; about 6-9 h; about 7-10 h; after administration or any Tmax in a range limited by, or between, any such values.

[0085] In some embodiments, a dosage form comprising meloxicam can result in a plasma concentration of meloxicam at 12 hours that is about 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.63.8 μg/mL; about 3.7-3.9 μg/mL; about 3.8-4 μg/mL; or any 12-hour meloxicam plasma concentration within a range limited by, or between, any such values.

[0086] In some embodiments, meloxicam is administered at a dose that results in an average meloxicam plasma level (such as a Cave, or average plasma level) of about 0.01-0.5 μg/mL; about 0.50.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.63.8 μg/mL; about 3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 0.1-20 μg/mL; about 0.5-15 μg/mL; about 0.5-10 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 mean plasma level in a range limited by, or between, any such values.

[0087] In some embodiments, a dosage form comprising frovatriptan may result in a 12-hour plasma concentration of frovatriptan that is about 0.01-0.5 μg/mL; about 0.50.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.63.8 μg/mL; about 3.7-3.9 μg/mL; about 3.8-4 μg/mL; or any 12-hour plasma concentration of frovatriptan within a range limited by, or between, any such values.

[0088] In some embodiments, frovatriptan is administered at a dose that results in an average plasma level of frovatriptan (such as a Cave, or average plasma level) of about 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.71.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about 3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 0.1-20 μg/mL; about 0.5-15 μg/mL; about 0.5-10 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 frovatriptan mean plasma level in a range limited by, or between, any such values.

[0089] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or an edible carrier, or may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet. For oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, coated tablets, lozenges, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, plasters and the like. .

[0090] Tablets, lozenges, pills, capsules and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as mint, oil of wintergreen or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coating, for example tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparaben as preservatives, a coloring and flavoring, such as cherry or orange flavor. It may be desirable that material in a dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amounts employed.

[0091] Some compositions or dosage forms may be a liquid, or may comprise a solid phase dispersed in a liquid.

[0092] The dosage form may further comprise an additional therapeutically active agent, such as an acid inhibitor or an analgesic.

[0093] In some embodiments, the dosage form may further comprise an acid inhibitor present in an amount effective to raise a patient's gastric pH to at least 2, to at least 2.5, to at least 3, to at least at least 3.5, to at least 4 and more to at least 5, when one or more unit dosage forms are administered. The term “acid inhibitor” refers to agents that inhibit gastric acid secretion and increase gastric pH. Specific H2 blockers, also called H2 antagonists or histamine H2 blockers or antagonists, that may be used include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine, or combinations thereof.

[0094] Other agents that can be used effectively as acid inhibitors are proton pump inhibitors, such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments, the daily dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 50-100 mg, about 1-50 mg, about 40-80 mg, about 5 -50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg , about 20 mg, about 30 mg, about 40 mg, or any other amount in a range limited by, or between, any of these values.

[0095] Examples of proton pump inhibitors include esomeprazole, present in unit dosage forms in an amount of between 5 mg and 50 mg; omeprazole, present in unit dosage forms in an amount of between 5 mg and 50 mg; lansoprazole, present in unit dosage forms in an amount of between 5 mg and 150 mg (and preferably in between 5 mg and 30 mg); and pantoprazole, present in unit dosage forms in an amount of between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is present in dosage form in an amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newer class of acid inhibitor has been developed that competes with potassium in the acid pump. Compounds in this class have been called “reversible proton pump inhibitors” or “acid pump antagonists” and can also be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO9605177 and WO9605199). Other compounds in this group are H-335/25 (AstraZeneca, Dialogue File 128, accession number 020806); Sch-28080 (Schering Plow, Dialog File 128, accession number 009663); Sch-32651 (Schering Plow, Dialog File 128, accession number 006883) and SK&F-96067 (CAS Registry No. 115607-61-9).

[0096] Additional therapeutically active agents may include an analgesic, such as a second non-steroidal anti-inflammatory drug, an opioid, a steroid, a triptan, etc. In some embodiments, the dosage form or treatment also further comprises administering a second non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. It will be understood that, for the purposes of the present description, reference to an acid inhibitor, NSAID, or analgesic agent includes all common forms of such compounds and, in particular, pharmaceutically acceptable salts thereof. The amounts of NSAIDs that are therapeutically effective may be lower in current embodiments than otherwise experienced in practice due to a possible positive kinetic interaction and absorption of NSAID in the presence of an acid quencher and/or in the presence of a buffering agent. .

[0097] In other embodiments, the dosage form or treatment may further comprise administering an opioid in an amount effective to reduce or eliminate pain or inflammation. The opioid may include, but is not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine, bezitramide, buprenorphine, butorphanol, carfentanil, desmethylprodine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, Dipipanona, etorfine, fentanil, ketobemidone, lefetamine, levacetytadol, levomethafan, levorophanol, loperamide, meperidine, methylmorphine, morphine, nalmephene, nalxona, naltrexone, nicomorphine, omefentanil, oxcodo, oxycod na, oxymorphone, pepap, paramorphine, pentazocine, fenazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.

[0098] The term “unit dosage form” as used herein refers to a single entity for drug administration. For example, a single tablet or capsule that combines a triptan and an NSAID may be a unit dosage form. A “unit dosage form” (or “unit dose form”) may also be called a “fixed dosage form” (or “fixed dose form”) or a “fixed dosage combination” (or “fixed dose combination”). fixed”), which are otherwise interchangeable. In one embodiment, the unit dosage form is a multilayer tablet.

[0099] 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 another embodiment, the unit dosage form is a multilayer tablet comprising a single core and one or more layers outside the core. In some embodiments, the pharmaceutical composition may have an effective amount of a triptan (such as rizatriptan or frovatriptan), a cyclodextrin, and a bicarbonate to increase the bioavailability of frovatriptan. In other embodiments, the pharmaceutical composition may have an effective amount of the triptan, sulfobutylether-β-cyclodextrin (SBEβCD), and sodium bicarbonate to increase the bioavailability of the triptan or reduce the Tmax of the triptan.

[00100] Some dosage forms may comprise a first layer comprising meloxicam, an SBEβCD, and a bicarbonate; and a second layer comprising a triptan and a bicarbonate.

[00101] The first layer may contain, for example, any amount of meloxicam in one of the ranges mentioned above. For example, all of the meloxicam in the dosage form may be present in the first layer. The second layer may contain all of the triptan, so that any amount in the ranges cited above with respect to triptan may apply to the second layer.

[00102] In some embodiments, the first layer contains about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of the bicarbonate, such as sodium bicarbonate, or any amount of the bicarbonate in a range limited by any such values.

[00103] In some embodiments, the second layer contains about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of the bicarbonate, such as sodium bicarbonate, or any amount of the bicarbonate in a range limited by any such values.

[00104] Some oral dosage forms may have enteric coatings or film coatings. In some embodiments, a dosage form may comprise a tablet or capsule with an enteric coating. In some embodiments, a dosage form may comprise a tablet or capsule with a film coating.

[00105] One embodiment of the present description is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: (a) dexketoprofen, which may or may not be surrounded by an enteric coating; (b) sodium or potassium bicarbonate and/or sodium or potassium carbonate; and (c) frovatriptan, which may or may not be formulated with a cyclodextrin and which may or may not be surrounded by an enteric coating.

[00106] In certain embodiments, the pharmaceutical composition results in faster release or dissolution of a drug (e.g., meloxicam or other NSAID, rizatriptan, frovatriptan, or other triptan) from the dosage form compared to a dosage form containing the same drug, but not containing the acid inhibitor, or not containing the buffering agent.

[00107] The following modalities are contemplated: Modality 1. a meloxicam inclusion complex in a cyclodextrin.

[00108] Modality 2. A dosage form comprising: 1) the inclusion complex of modality 1, or 2) meloxicam and a carbonate or a bicarbonate.

[00109] Modality 3. The dosage form of modality 2 comprising the inclusion complex, wherein the cyclodextrin comprises substituted β-cyclodextrin.

[00110] Modality 4. The dosage form of modality 3, in which the substituted β-cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPBCD).

[00111] Modality 5. The dosage form of modality 4, in which the cyclodextrin is SBEβCD.

[00112] Modality 6. The dosage form of modality 5, in which the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[00113] Modality 7. The dosage form of modality 6, in which meloxicam and SBEβCD have a molar ratio of about 0.8 to about 1.2.

[00114] Modality 8. The dosage form of modality 6, in which meloxicam and SBEβCD have a molar ratio of about 1.

[00115] Modality 9. The dosage form of modality 2, 3, 4, 5, 6, 7, or 8, comprising a bicarbonate.

[00116] Modality 10. The dosage form of modality 9, in which the bicarbonate comprises sodium bicarbonate.

[00117] Modality 11. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is an oral dosage form.

[00118] Modality 12. The dosage form of modality 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.

[00119] Modality 13. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, in which the carbonate or bicarbonate is present in an amount in a range of about 400 mg to about 600 mg.

[00120] Modality 14. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, in which the Tmax of meloxicam is decreased compared to a form dosage form that does not have a carbonate, a bicarbonate, or a cyclodextrin.

[00121] Modality 15. The method of modality 14, in which the Tmax of meloxicam is reached in the patient in a time ranging from about 10 minutes to about 180 minutes after administration.

[00122] Modality 16. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, which has an oral bioavailability of meloxicam that is higher than a dosage form that does not have a carbonate, a bicarbonate, or a cyclodextrin.

[00123] Modality 17. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, which additionally comprises an acid inhibitor .

[00124] Modality 18. The dosage form of modality 17, in which the acid inhibitor is a proton pump inhibitor.

[00125] Modality 19. The dosage form of modality 18, in which the proton pump inhibitor is esomeprazole.

[00126] Modality 20. The dosage form of modality 19, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form.

[00127] Modality 21. A method for administering meloxicam orally, comprising orally administering a dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, or 20 to a patient in need of treatment.

[00128] Modality 22. The method of modality 21, in which the dosage form is administered to treat pain.

[00129] Modality 23. The method of modality 21, in which the dosage form is administered to treat inflammatory pain.

[00130] Modality 24. The method of modality 21, in which the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[00131] Modality 25. A method for administering meloxicam intravenously, comprising intravenously administering a dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 , or 15, to a patient in need of treatment.

[00132] Modality 26. A frovatriptan inclusion complex in a cyclodextrin.

[00133] Mode 2-1. A dosage form comprising: 1) the inclusion complex of frovatriptan in a cyclodextrin, or 2) frovatriptan and a carbonate or a bicarbonate.

[00134] Mode 2-2. The dosage form of modality 2-1, comprising the inclusion complex, wherein the cyclodextrin comprises a sulfobutyl ether β-cyclodextrin (SBEβCD) or a hydroxypropyl β-cyclodextrin (HPβCD).

[00135] Modality 2-3. The dosage form of embodiment 2-2, wherein the cyclodextrin is SBEβCD and has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[00136] Modality 2-4. The dosage form of embodiment 2-3, which further comprises a bicarbonate.

[00137] Modality 2-5. The dosage form of embodiment 2-4, wherein the bicarbonate comprises sodium bicarbonate.

[00138] Modality 2-6. The dosage form of embodiment 2-3, wherein frovatriptan and SBEβCD have a molar ratio of about 0.8 to about 1.2.

[00139] Modality 2-7. The dosage form of embodiment 2-6, which further comprises a bicarbonate.

[00140] Mode 2-8. The dosage form of embodiment 2-7, wherein the bicarbonate comprises sodium bicarbonate.

[00141] Mode 2-9. The dosage form of modality 2-1, which is an oral dosage form.

[00142] Mode 2-10. The dosage form of embodiment 2-2, comprising the inclusion complex, wherein about 50 mg to about 200 mg of the SBEβCD is present in a unit dosage form.

[00143] Modality 2-11. The dosage form of modality 2-1, which comprises frovatriptan and the carbonate or bicarbonate.

[00144] Modality 2-12. The dosage form of modality 2-1, in which the Tmax of frovatriptan is decreased compared to a dosage form without a carbonate, a bicarbonate, or a cyclodextrin.

[00145] Modality 2-13. The method of modality 2-1, in which the Tmax of frovatriptan is reached in the patient at a time in a range of about 10 minutes to about 180 minutes after administration.

[00146] Modality 2-14. The dosage form of modality 2-1, which has an oral bioavailability of frovatriptan that is higher than a dosage form without a carbonate, a bicarbonate, or a cyclodextrin.

[00147] Modality 2-15. The dosage form of embodiment 2-11, wherein the carbonate or bicarbonate is present in a unit dosage form in an amount in a range of about 400 mg to about 600 mg.

[00148] Modality 2-16. The dosage form of embodiment 2-15, wherein the carbonate or bicarbonate is sodium bicarbonate.

[00149] Modality 2-17. The dosage form of embodiment 2-11, which further comprises an NSAID.

[00150] Mode 2-18. The dosage form of modality 2-17, wherein the NSAID is dexketoprofen or meloxicam.

[00151] Modality 2-19. The dosage form of modality 2-18, wherein the NSAID is dexketoprofen.

[00152] Mode 2-20. The dosage form of embodiment 2-19, wherein about 10 mg to about 50 mg of dexketoprofen is present in a unit dosage form.

[00153] Modality 2-21. A method for administering frovatriptan orally, comprising orally administering the dosage form of embodiment 2-1 to a patient in need of treatment.

[00154] Modality 2-22. The method of embodiment 2-21, wherein the dosage form comprises the inclusion complex, wherein the cyclodextrin is SBEβCD, and further comprises a bicarbonate.

[00155] Modality 2-23. The method of embodiment 2-22, wherein the bicarbonate is sodium bicarbonate.

[00156] Mode 2-24. The method of embodiment 2-23, wherein a unit dosage form contains about 300 mg to about 600 mg of sodium bicarbonate.

[00157] Modality 2-25. The method of embodiment 2-22, wherein the dosage form further comprises an NSAID.

[00158] Modality 2-26. The method of modality 2-25, wherein the NSAID is dexketoprofen, meloxicam, naproxen, ibuprofen, or celecoxib.

[00159] Modality 2-27. The method of embodiment 2-21, wherein the dosage form is administered to treat pain.

[00160] Mode 2-28. The method of embodiment 2-21, wherein the dosage form is administered to treat inflammatory pain.

[00161] Modality 2-29. The method of embodiment 2-21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[00162] Mode P-1. A dosage form comprising: meloxicam; a sulfobutyl ether β-cyclodextrin (SBEβCD); a bicarbonate; and a triptan wherein the dosage form is an oral dosage form that has a shorter Tmax of meloxicam than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain an SBEβCD, and 3 ) does not contain a bicarbonate.

[00163] Mode P-2. The dosage form of modality P-1, which comprises an inclusion complex of 1) meloxicam or triptan and 2) SBEβCD.

[00164] Mode P-3. The dosage form of modality P-1 or 2, which contains about 10 mg to about 20 mg of meloxicam.

[00165] Mode P-4. The P-3 modality dosage form, which contains about 15 mg of meloxicam.

[00166] Mode P-5. The dosage form of embodiment P-1, P-2, P-3, or P-4, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[00167] Mode P-6. The dosage form of embodiment P-1, P-2, P-3, P-4, or P-5, which contains about 50 mg to about 200 mg of SBEβCD.

[00168] Mode P-7. The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, or P-6, wherein the triptan is rizatriptan.

[00169] Mode P-8. The dosage form of modality P-7, which contains about 5 mg to about 20 mg of rizatriptan.

[00170] Mode P-9. The P-8 modality dosage form, which contains about 10 mg of rizatriptan.

[00171] P-10 modality. The P-6 modality dosage form, which contains about 100 mg of SBEβCD.

[00172] Mode P-11. The dosage form of embodiment P-1, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, or P-10, wherein the bicarbonate comprises sodium bicarbonate.

[00173] P-12 modality. The dosage form of modality P-10, which contains about 400 mg to about 600 mg of the bicarbonate.

[00174] Modality P-13. The P-12 modality dosage form, which contains about 500 mg of sodium bicarbonate.

[00175] Modality P-14. The dosage form of modality P-1, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, or P -12, where the oral dosage form has been shown to have a median Tmax of meloxicam that is less than about 3 hours.

[00176] P-15 modality. The P-14 modality dosage form, wherein the oral dosage form has been shown to have a median Tmax of meloxicam that is less than about 2 hours.

[00177] Modality P-16. The P-14 modality dosage form, wherein the oral dosage form has been shown to have a median Tmax of meloxicam that is less than about 1 hour.

[00178] Modality P-17. The dosage form of modality P-1, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P- 12, P-13, P-14, P-15, or P16, wherein the oral dosage form has increased bioavailability of meloxicam compared to the reference dosage form when administered to a mammal.

[00179] Modality P-18. The dosage form of modality P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, or P-17, wherein the oral dosage form has improved meloxicam pharmacokinetics compared to the reference dosage form when administered to a mammal.

[00180] Modality P-19. The dosage form of modality P-1, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P- 12, P-13, P-14, P-15, P-16, P-17, or P-18, wherein the oral dosage form has increased bioavailability of the triptan compared to the reference dosage form when administered to a mammal.

[00181] P-20 modality. The dosage form of modality P-1, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P- 12, P-13, P-14, P-15, P-16, P-17, P-18, or P-19, wherein the oral dosage form has improved triptan pharmacokinetics compared to the oral dosage form reference when administered to a mammal.

[00182] Modality P-21. A method for improving the pharmacokinetics of a triptan or an NSAID, comprising orally administering a dosage form according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a mammal or human in need of treatment with the triptan or NSAID.

[00183] Modality P-22. The method for treating pain, which comprises orally administering a dosage form of modality P-1, P-2, P-3, P4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P18, P-19, or P-20 to a mammal or human in need of the same.

[00184] Modality P-23. The P-22 modality method, where the pain is migraine.

[00185] Modality P-24. The P-22 modality method, where the pain is inflammatory pain.

Example 1

[00186] The effect of varying amounts of potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) on the pH of acidic media was tested. Acidic media were chosen to simulate gastric illnesses. K2CO3 or NaHCO3 was added to 50 mL of a 0.01 N HCl solution (pH 2). The pH of the solution was measured after the addition of K2CO3 or NaHCO3. Deionized water (240 mL) was then added to the mixture and the pH was measured again. The results are shown in Tables 1-4. Table 1. Results with K2CO3 (0.01 N HCl) Table 2. Results with K2CO3 (0.01 N HCl + water) Table 3. Results with NaHCO3 (0.01 N HCl) Table 4. Results with NaHCO3 (0.01 N HCl + water)

Example 2

[00187] Tablets containing meloxicam and combinations of cyclodextrin, K2CO3, or NaHCO3 were manufactured and tested for dissolution. Tablets containing only meloxicam (MOBIC®) were purchased and also tested for dissolution. The tablets tested are listed in Table 5. Meloxicam in the form of meloxicam/cyclodextrin inclusion complexes was used in tablets containing meloxicam and cyclodextrin. Inclusion complexes were formed by mixing meloxicam and cyclodextrin in a pH-adjusted aqueous solution. The pH of the solution was adjusted using buffering agents. The resulting soluble meloxicam/cyclodextrin inclusion complexes were then spray dried. This spray-dried dispersion was used in the manufacture of cyclodextrin-containing tablets. Table 5. Tablets

[00188] Dissolution tests in an acidic medium (chosen to simulate gastric illnesses) were carried out by placing the tablets in a solution of 0.01 N HCl, at a rate of 75 RPM, and a vessel temperature of approximately 37 °C . The results are presented in Tables 6 and Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percentage (%) of meloxicam dissolved. Table 6. Dissolution results

[00189] Meloxicam dissolution was greater with tablets containing various combinations of meloxicam and cyclodextrin, K2CO3, or NaHCO3, compared to tablets containing meloxicam alone. For example, after 120 minutes, dissolution of meloxicam tablets containing NaHCO3 was 95% compared to 2% for tablets containing meloxicam alone.

[00190] Meloxicam dissolution increases with increasing amounts of K2CO3 in the absence of cyclodextrin. However, in the presence of cyclodextrin, increasing amounts of K2CO3 did not appear to increase meloxicam dissolution. At the highest dose of potassium bicarbonate tested, meloxicam dissolution in the presence of cyclodextrin was reduced by approximately 50% compared to meloxicam dissolution in the absence of cyclodextrin at 120 minutes.

[00191] The dissolution of meloxicam with NaHCO3 was significantly greater than that observed with the highest dose of K2CO3 at 15 minutes (50% versus 30%), and at 120 minutes (92% versus 23%). Meloxicam dissolution in the presence of cyclodextrin was also significantly greater with NaHCO3 compared to the highest dose of K2CO3 at 15 minutes (85% versus 26%), and at 120 minutes (86% versus 12%). NaHCO3 in the presence of cyclodextrin increased the dissolution of meloxicam by 15 minutes compared to potassium bicarbonate which resulted in a reduction in dissolution.

Example 3

[00192] A double-layer tablet containing 1) an inclusion complex of SBEβCD with meloxicam, and 2) sodium bicarbonate that was prepared (SBEβCD-Meloxicam/bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam and 100 mg SBEβCD, and 100 mg sodium bicarbonate. The second layer contained 40 mg of esomeprazole and 400 mg of sodium bicarbonate.

[00193] A total of 20 human subjects were randomly assigned in a 1:1 ratio to treatment with the SBEβCD-Meloxicam/bicarbonate tablets described above or Mobic® tablets (15 mg meloxicam), once daily for 6 days under fasting conditions.

[00194] On the first day of dosing, plasma samples were collected for meloxicam concentration analysis at various time points. Meloxicam concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were calculated. The results are represented in FIG. 11

[00195] The median Tmax for meloxicam, the main purpose of the trial, was 9 times faster for SBEβCD- Meloxicam/bicarbonate tablets compared to Mobic® (0.5 hour versus 4.5 hours respectively, p<0. 0001).

[00196] SBEβCD-Meloxicam/bicarbonate tablets also demonstrated a higher median maximum plasma concentration (Cmax) (p=0.0018), faster time to therapeutic plasma concentration (p<0.0001), and longer time rapid up to semi-maximal plasma concentration (p<0.0001) compared to Mobic®.

[00197] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties, such as molecular weight, reaction conditions and so on, used in the specification and claims must be understood in all cases as indicating both the exact values as shown and as being modified by the term “about”. Therefore, unless otherwise indicated, the numerical parameters presented in the specification and in the attached claims are approximations that may vary depending on the desired properties sought to be obtained. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter must at least be interpreted in light of the number of significant digits reported and applying common rounding techniques.

[00198] The terms “a”, “a”, “the”, “a” and similar referents used in the context of describing the invention (especially in the context of the following claims) should be interpreted as covering both the singular and the plural , unless otherwise indicated herein or clearly contradicted by the context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly otherwise contradicted by the context. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is intended merely to further illuminate the invention 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 invention.

[00199] Groupings of alternative modalities or elements described in this document should not be interpreted as limitations. Each group member may be referred to and claimed individually or in any combination with other group members or other elements noted herein. It is expected that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is considered to contain the group as modified, thus complying with the written description of all Markush groups used in the attached claims.

[00200] Certain embodiments are described herein, including the best way known to the inventors to carry out the invention. Obviously, variations in these described embodiments will be apparent to those ordinarily skilled in the art upon reading the preceding description. The inventor expects those skilled in the art to employ appropriate variations, and the inventors intend for the invention to be practiced other than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter cited in the claims as permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations thereof is contemplated unless otherwise indicated herein or clearly otherwise contradicted by the context.

[00201] In closing, it should be understood that the modalities described in this document are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not limitation, alternative embodiments may be used in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims (19)

1. Solid dosage form, characterized by the fact that it comprises: an inclusion complex of meloxicam with a sulfobutyl-ether-e-cyclodextrin (SBEβCD); about 400mg to about 1000mg of a bicarbonate; and a rizatriptan wherein the dosage form is an oral dosage form having a shorter Tmax of meloxicam than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain rizatriptan; 3) does not contain an SBEβCD, and 4) does not contain a bicarbonate when administered to a human. 2. Solid dosage form according to claim 1, characterized by the fact that it comprises an inclusion complex including 1) meloxicam or rizatriptan and 2) SBEβCD. 3. Solid dosage form according to claim 1, characterized in that it contains about 10 mg to about 20 mg of meloxicam. 4. Solid dosage form according to claim 3, characterized in that it contains about 15 mg of meloxicam. 5. Solid dosage form according to claim 1, characterized by the fact that SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin. 6. Solid dosage form according to claim 1, characterized by the fact that it contains about 50 mg to about 200 mg of SBEβCD. 7. Solid dosage form according to claim 1, characterized in that it contains about 5 mg to about 20 mg of rizatriptan. 8. Solid dosage form according to claim 1, characterized in that the bicarbonate comprises sodium bicarbonate. 9. Solid dosage form according to claim 8, characterized in that it contains about 400 mg to about 600 mg of sodium bicarbonate. 10. Solid dosage form according to claim 1, characterized by the fact that the oral dosage form has been shown to have an average Tmax of meloxicam that is less than about 3 hours. 11. Solid dosage form according to claim 1, characterized by the fact that the oral dosage form has been shown to have an average Tmax of meloxicam that is less than about 2 hours. 12. Solid dosage form according to claim 1, characterized by the fact that the oral dosage form increased the bioavailability of meloxicam compared to the reference dosage form when administered to a mammal. 13. Solid dosage form according to claim 1, characterized by the fact that the oral dosage form improved the pharmacokinetics of meloxicam compared to the reference dosage form when administered to a mammal. 14. Solid dosage form according to claim 1, characterized by the fact that the oral dosage form increased the bioavailability of rizatriptan compared to the reference dosage form when administered to a mammal. 15. Solid dosage form according to claim 1, characterized by the fact that the oral dosage form improved the pharmacokinetics of rizatriptan compared to the reference dosage form when administered to a mammal. 16. Solid dosage form for use in improving the pharmacokinetics of a rizatriptan or an NSAID, characterized in that it comprises orally administering the dosage form as defined in claim 1 to a mammal or a human being in need of treatment with rizatriptan or the NSAID. 17. Solid dosage form for use in treating pain, characterized by the fact that it comprises orally administering a dosage form as defined in claim 1 to a mammal or a human being in need thereof. 18. Solid dosage form according to claim 17, characterized by the fact that the pain is migraine. 19. Solid dosage form according to claim 17, characterized by the fact that the pain is inflammatory pain.