dosage form, and, methods to improve the pharmacokinetics of a triptan or an nossaid and to treat pa

专利摘要:
compositions comprising a drug such as a triptan (e.g., rizatriptan) and / or ansaid (e.g., meloxicam) in combination with a cyclodextrin and / or a carbonate or a bicarbonate are described herein. such compositions can be administered orally, for example, to improve the bioavailability or pharmacokinetics of the drug for the treatment of diseases such as pain.
公开号:BR112019013901A2
申请号:R112019013901
申请日:2018-01-04
公开日:2020-02-04
发明作者:Tabuteau Herriot
申请人:Axsome Therapeutics Inc；
IPC主号:

专利说明:

DOSAGE FORM
CROSS REFERENCE TO RELATED APPLICATIONS [001] This application claims the benefit of US provisional patent applications number 62 / 442,136, filed on January 4, 2017; 62 / 504,105, deposited May 10, 2017; and 62 / 536,466, filed on July 25, 2017, which are all incorporated into this document for reference in their entirety.
FUNDAMENTALS [002] There remains 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 cyclodextrin, such as β-cyclodextrin sulfobutileter (SBEpCD), 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 modalities include dosage forms comprising a triptan (such as rizatriptan or frovatriptan), in combination with a cyclodextrin (optionally as an inclusion complex of triptan and cyclodextrin), and / or a bicarbonate, and methods of treatment using the dosage form.
[005] Some embodiments include a dosage form comprising: meloxicam; a β-cyclodextrin sulfobutyl ether (SBEPCD); a bicarbonate; and a triptan, where the dosage form is an oral dosage form that has a shorter T _max of meloxicam than a reference dosage form that: 1) contains the same amount of meloxicam, 2)
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2/58 does not contain an SBEpCD, and 3) does not contain a bicarbonate.
[006] Some modalities include a triptane inclusion complex such as rizatriptan or frovatriptan in a cyclodextrin.
[007] Some embodiments include a dosage form comprising: 1) a triptan inclusion complex, 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 administration of 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 modalities may also include increasing the bioavailability of a triptan, such as rizatriptan or frovatriptan, or increasing the rate at which triptan is made bioavailable in a subject in need of it compared to a formulation without a cyclodextrin or carbonate / bicarbonate.
[009] Some modalities 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 triptan or NSAID.
[0010] The method for 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
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3/58
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 plasma concentration of meloxicam at various points in time for the first 24 hours for a modality of a dosage form described herein and a commercially available meloxicam dosage form.
DETAILED DESCRIPTION [0022] Meloxicam and some other NSAIDs have poor quality 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 achieved using a dosage form, such as an oral dosage form, containing a triptan (such as
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4/58 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 can increase the bioavailability of triptan (eg, rizatriptan) or NSAID (eg, meloxicam) in the patient or increase the rate at which triptan (eg, rizatriptan) or NSAID (eg meloxicam) is made bioavailable, or increases the rate at which the plasma concentration of triptan or NSAID increases. For example, triptan or NSAID may have a shorter T _max , or may have an increased Cmax or area under the plasma concentration curve (AUC) as a result of administering this type of dosage form.
[0024] Any suitable triptan may be used, such as sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan, zolmatriptan, etc., including combinations or salts thereof. In some embodiments, triptan comprises rizatriptan, which has the structure as shown below.
Rizatriptan [0025] NSAID may include, but is not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE522, L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID for the purposes of this description), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozine, etodolac, indomethacin, ketorolac, lomoxicam,
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5/58 meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenphenprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, or combination of proppropylazone, fenpropylazone, fenpropylazone, or fenpropylazone. [0026] In some modalities, 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) that is involved in the initial stages of the arachidonic acid cascade, resulting in reduced formation of prostaglandins, thromboxanes and prostacyclin.
[0028] A dosage form can be provided enterally including, but not limited to, oral, sublingual, or rectal, 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 would otherwise affect the structure or any function of the human body 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, pain
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6/58 neuropathic, chronic pain, acute pain, localized pain, systemic pain, cancer-related pain, acute pain, pain due to injury, pain due to illness (eg, fever), postoperative pain, etc. In some instances, pain relief may be palliative, or pain relief may be provided regardless of the improvement of the illness or disease or the underlying cause of the illness or disease. For example, although the underlying disease may not improve, or may continue to progress, an individual suffering from the disease may experience pain relief. In some modalities, pain affects a muscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths, pouches or joint.
[0031] Migraine is a headache disorder distinguished by recurring headaches that can be moderate to severe. Headaches can affect one half of the head, can be pulsating in nature and can last from 2 to 72 hours. Associated symptoms can include nausea, vomiting and sensitivity to light (photophobia), sound (phonophobia), or smell. Pain can be made worse by physical activity. Migraines can be associated with an aura, which can 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 modalities, the inflammatory pain can be chronic or acute.
[0033] In some embodiments, the dosage form (for example, a dosage form containing a triptan such as rizatriptan or frovatriptan, and / or an NSAID such as meloxicam) can 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
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7/58 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, axillary spondyloarthritis hip, vertebral crush fractures, osteoporosis and neuropathic arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. In other modalities, arthritis pain can be chronic or acute.
[0034] In some embodiments, the dosage form (for example, a dosage form containing a triptan such as rizatriptan or frovatriptan, and / or an NSAID such as meloxicam) can also be administered to relieve neuropathic pain, including diabetic peripheral neuropathy , post herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, sciatica, pudendal neuralgia and central pain. Other causes of neuropathic pain may include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy and radiotherapy or associated neuropathy with chemotherapy. Neuropathic pain can be chronic or acute.
[0035] For some methods, the dosage form (for example, 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 (eg, lumbosacral pain), neck pain, infection, cramps, tendonitis, epidondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to injury, tunnel syndromes, pain associated with bone fractures, sprains, fibrous dysplasia, imperfect osteogenesis, Paget's bone disease, transient osteoporosis and transient hip osteoporosis. In other modalities, pain
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8/58 musculoskeletal can be chronic or acute.
[0036] For some methods, administration of the dosage form (for example, 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 an 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 seen in about 10 minutes, in about 30 minutes, in about an hour, in about two hours, in about three hours, in about four hours, about five hours, 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, three hours or less, or another period limited by these ranges, after administration of the dosage form.
[0037] A human being treated for a disease or illness with any of the dosage forms described in this document (for example, 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 be about 10-90 years old, about 20-80 years old, about 30-75 years old, about 40-70 years old, about 1-16 years old, about 80-95 years, about 18 or more, about 20 or more, about 25 or more, about 30 or more, about 40 or more, about 45 or more, about 50 or more , about 55 or over, about 60 or over, about 65 or 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 (for example, a dosage form containing a triptan such as rizatriptan or
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9/58 frovatriptan, and / or an NSAID such as meloxicam) suffered from the pain or illness associated with the 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) can include a cyclodextrin, a cyclodextrin derivative, and / or a salt thereof. Cyclodextrins (also known as cycloamylases) 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 to a hydrophobic medium. Naturally occurring cyclodextrins include six, seven and eight glucose units (α, β, and γ-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or less glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (ie, 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] A drug inclusion complex (including meloxicam or another NSAID, rizatriptan, frovatriptan, or another triptan) and cyclodextrin
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10/58 can be more soluble in water compared to the drug without complexes. The cyclodextrin can be a naturally occurring cyclodextrin (for example, α, β, or γ-cyclodextrins) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrins, derivatives, or salts thereof can be used. Α-cyclodextrins may include, but are not limited to, (2,3,6tri-O-acetyl) -a-cyclodextrin, (2,3,6-tri-O-methyl) -a-cyclodextrin, (2,3, 6-tri-Ooctyl) -a-cyclodextrin, 6-bromo-6-deoxy-a-cyclodextrin, 6-iodo-6-deoxy-acyclodextrin, (6-O-tert-butyl-dimethylsilyl) -a-cyclodextrin, butyl -acyclodextrin, succinyl-a-cyclodextrin, (2-hydroxypropyl) -a-cyclodextrin, or combinations thereof.
[0041] In some modalities, β-cyclodextrins, derivatives, or salts thereof can be used. Β-cyclodextrins may include, but are not limited to, hydroxypropyl ^ -cyclodextrin, 6-monodeoxy-6-monoamino ^ cyclodextrin, glycosyl ^ -cyclodextrin, maltosyl ^ -cyclodextrin, 6-Oa-Dglicosil ^ -cyclodextrin, 6-Oa ^ -cyclodextrin, 6-azido-6-deoxy ^ cyclodextrin, (2,3-di-O-acetyl-6-O-sulfo) ^ - cyclodextrin, methyl-βcyclodextrin, dimethyl ^ -cyclodextrin (ΌΜβΟΏ), trimethyl ^ - cyclodextrin (ΤΜβΟϋ), (2,3-di-O-methyl-6-O-sulfo) ^ - cyclodextrin, (2,6-di-O-methyl) ^ -
cyclodextrin, (2,6-di-O-ethyl) ^ - cyclodextrin, (2,3,6-tri-O-methyl) ^ - cyclodextrin, (2,3,6-tri-O-acetyl) ^ - cyclodextrin, - (2,3,6-tri-O-benzoyl) ^ - cyclodextrin, (2,3,6-tri-O-ethyl) ^ - cyclodextrin, 6-iodo-6-deoxy ^ - cyclodextrin, 6- (dimethyl-tert-butylsilyl) -6-deoxy ^ -cyclodextrin, 6-bromo-6-
deoxy ^ -cyclodextrin, monoacetyl ^ -cyclodextrin, diacetyl ^ -cyclodextrin, triacetyl ^ -cyclodextrin, (3-O-acetyl-2,6-di-O-methyl) ^ - cyclodextrin, (6-0maltosyl) ^ - cyclodextrin, (6-O-sulfo) ^ - cyclodextrin, (6-Ot-butyldimethylsilyl-
2,3-di-O-acetyl) ^ - cyclodextrin, succinyl- (2-hydroxypropyl) ^ - cyclodextrin, (2,6-di-O-) ethyl ^ -cyclodextrin, (2-carboxyethyl) ^ - cyclodextrin (ΟΜΕβΟϋ ), hydroxyethyl ^ -cyclodextrin (ΗΕβΟϋ), (2-hydroxypropyl) ^ - cyclodextrin, (2hydroxypropyl) ^ - cyclodextrin (ΗΡβΟϋ), (3-hydroxypropyl) ^ - cyclodextrin
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11/58 (3HP3CD), (2,3-hydroxypropyl) -3-cyclodextrin (DHPpCD), butyl-βcyclodextrin, methyl-P-cyclodextrin, silyl ((6-O-tert-butyldimethyl) -2,3, -di -Oacetyl) -3-cyclodextrin, succinyl-P-cyclodextrin, (2-hydroxy-isobutyl) -3cyclodextrin, 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 ^ -cyclodextrin (for example, δΒΕβΟϋ, betadex, CAPTISOL®). In some embodiments, a δΒΕβΟϋ can have about 48, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per molecule of cyclodextrin.
[0043] In some embodiments, γ-cyclodextrins, derivatives, or salts thereof can be used. Γ-cyclodextrins can include carboxymethyl-y-cyclodextrin, (2,3,6-tri-O-acetyl) -y-cyclodextrin, (2,3,6-tri-Omethyl) -y-cyclodextrin, (2,6 -di-O-pentyl) -y-cyclodextrin, 6- (dimethyl-tert-butylsilyl) -6-deoxy-y-cyclodextrin, 6-bromo-6-deoxy-y-cyclodextrin, 6-iodine-6deoxy-y-cyclodextrin, (6-Ot-butyldimethylsilyl) -y-cyclodextrin, succinyl-ycyclodextrin, 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 can help increase the pharmacokinetics or bioavailability of meloxicam or another drug, such as rizatriptan.
[0045] In some embodiments, the enhanced bioavailability of a drug, such as meloxicam or a triptan (e.g., rizatriptan), in the dosage form can be achieved by administering a dosage form comprising a drug salt form, generating a drug inclusion complex with cyclodextrin, and / or including
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12/58 a bicarbonate. This can allow a reduced molar amount of the drug to be used in comparison to other dosage forms containing the drug in the treatment of diseases or disorders.
[0046] Unless otherwise stated, any reference to a compound in this document, such as meloxicam, an NSAID, a triptan, rizatriptan, or a cyclodextrin, by structure, name, or any other means, 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 in this document 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 in between, any of these values compared to administering 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 of these values in comparison
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13/58 with the triptan administration 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 (eg, rizatriptan or frovatriptan) or an NSAID (for 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 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 mol, at least about 85 mol% less, and / or up to about 90 mol% less, 95 mol% less, 98 mol% less, or any amount in a range limited by , or in between, any of those meloxicam values than would otherwise be administered meloxicam alone.
[0050] In other modalities, 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 of these values when administered with a drug, such as a triptan (for example, rizatriptan) or an NSAID (for example, meloxicam), with a cyclodextrin and / or a bicarbonate, compared to the administration of NSAID, opioid, or other pain medication alone.
[0051] In some embodiments, a dosage form may contain
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14/58 an NSAID, such as 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 this description) , ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozine, etodolac, indomethacin, ketorolac, lomoxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunofen, supranophenyl, sulprofaco, tolindach, tolindach, tolindach , oxyfembutazone, azapropazone, phenylbutazone, in an amount of about 1-1000 mg, about 1-500 mg, about 1-400 mg, about 1-300 mg, about 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 to 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 amount in a range limited by, or between, any of those values. These doses can be a safe dose for repeated administration, such as 1, 2, 3 or 4 times a day, or repeated over 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 modalities, a dosage form may contain
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15/58 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 amount in a range limited by, or between, any of those values. These doses can be a safe dose for repeated administration, such as 1, 2, 3 or 4 times a day, or repeated over 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 the substituted βcyclodextrin or other cyclodextrin that can be formulated in a solid dosage form. Such a dosage form may be suitable for oral administration. A pharmacocyclodextrin inclusion complex can also be dissolved in water or another 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 a drug inclusion complex (such as meloxicam, frovatriptan or rizatriptan) and a cyclodextrin can
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16/58 help to improve the properties of a dosage form. For some inclusion complexes, the drug and cyclodextrin (for example, SBEpCD) can have a molar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 mol of the drug to 1 mol of cyclodextrin ), about 0.5-0.7, about 0.60.8, 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 (1) by mixing a homogeneous solution of a drug, such as meloxicam or a triptan, with a homogeneous solution of cyclodextrin to form a homogeneous solution of the drug and cyclodextrin, and (2) evaporating the solvent from the homogeneous drug and cyclodextrin solution to form the complex comprising the drug inclusion complex in a cyclodextrin. In some embodiments, the solutions may be aqueous solutions with an adjusted pH. The pH can be adjusted using a buffering agent. In some embodiments, evaporation comprises lyophilization. In other embodiments, evaporation comprises spray drying. In some embodiments, evaporation comprises vacuum drying.
[0056] For some dosage forms, a cyclodextrin (eg SBEpCD) can be employed in a weight ratio for meloxicam within the range of about 1-1000 (eg 1 g cyclodextrin per 1 g 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
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0.8-1, or any weight ratio in a range limited by, or between, any of these values. Each type of cyclodextrin employed may have a different weight ratio for meloxicam in the dosage form.
[0057] For some dosage forms, a cyclodextrin (for example, SBEpCD) can be used in a weight ratio for triptan, for example, rizatriptan or frovatriptan, within the range of about 1-1000 (for example, 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 weight ratio in a range limited by, or between, any of those values. Each type of cyclodextrin employed may have a different weight ratio to triptan in the dosage form.
[0058] For some dosage forms, a cyclodextrin (eg, SBEpCD) can be employed in a weight ratio to rizatriptan within the range of about 1-1000 (eg 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 any weight ratio in a range limited by, or between, any of these values. Each type of cyclodextrin employed may have a different weight ratio for rizatriptan in the dosage form.
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18/58 [0059] In some modalities; a dosage form can 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 amount in a range limited by, or between, any of those values. These doses can be a safe dose for repeated administration, such as 1, 2, 3 or 4 times a day, or repeated over 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 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; fence
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19/58 of 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 amount in a range limited by, or between, any of those values. These doses can be a safe dose for repeated administration, such as 1, 2, 3 or 4 times a day, or repeated over 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 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 can 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 100 120 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
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60-62 mg, or any amount in a range limited by, or between, any of these values.
[0063] For some dosage forms, a drug inclusion complex (such as meloxicam or another NSAID, or rizatriptan, frovatriptan or another triptan) and cyclodextrin is about 1-10%, 5-20%, 515%, 6-16%, 7-17%, 8-18%, 9-19%, 10-20%, 15-30%, 30-40%, 40-50%, 5070%, or 70-90% by weight total dosage form, or any percentage in a range limited by any of these values.
[0064] Some dosage forms contain a bicarbonate (for example, 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 amount in a range limited by, or between, any of those values. A bicarbonate, such as sodium bicarbonate, can 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 modalities, the daily dose of meloxicam, or the
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21/58 amount of meloxicam administered in a single day (or in one administration, or by more than one divided dose reaching the daily dose) is about 2-5 mg, about 2-6 mg, about 2-7 mg , about 2-8 mg, about
2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2 -16 mg, about 2-17 mg, about 2-18 mg, about 2-22 mg, about 2-26 mg, about 2-30 mg, about 2-50 mg, about 2-19 mg, about 2-20 about 2-23 mg, about 2-24 about 2-27 mg, about 2-28 about 2-35 mg, about 2-40 about 2-55 mg , about 2-60 mg, about 2-21 mg mg, about 2-25 mg mg, about 2-29 mg mg, about 2-45 mg 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 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 2 7-32 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
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20-25 mg, about 25-30 mg, about 30-35 mg, or any amount in a range limited by any of these values. The daily dose can be given as a single dose, given once a day, or it can be given in 2, 3, 4, or more doses divided over a day.
[0066] In some modalities, 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 amount in a range limited by, or between, any of those values. The weekly dose can be given as a single dose, given once a week, or it can be given in 2, 3, 4, 5, 6 or 7 individual doses over a week.
[0067] In some modalities, the monthly dose of meloxicam (for example, 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;
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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 500
550 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 1050-1100 mg;
about 1080-1130 mg;
about 1110-1160 mg;
about 1140-1190 mg;
about 1170-1220 mg;
about 1200-1250 mg;
about 1030-1080 mg;
about 1060-1110 mg;
about 1090-1140 mg;
about 1120-1170 mg;
about 1150-1200 mg;
about 1180-1230 mg;
about 1210-1260 mg;
about 1040-1090 mg;
about 1070-1120 mg;
about 1100-1150 mg;
about 1130-1180 mg;
about 1160-1210 mg;
about 1190-1240 mg;
about 1220-1270 mg;
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fence in 1230-1280 mg; about 1240-1290 mg; about 1250-1300 mg; fence in 1260-1310 mg; about 1270-1320 mg; about 1280-1330 mg; fence in 1290-1340 mg; about 1300-1350 mg; about 1310-1360 mg; fence in 1320-1370 mg; about 1330-1380 mg; about 1340-1390 mg; fence in 1350-1400 mg; about 1360-1410 mg; about 1370-1420 mg; fence in 1380-1430 mg; about 1390-1440 mg; about 1400-1450 mg; fence in 1410-1460 mg; about 1420-1470 mg; about 1430-1480 mg; fence in 1440-1490 mg; about 1450-1500 mg; about 1460-1510 mg; fence in 1470-1520 mg; about 1480-1530 mg; about 1490-1540 mg; fence in 1500-1550 mg; about 1510-1560 mg; about 1520-1570 mg; fence in 1530-1580 mg; about 1540-1590 mg; about 1550-1600 mg; fence in 1560-1610 mg; about 1570-1620 mg; about 1580-1630 mg; fence in 1590-1640 mg; about 1600-1650 mg; about 1610-1660 mg; fence in 1620-1670 mg; about 1630-1680 mg; about 1640-1690 mg; fence in 1650-1700 mg; about 1660-1710 mg; about 1670-1720 mg; fence in 1680-1730 mg; about 1690-1740 mg; about 1700-1750 mg; fence in 1710-1760 mg; about 1720-1770 mg; about 1730-1780 mg; fence in 1740-1790 mg; about 1750-1800 mg; about 1760-1810 mg; fence in 1770-1820 mg; about 1780-1830 mg; about 1790-1840 mg; fence in 1800-1850 mg; about 1810-1860 mg; about 1820-1870 mg; fence in 1830-1880 mg; about 1840-1890 mg; about 1850-1900 mg; fence in 1860-1910 mg; about 1870-1920 mg; about 1880-1930 mg; fence in 1890-1940 mg; about 1900-1950 mg; about 1910-1960 mg; fence in 1920-1970 mg; about 1930-1980 mg; about 1940-1990 mg; fence in 1950-2000 mg; about 1960-2010 mg; about 1970-2020 mg; fence in 1980-2030 mg; about 1990-2040 mg; about 2000-2050 mg; fence in 2010-2060 mg; about 2020-2070 mg; about 2030-2080 mg; fence in 2040-2090 mg; about 2050-2100 mg; about 2060-2110 mg; fence in 2070-2120 mg; about 2080-2130 mg; about 2090-2140 mg;
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25/58 about 2100-2150 mg; about 2110-2160 mg; about 2120-2170mg;
about 2130-2180 mg; about 2140-2190 mg; about 2150-2200mg;
about 2160-2210 mg; about 2170-2220 mg; about 2180-2230mg;
about 2190-2240 mg; about 2200-2250 mg; about 2210-2260mg;
about 2220-2270 mg; about 2230-2280 mg; about 2240-2290mg;
about 2250-2300 mg; about 2260-2310 mg; about 2270-2320mg;
about 2280-2330 mg; about 2290-2340 mg; about 2300-2350mg;
about 2310-2360 mg; about 2320-2370 mg; about 2330-2380mg;
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 of these values. A monthly dose can be given as a single dose, or as two or more individual doses administered during the month.
In some modalities, the monthly dose is administered fortnightly in 2 or 3 divided doses. In some modalities, the monthly dose is administered weekly in 4 or 5 divided doses. In some modalities, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses or more. In some modalities, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose can be administered for only 1 month, or it can be administered repeatedly for 2, 3, 4, 5, 6 or more months.
[0068] In some embodiments, the daily dose of frovatriptan or another triptan (for example, an oral dose, a parenteral dose, etc.) is about
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26/58 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- 29mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount in a range limited by any of these 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 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, ce about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg, about 47-52 mg, about 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 can be given as a single dose, given once a day, or it can be given in 2, 3, 4, or
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27/58 more divided doses during one day.
[0070] In some embodiments, the weekly dose of frovatriptan or another triptan (for example, 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 100 150 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 amount in a range limited by, or between, any of those values. The weekly dose can be given as a single dose, given once a week, or it can 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; fence
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28/58 of 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 amount in a range limited by, or between, any of those values. The weekly dose can be given as a single dose, given once a week, or it can 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 (for example, 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 5,000 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 of these values. A monthly dose can be given as a single dose, or as two or more individual doses administered during the month. In some modalities, the monthly dose is administered fortnightly in 2 or 3 divided doses. In some modalities, the monthly dose is administered weekly in 4 or 5 divided doses. In some modalities, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses or more. In some modalities, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose can be administered for only 1 month, or it can be
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29/58 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 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 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
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30/58 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; fence in 1020-1070 mg; about 1030-1080 mg; fence in 1040-1090 mg; fence in 1050-1100 mg; about 1060-1110 mg; fence in 1070-1120 mg; fence in 1080-1130 mg; about 1090-1140 mg; fence in 1100-1150 mg; fence in 1110-1160 mg; about 1120-1170 mg; fence in 1130-1180 mg; fence in 1140-1190 mg; about 1150-1200 mg; fence in 1160-1210 mg; fence in 1170-1220 mg; about 1180-1230 mg; fence in 1190-1240 mg; fence in 1200-1250 mg; about 1210-1260 mg; fence in 1220-1270 mg; fence in 1230-1280 mg; about 1240-1290 mg; fence in 1250-1300 mg; fence in 1260-1310 mg; about 1270-1320 mg; fence in 1280-1330 mg; fence in 1290-1340 mg; about 1300-1350 mg; fence in 1310-1360 mg; fence in 1320-1370 mg; about 1330-1380 mg; fence in 1340-1390 mg; fence in 1350-1400 mg; about 1360-1410 mg; fence in 1370-1420 mg; fence in 1380-1430 mg; about 1390-1440 mg; fence in 1400-1450 mg; fence in 1410-1460 mg; about 1420-1470 mg; fence in 1430-1480 mg; fence in 1440-1490 mg; about 1450-1500 mg; fence in 1460-1510 mg; fence in 1470-1520 mg; about 1480-1530 mg; fence in 1490-1540 mg; fence in 1500-1550 mg; about 1510-1560 mg; fence in 1520-1570 mg; fence in 1530-1580 mg; about 1540-1590 mg; fence in 1550-1600 mg; fence in 1560-1610 mg; about 1570-1620 mg; fence in 1580-1630 mg; fence in 1590-1640 mg; about 1600-1650 mg; fence in 1610-1660 mg; fence in 1620-1670 mg; about 1630-1680 mg; fence in 1640-1690 mg; fence in 1650-1700 mg; about 1660-1710 mg; fence in 1670-1720 mg; fence in 1680-1730 mg; about 1690-1740 mg; fence in 1700-1750 mg; fence in 1710-1760 mg; about 1720-1770 mg; fence in 1730-1780 mg; fence in 1740-1790 mg; about 1750-1800 mg; fence in 1760-1810 mg;
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31/58 about 1770-1820 mg;
about 1800-1850 mg;
about 1830-1880 mg;
about 1860-1910 mg;
about 1890-1940 mg;
about 1920-1970 mg;
about 1950-2000 mg;
about 1980-2030 mg;
about 2010-2060 mg;
about 2040-2090 mg;
about 2070-2120 mg;
about 2100-2150 mg;
about 2130-2180 mg;
about 2160-2210 mg;
about 2190-2240 mg;
about 2220-2270 mg;
about 2250-2300 mg;
about 2280-2330 mg;
about 2310-2360 mg;
about 1780-1830 mg;
about 1810-1860 mg;
about 1840-1890 mg;
about 1870-1920 mg;
about 1900-1950 mg;
about 1930-1980 mg;
about 1960-2010 mg;
about 1990-2040 mg;
about 2020-2070 mg;
about 2050-2100 mg;
about 2080-2130 mg;
about 2110-2160 mg;
about 2140-2190 mg;
about 2170-2220 mg;
about 2200-2250 mg;
about 2230-2280 mg;
about 2260-2310 mg;
about 2290-2340 mg;
about 2320-2370 mg;
about 1790-1840 mg;
about 1820-1870 mg;
about 1850-1900 mg;
about 1880-1930 mg;
about 1910-1960 mg;
about 1940-1990 mg;
about 1970-2020 mg;
about 2000-2050 mg;
about 2030-2080 mg;
about 2060-2110 mg;
about 2090-2140 mg;
about 2120-2170 mg;
about 2150-2200 mg;
about 2180-2230 mg;
about 2210-2260 mg;
about 2240-2290 mg;
about 2270-2320 mg;
about 2300-2350 mg;
about 2330-2380 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 of these values. A monthly dose can be given as a single dose, or as two or more individual doses administered during the month. In some
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32/58 modalities, the monthly dose is administered fortnightly in 2 or 3 divided doses. In some modalities, the monthly dose is administered weekly in 4 or 5 divided doses. In some modalities, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses or more. In some modalities, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose can be administered for only 1 month, or it can be administered repeatedly for 2, 3, 4, 5, 6 or more months.
[0074] In other modalities, the dosage form can be administered weekly for about one, two, three, four, or more consecutive weeks, every two weeks or fortnightly, or once every three weeks. This regimen can be repeated once a week, twice a month, three times a month, once a month, once every two months, once every three months, or as directed by a medical professional.
[0075] In certain embodiments, administering the pharmaceutical composition results in improved pharmacokinetics, such as increased bioavailability (for example, reduced T _max , increased Cmax, increased AUC, etc.) of a drug, such as meloxicam or another NSAID, rizatriptan , frovatriptan, or other triptan, in dosage form as compared to a dosage form containing the drug, but not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate). In some embodiments, the drug's bioavailability 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
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33/58 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 of those values; compared to the bioavailability of the drug in a dosage form not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).
[0076] Administering some of the dosage forms to a human can 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 pg-h / mL; about 10-30 pg-h / ml; about 20-40 pg-h / ml; about 30-50 pg-h / ml; about 40-60 pg-h / ml; about 50-70 pg-h / ml; about 60-80 pg-h / ml; about 70-90 pg-h / ml; about 80-100 pg-h / ml; about 10-100 pg-h / ml; about 50-150 pg-h / ml; about 25-125 pg-h / ml; about 75-150 pg-h / ml; about 20-50 pg-h / ml; about 40-70 pg-h / ml; about 60-90 pg-h / ml; about 80-110 pg-h / ml; about 100-130 pg-h / ml; about 120-150 pg-h / ml; about 100-150 pg-h / ml; or any AUC in a range limited by, or between, any of those values.
[0077] Administering some of the dosage forms to a human can 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 an AUC of frovatriptan or another triptan of about 1-150 pg-h / mL; about 10-30 pg-h / ml; about 20-40 pg-h / ml; about 30-50 pg-h / ml; about 40-60 pg-h / ml; about 50-70 pg-h / ml; about 60-80 pg-h / ml; about 70-90 pg-h / ml; about 80-100 pg-h / ml; about 10-100 pg-h / ml; about 50150 pg-h / ml; about 25-125 pg-h / ml; about 75-150 pg-h / ml; about 20-50 pg-h / ml; about 40-70 pg-h / ml; about 60-90 pg-h / ml; about 80-110 pg-h / ml; about 100-130 pg-h / ml; about 120-150 pg-h / ml; or
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34/58 any AUC in a range limited by, or between, any of those values. [0078] Unless otherwise indicated, the AUC refers to the AUC calculated in relation to the last measured concentration (AUCO-t), over a period of 24 hours (AUCO-24), or extrapolated to infinity (AUCO -inf).
[0079] For some acute pain disorders, such as migraine and other types of headache, the short-term AUC after oral administration, such as an AUC measured over 6 hours (or AUCO-6), may be particular interest, for example, for rapid pain relief. For example, some dosage forms can result in an AUCO-6 of meloxicam of at least about 6 pg-h / mL; at least about 7 pg-h / ml; at least about 8 pg-h / ml; at least about 9 pg-h / ml; about 610 pg-h / ml; about 7-11 pg-h / ml; about 8-12 pg-h / ml; about 9-13 pg-h / ml; or any AUCO-6 in a range limited by, or between, any of those values.
[0080] In some embodiments, the dosage form may 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 of those values.
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35/58 [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 of those values.
[0082] For example, a method described in this document can reduce the T _max of meloxicam. In some embodiments, the method may include treating a patient to achieve the T _max 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 1-10 h; about 2-9 h; about 3-7 h; about 4-6 h; about 1-5 h; about 2-7 h; about 3-8 h; about 4-9 h; about 1-4 h; about 2-5 h; about 3-6 h; about 4-7 h; about 5-8 h; about 6-9 h; about 7-10 h; or any T _max in a range limited by, or between, any of those values; after
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36/58 administration of the dosage forms described above.
[0083] In some modalities, an oral dosage form may have a T _max 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 T _max of meloxicam that is shorter, or may increase plasma levels of meloxicam at a faster rate, by a factor of at least about 1.5, about 2 , about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20, or by a factor of about 1.12, 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 of these values, compared to that observed by intramuscular injection.
[0084] For example, a method described in this document can reduce the T _max of frovatriptan. In some embodiments, the method may include treating a patient to achieve frovatriptan T _max 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 hours; about 0.5-1 hour; about 1-10 h; about 2-9 h; about 3-7 h; about 4-6 h; about 1-5 h; about 2-7 h; about 3-8 h; about 4-9 h; about 1-4 h; about 2-5 h; about 3-6 h; about 4-7 h; about 5-8 h; about 6-9 h; about 7-10 h; after administration or any T _max in a range limited by, or between,
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37/58 any of those values.
[0085] In some embodiments, a dosage form comprising meloxicam may result in a plasma concentration of meloxicam in 12 hours that is about 0.01-0.5 pg / mL; about 0.5-0.7 pg / ml; about 0.6-0.8 pg / ml; about 0.7-0.9 pg / ml; about 0.8-1 pg / ml; about 0.9-1.1 pg / ml; about 1-1.2 pg / ml; about 1.1-1.3 pg / ml; about 1.2-1.4 pg / ml; about 1.3-1.5 pg / ml; about 1.4-1.6 pg / ml; about 1.5-1.7 pg / ml; about 1.6-1.8 pg / ml; about 1.7-1.9 pg / ml; about 1.8-2 pg / ml; about 1.9-2.1 pg / ml; about 2-2.2 pg / ml; about 2.1-2.3 pg / ml; about 2.2-2.4 pg / ml; about 2.3-2.5 pg / ml; about 2.4-2.6 pg / ml; about 2.5-2.7 pg / ml; about 2.6-2.8 pg / ml; about 2.7-2.9 pg / ml; about 2.8-3 pg / ml; about 2.9-3.1 pg / ml; about 3-3.2 pg / ml; about 3.1-3.3 pg / ml; about 3.2-3.4 pg / ml; about
3.3-3.5 pg / ml; about 3.4-3.6 pg / ml; about 3.5-3.7 pg / ml; about 3.6-
3.8 pg / ml; about 3.7-3.9 pg / ml; about 3.8-4 pg / ml; or any plasma concentration of meloxicam in 12 hours in a range limited by, or between, any of these values.
[0086] In some embodiments, meloxicam is administered in a dose that results in an average plasma level of meloxicam (such as a cave, or average plasma level) of about 0.01-0.5 pg / mL; about 0.50.7 pg / ml; about 0.6-0.8 pg / ml; about 0.7-0.9 pg / ml; about 0.8-1 pg / ml; about 0.9-1.1 pg / ml; about 1-1.2 pg / ml; about 1.1-1.3 pg / ml; about 1.2-1.4 pg / ml; about 1.3-1.5 pg / ml; about 1.4-1.6 pg / ml; about 1.5-1.7 pg / ml; about 1.6-1.8 pg / ml; about 1.7-1.9 pg / ml; about 1.8-2 pg / ml; about 1.9-2.1 pg / ml; about 2-2.2 pg / ml; about 2.1-2.3 pg / ml; about 2.2-2.4 pg / ml; about 2.3-2.5 pg / ml; about 2.4-2.6 pg / ml; about 2.5-2.7 pg / ml; about 2.6-2.8 pg / ml; about 2.7-2.9 pg / ml; about 2.8-3 pg / ml; about 2.9-3.1 pg / ml; about 3-3.2 pg / ml; about 3.1-3.3 pg / ml; about 3.2-3.4 pg / ml; about
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38/58
3.3-3.5 pg / ml; about 3.4-3.6 pg / ml; about 3.5-3.7 pg / ml; about 3.6-
3.8 pg / ml; about 3.7-3.9 pg / ml; about 3.8-4 pg / ml; about 0.1-20 pg / ml; about 0.5-15 pg / ml; about 0.5-10 pg / ml; about 5-15 pg / ml; about 10-20 pg / ml; about 7.5-15 pg / ml; about 2-10 pg / ml; about 1-8 pg / ml; about 1-6 pg / ml; about 1-2 pg / ml; about 0.5-3.5 pg / ml; about 0.5-7 pg / ml; about 12-20 pg / ml; about 8-12 pg / ml; about 1-4 pg / ml; about 4-7 pg / ml; about 7-11 pg / ml; about 11-15 pg / ml; about 15-19 pg / ml; about 16-20 pg / ml; or any amount of average plasma level of meloxicam in a range limited by, or between, any of these values.
[0087] In some embodiments, a dosage form comprising frovatriptan can result in a plasma concentration of frovatriptan in 12 hours that is about 0.01-0.5 pg / mL; about 0.50.7 pg / ml; about 0.6-0.8 pg / ml; about 0.7-0.9 pg / ml; about 0.8-1 pg / ml; about 0.9-1.1 pg / ml; about 1-1.2 pg / ml; about 1.1-1.3 pg / ml; about 1.2-1.4 pg / ml; about 1.3-1.5 pg / ml; about 1.4-1.6 pg / ml; about 1.5-1.7 pg / ml; about 1.6-1.8 pg / ml; about 1.7-1.9 pg / ml; about 1.8-2 pg / ml; about 1.9-2.1 pg / ml; about 2-2.2 pg / ml; about 2.1-2.3 pg / ml; about 2.2-2.4 pg / ml; about 2.3-2.5 pg / ml; about 2.4-2.6 pg / ml; about 2.5-2.7 pg / ml; about 2.6-2.8 pg / ml; about 2.7-2.9 pg / ml; about 2.8-3 pg / ml; about 2.9-3.1 pg / ml; about 3-3.2 pg / ml; about 3.1-3.3 pg / ml; about 3.2-3.4 pg / ml; about
3.3-3.5 pg / ml; about 3.4-3.6 pg / ml; about 3.5-3.7 pg / ml; about 3.6-
3.8 pg / ml; about 3.7-3.9 pg / ml; about 3.8-4 pg / ml; or any 12-hour plasma concentration of frovatriptan in a range limited by, or between, any of these values.
[0088] In some embodiments, frovatriptan is administered in 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 pg / mL;
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39/58 about 0.5-0.7 pg / ml; about 0.6-0.8 pg / ml; about 0.7-0.9 pg / ml; about 0.8-1 pg / ml; about 0.9-1.1 pg / ml; about 1-1.2 pg / ml; about 1.1-1.3 pg / ml; about 1.2-1.4 pg / ml; about 1.3-1.5 pg / ml; about
1.4-1.6 pg / ml; about 1.5-1.7 pg / ml; about 1.6-1.8 pg / ml; about 1.7-
1.9 pg / ml; about 1.8-2 pg / ml; about 1.9-2.1 pg / ml; about 2-2.2 pg / ml; about 2.1-2.3 pg / ml; about 2.2-2.4 pg / ml; about 2.3-2.5 pg / ml; about 2.4-2.6 pg / ml; about 2.5-2.7 pg / ml; about 2.6-2.8 pg / ml; about 2.7-2.9 pg / ml; about 2.8-3 pg / ml; about 2.9-3.1 pg / ml; about 3-3.2 pg / ml; about 3.1-3.3 pg / ml; about 3.2-3.4 pg / ml; about 3.3-3.5 pg / ml; about 3.4-3.6 pg / ml; about 3.5-3.7 pg / ml; about 3.6-3.8 pg / ml; about 3.7-3.9 pg / ml; about 3.8-4 pg / ml; about 0.1-20 pg / ml; about 0.5-15 pg / ml; about 0.5-10 pg / ml; about 5-15 pg / ml; about 10-20 pg / ml; about 7.5-15 pg / ml; about 2-10 pg / ml; about 1-8 pg / ml; about 1-6 pg / ml; about 1-2 pg / ml; about 0.5-3.5 pg / ml; about 0.5-7 pg / ml; about 12-20 pg / ml; about 8-12 pg / ml; about 1-4 pg / ml; about 4-7 pg / ml; about 7-11 pg / ml; about 11-15 pg / ml; about 15-19 pg / ml; about 16-20 pg / ml; or any amount of frovatriptan average plasma level in a range limited by, or between, any of these values.
[0089] In some embodiments, the dosage form can be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it can be enclosed in soft or hard-shell gelatin capsules, compressed into tablets, or incorporated directly into the diet food. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of ingestible tablets, oral tablets, coated tablets, lozenges, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, plasters and the like .
[0090] Tablets, lozenges, pills, capsules and the like can
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40/58 also contain one or more of the following: a binder such as 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, wintergreen oil 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 a coating, for example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir can contain the active compound, sucrose as a sweetening agent, methyl and propylparaben as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts employed.
[0091] Some compositions or dosage forms may be a liquid, or may comprise a solid phase dispersed in a liquid.
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 additionally comprise an acid inhibitor present in an amount effective to raise a patient's gastric pH to at least 2, at least 2.5, at least 3, at least minus 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 blockers or
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41/58 histamine H2 antagonists, which 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 between 5 mg and 30 mg); and pantoprazole, present in unit dosage forms in an amount 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. The compounds in this class were called "reversible proton pump inhibitors" or "acid pump antagonists" and can also be used. Examples include AZD-0865, ARH047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO9605177 and
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42/58
WO9605199). Other compounds in this group are H-335/25 (AstraZeneca, Dialog 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 or treatment form 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 these compounds and, in particular, their pharmaceutically acceptable salts. The amounts of NSAIDs that are therapeutically effective may be lower in current modalities than otherwise seen in practice due to possible positive kinetic interaction and absorption of NSAID in the presence of an acid inhibitor and / or in the presence of a buffering agent .
[0097] In other embodiments, the dosage or treatment form may additionally 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, allyprodin, bezitramide, buprenorphine, butorphanol, carfentanyl, demethylprodin, dextromoramide, tenocine, diacetylmorphine, dihydroxodone, dihydrocodeinone, dihydrocodeinone, dihydrocode etorfine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levometorfano, levorfanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbufine, nalmefene, naloxone, naltrexone, naltrexone, nortronone, nortrone, nortrone, nortronone,
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43/58 pentazocine, phenazocine, piritramide, prodina, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.
[0098] The term "unit dosage form" as used in this document refers to a single entity for drug administration. For example, a single pill or capsule that combines a triptan and an NSAID can be a unit dosage form. A "unit dosage form" (or "unit dose form") can also be called a "fixed dosage form" (or "fixed dose form") or "fixed dosage combination" (or "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-P-cyclodextrin (SBEpCD), and sodium bicarbonate to increase the bioavailability of the triptan or to reduce the T _max of the triptan.
[00100] Some dosage forms may comprise a first layer comprising meloxicam, an SBEpCD, and a bicarbonate; and a second layer comprising a triptan and a bicarbonate.
[00101] The first layer can contain, for example, any amount of meloxicam in one of the ranges mentioned above. For example, all meloxicam in dosage form may be present in the first
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44/58 layer. The second layer can contain the entire triptan, so that any amount in the ranges mentioned above with respect to the triptan can be applied 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 bicarbonate, such as sodium bicarbonate, or any amount of bicarbonate in a range limited by any of these 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 bicarbonate, such as sodium bicarbonate, or any amount of bicarbonate in a range limited by any of these values.
[00104] Some oral dosage forms may have enteric coatings or film coatings. In some embodiments, a dosage form may comprise an enteric-coated tablet or capsule. 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
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45/58 faster release or dissolution of a drug (for example, meloxicam or another NSAID, rizatriptan, frovatriptan, or other triptan) of the dosage form compared to a dosage form containing the same drug, but not containing the inhibitor of acidic, or not containing the buffering agent.
[00107] The following modalities are contemplated:
Mode 1. a meloxicam inclusion complex in a cyclodextrin.
[00108] Mode 2. A dosage form comprising: 1) the inclusion complex of mode 1, or 2) meloxicam and a carbonate or a bicarbonate.
[00109] Mode 3. The dosage form of mode 2 comprising the inclusion complex, wherein the cyclodextrin comprises substituted β-cyclodextrin.
[00110] Mode 4. The dosage form of mode 3, in which the substituted β-cyclodextrin is a sulfobutyl ether β-cyclodextrin (δΒΕβΟϋ) or hydroxypropyl β-cyclodextrin (HPBCD).
[00111] Mode 5. The dosage form of mode 4, in which cyclodextrin is δΒΕβΟϋ.
[00112] Modality 6. The dosage form of modality 5, in which δΒΕβΟϋ has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.
[00113] Mode 7. The dosage form of mode 6, in which meloxicam and δΒΕβΟϋ have a molar ratio of about 0.8 to about
1.2.
[00114] Mode 8. The dosage form of mode 6, in which meloxicam and δΒΕβΟϋ have a molar ratio of about 1.
[00115] Mode 9. The dosage form of mode 2, 3, 4, 5, 6, 7, or 8, comprising a bicarbonate.
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46/58 [00116] Mode 10. The dosage form of mode 9, in which the bicarbonate comprises sodium bicarbonate.
[00117] Mode 11. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is an oral dosage form.
[00118] Mode 12. The dosage form of mode 2, 3, 4, 5, 6, 9, 10, or 11, wherein about 50 mg to about 200 mg of SBEpCD is present in the dosage form.
[00119] Mode 13. The dosage form of mode 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, in which carbonate or bicarbonate is present in an amount in a range of about 400 mg to about 600 mg.
[00120] Modality 14. The dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, in which the T _max of meloxicam is decreased in comparison with a dosage form that does not have a carbonate, bicarbonate, or cyclodextrin.
[00121] Mode 15.0 method of mode 14, in which the T _max of meloxicam is reached in the patient at a time in a range of about 10 minutes to about 180 minutes after administration.
[00122] Mode 16. The dosage form of mode 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, which has an oral bioavailability of meloxicam which is higher than a dosage form that does not have a carbonate, bicarbonate, or cyclodextrin.
[00123] Mode 17. The dosage form of mode 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, which further comprises an acid inhibitor .
[00124] Mode 18. The dosage form of mode 17, in which the acid inhibitor is a proton pump inhibitor.
[00125] Mode 19. The dosage form of mode 18, in which the proton pump inhibitor is esomeprazole.
[00126] Modality 20. The dosage form of modality 19, in
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47/58 that about 30 mg to about 50 mg of esomeprazole is present in the dosage form.
[00127] Mode 21. A method for administering meloxicam orally, which comprises administering orally a dosage form of mode 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] Mode 22. The method of mode 21, in which the dosage form is administered to treat pain.
[00129] Mode 23. The method of mode 21, in which the dosage form is administered to treat inflammatory pain.
[00130] Mode 24. The method of mode 21, in which the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.
[00131] Mode 25. A method for administering meloxicam intravenously, which comprises administering intravenously a dosage form of modality 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 , or 15, to a patient in need of treatment.
[00132] Mode 26. A frovatriptan inclusion complex in a cyclodextrin.
[00133] Mode 2-1. A dosage form comprising: 1) the frovatriptan inclusion complex in a cyclodextrin, or 2) frovatriptan and a carbonate or bicarbonate.
[00134] Mode 2-2. The dosage form of modality 2-1, which comprises the inclusion complex, wherein the cyclodextrin comprises a sulfobutyl ether β-cyclodextrin (SBEPCD) or a hydroxypropyl βcyclodextrin (ΗΡβΟΟ).
[00135] Mode 2-3. The 2-2 modality dosage form, wherein the cyclodextrin is 8 aβυϋ and has about 6 to about 7 sulfobutyl ether groups for each β-cyclodextrin molecule.
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48/58 [00136] Mode 2-4. The dosage form of mode 2-3, which further comprises a bicarbonate.
[00137] Mode 2-5. The dosage form of mode 2-4, wherein the bicarbonate comprises sodium bicarbonate.
[00138] Mode 2-6. The 2-3 dosage form, in which frovatriptan and SBEpCD have a molar ratio of about 0.8 to about 1.2.
[00139] Mode 2-7. The dosage form of mode 2-6, which further comprises a bicarbonate.
[00140] Mode 2-8. The dosage form of mode 2-7, wherein the bicarbonate comprises sodium bicarbonate.
[00141] Mode 2-9. The 2-1 dosage form, which is an oral dosage form.
[00142] Mode 2-10. The 2-2 modality dosage form, which comprises the inclusion complex, in which about 50 mg to about 200 mg of SBEpCD is present in a unit dosage form.
[00143] Mode 2-11. The dosage form of modality 2-1, which comprises frovatriptan and carbonate or bicarbonate.
[00144] Mode 2-12. The dosage form of mode 2-1, wherein the T _max of frovatriptan is decreased compared to a dosage form without a carbonate, bicarbonate, or cyclodextrin.
[00145] Mode 2-13. The 2-1 modality method, in which the T _max of frovatriptan is achieved in the patient in a time in a range of about 10 minutes to about 180 minutes after administration.
[00146] Mode 2-14. The 2-1 dosage form, which has an oral bioavailability of frovatriptan that is higher than a dosage form without a carbonate, bicarbonate, or cyclodextrin.
[00147] Mode 2-15. The 2-11 dosage form, in which carbonate or bicarbonate is present in a dosage form
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49/58 unit in an amount ranging from about 400 mg to about 600 mg.
[00148] Mode 2-16. The dosage form of mode 2-15, wherein the carbonate or bicarbonate is sodium bicarbonate.
[00149] Mode 2-17. The dosage form of mode 2-11, which further comprises an NSAID.
[00150] Mode 2-18. The dosage form of modality 2-17, wherein the NSAID is a dexketoprofen or meloxicam.
[00151] Mode 2-19. The dosage form of modality 2-18, wherein the NSAID is dexketoprofen.
[00152] Mode 2-20. The 2-19 modality dosage form, wherein about 10 mg to about 50 mg of dexketoprofen is present in a unit dosage form.
[00153] Mode 2-21. A method for administering frovatriptan orally, which comprises administering the 2-1 dosage form orally to a patient in need of treatment.
[00154] Mode 2-22. The 2-21 method, wherein the dosage form comprises the inclusion complex, wherein the cyclodextrin is SBEpCD, and further comprises a bicarbonate.
[00155] Mode 2-23. Method 2-22, wherein the bicarbonate is sodium bicarbonate.
[00156] Mode 2-24. The 2-23 method, wherein a unit dosage form contains about 300 mg to about 600 mg of sodium bicarbonate.
[00157] Mode 2-25. The method of mode 2-22, wherein the dosage form further comprises an NSAID.
[00158] Mode 2-26. The 2-25 method, where the NSAID is dexketoprofen, meloxicam, naproxen, ibuprofen or celecoxib.
[00159] Mode 2-27. The 2-21 method, in which the
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50/58 dosage form is administered to treat pain.
[00160] Mode 2-28. The 2-21 method, wherein the dosage form is administered to treat inflammatory pain.
[00161] Mode 2-29. The 2-21 method, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.
[00162] P-1 modality. A dosage form comprising:
meloxicam;
a β-cyclodextrin (δΒΕβΟϋ) sulfobutyl ether;
a bicarbonate; and a triptan in which the dosage form is an oral dosage form that has a shorter T _max of meloxicam than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain a δΒΕβΟϋ, and 3) does not contain a bicarbonate.
[00163] P-2 modality. The dosage form of the P-1 modality, which comprises an inclusion complex 1) of meloxicam or triptan and 2) of δΒΕβυϋ.
[00164] P-3 modality. The dosage form of the P-1 or 2 modality, which contains about 10 mg to about 20 mg of meloxicam.
[00165] P-4 mode. The dosage form of the P-3 modality, which contains about 15 mg of meloxicam.
[00166] P-5 modality. The dosage form of the P-1, P-2, P-3, or P-4 modality, wherein δΒΕβΟϋ has about 6 to about 7 sulfobutyl ether groups for each β-cyclodextrin molecule.
[00167] P-6 modality. The dosage form of the P-1, P-2, P-3, P-4, or P-5 modality, which contains about 50 mg to about 200 mg of δΒΕβΟϋ.
[00168] P-7 modality. The dosage form of the P-1, P-2, P-3, P-4, P-5, or P-6 modality, in which triptan is rizatriptan.
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51/58 [00169] P-8 modality. The dosage form of the P-7 modality, which contains about 5 mg to about 20 mg of rizatriptan.
[00170] P-9 mode. The dosage form of the P-8 modality, which contains about 10 mg of rizatriptan.
[00171] P-10 mode. The dosage form of the P-6 modality, which contains about 100 mg of SBEpCD.
[00172] P-11 modality. The dosage form of mode 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 the P-10 modality, which contains about 400 mg to about 600 mg of bicarbonate.
[00174] P-13 modality. The dosage form of the P-12 modality, which contains about 500 mg of sodium bicarbonate.
[00175] P-14 modality. The dosage form of mode P-1, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, or P -12, in which the oral dosage form has been shown to have a median T _max of meloxicam that is less than about 3 hours.
[00176] P-15 modality. The dosage form of the P-14 modality, in which the oral dosage form was shown to have a median T _max of meloxicam that is less than about 2 hours.
[00177] P-16 modality. The dosage form of the P-14 modality, in which the oral dosage form was shown to have a median T _max of meloxicam that is less than about 1 hour.
[00178] P-17 modality. The dosage form of the 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, where the oral dosage form has increased bioavailability of meloxicam compared to the reference dosage form when administered to a mammal.
[00179] P-18 modality. The dosage form of the P-l modality, PPetition 870190076324, of 08/08/2019, p. 57/74
52/58
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, where the oral dosage form has improved pharmacokinetics of meloxicam compared to the reference dosage form when administered to a mammal.
[00180] P-19 modality. The dosage form of the mode Pl, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-ll, P-12, P-13, P-14, P-15, P-16, P-17, or P-l8, where the oral dosage form has increased bioavailability of triptan compared to the reference dosage form when administered to a mammal.
[00181] P-20 mode. The dosage form of the mode Pl, P2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-ll, P-12, P-13, P-14, P-15, P-16, P-17, P-l8, or P-19, where the oral dosage form has improved pharmacokinetics of triptan compared to the reference dosage form when administered to a mammal.
[00182] P-21 modality. A method for improving the pharmacokinetics of a triptan or an NSAID, which comprises administering orally 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 triptan or NSAID.
[00183] P-22 modality. The method for treating pain, which comprises orally administering a dosage form of the mode Pl, 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 thereof .
[00184] P-23 mode. The P-22 method, in which the pain is migraine.
[00185] P-24 modality. The P-22 method, in which pain is inflammatory pain.
Example 1 [00186] The effect of varying amounts of potassium carbonate
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53/58 (K2CO3) and sodium bicarbonate (NaHC03) at the pH of acidic media was tested. Acidic media were chosen to simulate gastric diseases. K2CO3 or NaHC03 was added to 50 ml of a 0.01 N HCl solution (pH 2). The pH of the solution was measured after adding 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) ________
K2CO3 (mg) PH 25 2.84 35 6.29 45 8.05 50 8.29 100 9.43 200 10.14 300 10.39 400 10.55 450 10.58
Table 2. Results with K2CO3 (0.01 N HCl + water)
K2CO3 (mg) PH 200 10.27 300 10.46 400 10.57 450 10.63
Table 3. Results with NaHCO3 (0.01 N HCl)
XaHCCh (mg) PH 200 5.28 300 5.90 400 6.44 450 6.86 500 8.23 750 8.30 1000 8.36
Table 4. Results with NaHCO3 (0.01 N HCl + water)
aHCO3 (mg) PH 200 5.41 300 5.89 400 6.11 450 6.46 500 8.33 750 8.54 1000 8.60
Example 2 [00187] Tablets containing meloxicam and combinations of cyclodextrin, K2CO3, or NaHCO3 were manufactured and tested for dissolution. Tablets containing meloxicam (MOBIC®) were
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54/58 acquired and also tested for dissolution. The tested pills are listed in Table 5. Meloxicam in the form of meloxicam / cyclodextrin inclusion complexes was used in the tablets containing meloxicam and cyclodextrin. Inclusion complexes were formed by mixing meloxicam and cyclodextrin in an aqueous solution with adjusted pH. 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 tablets containing cyclodextrin.
Table 5. Tablets________________________________________
Tablet A 15 mg meloxicam + 25 mg K1CO3 Tablet B 15 mg meloxicam + 50 mg K1CO3 Pill C 15 mg meloxicam + 100 mg K1CO3 Tablet D 15 mg meloxicam +150 mg K1CO3 Tablet E 15 mg meloxicam + 500 mg NaHCO3 Tablet F 15 mg meloxicam + 100 mg SBE3CD Tablet G 15 mg meloxicam + 100 mg SBE3CD + 25 mg K1CO3 Tablet H 15 mg meloxicam + 100 mg SBE3CD + 50 mg K1CO3 Pill I 15 mg meloxicam + 100 mg SBEfíCD + 100 mg K1CO3 Tablet J 15 mg meloxicam + 100 mg SBE3CD +150 mg K1CO3 K tablet 15 mg meloxicam + 100 mg SBE3CD + 500 mg NaHCO3 Tablet L 15 mg meloxicam (MOBIC®)
[00188] The acid dissolution tests (chosen to simulate gastric diseases) were performed by placing the tablets in a solution of 0.01 N HCI, at a rate of 75 RPM, and a vessel temperature of approximately 37 ° C . The results are shown in Tables 6 and Figures 1-10. Results at various points in time (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as a percentage (%) of dissolved meloxicam.
Table 6. Dissolution results
0 min 15 min 30 min 45 min 60 min 90 min 120 min Tablet A 0% 23% 17% 15% 13% 12% 11% Tablet B 0% 27% 20% 17% 16% 17% 15% Pill C 0% 31% 26% 25% 24% 23% 21% Tablet D 0% 30% 26% 25% 24% 23% 22% Tablet E 0% 50% 66% 77% 84% 92% 95% Tablet F 0% 26% 17% 14% 12% 11% 10% Tablet G 0% 48% 39% 26% 20% 16% 14% Tablet H 0% 44% 30% 22% 17% 16% 13% Pill I 0% 32% 33% 27% 21% 16% 15% Tablet J 0% 26% 27% 19% 15% 12% 11%
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Tablet K 0% 85% 86% 86% 86% 86% 86%
L 0% 2% 2% 2% 2% 2% 2% [00189] Dissolution of meloxicam 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, the dissolution of meloxicam tablets containing NaHCO3 was 95% compared to 2% for tablets containing meloxicam alone.
[00190] The dissolution of meloxicam 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 the dissolution of meloxicam. At the highest dose of potassium bicarbonate tested, dissolution of meloxicam in the presence of cyclodextrin was reduced by approximately 50% compared to dissolution of meloxicam in the absence of cyclodextrin in 120 minutes.
[00191] The dissolution of meloxicam with NaHCO3 was significantly greater than that observed with the highest dose of K2CO3 in 15 minutes (50% versus 30%), and in 120 minutes (92% versus 23%). Dissolution of meloxicam in the presence of cyclodextrin was also significantly greater with NaHCO3 compared to the highest dose of K2CO3 in 15 minutes (85% versus 26%), and in 120 minutes (86% versus 12%). NaHCO3 in the presence of cyclodextrin increased the dissolution of meloxicam in 15 minutes compared to potassium bicarbonate which resulted in a reduction in dissolution.
Example 3 [00192] A double layer tablet containing 1) an SBEpCD inclusion complex with meloxicam, and 2) sodium bicarbonate that has been prepared (SBEpCD-Meloxicam / bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam and 100 mg SBEpCD, and 100 mg sodium bicarbonate. The second layer contained 40 mg of
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56/58 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 SBEpCD-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 analysis of meloxicam concentration at various points in time. The concentrations of meloxicam were determined using LCMS / MS. The pharmacokinetic parameters were calculated. The results are shown in FIG. 11 [00195] The median OT _max for meloxicam, the main purpose of the trial, was 9 times faster for δΒΕβΟϋMeloxicam / bicarbonate tablets compared to Mobic® (0.5 hour versus 4.5 hours respectively, p <0.0001 ).
[00196] SBEpCD-Meloxicam / bicarbonate tablets also showed a higher maximum median plasma concentration (Cmax) (p = 0.0018), faster time to therapeutic plasma concentration (p <0.0001), and longer time fast to semi-maximum plasma concentration (p <0.0001) compared to Mobic®.
[00197] Unless otherwise stated, all numbers expressing quantities of ingredients, properties, such as molecular weight, reaction conditions and so on, used in the specification and in the 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 that are sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of
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57/58 claims, each numeric parameter must at least be interpreted in light of the number of significant digits reported and applying common rounding techniques.
[00198] The terms "one", "one", "o", "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 stated in this document or clearly contradicted by the context. All methods described in this document may be carried out in any appropriate order unless otherwise indicated in this document or clearly otherwise contradicted by the context. The use of any and all examples or exemplary language (for example, "as") provided herein is intended merely to better illuminate the invention and is not a limitation on the scope of any claim. No language in the specification should be interpreted 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 member of the group can be referred and claimed individually or in any combination with other members of the group or other elements verified in this document. It is expected that one or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any inclusion or deletion like this occurs, the specification is considered to contain the group as modified, thus fulfilling the written description of all Markush groups used in the attached claims.
[00200] Certain modalities are described in this document, including the best way known by the inventors to carry out the invention. Obviously, variations in these described modalities will be apparent to
Petition 870190076324, of 08/08/2019, p. 63/74
58/58 ordinarily skilled in the art by reading the preceding description. The inventor expects those skilled in the art to employ the appropriate variations, and the inventors intend for the invention to be practiced in a manner other than that specifically described herein. Accordingly, the claims include all modifications and equivalents of the matter cited in the claims as permitted by applicable law. In addition, any combination of the elements described above in all possible variations of them is contemplated unless otherwise indicated in this document or clearly otherwise contradicted by the context.
[00201] In conclusion, it should be understood that the modalities described in this document are illustrative of the principles of the claims. Other modifications that can be employed are within the scope of the claims. Thus, by way of example, but not by way of limitation, alternative modalities can be used in accordance with the teachings in this document. Therefore, the claims are not limited to the modalities precisely as shown and described.

权利要求:
Claims (20)
[1]
1. Dosage form, characterized by the fact that it comprises:
meloxicam;
a sulfobutyl-ether-P-cyclodextrin (SBEpCD);
a bicarbonate; and a triptan in which the dosage form is an oral dosage form having a shorter T _max of meloxicam than a reference dosage form which: 1) contains the same amount of meloxicam, 2) does not contain an SBEpCD, and 3) does not contain a bicarbonate.
[2]
2. Dosage form according to claim 1, characterized by the fact that it comprises an inclusion complex 1) of meloxicam or triptan and 2) of SBEPCD.
[3]
Dosage form according to claim 1, characterized in that it contains about 10 mg to about 20 mg meloxicam.
[4]
Dosage form according to claim 3, characterized in that it contains about 15 mg of meloxicam.
[5]
5. Dosage form according to claim I, characterized by the fact that SBEPCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.
[6]
6. Dosage form according to claim 1, characterized by the fact that it contains about 50 mg to about 200 mg of SBEpCD.
[7]
7. Dosage form according to claim I, characterized by the fact that triptan is rizatriptan.
[8]
8. Dosage form according to claim 7, characterized in that it contains about 5 mg to about 20 mg of
Petition 870190076369, of 08/08/2019, p. 11/11
2/3 rizatriptan ο.
[9]
Dosage form according to claim 1, characterized in that the bicarbonate comprises sodium bicarbonate.
[10]
Dosage form according to claim 9, characterized in that it contains about 400 mg to about 600 mg of sodium bicarbonate.
[11]
11. Dosage form according to claim 1, characterized in that the oral dosage form has been shown to have an average m _max of meloxicam which is less than about 3 hours.
[12]
12. Dosage form according to claim 1, characterized in that the oral dosage form has been shown to have an average T _max of meloxicam which is less than about 2 hours.
[13]
13. Dosage form according to claim 1, characterized by the fact that the oral dosage form has increased the bioavailability of meloxicam compared to the reference dosage form when administered to a mammal.
[14]
14. Dosage form according to claim 1, characterized by the fact that the oral dosage form has improved the pharmacokinetics of meloxicam compared to the reference dosage form when administered to a mammal.
[15]
15. Dosage form according to claim 1, characterized by the fact that the oral dosage form increased the bioavailability of triptan compared to the reference dosage form when administered to a mammal.
[16]
16. Dosage form according to claim 1, characterized by the fact that the oral dosage form has improved the pharmacokinetics of triptan compared to the reference dosage form when administered to a mammal.
Petition 870190076369, of 08/08/2019, p. 9/11
3/3
[17]
17. Dosage form for use in improving the pharmacokinetics of a triptan or an NSAID, characterized by the fact that it comprises orally administering the dosage form as defined in claim 1 to a mammal or a human in need of treatment with the triptan or the NSAID.
[18]
18. Dosage form for use in the treatment of pain, characterized by the fact that it comprises orally administering a dosage form as defined in claim 1 to a mammal or a human in need thereof.
[19]
19. Dosage form according to claim 18, characterized by the fact that the pain is migraine.
[20]
20. Dosage form according to claim 18, characterized by the fact that pain is inflammatory pain.

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法律状态:
2021-04-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-05-11| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762442136P| true| 2017-01-04|2017-01-04|

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US201762504105P| true| 2017-05-10|2017-05-10|

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US201762536466P| true| 2017-07-25|2017-07-25|

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PCT/US2018/012433|WO2018129220A1|2017-01-04|2018-01-04|Pharmaceutical compositions comprising meloxicam|

---