Solid pharmaceutical compositions comprising meloxicam

Abstract

To provide compositions for improving bioavailability or pharmacokinetics of NSAID for treating symptoms such as a pain.SOLUTION: The present invention discloses a solid pharmaceutical composition comprising: 1) a clathrate complex of cyclodextrin and meloxicam; and 2) bicarbonate, the solid pharmaceutical composition to be orally administered to the human.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is based on U.S. Provisional Application No. 62 / 114,215 filed on February 10, 2015, and U.S. Provisional Application No. 62 / 259,993 filed on November 25, 2015, including the specifications, claims, drawings, and abstracts thereof. The disclosures of the above-mentioned Japanese patent applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Meloxicam, having the following structure, is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activity. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthetase (cyclooxygenase, COX), which is involved in the early steps of the arachidonic acid cascade, reducing the formation of prostaglandins, thromboxanes, and prostacylin.

[0003] [ka] Summary of the Invention [Means for solving the problem]

[0004] Meloxicam and some other NSAIDs are poorly water-soluble, which can reduce their bioavailability and delay the onset of pain relief resulting from their use. One means of increasing the solubility and bioavailability of meloxicam is through the use of cyclodextrins. Cyclodextrins (also known as cycloamylose) are generally cyclic polysaccharides that form a bucket-like shape. Cyclodextrins help increase the bioavailability of other molecules because the cyclodextrin has a hydrophobic interior and a hydrophilic interior that helps facilitate the transport of molecules. Naturally occurring cyclodextrins contain six, seven, and eight glucose units (α-, β-, and γ-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are possible. In aqueous solution, cyclodextrins can form complexes (i.e., inclusion complexes) with drugs by incorporating the drug into the central / hydrophobic portion of the cyclodextrin ring. Cyclodextrin compounds are also known to aggregate around drugs in micellar structures. This ability of cyclodextrins allows them to act as carriers, potentially increasing the bioavailability of less soluble drugs.

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

[0006] Some embodiments include dosage forms comprising 1) an inclusion complex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or bicarbonate salt.

[0007] Some embodiments include a method of orally administering meloxicam comprising orally administering to a patient in need of treatment a dosage form described herein.

[0008] Some embodiments include a method of administering meloxicam intravenously, comprising administering a dosage form described herein intravenously to a patient in need of treatment.

[0009] Disclosed herein are formulations of an inclusion complex of cyclodextrin and meloxicam formulated with bicarbonate and methods of use thereof.

[0010] Disclosed herein are formulations and methods for delivering meloxicam with a cyclodextrin to a subject by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal or other parenteral means.

[0011] Also disclosed are methods of treating pain and pain-related conditions by delivering to a subject by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal or other parenteral means a dosage form comprising meloxicam, a cyclodextrin and a bicarbonate. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a diagram of the results described in Example 2 and included in Table 6. [Figure 2] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 3] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 4] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 5] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 6] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 7] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 8] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 9] FIG. 1 is another view of the results described in Example 2 and included in Table 6. [Figure 10] FIG. 1 is another view of the results described in Example 2 and included in Table 6. DETAILED DESCRIPTION OF THE INVENTION

[0013] Provided herein are dosage forms and methods of treatment using the dosage forms that include an NSAID (eg, meloxicam) and a cyclodextrin (optionally in an inclusion complex), and / or bicarbonate.

[0014] Dosage forms may be administered enterally, including but not limited to oral, sublingual or rectal delivery, or parenterally, including but not limited to intravenous, intramuscular, intranasal or subcutaneous delivery.

[0015] Some methods include administering a combination product of an NSAID formulated with a) a cyclodextrin and / or b) a buffering agent. In some embodiments, the method includes treating a patient with a pharmaceutical formulation comprising meloxicam and a cyclodextrin and / or a carbonate / bicarbonate. Method embodiments can also include treating a patient to increase the bioavailability of meloxicam in the patient or to increase the rate at which meloxicam becomes bioavailable.

[0016] The term "treat" or "treatment" broadly includes any kind of therapeutic activity, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any activity that, while not therapeutic, affects the structure or any function of the body of a human or other animal.

[0017] The dosage form can be used to treat or provide relief from any type of pain, including, but not limited to, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, generalized pain, cancer-related pain, acute pain, pain due to injury, pain due to illness (e.g., fever), postoperative pain, etc. In some cases, pain relief can be temporary, or pain relief can be provided regardless of improvement of the disease or condition or the underlying cause of the disease or condition. For example, an individual suffering from a disease may experience pain relief, even though the underlying disease may not improve or may continue to progress. In some embodiments, the pain affects muscles, nerves, cartilage, bones, ligaments, tendons, tendon sheaths, eardrums, or joints.

[0018] In some embodiments, the dosage form may be administered to relieve arthritis pain. In some embodiments, the dosage form may be administered to relieve other signs and / or symptoms of arthritis. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (small and polyarticular), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid), arthropathy, non-articular rheumatoid arthritis, periarticular disorders, axial spondyloarthritis, transient osteoarthritis of the hip, vertebral contusion fractures, osteoporosis, and neuropathic arthropathy including Charcot foot, spondyloarthropathy including ankylosing spondylitis, and SAPHO syndrome. In other embodiments, arthritis pain may be chronic or acute. In some embodiments, the dosage form may be administered to relieve signs and / or symptoms of arthritis, including but not limited to osteoarthritis.

[0019] In some methods, administration of the dosage form can achieve pain relief that lasts for at least about 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at least about 8 hours, about 8 hours to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form can achieve pain relief that is observed at about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, less than 15 minutes, less than 20 minutes, 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or other time periods bounded by these ranges, after administration of the dosage form.

[0020] In some embodiments, the dosage form can be administered to relieve neuropathic pain, including diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monocuspid neuralgia, phantom limb pain, sciatica, pudendal neuralgia and central pain.Other causes of neuropathic pain can include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy and neuropathy associated with radiation therapy or chemotherapy treatment.The neuropathic pain to be treated can be chronic or acute.

[0021] In some methods, the dosage form can be administered to relieve inflammatory pain, including inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndrome. In other embodiments, the inflammatory pain can be chronic or acute.

[0022] Arthritis refers to the inflammatory joint disease that can be associated with pain.The example of arthritis pain includes but is not limited to osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy including Charcot foot, axonal spondyloarthropathy including ankylosing spondylitis, and the pain associated with SAPHO syndrome.The inflammatory joint disease that is treated can be chronic or acute.

[0023] In some methods, meloxicam can be administered to relieve musculoskeletal pain.Examples of musculoskeletal pain can include, but are not limited to, lower back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, spasm, tendonitis, thyroiditis, carpal tunnel syndrome, arthralgia, fibromyalgia, pain due to injury, carpal tunnel syndrome, pain associated with fracture, sprain, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis and transient osteoporosis of the hip joint.In other embodiments, musculoskeletal pain can be chronic or acute.

[0024] Humans treated for a disease or condition with the dosage forms described herein can be of any age, for example, about 10 to about 90 years old, about 20 to about 80 years old, about 30 to about 75 years old, about 40 to about 70 years old, about 1 to about 16 years old, about 80 to about 95 years old, about 18 years old or older, about 20 years old or older, about 25 years old or older, about 30 years old or older, about 40 years old or older, about 45 years old or older, about 50 years old or older, about 55 years old or older, about 60 years old or older, about 65 years old or older, or any other age bounded by or within a range therebetween.

[0025] In some embodiments, the human being treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has suffered from pain or a condition associated with pain for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or any period bounded by or within a range therebetween.

[0026] The cyclodextrin used in dosage forms containing meloxicam can include cyclodextrin, cyclodextrin derivatives, and / or salts thereof. Meloxicam and cyclodextrin inclusion complexes can be more water-soluble than uncomplexed meloxicam. The cyclodextrin can be a natural cyclodextrin (e.g., α-, β-, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, its derivatives, or salts can be used. The α-cyclodextrin may include, but is not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or a combination thereof.

[0027] In some embodiments, β-cyclodextrin, its derivatives or salts may be used. β-cyclodextrins include, but are not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin, (2 , 6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3,6-tri-O-methyl)-β-cyclodextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, (2,3,6-tri-O-benzoyl)-β-cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin, 6-butyl Bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-Ot-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,The cyclodextrins may include 6-di-O-ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl(6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin, succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomly methylated β-cyclodextrin, branched-β-cyclodextrin, or combinations thereof. ,

[0028] In other embodiments, the β-cyclodextrin may be a sulfoalkyl ether cyclodextrin, a derivative, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives include, but are not limited to, sulfobutyl ether-β-cyclodextrin (e.g., SBEβCD, Betadex, CAPTISOL®). In some embodiments, the SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0029] In some embodiments, gamma-cyclodextrin, a derivative or a salt thereof may be used. The gamma-cyclodextrin may include carboxymethyl-gamma-cyclodextrin, (2,3,6-tri-O-acetyl)-gamma-cyclodextrin, (2,3,6-tri-O-methyl)-gamma-cyclodextrin, (2,6-di-O-pentyl)-gamma-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-gamma-cyclodextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, 6-iodo-6-deoxy-gamma-cyclodextrin, (6-Ot-butyldimethylsilyl)-gamma-cyclodextrin, succinyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin (2-hydroxypropyl)-gamma-cyclodextrin, acetyl-gamma-cyclodextrin, butyl-gamma-cyclodextrin, or a combination thereof.

[0030] In some embodiments, the dosage form may include a bicarbonate salt, such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or a combination thereof, which may help increase the bioavailability of meloxicam.

[0031] In other embodiments, the dosage form may include a carbonate, its derivatives or salts. Examples of carbonates may include aluminum carbonate, ammonium carbonate, barium carbonate, calcium carbonate, cobalt (II) carbonate, lanthanum carbonate, lithium carbonate, magnesium carbonate, manganese (II) carbonate, potassium carbonate, sodium carbonate, or combinations thereof.

[0032] In some embodiments, enhanced bioavailability of a dosage form may be achieved in the treatment of one of these conditions by administering a dosage form containing a salt form of meloxicam, by forming an inclusion complex of meloxicam with a cyclodextrin, and / or by including a bicarbonate salt, which allows for a reduced molar amount of meloxicam to be used compared to other meloxicam dosage forms.

[0033] Unless otherwise indicated, the compounds herein, e.g., meloxicam or cyclodextrins, by structure, name, or any other means, include other solid forms such as pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species that can be rapidly converted to the compounds described herein under the conditions in which the compounds described herein are used.

[0034] In some embodiments, the use of cyclodextrin, carbonate or bicarbonate may increase the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any amount bounded by or within a range therebetween compared to administration of meloxicam alone.

[0035] Due to the improved bioavailability, the dosage form can contain or be administered to a subject on a molar basis less meloxicam than would otherwise be administered. For example, the dosage form can contain or be administered to a mammal at least about 10 molar% less, at least about 20 molar% less, at least about 30 molar% less, at least about 40 molar% less, at least about 50 molar% less, at least about 60 molar% less, at least about 70 molar% less, at least about 80 molar% less, at least about 85 molar% less, and / or up to about 90 molar% less, 95 molar% less, or any amount of meloxicam bounded by or within a range therebetween, than would otherwise be administered.

[0036] In other embodiments, the use of other NSAIDs, opioids, or other analgesics may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, up to about 100%, compared to the use of other NSAIDs, opioids, or other analgesics without administering meloxicam with a cyclodextrin, carbonate, and / or bicarbonate.

[0037] In some embodiments, the dosage form may contain about 1-50 mg, about 1-10 mg, about 1-5 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg, about 5-10 mg, about 5-15 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 30 mg, or any amount of meloxicam bounded by or within a range therebetween. These doses may be safe for repeated administration, such as once hourly to once daily, twice daily, 1-12 times daily, 3, 4, 5, or 6 times daily. In some embodiments, meloxicam can be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times daily, about 3 to about 10 times daily, once daily, or less frequently, such as once a week, once every two weeks, once a month, etc.

[0038] In some dosage forms, meloxicam is complexed with substituted β-cyclodextrin or other cyclodextrins that can be formulated into solid dosage forms. Such dosage forms may be suitable for oral administration. The meloxicam-cyclodextrin inclusion complex may also be dissolved in water or another solvent to form a parenteral formulation. However, physical mixtures of meloxicam with substituted β-cyclodextrin or other cyclodextrins may also be used in oral or parenteral dosage forms.

[0039] Formation of an inclusion complex between meloxicam and a cyclodextrin can help improve the properties of the dosage form. For some inclusion complexes, the molar ratio of meloxicam and a cyclodextrin (e.g., SBEβCD) can be about 0.5-2 (a molar ratio of 0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or any range bounded by or between these values.

[0040] In some dosage forms, cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of about 1 to 1000 (e.g., 1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1), about 1 to 20, about 1 to 10, about 1 to 15, about 2 to 4, about 3 to 5, about 4 to 6, about 5 to 7, about 6 to 8, about 7 to 9, about 8 to 10, or any range bounded by or therebetween. In some dosage forms, a cyclodextrin (e.g., SBEβCD) may be used in a weight ratio to meloxicam of about 0.001 to 1 (e.g., a weight ratio of 0.1 g of cyclodextrin per 1 g of meloxicam), 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 range bounded by or between these values. Each type of cyclodextrin used may have a different ratio.

[0041] In some dosage forms, the cyclodextrin may be present in an amount of about 1-200 mg, about 25-175 mg, about 50-150 mg, about 25-100 mg, about 75-150 mg, about 100-175 mg, about 20-80 mg, about 25-50 mg, about 60-100 mg, about 80-100 mg, about 80-120 mg, about 100-120 mg, about 100-140 mg, about 120-160 mg, about 140-180 mg, about 30-90 mg, about 40-80 mg, about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount bounded by or within a range therebetween.

[0042] In some methods, an inclusion complex of meloxicam and a cyclodextrin (e.g., a substituted β-cyclodextrin) is delivered orally (e.g., via a tablet, capsule, elixir, etc.). Other possible routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal, or other parenteral means. Meloxicam may be delivered alone or as an uncomplexed cyclodextrin.

[0043] Some dosage forms include about 1-2000 mg, about 1-1000 mg, about 100-1000 mg, about 200-800 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, and about 250-750 mg. 50 mg, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any amount of bicarbonate (e.g., sodium bicarbonate) bounded by or within ranges therebetween.

[0044] Some dosage forms include about 1-1000 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 200-800 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, and about 250-750 mg. g, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 150-650 mg, about 350-850 mg, or any amount of carbonate bounded by or within ranges therebetween.

[0045] In some embodiments, the daily dose of meloxicam (e.g., oral dose, parenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg About 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount bounded by or within ranges therebetween.

[0046] In some embodiments, the weekly dose (e.g., oral dose) of meloxicam is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30-70 mg, about 40-60 mg, about 50-70 mg, about 70-90 mg, about 90-110 mg, about 50 mg, about 55 mg, about 100-150 mg, about 30-100 mg, or any amount bounded by or within a range therebetween. The weekly dose may be given as a single dose given once per week, or may be given in separate doses 2, 3, 4, 5, 6, or 7 times per week.

[0047] In some embodiments, the monthly dose (e.g., oral dose) of meloxicam, or the 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 to 4000 mg, about 1 to 1000 mg, about 10 to 1000 mg, about 50 to 1000 mg, about 10 to 600 mg, about 40 to 600 mg, about 50 to 600 mg, about 40 to 400 mg, about 50 to 200 mg, about 20 to 300 mg, about 30 to 400 mg, about 30 to 5 ... The monthly dose may be 0-240 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, or about 100-1000 mg, or any amount bounded by or within a range therebetween. The monthly dose may be given as a single dose or as two or more separate doses administered during the month. In some embodiments, the monthly dose is administered in two or three biweekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28 to 31 daily doses, or 56 to 62 daily doses or more. In some embodiments, the monthly dose is administered in 5 to 15 separate doses per month. The monthly dose may be administered for one month or repeatedly for two or more months.

[0048] In other embodiments, the dosage form can be administered every week for about 1, 2, 3, 4, or more consecutive weeks, every other week, or once every three weeks. This regimen can be repeated weekly, twice a month, three times a month, once a month, once every two months, once every three months, or as directed by a healthcare professional.

[0049] In certain embodiments, the pharmaceutical composition exhibits improved bioavailability (e.g., T) of meloxicam from a dosage form compared to a dosage form containing meloxicam but not containing a cyclodextrin, an acid inhibitor, or a buffering agent (e.g., bicarbonate). max Decrease in C max In some embodiments, the bioavailability of meloxicam increases with multiple administration. For example, the bioavailability of meloxicam in the dosage form may increase after about 1-10 days after administration, about 2-6 days after administration, about 3-5 days after administration, about 4-6 days after administration, about 5-8 days after administration, about 5 days after administration, about 6 days after administration, about 7 days after administration, about 8 days after administration, about 10 days after administration, about 15 days after administration, or any time period bounded by or within ranges therebetween, compared to the bioavailability of meloxicam in a dosage form that does not contain a cyclodextrin, an acid inhibitor, or a buffering agent (e.g., bicarbonate).

[0050] Some dosage forms can provide a desired range of area under the plasma concentration curve (AUC) for meloxicam. For example, meloxicam doses can range from about 1 to 150 μg·hr / mL, about 10 to 30 μg·hr / mL, about 20 to 40 μg·hr / mL, about 30 to 50 μg·hr / mL, about 40 to 60 μg·hr / mL, about 50 to 70 μg·hr / mL, about 60 to 80 μg·hr / mL, about 70 to 90 μg·hr / mL, about 80 to 100 μg·hr / mL, and about 10 to 100 μg·hr. / mL, about 50-150 μg·hr / mL, about 25-125 μg·hr / mL, about 75-150 μg·hr / mL, about 20-50 μg·hr / mL, about 40-70 μg·hr / mL, about 60-90 μg·hr / mL, about 80-110 μg·hr / mL, about 100-130 μg·hr / mL, about 120-150 μg·hr / mL, or any AUC bounded by or within a range therebetween.

[0051] Unless otherwise indicated, AUC is calculated using the last measured concentration (AUC 0-t ) and 24-hour (AUC 0-24) or extrapolated to infinity (AUC 0-inf )AUC.

[0052] In some embodiments, the dosage form contains about 10-2500 ng / mL, about 100-2250 ng / mL, about 500-2000 ng / mL, about 1000-2500 ng / mL, about 1000-2000 ng / mL, about 100-900 ng / mL, about 750-1500 ng / mL, about 1250-2000 ng / mL, about 1500-2300 ng / mL, about 800-1200 ng / mL, about 1900-2400 ng / mL, about 50-500 ng / mL, about 400-950 ng / mL, about 900-1500 ng / mL, about 1100-2200 ng / mL, about 1300-1600 ng / mL, about 1200-150 C of meloxicam: 0ng / mL, about 1400-2100ng / mL, about 1500-1900ng / mL, about 1600-2100ng / mL, about 1700-2000ng / mL, about 1800-2000ng / mL, about 1900-2500ng / mL, about 150-1700ng / mL, about 1600-1800ng / mL, about 1700-1900ng / mL, about 1800-2000ng / mL, about 1900-2100ng / mL, about 2000-2200ng / mL, about 2100-2300ng / mL, about 2200-2400ng / mL, about 2300-2500ng / mL, about 2500-3000ng / mL max , or any C bounded by or in the range between these values max This can result in:

[0053] For example, the methods described herein may be used to treat T max In some embodiments, the method can reduce the T of meloxicam within or after about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, or about 7-10 hours.max , or any T bounded by or in the range between these values max This may include treating the patient to achieve

[0054] In some embodiments, the dosage form containing meloxicam is about 0.01 to 0.5 μg / mL, approximately 0.5~0.7μg / mL, approximately 0.6~0.8μg / mL, approximately 0.7~0.9μg / mL, approximately 0.8~1μg / mL, approximately 0.9~1.1μg / mL, approximately 1~1.2μg / mL, approximately 1.1~1.3μg / mL, approximately 1.2~1.4μg / mL, approximately 1.3~1.5μg / m L, about 1.4-1.6μg / mL, about 1.5-1.7μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1.8-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, The dose may result in a plasma concentration of meloxicam at 12 hours that is about 2.3-2.5 μg / mL, about 2.4-2.6 μg / mL, about 2.5-2.7 μg / mL, about 2.6-2.8 μg / mL, about 2.7-2.9 μg / mL, about 2.8-3 μg / mL, about 2.9-3.1 μg / mL, about 3-3.2 μg / mL, about 3.1-3.3 μg / mL, about 3.2-3.4 μg / mL, about 3.3-3.5 μg / mL, about 3.4-3.6 μg / mL, about 3.5-3.7 μg / mL, about 3.6-3.8 μg / mL, about 3.7-3.9 μg / mL, about 3.8-4 μg / mL, or any plasma concentration bounded by or within ranges therebetween.

[0055] In some embodiments, meloxicam is administered in a concentration of about 0.01 to 0.5 μg / mL, about 0.5 to 0.7 μg / mL, about 0.6 to 0.8 μg / mL, about 0.7 to 0.9 μg / mL, about 0.8 to 1 μg / mL, about 0.9 to 1.1 μg / mL, about 1 to 1.2 μg / mL, about 1.1 to 1.3 μg / mL, about 1.2 to 1.4 μg / mL, about 1.3 to 1.5 μg / mL, about 1.4 to 1.6 μg / mL, about 1.5 to 1.7 μg / mL, or about 1.6 to 1.8 μg / mL. / mL, approximately 1.7~1.9μg / mL, approximately 1.8~2μg / mL, approximately 1.9~2.1μg / mL, approximately 2~2.2μg / mL, approximately 2.1~2.3μg / mL, approximately 2.2~2.4μg / mL, approximately 2.3~2.5μg / mL , about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2.9-3.1μg / mL, about 3-3.2μg / mL, about 3. 1~3.3μg / mL, approx. 3.2~3.4μg / mL, approx. 3.3~3.5μg / mL, approx. 3.4~3.6μg / mL, approx. 3.5~3.7μg / mL, approx. 3.6~3.8μg / mL, approx. 3.7~3.9μg / mL, approx. 3 .8~4μg / mL, approx. 0.1~20μg / mL, approx. 0.5~15μg / mL, approx. 0.5~10μg / mL, approx. 5~15μg / mL, approx. 10~20μg / mL, approx. 7.5~15μg / mL, approx. 2~10μg / mL, approx. 1 ~8 μg / mL, about 1-6 μg / mL, about 1-2 μg / mL, about 0.5-3.5 μg / mL, about 0.5-7 μg / mL, about 12-20 μg / mL, about 8-12 μg / mL, about 1-4 μg / mL, about 4-7 μg / mL, about 7-11 μg / mL, about 11-15 μg / mL, about 15-19 μg / mL, about 16-20 μg / mL, or any meloxicam plasma level (e.g., C ave or mean plasma level).

[0056] One embodiment is a method for reducing the risk of gastrointestinal side effects and improving the bioavailability of NSAIDs in people taking NSAIDs for pain relief and other conditions, particularly during chronic treatment. In one embodiment, the method involves administering a product that combines a) an agent that actively elevates gastric pH and b) an NSAID formulated with cyclodextrin. In another embodiment, the method involves administering a product that combines a) an agent that actively elevates gastric pH, b) an NSAID formulated with cyclodextrin, and c) a buffering agent. Either short- or long-acting acid inhibitors can be effectively used in the dosage form. This method has the additional advantage of protecting patients from other sources of gastrointestinal ulcers, the effects of which may be enhanced by the breakdown of gastroprotective prostaglandins caused by NSAID therapy.

[0057] Aqueous parenteral meloxicam formulations may contain a buffer to adjust the pH of the aqueous formulation to about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or any other pH bounded by or within these values. Oral meloxicam formulations may contain a buffer to adjust the pH of the gastric juice to about 2 to about 5, about 3.5 to about 5, about 5 to about 11, about 6 to about 9, about 6 to about 8, about 6 to about 7, or any other pH bounded by or within these values. Examples of buffers suitable for use herein include sulfate buffer, phosphate buffer, borate buffer, carbonate buffer, citrate buffer, etc.

[0058] In some embodiments, dosage forms may be formulated for oral administration with, for example, an inert diluent or an edible carrier, or may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or included directly in dietary foods. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, and the like.

[0059] Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders such as tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; or flavorings such as peppermint, wintergreen oil, or cherry flavoring. If the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above-mentioned materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methylparaben and propylparaben as preservatives, and a dye and flavoring such as cherry or orange flavoring. It can be desirable for materials in dosage forms or pharmaceutical compositions to be pharmaceutically pure and substantially non-toxic in the amounts used.

[0060] Some compositions or dosage forms may be liquid or may contain a solid phase dispersed in a liquid.

[0061] In some embodiments, the dosage form can further comprise an acid inhibitor present in an amount effective to raise the patient's gastric pH to at least 2, at least 2.5, at least 3, at least 3.5, at least 3.5, at least 4, and higher, at least 5, when one or more unit dosage forms are administered. The term "acid inhibitor" refers to an agent that inhibits gastric acid secretion and raises gastric pH. Specific H2 blockers, also known as H2 antagonists or histamine H2 blockers or antagonists, include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, locustidine, famotidine, or combinations thereof.

[0062] Other drugs that can be effectively used as acid inhibitors are proton pump inhibitors, such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole, and tenatoprazole. In some embodiments, the daily dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or any amount bounded by or within a range therebetween.

[0063] Examples of specific proton pump inhibitors include esomeprazole, present in a unit dosage form in an amount between 5 mg and 50 mg; omeprazole, present in a unit dosage form in an amount between 5 mg and 50 mg; lansoprazole, present in a unit dosage form in an amount between 5 mg and 150 mg (preferably between 5 mg and 30 mg); and pantoprazole, present in a unit dosage form in an amount between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is present in a 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 inhibitors has been developed that compete with potassium for the acid pump. Compounds in this class are referred to as "reversible proton pump inhibitors" or "acid pump antagonists" and may be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan, and soraprazan (see WO 96 / 05177 and WO 96 / 05199). Other compounds in this group are H-335 / 25 (AstraZeneca, Dialog File 128, Accession No. 020806), Sch-28080 (Schering-Plough, Dialog File 128, Accession No. 009663), Sch-32651 (Schering-Plough, Dialog File 128, Accession No. 006883), and SK&F-96067 (CAS Registry No. 115607-61-9).

[0064] In some embodiments, the dosage form or treatment also further comprises administering a second nonsteroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. NSAIDs include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID for purposes of this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof. For purposes of this disclosure, acid inhibitors, NSAIDs, or analgesics are understood to include all common forms of these compounds, particularly pharmaceutically acceptable salts thereof. The therapeutically effective amount of NSAID may actually be lower in the current embodiment than found elsewhere due to potential positive kinetic interactions and NSAID absorption in the presence of acid inhibitors or in the presence of buffers.

[0065] In other embodiments, the dosage form or treatment can further comprise administering an opioid in an amount effective to reduce or eliminate pain or inflammation, including, but not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine, bezitramide, buprenorphine, butorphanol, carfentanil, desmethylprodine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levometiridine ... These may include methoφhine, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, omefentanil, oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenatazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.

[0066] The pharmaceutical composition may be in the form of a tablet or capsule having (a) an acid inhibitor, and / or (b) a buffering agent, and (c) a nonsteroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in a patient upon administration of one or more of said unit dosage forms. The components of the pharmaceutical composition, individually or collectively, may be in immediate-release or sustained-release form.

[0067] The term "unit dosage form" as used herein refers to a single entity for drug administration.For example, a single tablet or capsule that combines both an acid inhibitor and an NSAID will be a unit dosage form.A "unit dosage form" (or "unit dosage form") is also called a "fixed dosage form" (or "fixed dosage form") or a "fixed dosage form combination" (or "fixed dosage form combination"), and is interchangeable in other documents.In one embodiment, the unit dosage form is a multi-layer tablet.

[0068] In other embodiments, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In yet another embodiment, the unit dosage form is a multi-layer tablet comprising a single core and one or more layers outside the core. In some embodiments, the pharmaceutical composition can have an effective amount of meloxicam, cyclodextrin, and carbonate or bicarbonate to increase the bioavailability of meloxicam. In other embodiments, the pharmaceutical composition can increase the bioavailability of meloxicam or the T of meloxicam. max To reduce the risk of urinary tract infection, the composition may have effective amounts of meloxicam, sulfobutylether-β-cyclodextrin (SBEβCD), and sodium bicarbonate.

[0069] Some oral dosage forms may have an enteric coating or a film coating. In some embodiments, the dosage form may comprise a tablet or capsule with an enteric coating. In some embodiments, the dosage form may comprise a tablet or capsule with a film coating.

[0070] One embodiment of the present disclosure is a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: (a) esomeprazole, which may or may not be surrounded by an enteric coating; (b) sodium or potassium bicarbonate and / or sodium or potassium carbonate, and (c) Meloxicam, which may or may not be formulated with a cyclodextrin and may or may not be surrounded by an enteric coating. The present invention relates to a pharmaceutical composition comprising:

[0071] In certain embodiments, the pharmaceutical composition provides for faster release or dissolution of meloxicam from the dosage form compared to a dosage form containing meloxicam but without an acid inhibitor or without a buffering agent.

[0072] The following embodiments are contemplated: Embodiment 1. An inclusion complex of meloxicam in a cyclodextrin. Embodiment 2. A dosage form comprising: 1) the inclusion complex of embodiment 1; or 2) meloxicam and a carbonate or bicarbonate salt. Embodiment 3 The dosage form of embodiment 2 comprising an inclusion complex, wherein the cyclodextrin comprises a substituted β-cyclodextrin. Embodiment 4. The dosage form of embodiment 3, wherein the substituted β-cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPBCD). Embodiment 5. The dosage form of embodiment 4, wherein the cyclodextrin is SBEβCD. Embodiment 6. The dosage form of embodiment 5, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin. Embodiment 7. The dosage form of embodiment 6, wherein the meloxicam and SBEβCD have a molar ratio of about 0.8 to about 1.2. Embodiment 8 The dosage form of embodiment 6, wherein the meloxicam and SBEβCD have a molar ratio of about 1. Embodiment 9. The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, comprising bicarbonate. Embodiment 10. The dosage form of embodiment 9, wherein the bicarbonate comprises sodium bicarbonate. Embodiment 11. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is an oral dosage form. Embodiment 12. The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form. Embodiment 13. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the carbonate or bicarbonate is present in an amount ranging from about 400 mg to about 600 mg. Embodiment 14. Meloxicam T max 14. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the amount of hydroxybenzoate in the hydroxybenzoate is reduced compared to a dosage form without the carbonate, bicarbonate, or cyclodextrin. Embodiment 15. Meloxicam T maxis achieved in the patient at a time ranging from about 10 minutes to about 180 minutes after administration. Embodiment 16. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 having a higher oral bioavailability of meloxicam than a dosage form without carbonate, bicarbonate, or cyclodextrin. Embodiment 17. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, further comprising an acid inhibitor. Embodiment 18. The dosage form of embodiment 17, wherein the acid inhibitor is a proton pump inhibitor. Embodiment 19. The dosage form of embodiment 18, wherein the proton pump inhibitor is esomeprazole. Embodiment 20. The dosage form of embodiment 19, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form. Embodiment 21. A method of orally administering meloxicam, comprising orally administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need of such treatment. Embodiment 22 The method of embodiment 21, wherein the dosage form is administered to treat pain. Embodiment 23 The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain. Embodiment 24 The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis. Embodiment 25. A method of intravenously administering meloxicam, comprising intravenously administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, or 15 to a patient in need of treatment.

[0073] Example 1 The effect of varying amounts of potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) on the pH of an acidic medium was tested. The acidic medium was chosen to simulate gastric conditions. K2CO3 or NaHCO3 was added to 50 mL of 0.01 N HCl solution (pH 2). After the addition of K2CO3 or NaHCO3, the pH of the solution was measured. Deionized water (240 mL) was then added to the mixture, and the pH was measured again. The results are shown in Tables 1-4.

[0074] [Table 1]

[0075] [Table 2]

[0076] [Table 3]

[0077] [Table 4]

[0078] Example 2 Tablets containing a combination of meloxicam and cyclodextrin, K2CO3, or NaHCO3 were prepared and tested for dissolution. Tablets containing meloxicam alone (MOBIC®) were purchased and also tested for dissolution. The tablets tested are listed in Table 5. Meloxicam in the form of a meloxicam / cyclodextrin inclusion complex was used in the tablets containing meloxicam and cyclodextrin. The inclusion complex was formed by mixing meloxicam and cyclodextrin in a pH-adjusted aqueous solution. The pH of the solution was adjusted using a buffer. The resulting soluble meloxicam / cyclodextrin inclusion complex was then spray-dried. This spray-dried dispersion was used to prepare tablets containing cyclodextrin.

[0079] [Table 5]

[0080] Dissolution testing in acidic media (selected to simulate gastric conditions) was performed by placing tablets in 0.01 N HCl solution at a stirring rate of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 6 and Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent (%) of meloxicam dissolved.

[0081] [Table 6]

[0082] Meloxicam dissolution was greater in tablets containing various combinations of meloxicam and cyclodextrin, K2CO3, or NaHCO3 compared to tablets containing meloxicam alone. For example, after 120 minutes, dissolution of meloxicam tablets containing NaHCO3 was 95% compared to 2% for tablets containing meloxicam alone.

[0083] Meloxicam dissolution increased with increasing amounts of K2CO3 in the absence of cyclodextrin. However, in the presence of cyclodextrin, increasing amounts of K2CO3 did not appear to increase meloxicam dissolution. At the highest dose of potassium bicarbonate tested, meloxicam dissolution in the presence of cyclodextrin was reduced by approximately 50% compared to meloxicam dissolution in the absence of cyclodextrin at 120 minutes.

[0084] Meloxicam dissolution with NaHCO3 was significantly greater than that observed with the highest dose of K2CO3 at 15 minutes (50% vs. 30%) and 120 minutes (92% vs. 23%). Meloxicam dissolution in the presence of cyclodextrin was also significantly greater with NaHCO3 compared to the highest dose of K2CO3 at 15 minutes (85% vs. 26%) and 120 minutes (86% vs. 12%). NaHCO3 in the presence of cyclodextrin increased meloxicam dissolution at 15 minutes compared to potassium bicarbonate, which reduced dissolution.

[0085] Unless otherwise indicated, all numbers expressing properties such as quantities of ingredients, molecular weights, reaction conditions, and the like used in the specification and claims are to be understood in all instances as modified by the precise value as indicated and the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in accordance with the number of reported significant digits and by applying ordinary skill in the art.

[0086] The terms "a," "an," "the," and similar referents as used in the context of describing the invention (particularly in the context of the appended claims) should be construed to encompass both the singular and the plural, and unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "etc."), are intended solely to better illustrate the invention and do not limit the scope of the claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0087] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members within the group or other elements described herein. It is anticipated that one or more group members may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group and, therefore, to satisfy all Markush group descriptions used in the appended claims.

[0088] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as they see fit, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or clearly contradicted by context.

[0089] Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be used are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to the exact embodiments as shown and described.

[0090] (Addendum) (Appendix 1) Inclusion complex of meloxicam in cyclodextrins.

[0091] (Appendix 2) A dosage form comprising 1) an inclusion complex as described in Appendix 1, or 2) meloxicam and a carbonate or bicarbonate.

[0092] (Appendix 3) 3. The dosage form of claim 2, comprising the inclusion complex, wherein the cyclodextrin comprises a substituted β-cyclodextrin.

[0093] (Appendix 4) 4. The dosage form of claim 3, wherein the substituted β-cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPBCD).

[0094] (Appendix 5) 5. The dosage form of claim 4, wherein the cyclodextrin is SBEβCD.

[0095] (Appendix 6) 6. The dosage form of claim 5, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

[0096] (Appendix 7) 7. The dosage form of claim 6, wherein the meloxicam and the SBEβCD have a molar ratio of about 0.8 to about 1.2.

[0097] (Appendix 8) 7. The dosage form of claim 6, wherein the meloxicam and the SBEβCD have a molar ratio of about 1.

[0098] (Appendix 9) 6. The dosage form of claim 5, further comprising bicarbonate.

[0099] (Appendix 10) 10. The dosage form of claim 9, wherein the bicarbonate comprises sodium bicarbonate.

[0100] (Appendix 11) 8. The dosage form of claim 7, further comprising bicarbonate.

[0101] (Appendix 12) 12. The dosage form of claim 11, wherein the bicarbonate comprises sodium bicarbonate.

[0102] (Appendix 13) 2. A dosage form according to claim 1, wherein the dosage form is an oral dosage form.

[0103] (Appendix 14) 3. The dosage form of claim 2, comprising the inclusion complex, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form.

[0104] (Appendix 15) 3. The dosage form of claim 2, comprising the meloxicam and a carbonate or bicarbonate, wherein the carbonate or bicarbonate is present in an amount ranging from about 400 mg to about 600 mg.

[0105] (Appendix 16) The T of meloxicam max 3. The dosage form of claim 2, wherein the amount of cyclodextrin in a given sample is reduced compared to a dosage form without carbonate, bicarbonate, or cyclodextrin.

[0106] (Appendix 17) Meloxicam T max is achieved in the patient at a time point ranging from about 10 minutes to about 180 minutes after administration.

[0107] (Appendix 18) 3. The dosage form of claim 2, wherein the oral bioavailability of meloxicam is greater than a dosage form without carbonate, bicarbonate, or cyclodextrin.

[0108] (Appendix 19) 10. A dosage form as described in Appendix 2, comprising meloxicam and a carbonate or bicarbonate.

[0109] (Appendix 20) 20. The dosage form of claim 19, wherein the carbonate or bicarbonate is sodium bicarbonate, and the sodium bicarbonate is present in an amount ranging from about 400 mg to about 600 mg.

[0110] (Appendix 21) 10. The dosage form of claim 9, further comprising an acid inhibitor.

[0111] (Appendix 22) 22. The dosage form of claim 21, wherein the acid inhibitor is a proton pump inhibitor.

[0112] (Appendix 23) 23. The dosage form of claim 22, wherein the proton pump inhibitor is esomeprazole.

[0113] (Appendix 24) 24. The dosage form of claim 23, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form.

[0114] (Appendix 25) A method for orally administering meloxicam, comprising orally administering the dosage form described in Appendix 2 to a patient in need of treatment.

[0115] (Appendix 26) 26. The method of claim 25, wherein the dosage form contains an inclusion complex of meloxicam in SBEβCD and contains bicarbonate.

[0116] (Appendix 27) 26. The method of claim 25, wherein the bicarbonate is sodium bicarbonate.

[0117] (Appendix 28) 28. The method of claim 27, wherein the dosage form contains about 300 mg to about 600 mg of sodium bicarbonate.

[0118] (Appendix 29) 26. The method of claim 25, wherein the dosage form is administered to treat pain.

[0119] (Appendix 30) 27. The method of claim 26, wherein the dosage form is administered to treat pain.

[0120] (Appendix 31) 31. The method of claim 30, wherein the dosage form is administered to treat inflammatory pain.

[0121] (Appendix 32) 31. The method of claim 30, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[0122] (Appendix 33) 26. The method of claim 25, wherein the dosage form comprises meloxicam and a carbonate or bicarbonate salt.

Claims

1. A solid pharmaceutical composition for use in the treatment of pain in a person requiring treatment, the solid pharmaceutical composition comprising: 1) an inclusion complex of sulfobutyl ether β-cyclodextrin (SBEβCD) or a pharmaceutically acceptable salt thereof and meloxicam or a pharmaceutically acceptable salt thereof; and 2) about 400 mg to about 800 mg of sodium bicarbonate, wherein the T max of meloxicam is achieved in the person at a time in the range of about 90 minutes to about 180 minutes after administration, and the solid pharmaceutical composition is administered orally to the person.

2. The sulfobutyl ether β-cyclodextrin (SBEβCD) has about 6 to about 7 sulfobutyl ether groups in each molecule of β-cyclodextrin. The solid pharmaceutical composition according to claim 1.

3. The solid pharmaceutical composition according to claim 2, wherein the molar ratio of meloxicam to 1 mole of SBEβCD is about 0.8 to about 1.

2.

4. The solid pharmaceutical composition according to claim 3, wherein the molar ratio of meloxicam to 1 mole of SBEβCD is about 1.

5. The solid pharmaceutical composition according to any one of claims 1 to 4, wherein about 50 mg to about 200 mg of SBEβCD is present in the solid pharmaceutical composition.

6. The solid pharmaceutical composition according to any one of claims 1 to 5, wherein about 100 mg to about 120 mg of SBEβCD is present in the solid pharmaceutical composition.

7. The solid pharmaceutical composition according to any one of claims 1 to 6, wherein the sodium bicarbonate is present in the solid pharmaceutical composition in an amount of about 500 mg.

8. The solid pharmaceutical composition according to any one of claims 1 to 7, wherein about 5 mg to about 50 mg of meloxicam is present in the solid pharmaceutical composition.

9. The solid pharmaceutical composition according to any one of claims 1 to 8, wherein about 10 mg to about 20 mg of meloxicam is present in the solid pharmaceutical composition.

10. The solid pharmaceutical composition according to any one of claims 1 to 9, wherein approximately 20 mg of meloxicam is present in the solid pharmaceutical composition.

11. The solid pharmaceutical composition according to any one of claims 1 to 10, further comprising a proton pump inhibitor.

12. The solid pharmaceutical composition according to claim 11, wherein the proton pump inhibitor is esomeprazole.

13. The solid pharmaceutical composition according to claim 12, wherein approximately 30 mg to approximately 50 mg of esomeprazole is present in the solid pharmaceutical composition.

14. The solid pharmaceutical composition according to any one of claims 1 to 13, which has higher oral bioavailability of meloxicam than meloxicam alone.

15. The solid pharmaceutical composition according to any one of claims 1 to 12, wherein oral administration of the solid pharmaceutical composition to a human reduces the Tmax of meloxicam more than oral administration of meloxicam alone.

16. The solid pharmaceutical composition according to any one of claims 1 to 15, wherein oral administration of the solid pharmaceutical composition to a human causes a faster release of meloxicam compared to oral administration of meloxicam alone.

17. The solid pharmaceutical composition according to any one of claims 1 to 16, wherein the meloxicam is in the form of a free acid.

18. The solid pharmaceutical composition according to any one of claims 1 to 16, wherein the meloxicam is in salt form.

19. A solid pharmaceutical composition for use in the treatment of pain in a person requiring treatment, wherein the solid pharmaceutical composition comprises 1) an inclusion complex of sulfobutyl ether β-cyclodextrin (SBEβCD) and meloxicam, and 2) about 500 mg of sodium bicarbonate, 20 mg of meloxicam, and about 50 mg to about 200 mg of sulfobutyl ether β-cyclodextrin (SBEβCD), wherein the T max of meloxicam is achieved in the person at a time in the range of about 90 minutes to about 180 minutes after administration, and is administered orally to the person.

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