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US-12616752-B2 - Pharmaceutical compositions comprising meloxicam

US12616752B2US 12616752 B2US12616752 B2US 12616752B2US-12616752-B2

Abstract

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

Inventors

  • Herriot Tabuteau

Assignees

  • AXSOME THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20250605

Claims (19)

  1. 1 . A method of rapidly delivering meloxicam to the blood of a human being comprising orally administering a solid dosage form to a human being in need of treatment of pain, wherein the dosage form comprises meloxicam or a pharmaceutically acceptable salt thereof and 1 mg to 1000 mg of a bicarbonate, and wherein the solid dosage form provides a T max of meloxicam in the human being that is less than 4 hours.
  2. 2 . The method of claim 1 , wherein the T max of meloxicam in the human being is less than 1 hour.
  3. 3 . The method of claim 1 , wherein the T max of meloxicam in the human being is between 1-4 hours.
  4. 4 . The method of claim 1 , wherein the T max of meloxicam in the human being is between 10 minutes-180 minutes.
  5. 5 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that is observed at less than 15 minutes.
  6. 6 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that is observed at less than 20 minutes.
  7. 7 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that is observed at less than 30 minutes.
  8. 8 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that is observed at less than one hour.
  9. 9 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that lasts at least four hours.
  10. 10 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that lasts at least eight hours.
  11. 11 . The method of claim 1 , wherein orally administering the solid dosage form achieves a reduction in pain that lasts at least twenty-four hours.
  12. 12 . The method of claim 1 , wherein the solid dosage form comprises 1-50 mg meloxicam.
  13. 13 . The method of claim 1 , wherein the solid dosage form comprises 1-15 mg meloxicam.
  14. 14 . The method of claim 1 , wherein the pain is an acute pain.
  15. 15 . The method of claim 1 , wherein the pain is a pain affecting a muscle.
  16. 16 . The method of claim 1 , wherein the pain is a pain affecting a bone.
  17. 17 . The method of claim 1 , wherein the pain is a pain affecting a ligament.
  18. 18 . The method of claim 1 , wherein the pain is a pain affecting a tendon.
  19. 19 . The method of claim 1 , wherein the solid dosage form comprises a cyclodextrin or a pharmaceutically acceptable salt thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 18/582,561, filed Feb. 20, 2024; which is a continuation of U.S. patent application Ser. No. 18/185,477, filed Mar. 17, 2023, now U.S. Pat. No. 11,944,683; which is a continuation of U.S. patent application Ser. No. 17/656,602, filed Mar. 25, 2022, now U.S. Pat. No. 11,617,791; which is a continuation-in-part of U.S. patent application Ser. No. 17/325,616, filed May 20, 2021, now U.S. Pat. No. 11,285,215; which is a continuation of U.S. patent application Ser. No. 17/024,233, filed Sep. 17, 2020, now U.S. Pat. No. 11,020,483; which is a continuation of U.S. patent application Ser. No. 16/867,929, filed May 6, 2020, now U.S. Pat. No. 10,821,182; which is a continuation-in-part of U.S. patent application Ser. No. 16/689,970, filed Nov. 20, 2019, now U.S. Pat. No. 10,688,185; which is a continuation-in-part of U.S. patent application Ser. No. 16/454,319, filed Jun. 27, 2019, now U.S. Pat. No. 10,512,693; which is a continuation-in-part of U.S. patent application Ser. No. 16/248,449, filed Jan. 15, 2019, now U.S. Pat. No. 10,363,312; which is a continuation of U.S. patent application Ser. No. 15/986,215, filed May 22, 2018, now U.S. Pat. No. 10,195,278; which is a continuation of U.S. patent application Ser. No. 15/984,055, filed May 18, 2018, now U.S. Pat. No. 10,265,399; the above U.S. patent application Ser. No. 15/986,215 also claims the benefit of U.S. Provisional Pat. App. Nos. 62/526,884, filed Jun. 29, 2017, and 62/536,466, filed Jul. 25, 2017; all of the above applications, U.S. patents issued from, or U.S. publications of any of the above applications are incorporated by reference in their entirety. BACKGROUND Meloxicam, which has the structure: is a nonsteroidal anti-inflammatory (NSAID) drug that exhibits anti-inflammatory, analgesic, and antipyretic activities. The meloxicam mechanism of action may be related to prostaglandin synthetase (cyclo-oxygenase, COX) inhibition which is involved in the initial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. SUMMARY Meloxicam and some other NSAIDs have poor aqueous solubility which may reduce bioavailability and slow 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. Cyclodextrin (also known as cycloamyloses) are generally cyclic polysaccharides which form a bucket-like shape. Cyclodextrins help to increase bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the inside which helps to facilitate the transport of molecules. The 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 (i.e., an inclusion complex) with drugs by incorporating the drug into the center/hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around a drug in a micelle-type structure. This ability of cyclodextrins may allow them to act as carriers to increase the bioavailability of less soluble drugs. Some embodiments include a method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) a complex of meloxicam with a sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) a rizatriptan. Some embodiments include an inclusion complex of meloxicam in a cyclodextrin. Some embodiments include a dosage form comprising: 1) an inclusion complex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or a bicarbonate. Some embodiments include a method of administering meloxicam orally, comprising orally administering a dosage form described herein to a patient in need of treatment. Some embodiments include a method of administering meloxicam intravenously, comprising intravenously administering a dosage form described herein to a patient in need of treatment. Disclosed herein are formulations for an inclusion complex of cyclodextrin and meloxicam with bicarbonate and methods of use thereof. Disclosed herein are formulations and methods for delivering meloxicam with cyclodextrin to a subject by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means. Disclosed also are methods for treating pain and pain associated with conditions by delivering a dosage form with meloxicam, cyclodextrin, and bicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means to a subject. A combination of rizatriptan and me