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KR-20260066814-A - PHARMACEUTICAL COMPOSITIONS COMPRISING MELOXICAM

KR20260066814AKR 20260066814 AKR20260066814 AKR 20260066814AKR-20260066814-A

Abstract

Compositions comprising NSAIDs such as meloxicam and/or rizatriptan combined with cyclodextrin and/or carbonate or bicarbonate are disclosed herein. Such compositions may be administered orally to improve the bioavailability or pharmacokinetics of NSAIDs for the treatment of pain, such as migraine, arthritis, and other pathological conditions. Also disclosed herein is a method for treating migraine-like pain, comprising administering meloxicam and rizatriptan to a human suffering from migraine-like pain. In the case of migraine, such a method may be particularly useful when meloxicam and rizatriptan are administered while the human 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 such a manner that results in a T max of meloxicam of 3 hours or less.

Inventors

  • 타부토 헤리엇

Assignees

  • 액섬 테라퓨틱스, 인크.

Dates

Publication Date
20260512
Application Date
20200206
Priority Date
20190206

Claims (20)

  1. A method for treating migraine, comprising the steps of selecting a human migraine patient having a history of an inadequate response to previous migraine treatment, and orally administering a formulation to the migraine patient, wherein the formulation comprises a combination of 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) rizatriptan.
  2. A method in which a human migraine patient experiences relief of migraine pain as a result of orally administering a formulation to a migraine patient, wherein, in claim 1.
  3. A method according to claim 1 or 2 in which the formulation is orally administered to a human migraine patient and, after 2 hours, the human migraine patient has no migraine pain.
  4. A method according to any one of claims 1 to 3, wherein the migraine patient experiences a reduction in nausea as a result of orally administering a formulation to the migraine patient.
  5. A method according to any one of claims 1 to 4, wherein the formulation is orally administered to a human migraine patient and, after 2 hours, the human migraine patient does not experience nausea.
  6. A method according to any one of claims 1 to 5, wherein the migraine patient experiences a reduction in photophobia as a result of orally administering a formulation to the migraine patient.
  7. A method according to any one of claims 1 to 6, wherein the formulation is orally administered to a human migraine patient and, after 2 hours, the human migraine patient is free from photophobia.
  8. A method according to any one of claims 1 to 7, wherein the migraine patient experiences a reduction in phonophobia as a result of orally administering a formulation to the migraine patient.
  9. A method according to any one of claims 1 to 8, wherein the formulation is orally administered to a human migraine patient and, after 2 hours, the human migraine patient is free from phonophobia.
  10. A method according to any one of claims 1 to 9, wherein the formulation contains 400 mg to 600 mg of bicarbonate.
  11. A method according to any one of claims 1 to 10, wherein the formulation contains about 5 mg to about 50 mg of meloxicam.
  12. A method according to any one of claims 1 to 11, wherein the formulation contains about 50 mg to about 200 mg of SBEβCD.
  13. A method according to any one of claims 1 to 12, wherein the formulation is a solid oral formulation having a shorter T max of meloxicam in humans than a reference formulation that 1) contains an equal amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate.
  14. A method according to any one of claims 1 to 13, wherein about 1 mg to about 50 mg of rizatriptan is present in an oral formulation based on the weight of the free base form of rizatriptan.
  15. In paragraph 14, the rizatriptan is present in the form of a salt in an amount molar equivalent to about 10 mg of rizatriptan in the form of a free base.
  16. In paragraph 14 or 15, the method wherein rizatriptan exists as rizatriptan benzoate.
  17. A method according to any one of claims 1 to 16, wherein the oral formulation contains about 10 mg to about 30 mg of meloxicam.
  18. In paragraph 17, the oral formulation is a method containing about 20 mg of meloxicam.
  19. In paragraph 17, the oral formulation is a method containing about 15 mg of meloxicam.
  20. A method according to any one of claims 1 to 19, wherein SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Description

Pharmaceutical compositions comprising meloxicam Cross-reference regarding related applications The present application comprises U.S. Provisional Application No. 62/802,198 filed on February 6, 2019; U.S. Provisional Application No. 62/803,756 filed on February 11, 2019; U.S. Provisional Application No. 62/835,613 filed on April 18, 2019; U.S. Provisional Application No. 62/846,311 filed on May 10, 2019; U.S. Provisional Application No. 62/860,705 filed on June 12, 2019; U.S. Provisional Application No. 62/895,933 filed on September 4, 2019; and U.S. Provisional Application No. 62/895,956 filed on September 4, 2019. and claim the benefit of U.S. provisional application No. 62/955,905 filed on December 31, 2019, all of which are incorporated by reference. Meloxicam having the following structure is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities: The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthase (cyclo-oxygenase, COX), which is involved in the early stages of the arachidonic acid cascade, resulting in reduced formation of prostaglandins, thromboxanes, and prostacillins. outline Meloxicam and some other NSAIDs have poor water solubility, which can reduce bioavailability and delay the onset of pain relief from their use. One way to improve the solubility and bioavailability of meloxicam is to use cyclodextrins. Cyclodextrins (also known as cycloamylose) are cyclic polysaccharides that generally form a bucket-like shape. Because cyclodextrins are internally hydrophobic and internally hydrophilic, facilitating the movement of molecules, they help improve the bioavailability of other molecules. Naturally occurring cyclodextrins contain 6, 7, and 8 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 them into the central/hydrophobic portion of the cyclodextrin ring; Cyclodextrin compounds are also known to aggregate around drugs in a micelle structure. This ability of cyclodextrins can enable them to act as carriers that increase the bioavailability of less soluble drugs. Some embodiments comprise a method for treating migraine, comprising the steps of selecting a human migraine patient having a history of an inadequate response to previous migraine treatment, and orally administering a formulation to the migraine patient, wherein the formulation comprises a combination of the following: 1) a complex of meloxicam and sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) rizatriptan. Some embodiments include inclusion complexes of meloxicam in cyclodextrin. Some embodiments include 1) an inclusion complex in meloxicam and cyclodextrin, or 2) a formulation comprising meloxicam and a carbonate or bicarbonate. Some embodiments include a method of orally administering meloxicam, comprising orally administering the formulation described herein to a patient requiring treatment. Some embodiments include a method of administering meloxicam intravenously, comprising administering the formulation described herein intravenously to a patient requiring treatment. A formulation for an inclusion complex of cyclodextrin and meloxicam and a bicarbonate, and a method of using the same are disclosed herein. The present invention discloses a formulation and a method for delivering meloxicam together with cyclodextrin to a subject by oral, intestinal, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means. A method for treating pain and pain associated with pathological conditions is also disclosed by delivering a formulation having meloxicam, cyclodextrin, and bicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means. The combination of rizatriptan and meloxicam (referred to as the "target combination" for convenience in this institution) can be used to treat various pain conditions. Rizatriptan has the structure shown below. Lizatriptan Some embodiments include a target combination comprising 1) an inclusion complex of meloxicam and cyclodextrin, 2) rizatriptan, and 3) bicarbonate for treating human migraines. The migraine may be a treatment-resistant migraine. Humans may have a history of an inadequate response to previous treatments. Some embodiments include a combination of rizatriptan and meloxicam that has rapid, sustained, substantial, and statistically significant efficacy compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of inadequate response to previous acute treatment. Some embodiments include target combinations comprising rizatriptan and meloxicam that require significantly less use of a rescue drug compared to rizatriptan, meloxicam, or placebo. Figure 1 is a dr