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US-12622874-B2 - Trans-crocetin compositions and treatment regimens

US12622874B2US 12622874 B2US12622874 B2US 12622874B2US-12622874-B2

Abstract

Liposomal trans-crocetin pharmaceutical compositions, dosing regimens and methods of treating or preventing disorders and conditions associated with, but not limited to, infection, ischemia, hypoxia, ARDS, inflammation, sepsis, shock, stroke, traumatic injury, and proliferative disorders such as cancer are provided. Methods of using the provided trans-crocetin pharmaceutical compositions and dosing regimens to treat cardiovascular, renal, liver, inflammatory, metabolic, pulmonary, neurological, and other disorders and conditions are also provided, as are methods of increasing the delivery of oxygen and increasing the efficacy of a therapeutic agent using the provided compositions and dosing regimens.

Inventors

  • Clet Niyikiza
  • Victor Mandla MOYO

Assignees

  • L.E.A.F. HOLDINGS GROUP LLC

Dates

Publication Date
20260512
Application Date
20210409

Claims (20)

  1. 1 . A method of increasing the delivery of oxygen in a subject comprising administering an effective amount of one or more dose(s) of 2 mg/kg to 10 mg/kg liposomal trans-crocetin, or any range therein between, to a subject in need thereof, wherein the administered liposomal trans-crocetin comprises a pegylated liposome encapsulating trans-crocetin having the formula: Q-trans-crocetin-Q, wherein, Q is at least one multivalent cation selected from Ca 2+ , Mg 2+ , Zn 2+ , Cu 2+ , Co 2+ , Fe 2+ , a divalent organic cation, and a trivalent cation; and wherein the diameter of the liposome is 20 nm to 200 nm.
  2. 2 . The method of claim 1 , wherein one or more doses of liposomal trans-crocetin is administered to the subject in an amount of 2 mg/kg to 8 mg/kg, or any range therein between.
  3. 3 . The method of claim 1 , wherein one or more doses of liposomal trans-crocetin is administered to the subject in an amount of 2.5 mg/kg to 7.5 mg/kg, 2.5 mg/kg to 5 mg/kg (e.g., 2.5 mg/kg or 5 mg/kg), or any range therein between.
  4. 4 . The method of claim 1 , wherein the subject is administered 1 to 50, 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 doses of liposomal trans-crocetin in an amount of 2 mg/kg to 10 mg/kg, or any range therein between.
  5. 5 . The method of claim 2 , wherein the subject is administered 1 to 50, 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 doses of liposomal trans-crocetin in an amount of 2 mg/kg to 8 mg/kg, or any range therein between.
  6. 6 . The method of claim 2 , wherein the subject is administered 1 to 50, 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 doses of liposomal trans-crocetin in an amount of 2.5 mg/kg to 7.5 mg/kg, or any range therein between.
  7. 7 . The method of claim 2 , wherein the subject is administered 1 to 50, 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 doses of liposomal trans-crocetin in an amount of 2 mg/kg to 5.5 mg/kg, or any range therein between.
  8. 8 . The method of claim 1 , wherein one or more doses of the administered liposomal trans-crocetin is 2.5 mg/kg, 5.0 mg/kg, or 7.5 mg/kg.
  9. 9 . The method of claim 1 , wherein one or more doses of the administered liposomal trans-crocetin comprises liposomes encapsulating calcium trans-crocetinate or magnesium trans-crocetinate having a zeta potential of −25 to 0 mV, or any range therein between.
  10. 10 . The method of claim 1 , wherein one or more doses of the administered liposomal trans-crocetin comprises liposomes having a diameter of 80 nm to 120 nm, or any range therein between.
  11. 11 . The method of claim 1 , wherein one or more doses of the administered liposomal trans-crocetin comprises liposomes having a diameter of 80 nm to 120 nm or any range therein between and a zeta potential of −25 to 0 mV or any range therein between.
  12. 12 . The method of claim 1 , wherein the subject is administered two or more doses of liposomal trans-crocetin 1 hour to 48 hours, 1.5 hours to 24 hours, 2 hours to 18 hours, 4 hours to 16 hours, or 1 hour to 8 hours apart, or any range therein between, or one dose of liposomal trans-crocetin five times a day, four times a day, three times a day, twice a day, once a day, or once every other day.
  13. 13 . The method of claim 12 , wherein the subject is administered one dose of liposomal trans-crocetin in an amount of 2 mg/kg to 8 mg/kg, or any range therein between, five times a day, four times a day, three times a day, twice a day, once a day, or once every other day.
  14. 14 . The method of claim 1 , wherein the subject is administered one or more loading dose(s) of liposomal trans-crocetin at 2 mg/kg to 10 mg/kg, 2.5 mg/kg to 7.5 mg/kg, or 2.5 mg/kg to 5 mg/kg, or any range therein between, and wherein when more than one loading dose is administered, the doses are administered 1 hour to 48 hours, 1.5 hours to 24 hours, 2 hours to 18 hours, 4 hours to 16 hours, or 1 hour to 8 hours (e.g., 3 hours) apart, or any range therein between, or wherein the subject is administered a maintenance dose of liposomal trans-crocetin four times a day, three times a day, two times a day, once a day, or once every other day.
  15. 15 . The method of claim 14 , wherein the subject is further administered two or more maintenance dose(s) of liposomal trans-crocetin at 2 mg/kg to 10 mg/kg, 2.5 mg/kg to 7.5 mg/kg, or 2.5 mg/kg to 5 mg/kg, or any range therein between, of trans-crocetin.
  16. 16 . The method of claim 15 , wherein the subject is administered 1 to 50, 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5, or any range therein between, maintenance doses of liposomal trans-crocetin.
  17. 17 . The method of claim 16 , wherein the subject is administered 1 to 50, 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5, or any range therein between, maintenance doses of liposomal trans-crocetin at a concentration of 2 mg/kg to 5.5 mg/kg, or any range therein between.
  18. 18 . The method of claim 15 , wherein the subject is administered two or more maintenance dose(s) of liposomal trans-crocetin 1 hour to 48 hours, 1.5 hours to 24 hours, 2 hours to 18 hours, 4 hours to 16 hours, or 1 hour to 8 hours apart, or any range therein between, or the subject is administered one maintenance dose of liposomal trans-crocetin four times a day, three times a day, two times a day, once a day, or once every other day.
  19. 19 . The method of claim 1 , wherein the method treats ischemia or hypoxia in the subject.
  20. 20 . The method of claim 1 , wherein (1) the subject is in need of increased oxygen delivery; (2) the pharmaceutical composition is administered to increase the physical or mental performance of the subject; (3) the age of the subject is 50 or older; (4) the subject is immunocompromised; (5) the subject receives chemotherapy and/or is immune-suppressed; (6) the subject is a burn victim; and/or (7) the subject is critically ill.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the U.S. national phase of International Application No. PCT/US2021/026704 filed Apr. 9, 2021 which designated the U.S. and claims priority to U.S. Provisional Patent Application No. 63/077,989 filed Sep. 14, 2020, 63/125,908 filed Dec. 15, 2020, 63/007,884 filed Apr. 9, 2020, 63/029,362 filed May 22, 2020, 63/029,536 filed May 24, 2020, 63/057,208 filed Jul. 27, 2020, 63/063,809 filed Aug. 10, 2020, 63/064,281 filed Aug. 11, 2020, and 63/077,986 filed Sep. 14, 2020, the entire contents of each of which are hereby incorporated by reference. BACKGROUND Crocetin is a carotenoid with antioxidative properties that is sparingly soluble in water. Chemically, crocetin is a 20-carbon apocarotenoid molecule containing seven double bonds and a carboxylic acid group at each end. The administration of trans-crocetin (free acid), and its salt sodium trans-crocetinate in free form (e.g., unencapsulated) pharmaceutical formulations has been reported to offer promise in treatment for conditions caused by hypoxia, ischemia, and other medical conditions. However, neither has demonstrated sufficient impactful clinical therapeutic efficacy to warrant approval. This is partly due to the fact that formulations of trans-crocetin and its salt are limited by poor solubility, instability, low bioavailability and short half-life. For example, trans-crocetinate monovalent metal salt compositions such as sodium trans-crocetin (TSC), were presumably designed in an effort to overcome pharmacokinetic (PK) and pharmacodynamic (PD) issues associated with the low solubility and short half-life of crocetin (free acid), but the half-life of TSC is only about 30 minutes, which in a clinical setting leads to brief and transient therapeutic effect that limits the clinical development of this class of drugs. In view of the potential health benefits conferred by trans-crocetin and the low bioavailability outlined above, there is a need for providing trans-crocetin pharmaceutical compositions and dosing regimens that provide improved bioavailability and stability. The compositions and methods including dosing regimens provided herein, address the shortcomings that have limited the therapeutic use and applications of trans-crocetin. The provided compositions and methods will further help overcome the limitations of current therapeutic approaches to disease states linked to ischemia, acute respiratory distress syndrome (ARDS), pneumonia, sepsis, endotoxemia and hypoxia, and many other unmet medical needs. The provided compositions, methods and dosing regimens have applications as single agents and in combination with other therapies and therapeutic agents. BRIEF SUMMARY The disclosure provides pharmaceutical compositions comprising trans-crocetin and methods of using the compositions to treat or prevent disorders and conditions associated with, but not limited to, infection, ischemia, hypoxia, ARDS, inflammation, sepsis, shock, stroke, traumatic injury, and proliferative disorders such as cancer, that comprises administering one or more dose(s) of trans-crocetin to a subject in an amount effective to treat the disorder or condition. In some embodiments, the disclosure provides a method of treating a disorder or condition associated with ischemia that comprises administering one or more dose(s) of trans-crocetin to a subject in an amount effective to treat the disorder or condition. In some embodiments, the disclosure provides a method of treating a disorder or condition associated with acute respiratory distress syndrome (ARDS) caused by a viral infection (e.g., influenza or COVID-19) that comprises administering one or more dose(s) of trans-crocetin to a subject in an amount effective to treat the disorder or condition. Methods of using one or more dose(s) of trans-crocetin to treat a cardiovascular, renal, liver, inflammatory, metabolic, pulmonary, and/or neurological disorder or condition are also provided, as are methods of increasing the delivery of oxygen and increasing the efficacy of a therapeutic agent wherein the method comprises administering one or more dose(s) of trans-crocetin. In one embodiment, the disclosure provides a method of treating a disorder or condition in a subject that comprises a dosing regimen wherein at least one dose of 0.05 mg/kg to 10 mg/kg (e.g., 0.5 mg/kg to 7.5 mg/kg, and 1 mg/kg to 5 mg/kg) liposomal trans-crocetin is administered to the subject. In some embodiments, two or more doses of liposomal trans-crocetin are administered to the subject once every 1, 2, 3, 6, 12 hours (+/−3 hours), 24 hours (+/−6 hours), or 48 hours (+/−12 hours). In one embodiment, the disclosure provides a method of treating a disorder or condition in a subject that comprises a dosing regimen wherein at least one dose of 0.05 mg/kg to 2.5 mg/kg, 0.2 mg/kg to 2 mg/kg, 0.75 mg/kg to 2 mg/kg, or 0.15 to 0.5 mg/kg, liposomal trans-crocetin is administered to the subject. In some embod