Carotenoid compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-12458597-B2
Application number	US-201917052412-A
Country	US
Kind code	B2
Filing date	May 3, 2019
Priority date	May 3, 2018
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Provided herein are pharmaceutical compositions comprising carotenoids, including liposomes that encapsulate carotenoids including ionizable carotenoids such as trans-crocetin. The provided compositions have uses in treating diseases, disorders and conditions associated with, but not limited to, infection, endotoxemia, inflammation, sepsis, ischemia, hypoxia, shock, stroke, lung injury, wound healing, traumatic injury, reperfusion injury, cardiovascular disease, kidney disease, liver disease, inflammatory disease, metabolic disease, pulmonary disorders, blood related disorders and hyperproliferative diseases such as cancer. Methods of making, delivering, and using the pharmaceutical compositions are also provided.

First claim

What is claimed is:

1 . A pharmaceutical composition comprising a pegylated liposome encapsulating a trans-crocetin salt having the formula:
Q-trans-crocetin-Q, wherein Q is a multivalent cation counterion.

2 . The pharmaceutical composition of claim 1 , wherein the multivalent cation counterion (Q) is a divalent metal cation selected from Ca 2+ , Mg 2+ , Zn 2+ , Cu 2+ , Co 2+ and Fe 2+ , a divalent organic cation, or a trivalent cation.

3 . The pharmaceutical composition of claim 1 , wherein the multivalent cation counterion (Q) is selected from Ca 2+ , Mg 2+ , Zn 2+ , Cu 2+ , Co 2+ , and Fe 2+ .

4 . The pharmaceutical composition of claim 1 , wherein the liposome encapsulates magnesium trans-crocetinate.

5 . The pharmaceutical composition of claim 1 , wherein the liposome encapsulates calcium trans-crocetinate.

6 . The pharmaceutical composition of claim 1 , wherein the trans-crocetin lipid ratio is 30 to 150 g/M.

7 . The pharmaceutical composition of claim 1 , wherein the liposome has a diameter of 20 nm to 200 nm.

8 . The pharmaceutical composition of claim 1 , wherein the liposome is formed from liposomal components comprising: at least one of a cationic lipid, an anionic lipid and a neutral lipid; or at least one selected from: DSPE; DSPE-PEG; DSPE-PEG-maleimide; HSPC; HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide.

9 . The pharmaceutical composition of claim 1 , wherein the liposome comprises an oxidized phospholipid.

10 . The pharmaceutical composition of claim 8 , wherein the one or more liposomal components further comprises at least one steric stabilizer selected from monosialoganglioside (GM1); poly(vinyl pyrrolidone) (PVP); poly(acrylamide) (PAA); poly(2-methyl-2-oxazoline); poly(2-ethyl-2-oxazoline); phosphatidyl polyglycerol; poly[N-(2-hydroxypropyl) methacrylamide]; amphiphilic poly-N-vinylpyrrolidones; L-amino-acid-based polymer; oligoglycerol, copolymer containing polyethylene glycol and polypropylene oxide, Poloxamer 188, and polyvinyl alcohol.

11 . The pharmaceutical composition of claim 1 , wherein the liposome has a zeta potential that is less than or equal to zero.

12 . The pharmaceutical composition of claim 1 , which further comprises a pharmaceutically acceptable carrier.

13 . The pharmaceutical composition of claim 12 , wherein the pharmaceutically acceptable carrier comprises a tonicity agent at a concentration of 0.3% to 2.5% or a buffer at a concentration of 1 to 200 mM and a pH of 2 to 8.

14 . The pharmaceutical composition of claim 1 , which has a pH of 5-8.

15 . The pharmaceutical composition of claim 1 , wherein the liposome comprises between 10 to 100,000 molecules of trans-crocetin.

16 . The pharmaceutical composition of claim 1 , wherein the liposome further comprises a targeting moiety and wherein the targeting moiety has a specific affinity for a surface antigen on a target cell of interest.

17 . The pharmaceutical composition of claim 16 , wherein the targeting moiety is attached to one or both of a PEG and the exterior of the liposome by a covalent bond.

18 . The pharmaceutical composition of claim 16 , wherein the targeting moiety is a polypeptide, an antibody, a humanized antibody, an antigen binding fragment of an antibody, a single chain antibody, a single-domain antibody, a bi-specific antibody, a synthetic antibody, a pegylated antibody, or a multimeric antibody, optionally wherein the targeting moiety binds the surface antigen with an equilibrium dissociation constant (Kd) in a range of 50×10 −12 to 10×10 −6 as determined using surface plasmon resonance analysis.

19 . The pharmaceutical composition of claim 16 , wherein the liposome comprises 1 to 1000 targeting moieties.

20 . The pharmaceutical composition of claim 1 , further comprising at least one cryoprotectant selected from the group consisting of mannitol, trehalose, sorbitol, and sucrose.

21 . A method for treating or preventing a disease in a subject needing such treatment or prevention, the method comprising administering an effective amount of the pharmaceutical composition of claim 1 to the subject.

22 . The method of claim 21 , wherein the disease or condition is associated with endotoxemia, sepsis, or a lung disease or condition.

23 . The method of claim 21 , wherein the pharmaceutical composition is administered with another therapeutic agent.

24 . A method of preparing pharmaceutical composition comprising a liposome encapsulating trans-crocetin, the method comprising:
(a) preparing a liposomal solution comprising liposomes and a solution containing a weak acid salt of a multivalent metal; (b) adding trans-crocetin to the liposomal solution; and (c) maintaining the trans-crocetin in the liposomal solution for sufficient time to load trans-crocetin into liposomes.

25 . The method of claim 21 , wherein the disease or condition is characterized by ischemia or hypoxia, or nitric oxide deficiency.

26 . The method of claim 21 , wherein the disease or condition is cardiovascular disease; heart attack or stroke; or shock.

27 . The method of claim 21 , wherein the disease or condition is: an infection; inflammation; liver disease; kidney disease; an autoimmune disorder; a neurodegenerative disease; sclerosis: metabolic disease; insulin resistance; or diabetes.

28 . The method of claim 24 , wherein the weak acid is an organic acid and wherein the multivalent metal is a divalent metal.

29 . The method of claim 28 , wherein the organic acid is selected from acetic acid, gluconic acid, tartaric acid, glutamic acid, citric acid, formic acid, and glycinic acid.

30 . The method of claim 28 , wherein the divalent metal is selected from Ca 2+ , Mg 2+ , Zn 2+ , Cu 2+ , Co 2+ , and Fe 2+ .

31 . The method of claim 28 , wherein the organic acid is selected from acetic acid, gluconic acid, tartaric acid, glutamic acid, citric acid, formic acid, and glycinic acid, and the divalent metal is selected from Ca 2+ , Mg 2+ , Zn 2+ , Cu 2+ , Co 2+ , and Fe 2+ .

32 . The method of claim 28 , wherein the organic acid is acetic acid and the divalent metal is Ca 2+ .

33 . The pharmaceutical composition of claim 7 , wherein the liposome has a diameter of 80 nm to 120 nm.

34 . The pharmaceutical composition of claim 11 , wherein the liposome has a zeta potential of −50 to 0 mV.

35 . The pharmaceutical composition of claim 8 , wherein the liposome is formed from DSPE-PEG.

36 . The pharmaceutical composition of claim 15 , wherein the liposome comprises between 100 to 10,000 molecules of trans-crocetin.

37 . The pharmaceutical composition of claim 1 , wherein the trans-crocetin/lipid ratio is 20 g/M to 150 g/M.

38 . The method of claim 22 , wherein the lung disease or condition is selected from acute respiratory distress syndrome (ARDS), pulmonary fibrosis, pulmonary hemorrhage, lung injury, lung cancer, and chronic obstructive pulmonary disease (COPD).

39 . A pharmaceutical composition comprising a pegylated liposome encapsulating a calcium trans-crocetin salt,
wherein the liposome comprises DSPE-PEG, and has a zeta potential of −50 to 0 mV and a diameter of 80 to

Assignees

• L E A F Holdings Group Llc

Inventors

• Niyikiza Clet
• Moyo Victor Mandla
• Geng Bolin
• Xu Zhenghong
• KHALIFA Kaniz
• Kim Gwangseong

Classifications

• A61K9/1278

  Post-loading, e.g. by ion or pH gradient · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K31/122

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title

• A61K31/045

  Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates · CPC title

• A61K31/047

  having two or more hydroxy groups, e.g. sorbitol · CPC title