JPWO2019160733A5

JPWO2019160733A5 -

Info

Publication number: JPWO2019160733A5
Application number: JP2020543388A
Authority: JP
Publication date: 2022-02-16
Anticipated expiration: 2039-02-07

Claims

A liposome composition comprising gamma-polyglutamine-oxidized methotrexate, wherein the gamma-polyglutamine-oxidized methotrexate contains 4, 5, 2 to 10, 4 to 6 glutamil groups having a gamma-carboxyl group bond .

The liposome composition according to claim 1 , wherein the gamma polyglutamine oxide methotrexate is gamma tetraglutamine oxide methotrexate or gamma pentaglutamine oxide methotrexate .

The liposome composition according to claim 1 , wherein the gamma polyglutamine oxide methotrexate is gamma hexaglutamine oxide methotrexate.

(A) The gamma polyglutamine oxide methotrexate contains an L-type glutamil group having two or more gamma carboxyl group bonds.
(B) Each glutamil group of the gamma polyglutamine oxide methotrexate is L-type and has a gamma carboxyl group bond.
(C) At least one glutamil group of the gamma polyglutamine oxide methotrexate is D-type and has a gamma carboxyl group bond.
(D) Each glutamil group of the gamma polyglutamine oxidized methotrexate other than the glutamil group of methotrexate is D-type and has a gamma carboxyl group bond, or (e) the gamma polyglutamine oxidized methotrexate has a gamma carboxyl group bond. Containing two or more L-type glutamil groups having and at least one D-type glutamil group .
The liposome composition according to claim 1 .

The liposome composition according to claim 1 , wherein the liposome is pegged.

The liposome composition according to claim 1 , wherein the liposome has a diameter in the range of 20 nm to 500 nm, 20 nm to 200 nm , or 80 nm to 120 nm .

From the group consisting of at least one of anionic lipids and neutral lipids, DSPE; DSPE-PEG; DSPE-PEG-maleimide; HSPC; HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide. Formed from a liposome component containing at least one selected, the liposome component is optionally selected from the group consisting of DSPE; DSPE-PEG; DSPE-PEG-FITC; DSPE-PEG-maleimide; cholesterol; and HSPC. Polyethylene glycol (PEG); poly-L-lysine (PLL); monosialoganglioside (GM1); poly (vinylpyrrolidone) (PVP); poly (acrylamide) (PAA). Poly (2-methyl-2-oxazoline); Poly (2-ethyl-2-oxazoline); Phosphatidyl polyglycerol; Poly [N- (2-hydroxypropyl) methacrylicamide]; Parenteral poly-N-vinylpyrrolidone L-Amino acid-based polymer; one or more liposome components optionally selected from the group consisting of oligoglycerin, polyethylene glycol and polypropylene oxide-containing copolymers, poroxamer 188, and polyvinyl alcohol, further comprising a steric stabilizer. The liposome composition of claim 1 , wherein, optionally, the stereostabilizer is PEG, where PEG has a number average molecular weight (Mn) of 200-5000 daltons .

1 _ _ The liposome composition of the description.

The liposome has an internal space containing the gamma polyglutamine oxidized methotrexate and an aqueous pharmaceutically acceptable carrier , and optionally the pharmaceutically acceptable carrier at a concentration greater than 1%, dextrose. , Isotonic agents such as mannitol, glycerol, potassium chloride, sodium chloride, 1% to 50% trehalose, 5% dextrose suspended in HEEPS buffer, or a total concentration of sodium acetate from 50 mM to 500 mM and It contains calcium acetate, and optionally the internal space of the liposome has a pH of 5-8 or 6-7, or any range of pH between them, and optionally the liposome is 500. The liposome composition according to claim 1 , which comprises less than 000 or less than 200,000 said gamma polyglutamine oxidized methotrexate molecules, or 100 to 100,000 or any range of gamma polyglutamine oxidized methotrexate molecules in between. thing.

It further comprises a targeting moiety, wherein the targeting moiety has a specific affinity for a surface antigen on the target cell of interest , and optionally, the targeting moiety is covalently attached to the PEG and one or both of the outer surfaces of the liposome. And optionally, the targeting moiety binds to a surface antigen with an equilibrium dissociation constant (Kd) in the range ^0.5x10-10 to ^10x10-6 as measured by BIACORE® analysis. In selection, one or more of the targeting moieties are selected from the group consisting of folic acid receptor alpha (FR-α), folic acid receptor beta (FR-β), and folic acid receptor delta (FR-δ). The liposome composition according to claim 1 , which specifically binds to a folic acid receptor .

Each pegged liposome contains 1 to 1000 or 30 to 200 targeting moieties, optionally said targeting moiety is an antibody, humanized antibody, antibody antigen binding fragment, single chain antibody, single domain antibody. The liposome composition according to claim 1 , which comprises one or more selected from the group consisting of a bispecific antibody, a synthetic antibody, a pegging antibody, and a multimer antibody .

It further comprises one or more of an immunostimulator, a detectable marker and a maleimide, wherein the immunostimulant, the detectable marker or the maleimide is bound to the PEG or outer surface of the liposome and the immunostimulant. , Fluorescein, fluorescein isothiocyanate (FITC), DNP, beta-glucan, beta-1,3-glucan, beta-1,6-glucan, resolvin (eg, Resolvin D, Resolvin such as _Dn-6DPA _or Dn -3DPA). E, or T-series resolvins), and toll-like receptor (TLR) regulators such as oxidized low-density lipoproteins (eg, OXPAC, PGPC), and eritoran lipids (eg, E5564). 1 _ The liposome composition according to.

A pharmaceutical composition comprising the liposome composition according to claim 1 .

A composition comprising the liposome composition of any one of claims 1-12 , or the pharmaceutical composition of claim 13, for the treatment of cancer, immune system disorders or infectious diseases .

The composition according to claim 14, wherein the cancer is lung cancer, breast cancer, colon cancer, pancreatic cancer, gastric cancer, bladder cancer, head and neck cancer, ovarian cancer and Cervical cancer , non-Hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), fungal cystoma (cutaneous T-cell lymphoma), villous cancer, and villous adenomas, non-white blood medulla carcinomatosis, soft sarcoma It is a member selected from the group consisting of (genetic tendonoma, invasive fibromatosis), bladder cancer, and central nervous system (CNS) lymphoma , and the disorder of the immune system is an autoimmune disease, rheumatoid arthritis or inflammation. The composition, which is in a state .

A method for preparing a liposome composition containing the liposome composition according to any one of claims 1 to 12 , wherein a mixture containing a liposome component and gamma polyglutamine oxidized methotrexate is formed in a solution; The treatment step comprises, optionally, the step of homogenizing the mixture in the solution to form a liposome; and the step of treating the mixture to form a liposome containing gamma polyglutamine oxidized methotrexate. Thin film hydration, extrusion, in-line mixing, ethanol injection technology, freeze-thaw method, reverse-phase evaporation method, dynamic high-pressure microfluidization, microfluidic mixing, double emulsion, freeze-dry double emulsion, 3D printing, membrane contactor method, And one or more steps of stirring, or the treatment step comprises the step of imparting a targeting moiety on the surface of the liposome, wherein the targeting moiety is a folic acid receptor alpha (FR-α). , With specific affinity for at least one of the folic acid receptor beta (FR-β) and folic acid receptor delta (FR-δ), and optionally the treatment step is membrane hydration, extrusion. , In-line mixing, ethanol injection technique, freeze-thaw method, reverse-phase evaporation method, dynamic high-pressure microfluidization, microfluidic mixing, double emulsion, freeze-dry double emulsion, 3D printing, membrane contactor method, and stirring. One or more including one or more steps, or the treatment step resizing the liposome by one or more steps of extrusion, high pressure microfluidization, and / or ultrasonic treatment. A method, including steps.