WO2019142823A1 - Copolymère séquencé, composition de micelle et composition pharmaceutique - Google Patents

Copolymère séquencé, composition de micelle et composition pharmaceutique Download PDF

Info

Publication number
WO2019142823A1
WO2019142823A1 PCT/JP2019/001089 JP2019001089W WO2019142823A1 WO 2019142823 A1 WO2019142823 A1 WO 2019142823A1 JP 2019001089 W JP2019001089 W JP 2019001089W WO 2019142823 A1 WO2019142823 A1 WO 2019142823A1
Authority
WO
WIPO (PCT)
Prior art keywords
block copolymer
polymer segment
peg
group
fpba
Prior art date
Application number
PCT/JP2019/001089
Other languages
English (en)
Japanese (ja)
Inventor
オラシオ カブラル
ルイス エスペル
拓也 宮崎
恭子 小路
ジョージ ファン
片岡　一則
祐希 持田
藤　加珠子
亮 松元
Original Assignee
公益財団法人川崎市産業振興財団
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 公益財団法人川崎市産業振興財団 filed Critical 公益財団法人川崎市産業振興財団
Publication of WO2019142823A1 publication Critical patent/WO2019142823A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/36—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino acids, polyamines and polycarboxylic acids

Definitions

  • the present invention relates to block copolymers, micellar compositions and pharmaceutical compositions.
  • Priority is claimed on Japanese Patent Application No. 2018-5217, filed January 16, 2018, the content of which is incorporated herein by reference.
  • a block copolymer having a hydrophilic polymer segment and a hydrophobic polymer segment forms, in an aqueous solvent, a micelle consisting of a shell of the hydrophilic polymer segment and a core of the hydrophobic polymer segment.
  • Such micelles are attracting attention as carriers for drug delivery because they can encapsulate hydrophobic drugs in the core part.
  • Non-patent Document 1 Non-patent Document 1
  • the present invention has been made in view of the above circumstances, and is a novel pH-sensitive block copolymer whose decomposition in a normal tissue pH environment (pH 7.4) is reduced, a micelle composition containing the block copolymer, and the above
  • An object of the present invention is to provide a pharmaceutical composition comprising a micelle composition.
  • a block copolymer comprising a hydrophilic polymer segment and a hydrophobic polymer segment
  • a block copolymer in which the hydrophilic polymer segment and the hydrophobic polymer segment are linked by a divalent linking group including a structure represented by the following general formula (I).
  • X 1 to X 4 each independently represent a hydrogen atom or an electron withdrawing group. However, at least one of X 1 to X 4 is an electron withdrawing group. * Represents a bond.
  • the electron withdrawing group is a fluorine atom.
  • a micelle composition comprising micelles of the block copolymer according to any one of [1] to [4].
  • the micelle composition according to [5] further comprising a drug.
  • a pharmaceutical composition comprising the micelle composition according to any one of [5] to [8].
  • the pharmaceutical composition according to [9] which is a pharmaceutical composition for treating or preventing a tumor.
  • a novel pH-sensitive block copolymer a micelle composition comprising the block copolymer, and a pharmaceutical composition comprising the micelle composition, wherein the degradation in normal tissue pH environment (pH 7.4) is reduced.
  • FIG. 4A shows the results of measurement of the fluorescence spectrum of PEG-FPBA-CAT-P (Asp) or PEG-FPBA in HEPES buffer (pH 7.4).
  • FIG. 4B shows the result of measuring the fluorescence spectrum of PEG-FPBA-CAT-P (Asp) in HEPS buffer of different pH.
  • FIG. 4C shows the result of measuring the fluorescence spectrum of PEG-FPBA-CAT-P (Asp) in HEPS (pH 7.4) buffer containing different concentrations of glucose.
  • FIG. 4D is a graph showing the result in FIG. 4B as a relationship between pH and the remaining amount of PEG-FPBA-CAT-P (Asp).
  • FIG. 4E is a graph showing the relationship between the glucose concentration and the remaining amount of PEG-FPBA-CAT-P (Asp) by further adding the results at glucose concentrations of 10 mM and 30 mM to the results in FIG. 4C.
  • FIG. 16 is a graph showing the results of comparing the size distribution of micelles before and after PEG-FPBA-CAT-PBLA micelles were incubated for 24 hours in PBS (pH 7.4) containing 5 mM glucose.
  • FIG. 6A is a graph showing the results of measuring the Z-average particle size of PEG-FPBA-CAT-PBLA micelles over time in PBS containing 5 mM glucose (pH 7.4, pH 7 or pH 6.5).
  • FIG. 6B is a graph obtained by enlarging the range of 1 to 4 hours on the horizontal axis in the graph of FIG. 6A. The outline of the preparation method of doubly labeled PEG-FPBA-CAT-PBLA micelles is shown.
  • FIG. 8A shows fluorescence microscopy images of cells after incubation of B16-F10 mouse melanoma cells with dual labeled PEG-FPBA-CAT-PBLA at pH 7.4 or pH 6.5 for 6 hours.
  • FIG. 9A is a fluorescence microscope image in which FRET signal was detected in the earlobe of a mouse immediately after administration of dual labeled PEG-FPBA-CAT-PBLA micelles.
  • FIG. 9B shows the time-course of FRET signal intensity within a predetermined area (vested area in FIG.
  • FIG. 9A is a fluorescence microscope image in which Alexa 545 signal was detected in the earlobe of a mouse immediately after administration of dual labeled PEG-FPBA-CAT-PBLA micelles.
  • FIG. 9D shows the time course of Alexa 545 signal intensity within the predetermined area of blood vessels and skin (boxed area in FIG. 9C) in the earlobe of mice administered double labeled PEG-FPBA-CAT-PBLA micelles It is a graph.
  • FIG. 10A is a fluorescence microscope image in which FRET signal was detected in tumor tissue of a mouse immediately after administration of double labeled PEG-FPBA-CAT-PBLA micelle.
  • FIG. 10B shows the FRET signal intensity in a predetermined area (the area enclosed by a square in FIG. 10A) of tumor tissue of a mouse administered with double-labeled PEG-FPBA-CAT-PBLA micelles. It is the graph which showed a time-dependent change. It is shown as a relative value to the intensity in normal tissue blood vessels immediately after administration.
  • FIG. 10A is a fluorescence microscope image in which FRET signal was detected in tumor tissue of a mouse immediately after administration of double labeled PEG-FPBA-CAT-PBLA micelle.
  • FIG. 10B shows the FRET signal intensity in a predetermined area (the area enclosed by a square in FIG. 10A) of tumor tissue of a mouse administered with double-labeled PEG-FPBA-CAT-PBLA micelles. It is the graph which showed
  • FIG. 10C is a fluorescence microscope image in which Alexa 545 signal was detected in tumor tissue of a mouse to which double labeled PEG-FPBA-CAT-PBLA micelles were administered.
  • FIG. 10D shows Alexa 545 signal intensity in a predetermined area (the area enclosed by a square in FIG. 10C) of tumor tissue of a mouse intravenously injected with double-labeled PEG-FPBA-CAT-PBLA micelles. It is the graph which showed the time-dependent change of. It is shown as a relative value to the intensity in normal tissue blood vessels immediately after administration.
  • FIG. 11A is a graph showing the time course of intravascular FRET signal intensity in the earlobe of a mouse immediately after intravenous injection of dual labeled PEG-PBLA micelles.
  • FIG. 11B is a graph showing the time course of FRET signal intensity in blood vessels and in tumor interstitial tissue in tumor tissue of mice intravenously injected with dual labeled PEG-PBLA micelles. It is shown as a relative value to the intensity in normal tissue blood vessels immediately after administration.
  • the present invention is a block copolymer comprising a hydrophilic polymer segment and a hydrophobic polymer segment, wherein the hydrophilic polymer segment and the hydrophobic polymer segment are represented by the following general formula (I): Provided is a block copolymer linked by a divalent linking group containing a structure.
  • X 1 to X 4 each independently represent a hydrogen atom or an electron withdrawing group. However, at least one of X 1 to X 4 is an electron withdrawing group. When two or more of X 1 to X 4 are electron withdrawing groups, the plurality of electron withdrawing groups may be the same or different. * Represents a bond. ]
  • X 1 to X 4 are each independently a hydrogen atom or an electron withdrawing group. However, at least one of X 1 to X 4 is an electron withdrawing group. Preferably, at least one of X 1 and X 2 is an electron withdrawing group.
  • a pharmaceutically acceptable substituent is used for the electron withdrawing group in X 1 to X 4 . Examples of such an electron-withdrawing group include a halogen atom, a halogenated alkyl group, a halogenated alkoxy group, a halogenated aryloxy group, a halogenated alkylamino group, a halogenated alkylthio group, a cyano group, a nitro group and the like.
  • a halogen atom or a halogenated alkyl group is preferable.
  • a halogen atom a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. are mentioned, Especially a fluorine atom is preferable.
  • the halogenated alkyl group is preferably a halogenated alkyl group having 1 to 5 carbon atoms.
  • the halogenated alkyl group having 1 to 5 carbon atoms is a group in which part or all of the hydrogen atoms of the alkyl group having 1 to 5 carbon atoms are substituted with a halogen atom.
  • the alkyl group in the halogenated alkyl group may be linear or branched.
  • the halogenated alkyl group is more preferably a halogenated alkyl group having 1 to 3 carbon atoms, and still more preferably a halogenated alkyl group having 1 or 2 carbon atoms.
  • Examples of the halogen atom in the halogenated alkyl group include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is particularly preferable.
  • the halogenated alkoxy group, the halogenated alkylamino group and the halogenated alkylthio group preferably have 1 to 5 carbon atoms, and as the halogen atom, a fluorine atom is preferable.
  • the halogenated aryloxy group preferably has 6 to 12 carbon atoms, and as the halogen atom, a fluorine atom is preferable.
  • a fluorine atom is most preferable as the electron withdrawing group in X 1 to X 4 .
  • At least one of X 1 to X 4 is an electron withdrawing group
  • the rest may be a hydrogen atom or an electron withdrawing group.
  • the plurality of electron withdrawing groups may be the same or different, but are preferably the same.
  • at least one of X 1 and X 2 is an electron withdrawing group
  • X 3 and X 4 are hydrogen atoms. More preferably, only one of X 1 and X 2 among X 1 to X 4 is an electron withdrawing group, and the other is a hydrogen atom. More preferably, X 2 is an electron withdrawing group, and X 1 , X 3 and X 4 are hydrogen atoms.
  • the structure represented by the above general formula (I) cleaves phenylboronic acid catechol ester depending on pH. That is, phenylboronic acid catechol ester is not cleaved under the pH environment (about pH 7.4) of normal tissue, but phenylboronic acid catechol ester is under the pH environment (about pH 6.2 to 7.2) of tumor tissue. Cleavage.
  • phenylboronic acid catechol ester is not cleaved under the pH environment (about pH 7.4) of normal tissue, but phenylboronic acid catechol ester is under the pH environment (about pH 6.2 to 7.2) of tumor tissue. Cleavage.
  • X 1 to X 4 in the above general formula (I) as an electron-withdrawing group, in the pH range of normal tissue (about pH 7.4), phenyl It has the property that the boronic acid catechol ester does not cleave.
  • the hydrophilic polymer segment and the hydrophobic polymer segment are linked by a divalent linking group including the structure represented by the above general formula (I).
  • the “hydrophilicity” and “hydrophobicity” of the polymer segment are relative. That is, among polymer segments linked by a divalent linking group including the structure represented by the above (I), the more hydrophilic polymer segment is a hydrophilic polymer segment, and the less hydrophilic polymer segment is It is a hydrophobic polymer segment.
  • the hydrophilicity / hydrophobicity of the polymer can be defined, for example, by the log P value.
  • the log P value is the log value of the octanol / water partition coefficient (P ow ) and is an effective parameter that can characterize its hydrophilicity / hydrophobicity for a wide range of compounds.
  • P ow octanol / water partition coefficient
  • the hydrophilic polymer segment and the hydrophobic polymer segment may be a polymer having one kind of repeating unit, or may be a polymer having two or more kinds of repeating units.
  • the number of repeating units of the hydrophilic polymer segment may be, for example, 1 or more, 5 or more, 10 or more, 20 or more, or 45 or more.
  • the number of repeating units of the hydrophilic polymer segment may be, for example, 1000 or less, 700 or less, or 450 or less.
  • the molecular mass of the hydrophilic polymer segment may be, for example, 1,000 Da or more, 2,000 Da or more, or 5,000 Da or more.
  • the molecular mass of the hydrophilic polymer segment may be, for example, 40,000 Da or less, 30,000 Da or less, or 20,000 Da or less.
  • the number of repeating units of the hydrophobic polymer segment may be, for example, 5 or more, 10 or more, or 20 or more.
  • the number of repeating units of the hydrophobic polymer segment may be, for example, 200 or less, 100 or less, or 60 or less.
  • the molecular mass of the hydrophobic polymer segment may be, for example, 1,000 Da or more, or 2,000 Da or more.
  • the molecular mass of the hydrophobic polymer segment may be, for example, 30,000 Da or less, 16,000 Da or less, or 10,000 Da or less.
  • hydrophilic polymer segment examples include, for example, polyalkylene glycol, poly (2-oxazoline), polysaccharide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, polymethacrylamide, polyacrylic acid ester, polymethacrylic acid ester, poly (2-methacroyloxyethyl phosphoryl choline), poly (N- (2-hydroxypropyl) methacrylamide) (PHPMA) and their derivatives.
  • polyalkylene glycol, poly (2-oxazoline) and the like are preferable, and polyalkylene glycol is more preferable.
  • Polyalkylene glycols include polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol / polypropylene glycol, and the like, with polyethylene glycol being particularly preferred.
  • hydrophobic polymer segments include, for example, polymers having repeating units derived from amino acids and / or their derivatives. More specifically, polyamino acids or derivatives thereof can be mentioned. Examples of polyamino acids and derivatives thereof include polyaspartic acid, polyglutamic acid, polylysine, poly (benzylaspartic acid), poly (benzylglutamic acid) and the like.
  • the hydrophobic polymer segment may also contain, for example, repeating units derived from amino acids having alkyl or aralkyl side chains. Examples of amino acids having an alkyl group side chain include alanine, valine, leucine and isoleucine.
  • phenylalanine is mentioned as an amino acid which has an aralkyl group side chain.
  • the side chains may be identical or different.
  • the ratio of the repeating unit derived from the alkyl side chain amino acid or the aralkyl group side chain amino acid to the total repeating unit of the hydrophobic polymer segment is not particularly limited, and, for example, 20% or more, 35% or more, 40% or more, 50 %, 80% or more, 95% or more, 99% or more, or 100%.
  • the divalent linking group containing the structure represented by the above general formula (I) may be one or more, but is preferably one.
  • the number of hydrophilic polymer segments may be one or more, but is preferably one.
  • the number of hydrophobic polymer segments may be one or more, but is preferably one.
  • block copolymer of this embodiment the block copolymer represented by the following general formula (II) or (III) is mentioned, for example.
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 and R 2 are each independently a monovalent group
  • L 1 and L 2 are each independently a single bond or a divalent linking group
  • P 1 is a hydrophilic polymer segment
  • P 2 is a hydrophobic polymer segment.
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 and R 2 are each independently a monovalent group.
  • the monovalent group in R 1 and R 2 is not particularly limited, but is preferably one that does not prevent micelle formation of the block copolymer of the present embodiment.
  • R 1 and R 2 include, for example, a hydrogen atom, a C 1-6 alkoxy group, an aryloxy group, an aryl C 1-3 alkoxy group, a cyano group, a carboxyl group, an amino group, C 1-6 alkoxycarbonyl group, C 2-7 acylamide group, tri-C 1-6 alkylsiloxy group, siloxy group, silylamino group, saturated or unsaturated C 1 -C 29 aliphatic carbonyl group, arylcarbonyl group, hydroxyl group And saturated or unsaturated C 1 -C 30 aliphatic oxy groups, aryl-lower alkyloxy groups and the like.
  • L 1 and L 2 each independently represent a single bond or a divalent linking group.
  • the divalent linking group in L 1 and L 2 is not particularly limited, but is preferably one that does not interfere with micelle formation of the block copolymer of the present embodiment.
  • divalent linking group in L 1 and L 2 include, for example, -NH-, -Z-NH-, -NH-Z-, -Z-, -Z-S-Z-NH-,- NH-Z-S-Z-, -CO-Z-CO-, -Z-CO-Z-CO-, -CO-Z-CO-Z-, -NH-CO-Z-CO-, -CO-Z-CO-Z-, -NH-CO-Z-CO-, -CO-Z-CO-NH-Z-, -Z-S-Z-NH-, -Z-NH-Z-S- , -NH-CO-, -CO-NH-, -Z-NH-CO-, -CO-NH-Z-, -Z-NH-CO-Z-, -Z-CO-NH-Z- (Z And each independently represents an alkylene group having 1 to 6 carbon atoms.
  • P 1 is a hydrophilic polymer segment and P 2 is a hydrophobic polymer segment.
  • Examples of the hydrophilic polymer segment in P 1 include those mentioned above.
  • Examples of the hydrophobic polymer segment in P 2 include those mentioned above.
  • block copolymer represented by the above general formula (II) include block copolymers represented by the following general formula (II-1).
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 and R 2 are each independently a monovalent group
  • L 1 and L 2 are each independently a single bond or a divalent linking group
  • P 1 is a hydrophilic polymer segment.
  • R 3 represents the side chain of an amino acid or a derivative thereof.
  • m is an integer of 5 or more.
  • block copolymer represented by the above general formula (III) include block copolymers represented by the following general formula (III-1).
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 and R 2 are each independently a monovalent group
  • L 1 and L 2 are each independently a single bond or a divalent linking group
  • P 1 is a hydrophilic polymer segment.
  • R 3 represents the side chain of an amino acid or a derivative thereof.
  • m is an integer of 5 or more.
  • the block copolymer represented by the general formula (II-1) or (III-1) is a polyamino acid or a derivative thereof as a hydrophobic polymer segment in the block copolymer represented by the general formula (II) or (III)
  • the block copolymer represented by the general formula (II-1) or (III-1) is a polyamino acid or a derivative thereof as a hydrophobic polymer segment in the block copolymer represented by the general formula (II) or (III)
  • R 1 and R 2 are each independently a monovalent group.
  • R 1 include a C 1-6 alkoxy group, an aryloxy group, an aryl C 1-3 alkoxy group, a cyano group, a carboxyl group, an amino group, a C 1-6 alkoxycarbonyl group and a C 2-7 acylamide group And tri-C 1-6 alkylsiloxy groups, siloxy groups, silylamino groups and the like.
  • R 1 a hydrogen atom or a C 1-6 alkoxy group is preferable, and a hydrogen atom or a methoxy group is more preferable.
  • R 2 include a hydrogen atom, a saturated or unsaturated C 1 -C 29 aliphatic carbonyl group, an arylcarbonyl group and the like. Among them, a hydrogen atom is preferable as R 2 .
  • L 1 and L 2 are each independently a single bond or a divalent linking group.
  • L 1 examples include -NH-, -Z-NH-, -NH-Z-, -Z-, -Z-S-Z-NH-, -NH-Z-S-Z- and -CO.
  • L 2 examples include -NH-, -Z-NH-, -NH-Z-, -Z-, -Z-S-Z-NH-, and -NH-Z-S-Z- (Z is And each independently represents an alkylene group having 1 to 6 carbon atoms.
  • P 1 is a hydrophilic polymer segment. Examples of the hydrophilic polymer segment in P 1 include those mentioned above.
  • R 3 represents a side chain of an amino acid or a derivative thereof. The m R 3 s may be independently selected, and may be all the same or may be of multiple types.
  • R 3 examples include the side chain of aspartic acid (carboxymethyl group), the side chain of glutamic acid (carboxyethyl group), the side chain of lysine (4-aminobutyl group), and derivatives thereof (benzyloxycarbonylmethyl group And benzyloxycarbonylethyl group etc.
  • R 3 represents a side chain (methyl group) of alanine, a side chain (isopropyl group) of valine, a side chain (isobutyl group) of leucine, a side chain (sec-butyl group) of isoleucine, a side chain (benzyl) of phenylalanine Group), ornithine side chain (3-aminopropyl group), serine side chain (hydroxymethyl group), or histidine side chain (imidazoylmethyl group).
  • m represents an integer of 5 or more. m is preferably 10 or more, and more preferably 20 or more. Although the upper limit of m is not specifically limited, For example, 200 or less, 100 or less, or 60 or less is mentioned.
  • block copolymer represented by the above general formula (II-1) include block copolymers represented by the following general formula (II-2).
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 ⁇ R 3, P 1 , and m are the same as the R 1 ⁇ R 3, P 1 , and m in Formula (II-1).
  • L 1 ′ and L 2 ′ each independently represent an alkylene group having 1 to 6 carbon atoms.
  • block copolymer represented by the above general formula (III-1) include a block copolymer represented by the following general formula (III-2).
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 ⁇ R 3, P 1 , and m are the same as the R 1 ⁇ R 3, P 1 , and m in the general formula (III-1).
  • L 1 ′ and L 2 ′ each independently represent an alkylene group having 1 to 6 carbon atoms.
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 ⁇ R 3, P 1 and m have the general formula (II-1) and (III-1) in the R 1 ⁇ R 3, P 1 and Similar to m.
  • L 1 ′ and L 2 ′ each independently represent an alkylene group having 1 to 6 carbon atoms.
  • the alkylene group in L 1 ′ and L 2 ′ may be linear or branched, but is preferably linear.
  • L 1 ′ and L 2 ′ are each preferably an alkylene group having 1 to 3 carbon atoms, and more preferably an alkylene group having 1 or 2 carbon atoms.
  • Preferred examples of the block copolymer represented by the above general formula (II-2) include block copolymers represented by the following general formula (II-3).
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 ⁇ R 3, P 1 , and m are the same as the R 1 ⁇ R 3, P 1 , and m in Formula (II-1).
  • L 1 'and L 2' is the same as L 1 'and L 2' in the general formula (II-2).
  • n represents an integer of 1 or more.
  • block copolymer represented by the above general formula (III-2) include a block copolymer represented by the following general formula (III-3).
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 ⁇ R 3, P 1 , and m are the same as the R 1 ⁇ R 3, P 1 , and m in the general formula (III-1).
  • L 1 'and L 2' is the same as L 1 'and L 2' in the general formula (III-2).
  • n represents an integer of 1 or more.
  • the block copolymer represented by the general formula (II-3) or (III-3) is polyethylene as a hydrophilic polymer segment in the block copolymer represented by the general formula (II-2) or (III-2) It has a glycol.
  • X 1 ⁇ X 4 are the same as X 1 ⁇ X 4 in the general formula (I).
  • R 1 ⁇ R 3, P 1, and m is the general formula (III-1) and (III-1) in the R 1 ⁇ R 3, P 1 , And m.
  • L 1 'and L 2' is, L 1 similar to 'and L 2' in formula (II-2) and formula (III-2) is there.
  • n represents an integer of 1 or more.
  • n is preferably 5 or more, more preferably 10 or more, still more preferably 20 or more, and particularly preferably 45 or more.
  • the upper limit of n is not particularly limited, and examples thereof include 700 or less, or 450 or less.
  • the hydrophobic polymer segment P 2 is a repeating unit represented by any one of the following general formulas (P 2 -1) to (P 2 -3) hereinafter, each "repeating unit (P 2 -1)", “repeating unit (P 2 -2)", referred to as “repeating unit (P 2 -3).”
  • the repeating unit (P 2 -1) May contain at least one kind of repeating unit (P 2 -2).
  • R 3 represents an amino acid side chain or a derivative thereof.
  • R 4 and R 6 are each independently -O- or -NH-, and R 5 and R 7 are each independently a hydrogen atom, a phenyl group, a benzyl group,-(CH 2 ) 4 -phenyl group And an alkyl group having 4 to 16 carbon atoms which may be substituted with an amino group or a carbonyl group, or a residue of a sterol derivative.
  • y is 1 or 2;
  • repeating units hydrophobic polymer segment P 2 represented by any one of the following general formula (P 2 -4) ⁇ (P 2 -6)
  • repeating unit (P 2 -4) May contain at least one kind of repeating unit (P 2 -5).
  • R 3, R 4, R 6 , and y are the same as R 3, R 4, R 6 , and y in the above general formula (P 2 -1) ⁇ (P 2 -3). ]
  • R 3 represents a side chain or a derivative of an amino acid, similar to R 3 in the general formula (II-1) or (III-1) It is.
  • the hydrophobic polymer segment P 2 preferably contains one or more repeating units (P 2 -1), more preferably 5 or more, and 10 It is more preferable to include the above, and it is particularly preferable to include 20 or more.
  • the hydrophobic polymer segment P 2 preferably contains one or more repeating units (P 2 -4), more preferably 5 or more, and 10 It is more preferable to include the above, and it is particularly preferable to include 20 or more.
  • the hydrophobic polymer segment P 2 but not limited repeating unit (P 2 -1) or the number of the repeating unit represented by (P 2 -4) are particularly, for example, 200 or less, 100 or less, or 60 The following can be mentioned.
  • R 3 in each repeating unit can be independently selected, and all may be the same. It may exist, and it may consist of multiple types.
  • the hydrophobic polymer segment P 2 contains a plurality of repeating units (P 2 -1) or (P 2-4 ), 50% or more of R 3 in each repeating unit is an alkyl group having 1 to 8 carbon atoms or aralkyl It is preferable that it is an amino acid side chain containing a group or a derivative thereof.
  • the ratio may be 80% or more, 90% or more, 95% or more, 99% or more, or 100%.
  • R 4 is -O- or -NH-.
  • R 5 represents a hydrogen atom, a phenyl group, a benzyl group, a-(CH 2 ) 4 -phenyl group, an alkyl group having 4 to 16 carbon atoms which may be substituted with an amino group or a carbonyl group, or a residue of a sterol derivative is there.
  • y is 1 or 2;
  • the hydrophobic polymer segment P 2 can contain one or more repeating units (P 2 -2), and is 5 or more, 10 or more, or 20 The above may be included.
  • the hydrophobic polymer segment P 2 can contain one or more repeating units (P 2 -5), and is 5 or more, 10 or more, or 20 The above may be included.
  • the number of repeating units represented by repeating units (P 2 -2) or (P 2 -5) in the hydrophobic polymer segment P 2 is not particularly limited, but, for example, 200 or less, 100 or less, or 60 The following can be mentioned.
  • Hydrophobic polymer segment P 2 is, in formula the (P 2 -2) or repeating units represented by (P 2 -5) containing 2 or more, R 5 in each repeating unit, be chosen independently And all may be the same or may be of multiple types. Similarly, R 4 and y in each repeating unit can be independently selected.
  • R 6 is O- or -NH-.
  • R 7 represents a hydrogen atom, a phenyl group, a benzyl group, a-(CH 2 ) 4 -phenyl group, an alkyl group having 4 to 16 carbon atoms which may be substituted with an amino group or a carbonyl group, or a residue of a sterol derivative is there.
  • the hydrophobic polymer segment P 2 can contain one or more repeating units (P 2 -3), and is 5 or more, 10 or more, or 20 The above may be included.
  • the hydrophobic polymer segment P 2 can contain one or more repeating units (P 2 -6), and is 5 or more, 10 or more, or 20 The above may be included.
  • the number of repeating units represented by repeating units (P 2 -3) or (P 2 -6) in the hydrophobic polymer segment P 2 is not particularly limited, but, for example, 200 or less, 100 or less, or 60 The following can be mentioned.
  • R 7 in each repeating unit should be independently selected. And all may be the same or may be of multiple types. Similarly, R 6 in each repeating unit can be independently selected.
  • R 5 or R 7 is The repeating unit which is a hydrogen atom is 75% or less of the total of the repeating units (P 2 -2) and (P 2 -3).
  • R 5 or R 7 is The repeating unit which is a hydrogen atom is 75% or less of the total of the repeating units (P 2 -5) and (P 2 -6).
  • the hydrophobic polymer segment P 2 may be composed of any of the repeating units (P 2 -1) to (P 2 -3), It may contain other repeating units. Hydrophobic polymer segment P 2 is, may include repeating units (P 2 -1) ⁇ (P 2 -3) or two or more, they may be present randomly in the hydrophobic polymer segment P 2 , May exist as a block.
  • the hydrophobic polymer segment P 2 in the block copolymer represented by the general formula (II) preferably has any of the repeating units (P 2 -1) and (P 2 -2).
  • the hydrophobic polymer segment P 2 contains either a block of repeating unit (P 2 -1), a block of repeating unit (P 2 -2) or a block of repeating unit (P 2 -3)
  • the number of the blocks may be one or plural.
  • the proportion of the repeating unit (P 2 -1) to the total repeating units having hydrophobic polymer segment P 2 is, for example, 20-100% It is. Preferably, it is 35 to 100%, 40 to 100%, 50 to 100%, 80 to 100%, or 90 to 100%.
  • the ratio of the repeating unit (P 2 -2) to the entire repeating unit of the hydrophobic polymer segment P 2 is, for example, 10 to 100%. Preferably, it is 20 to 100%, 35 to 100%, 40 to 100%, 50 to 100%, 80 to 100%, or 90 to 100%.
  • the ratio of the repeating unit (P 2 -3) to the entire repeating unit of the hydrophobic polymer segment P 2 is, for example, 0 to 90%. Preferably, it is 0 to 80%, 0 to 65%, 0 to 50%, 0 to 20%, or 0 to 10%.
  • the hydrophobic polymer segment P 2 may be composed of any of the repeating units (P 2 -4) to (P 2 -6), It may contain other repeating units. Hydrophobic polymer segment P 2 is, may include repeating units (P 2 -4) ⁇ (P 2 -6) any two or more, they may be present randomly in the hydrophobic polymer segment P 2 , May exist as a block.
  • the hydrophobic polymer segment P 2 in the block copolymer represented by the general formula (III) preferably has any of the repeating units (P 2 -4) and (P 2 -5).
  • the hydrophobic polymer segment P 2 contains either a block of repeating unit (P 2 -4), a block of repeating unit (P 2 -5) and a block of repeating unit (P 2 -6)
  • the number of the blocks may be one or plural.
  • the proportion of the repeating unit (P 2 -4) to the total repeating units having hydrophobic polymer segment P 2 is, for example, 20-100% It is. Preferably, it is 35 to 100%, 40 to 100%, 50 to 100%, 80 to 100%, or 90 to 100%.
  • the ratio of the repeating unit (P 2 -5) to the entire repeating unit of the hydrophobic polymer segment P 2 is, for example, 10 to 100%. Preferably, it is 20 to 100%, 35 to 100%, 40 to 100%, 50 to 100%, 80 to 100%, or 90 to 100%.
  • the ratio of the repeating unit (P 2 -6) to the entire repeating unit of the hydrophobic polymer segment P 2 is, for example, 0 to 90%. Preferably, it is 0 to 80%, 0 to 65%, 0 to 50%, 0 to 20%, or 0 to 10%.
  • the block copolymer of the present embodiment can be synthesized by combining known methods. For example, a compound containing a hydrophilic polymer segment and a compound containing a hydrophobic polymer segment are respectively synthesized and purified so as to narrow the molecular mass distribution as needed. Thereafter, a compound containing a hydrophilic polymer segment or a compound containing a hydrophobic polymer segment is coupled with a phenylboronic acid derivative in which at least one of the meta positions of the boron atom is substituted with an electron withdrawing group. Next, a compound containing a polymer segment not coupled with the phenylboronic acid derivative is coupled with a catechol derivative. Next, an esterification reaction of a phenylboronic acid derivative coupled with a compound containing one polymer segment and a catechol derivative coupled with a compound containing the other polymer segment is performed according to this embodiment. Block copolymers can be produced.
  • a compound containing a hydrophilic polymer segment is a phenylboronic acid derivative in which at least one of the meta positions of the boron atom is substituted with an electron withdrawing group
  • react with a catechol derivative to carry out an esterification reaction of phenylboronic acid and catechol, and then use an N-carboxy amino acid anhydride or an N-carboxy amino acid derivative anhydride to form a polyamino acid or its amino acid Derivative synthesis may be performed.
  • a compound containing a hydrophilic polymer segment is coupled with a catechol derivative, and then a phenylboronic acid derivative in which at least one of the meta positions of the boron atom is substituted with an electron withdrawing group is reacted with phenylboronic acid and catechol.
  • synthesis of the polyamino acid or its derivative may be carried out using N-carboxy amino acid anhydride or N-carboxy amino acid derivative anhydride.
  • reaction (A) first, compounds containing a hydrophilic polymer segment P 1 (1) and subjected to coupling reaction with phenylboronic acid derivative (2) (A), to obtain the compound (3).
  • the reaction (A) may be carried out using, for example, a dehydration condensation agent such as N, N′-dicyclohexylcarbodiimide (DCC), N-hydroxysuccinimide (NHS), or a solvent such as N, N-dimethylformamide (DMF).
  • DCC N′-dicyclohexylcarbodiimide
  • NHS N-hydroxysuccinimide
  • DMF N-dimethylformamide
  • esterification reaction (B) of compound (3) with catechol derivative (4) is carried out to obtain compound (5).
  • the reaction (B) can be carried out using, for example, a toluene solvent.
  • a polymerization reaction (C) of N-carboxy amino acid (derivative) anhydride is performed starting from the amino group of the compound (5) to give a compound (7) (general formula (II-2)) Block copolymers) can be obtained.
  • the reaction (C) can be carried out using a solvent such as DMF, dichloromethane, tetrahydrofuran (THF) or the like.
  • the reaction temperature is, for example, 25 to 40 ° C.
  • the reaction time is, for example, 1 to 5 days.
  • a compound containing a hydrophilic polymer segment P 1 (1) and subjected to coupling reaction with catechol derivative (8) (D), give compound (9).
  • the reaction (D) may be, for example, N, N'-diisopropylethylamine (DIPEA), 1-hydroxybenzotriazole (HOBT), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl), etc. And the like.
  • esterification reaction (E) of compound (9) and phenylboronic acid derivative (10) is performed to obtain compound (11).
  • the reaction (E) can be carried out using, for example, a toluene solvent.
  • a polymerization reaction (F) of N-carboxy amino acid (derivative) anhydride is performed starting from the amino group of the compound (11) to obtain a compound (12) (general formula (III-2)) Block copolymers) can be obtained.
  • the reaction (F) can be carried out using a solvent such as DMF, dichloromethane, THF or the like.
  • the reaction temperature is, for example, 25 to 40 ° C., and the reaction time is, for example, 1 to 5 days.
  • the hydrophilic polymer segment and the hydrophobic polymer segment are linked by a divalent linking group including the structure represented by the general formula (I).
  • the phenylboronic acid catechol ester in the structure represented by the general formula (I) cleaves as the pH decreases. This separates the hydrophilic polymer segment and the hydrophobic polymer segment. Therefore, in the micelle formed by the block copolymer of the present embodiment, the hydrophilic polymer segment can be detached in a pH-dependent manner.
  • cleavage of the phenylboronic acid catechol ester in a normal tissue under pH environment is achieved by having an electric attractive group at at least one of the meta positions of phenylboronic acid. It does not occur.
  • low pH environment about pH 6.2 to 7.2
  • hydrophilic polymer segments and hydrophobic polymer segments can be separated in a tumor tissue-specific manner. Thereby, uptake of the block copolymer of the present embodiment into tumor cells can be promoted.
  • the present invention provides a micelle composition comprising micelles of the block copolymer of the above embodiment (hereinafter referred to as "the present block copolymer").
  • the micelle composition of the present embodiment includes micelles formed by the present block copolymer.
  • micelles formed by the present block copolymer.
  • the block copolymer when the block copolymer is dissolved or suspended in a lipophilic solvent and the solution or suspension is dispersed in a hydrophilic solvent, micelles having a core composed of hydrophobic polymer segments and a shell composed of hydrophilic polymer segments (Hereinafter referred to as "oil-in-water micelles").
  • the block copolymer is arranged radially with the hydrophobic polymer segments facing inward and the hydrophilic polymer segments facing outward.
  • the block copolymer when the block copolymer is dissolved or suspended in a hydrophilic solvent and the solution or suspension is dispersed in a lipophilic solvent, it has a core composed of hydrophilic polymer segments and a shell composed of hydrophobic polymer segments.
  • Form micelles hereinafter referred to as "water-in-oil micelles”
  • the block copolymer is arranged radially with the hydrophilic polymer segments facing inward and the hydrophobic polymer segments facing outward.
  • the micelles contained in the micelle composition of the present embodiment may be either oil-in-water micelles or water-in-oil micelles, but are preferably oil-in-water micelles.
  • FIG. 1 is a view showing an example of micelles of the present block copolymer.
  • the block copolymer 1 has a structure in which a hydrophilic polymer segment 2 and a hydrophobic polymer segment 3 are linked by an ester of phenylboronic acid 4 having an electron withdrawing group and catechol 5 .
  • the block copolymer 1 forms micelles 10 by self assembly in an aqueous medium.
  • the shell 20 composed of the hydrophilic polymer segment 2 and the core 30 composed of the hydrophobic polymer segment 3 are connected via the phenylboronic acid layer 40 and the catechol layer 50.
  • the phenylboronic acid layer 40 is outside the catechol layer 50, but may be reversed.
  • the catechol layer may be outside the phenylboronic acid layer.
  • the block copolymer represented by the above general formula (II) forms micelles in which the phenylboronic acid layer is outside the catechol layer, as shown in FIG. 1, in an aqueous medium.
  • the block copolymer represented by the above general formula (III) forms micelles in which the catechol layer is outside the phenylboronic acid layer in an aqueous medium.
  • the phenylboronic acid catechol ester forming the phenylboronic acid layer 40 and the catechol layer 50 is cleaved under a low pH environment (about pH 6.2 to 7.2) such as a tumor tissue.
  • a low pH environment about pH 6.2 to 7.2
  • the hydrophilic polymer segment 2 is detached from the core 30 composed of the hydrophobic polymer segment 3.
  • the detachment of the hydrophilic polymer segment 2 promotes the uptake of the core 30 of the hydrophobic polymer segment 3 into tumor cells.
  • the micelle composition of the present embodiment may contain a drug in addition to the micelles of the block copolymer.
  • the drug is encapsulated within the micelles of the block copolymer.
  • the drug when the drug is a hydrophobic compound, the drug can be easily encapsulated in the core consisting of the hydrophobic polymer segment of the oil-in-water micelle.
  • the encapsulation of the drug in the micelles is not particularly limited, and can be carried out by known methods.
  • drug-encapsulated micelles can be obtained by dissolving the block copolymer and the drug in an organic solvent and optionally adding an aqueous solvent by sonication.
  • a side chain having an opposite charge to the drug is introduced into the hydrophobic polymer segment of the block copolymer, and an oil-in-water micelle is obtained using electrostatic interaction.
  • the drug may be enclosed inside.
  • a functional group capable of binding a drug is introduced into the hydrophobic polymer segment of the block copolymer, and the drug is bound to the functional group to form a drug complex of the block copolymer and the drug, and the drug complex To form an oil-in-water micelle.
  • the functional group to be introduced into the hydrophobic polymer segment is not particularly limited, and examples thereof include an aromatic or aliphatic ketone group, an aromatic or aliphatic aldehyde group, and the like.
  • the drug is not particularly limited and may be arbitrary.
  • the drug may include the physiological activity of a compound known as an active ingredient of a pharmaceutical, and the chemical or physiological activity of a diagnostic agent to be administered and used in the body.
  • examples of the drug include antitumor agents, signal transduction inhibitors, antimetabolites, analgesics, anti-inflammatory agents, contrast agents and the like.
  • the drug is preferably an antitumor agent.
  • the oil-in-water micelles of this block copolymer are stable in the pH environment (about pH 7.4) of normal tissue but hydrophilic polymers under the low pH environment (about pH 6.2 to 7.2) such as tumor tissue Segment detaches.
  • the antitumor agent when the antitumor agent is encapsulated in micelles of the block copolymer and administered to a cancer patient, the antitumor agent is stably present in the micelles until delivery to tumor tissue.
  • the micelles reach the tumor tissue, in response to the low pH of the tumor tissue, the hydrophilic polymer segment detaches and promotes the uptake of the antitumor agent into cells. Therefore, an antitumor agent can be delivered specifically in tumor cells.
  • the antitumor agent is not particularly limited, but is preferably a vinca alkaloid such as vinblastine; a COX-2 selective nonsteroidal anti-inflammatory drug such as OSU-03012; a BET bromodomain inhibitor such as (+)-JQ1; such as K252A Staurosporine analogues; demethylating agents such as hydralazine; alkylating agents such as bendamustine and chlorambucil; fascinyltransferase inhibitors such as AZD 39; non-steroidal anti-inflammatory agents such as flurbiprofen etc. .
  • a vinca alkaloid such as vinblastine
  • COX-2 selective nonsteroidal anti-inflammatory drug such as OSU-03012
  • a BET bromodomain inhibitor such as (+)-JQ1
  • K252A Staurosporine analogues such as K252A Staurosporine analogues
  • demethylating agents such as hydralazine
  • examples of the hydrophobic antitumor agent include paclitaxel, topotecan, camptothecin, cisplatin, daunorubicin hydrochloride, methotrexate, mitomycin C, docetaxel, vincrestin sulfate, and derivatives thereof.
  • the agent may be an antitumor nucleic acid such as siRNA or antisense RNA; an antitumor peptide or the like.
  • the micelle composition of the present embodiment can be produced using a known micelle preparation method.
  • the block copolymer is dissolved in an organic solvent.
  • the obtained solution may be air dried, for example, dried in a nitrogen atmosphere to form a film, and if necessary, the organic solvent may be removed by drying under reduced pressure.
  • the solution of the drug to be contained is added to and mixed with the block copolymer thus treated. Then, micelles are formed while encapsulating the drug from the obtained mixed solution.
  • non-water miscible organic solvents such as dichloromethane, chloroform, diethyl ether, dibutyl ether, ethyl acetate, butyl acetate and the like as the organic solvent for dissolving the block copolymer, methanol, ethanol, propyl alcohol, isopropyl alcohol, dimethyl sulfoxide
  • water-miscible organic solvents such as dimethylformamide, dimethylacetamide, acetonitrile, acetone and tetrahydrofuran, and mixed solvents of these.
  • the micelle composition of the present embodiment may be produced by stirring a mixture of the block copolymer and the drug. Stirring of the mixed solution is preferably performed by applying energy such as ultrasonic waves. Further, in the micelle composition of the present embodiment, the present block copolymer in a dry state is made into a uniform powder using a mortar etc., and then the drug in powder or drug dissolved in a small amount of solution is added and mixed gently. It can also be carried out by adding a suitable buffer, stirring and sonicating with ice cooling.
  • the micelle composition of the present embodiment is prepared by adding an appropriate buffer to the block copolymer and sonicating in the same manner as described above to prepare empty micelles, and a drug dissolved in the same buffer there, or the buffer It can also be done by adding the drug diluted with and stirring gently or leaving still.
  • the buffer include phosphate buffer, phosphate buffered saline, citrate buffer, Tris buffer, TAPS buffer, MES buffer, HEPES buffer and the like.
  • the micelle composition of the present embodiment can be suitably used as a carrier for drug delivery.
  • the block copolymer oil-in-water micelles are particularly suitable as drug delivery carriers for anti-tumor agents because hydrophilic polymer segments are detached in the low pH environment of tumor tissue to promote their uptake into tumor cells. .
  • the present invention provides a pharmaceutical composition comprising the micelle composition of the above embodiment.
  • a micelle composition containing a drug can be used as a pharmaceutical composition.
  • the micelle composition can be directly administered to a living body, but may be formulated by mixing with other components as appropriate according to a known method.
  • the dosage form of the pharmaceutical composition of the present embodiment is not particularly limited, and emulsions, emulsions, solutions, gels, capsules, ointments, patches, patches, granules, tablets, contrast agents, etc. However, emulsions, solutions, capsules and the like are preferred.
  • the pharmaceutical composition of the present embodiment may contain other components in addition to the above-mentioned micelle composition.
  • Other components can be used without particular limitation as long as the micelle structure of the present block copolymer is maintained, components commonly used in the pharmaceutical field.
  • the pharmaceutical composition may be one in which micelles of the block copolymer are dissolved or suspended in a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier those customarily used in the pharmaceutical field can be used without particular limitation, and, for example, water, physiological saline, phosphate buffer, DMSO, dimethylacetamide, ethanol, glycerol, minerals Oil etc. can be mentioned.
  • solvents solubilizers, suspending agents, tonicity agents, buffers, pH adjusters, excipients, stabilizers, antioxidants, osmolytes, Preservatives, coloring agents, perfumes and the like can be mentioned.
  • the administration route of the pharmaceutical composition of the present embodiment is not particularly limited, and can be administered by oral or parenteral route.
  • the parenteral route includes all administration routes other than oral, for example, intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal and intraperitoneal administration, etc. Do. Also, administration may be local administration or systemic administration.
  • the pharmaceutical composition of the present embodiment can be administered in a single dose or multiple doses, and the administration period and interval may be the type of drug, type of disease and condition, etc., administration route, age of administration target, It can be selected as appropriate depending on the weight, sex and the like.
  • the dose of the pharmaceutical composition of the present embodiment can be appropriately selected depending on the type of drug, the type and condition of a disease, etc., the administration route, the age, weight and sex of an administration subject.
  • the dose of the pharmaceutical composition of the present embodiment can be a therapeutically effective amount of the drug contained in the pharmaceutical composition, for example, about 0.01 to 1000 mg / kg of body weight at a time, 0.1 to 500 mg The degree can be about 0.1 to 100 mg or the like.
  • the administration interval of the pharmaceutical composition of the present embodiment can be appropriately selected depending on the type of drug, the type and condition of disease, etc., the administration route and dose, the age, weight and sex of the administration subject.
  • the administration interval of the pharmaceutical composition of the present embodiment can be, for example, once to three times a day, every three days, every week, or the like.
  • the application disease may be selected according to the type of drug.
  • the pharmaceutical composition of the present embodiment is used to treat or prevent a tumor.
  • the oil-in-water micelles contained in the pharmaceutical composition of the present embodiment are stable under the pH environment (about pH 7.4) of normal tissue, but have a low pH environment (pH 6.) such as tumor tissue. Under 2 to about 7.2), detachment of the hydrophilic polymer segment occurs. Therefore, uptake of micelles containing the antitumor agent to tumor cells is promoted.
  • the pharmaceutical composition of the present embodiment can be efficiently delivered into the tumor cells of the antitumor agent.
  • the pharmaceutical composition of the present embodiment is a pharmaceutical composition for treating or preventing a tumor.
  • the present invention provides a method of treating or preventing a tumor, which comprises administering to a subject a pharmaceutical composition comprising the present block copolymer and an antineoplastic agent.
  • the present invention provides the use of the present block copolymer and an antitumor agent for the manufacture of a pharmaceutical composition for treating or preventing a tumor.
  • the invention provides the use of the block copolymer and the antineoplastic agent for treating or preventing a tumor.
  • the resulting modified PEG was precipitated with diethyl ether and the resulting precipitate was dialyzed with water at acidic pH for 1 day. The dialysis solution was lyophilized to recover the polymer. The final product was a white powder with a yield of 97%.
  • the proportion of PEG-FPBA was determined by H 1 -NMR analysis using D 2 O. 1 H-NMR (D 2 O, 400 MHz): ⁇ (ppm) 7.7-7.56 (m, phenyl 3 H), 3.71 (m, PEG), 3.40 (s, CH 3 )
  • PEG-FPBA-CAT (0.172 g, 0.014 mmol, 1 Eq.) was added to a solution of dehydrated CH 2 Cl 2 (4 mL) and stirred at 35 ° C. for 3 days. The product was precipitated with diethyl ether and dried (0.177 g, 64% yield).
  • ultracentrifugation analysis was performed using an analytical ultracentrifuge system (Berkman Coulter Optima XL-I Analytical Ultracentrifugation) (overnight).
  • FIGS. 4A-4E The results are shown in FIGS. 4A-4E.
  • FIG. 4A shows the results of measurement of the fluorescence spectrum of PEG-FPBA-CAT-P (Asp) or PEG-FPBA in HEPES buffer (pH 7.4).
  • PEG-FPBA-CAT-P Asp
  • FIG. 4B shows the result of measuring the fluorescence spectrum of PEG-FPBA-CAT-P (Asp) in HEPS buffer of different pH. The lower the pH of the buffer, the smaller the peak of phenylboronic acid catechol ester. At pH 6.82 or less, almost no peak of phenylboronic acid catechol ester was detected.
  • FIG. 4D is a graph showing the result in FIG. 4B as a relationship between pH and the remaining amount of PEG-FPBA-CAT-P (Asp).
  • FIG. 4C shows the results of measuring the fluorescence spectrum of PEG-FPBA-CAT-P (Asp) in HEPS buffer containing different concentrations of glucose.
  • FIG. 4C also shows the result of measuring the fluorescence spectrum of PEG-FPBA in glucose-free HEPS buffer. The higher the glucose concentration, the smaller the peak of phenylboronic acid catechol ester.
  • FIG. 4E is a graph showing the relationship between the glucose concentration and the remaining amount of PEG-FPBA-CAT-P (Asp) by adding the results at glucose concentrations of 10 mM and 30 mM to the results in FIG. 4C.
  • PEG-FPBA-CAT-PBLA micelles were prepared as described above, and size distribution and Z-average particle size were measured by dynamic light scattering (DLS) method. The measurements were performed at a temperature condition of 25 ° C. using a Zetasizer nano ZS (Malvern instruments, UK) with a green laser (532 nm) as the incident beam, at a detection angle of 173 °.
  • DLS dynamic light scattering
  • the size distribution of the micelles was determined before and after incubation of the PEG-FPBA-CAT-PBLA micelles in PBS containing 5 mM glucose (pH 7.4) for 24 hours.
  • the Z-average particle size of PEG-FPBA-CAT-PBLA micelles was measured over time in PBS (pH 7.4, pH 7 or pH 6.5) containing 5 mM glucose.
  • FIG. 6B is a graph obtained by enlarging the range of 1 to 4 hours on the horizontal axis in the graph of FIG. 6A. Precipitation was confirmed after 2 hours of incubation at pH 7 and pH 6.5. On the other hand, at pH 7.4, no precipitation was observed even after 24 hours of incubation. The results show that at pH 7 and pH 6.5, the PEG-FPBA-CAT-PBLA micelles were degraded during the 2 hour incubation.
  • the labeled polymer (Rhod-PEG-FPBA) was purified by dialysis against water of acidic pH and lyophilized. This was dissolved in N, N-dimethylacetamide (DMAC) to 10 g / L, and used as a stock solution.
  • DMAC N, N-dimethylacetamide
  • BLA-NCA BLA-NCA was performed. Ring-opening polymerization was carried out to synthesize N 3 -PEG-PBLA.
  • N 3 -PEG-PBLA (21.4 mg, 1 Eq.) was labeled with Alexa 545 (1 mg, 1E1.)
  • Alexa 545-PEG-PBLA was subjected to column purification (Sephadex L20, eluent: DMF). This was dissolved in DMAC so as to be 4 g / L, and used as a stock solution.
  • Rhod-PEG-FPBA (5 mg) is mixed with PEG-FPBA-CAT-PBLA (8.5 mg) in DMAC overnight to give similar rates of Rhod-PEG-FPBA-CAT-PBLA and PEG-FPBA-CAT-PBLA
  • FIG. 7 An outline of the method of preparing the dual labeled PEG-FPBA-CAT-PBLA micelles described above is shown in FIG. As shown in FIG. 7, a fluorescence resonance energy transfer (FRET) signal is detected when Rhodamine 110 and AlexaFluor 545 are adjacent on the micelle surface.
  • FRET fluorescence resonance energy transfer
  • FIGS. 8A and 8B The results are shown in FIGS. 8A and 8B.
  • FIG. 8A is a fluorescence microscope image of mouse melanoma cells after 6 hours incubation.
  • FIG. 8B is a graph quantifying the fluorescence intensity from the intracellular Alexa 545 signal.
  • Rhodamine 110 labeled PEG in healthy tissues > C57BL6 / J mice (female, 6 weeks old) with 2.0 to 3.0% isoflurane (Ablott JapanCo., Ltd., Tokyo Japan) using Univenter 400 Anesthesia unit (Univentor Ltd., Zejtun, Malta) I was anesthetized. The mice were then dosed by a tail vein catheter with a dual labeled micelle consisting of 1.8 mg / mL Alexa 545-PEG-PBLA and 0.2 mg / mL Rhod-PEG-FPBA-CAT-PBLA (200 ⁇ L; micelle 2 mg / ML).
  • FRET and Alexa 545 signal data were acquired by imaging snapshots in video mode every 10 minutes for 8 hours. The detection of FRET signal was performed with excitation light 488 nm and emission light 570 nm.
  • FIGS. 9A-9D The results are shown in FIGS. 9A-9D.
  • FIG. 9A is a fluorescence microscope image in which FRET signal was detected in the earlobe of a mouse immediately after intravenous injection of dual labeled micelles.
  • FIG. 9B is a graph showing a time-dependent change in FRET signal intensity in a predetermined region of blood vessels and skin (a region surrounded by a square in FIG. 9A) as a relative value to the intensity in blood vessels of normal tissue.
  • FIG. 9C is a fluorescence microscope image in which Alexa 545 signal was detected in the earlobe of a mouse immediately after administration of a dual labeled micelle.
  • FIG. 9A is a fluorescence microscope image in which FRET signal was detected in the earlobe of a mouse immediately after intravenous injection of dual labeled micelles.
  • FIG. 9B is a graph showing a time-dependent change in FRET signal intensity in a predetermined region of blood vessels and skin (a
  • 9D is a graph showing time-dependent changes in Alexa 545 signal intensity in predetermined regions of blood vessels and skin (region surrounded by a square in FIG. 9C). It is shown as a relative value to the intensity in normal tissue blood vessels immediately after administration. The intensities of FRET signal and Alexa 545 signal showed similar time course. This result indicates that in normal tissues, detachment of rhodamine 110-labeled PEG does not occur.
  • FIGS. 10A-10D The results are shown in FIGS. 10A-10D.
  • FIG. 10A is a fluorescence microscope image in which FRET signal was detected in tumor tissue of a mouse immediately after intravenous injection of dual labeled PEG-FPBA-CAT-PBLA micelles.
  • FIG. 10B is a graph showing a time-dependent change in FRET signal intensity in a predetermined region of blood vessels and tumor stromal tissue (a region surrounded by a square in FIG. 10A) as a relative value to the intensity in blood vessels of normal tissue.
  • FIG. 10C is a fluorescence microscope image in which Alexa 545 signal was detected in tumor tissue of a mouse to which double labeled PEG-FPBA-CAT-PBLA micelles were administered.
  • FIG. 10A is a fluorescence microscope image in which FRET signal was detected in tumor tissue of a mouse immediately after intravenous injection of dual labeled PEG-FPBA-CAT-PBLA micelles.
  • FIG. 10B is a graph showing
  • 10D is a graph showing the time course of Alexa 545 signal intensity in a predetermined region of blood vessels and tumor stromal tissue (a region surrounded by a square in FIG. 10C). It is shown as a relative value to the intensity in normal tissue blood vessels immediately after administration.
  • ALEXA 545 signal increased with elapsed time, but FRET signal decreased with elapsed time. This result indicates that, in the tumor tissue, detachment of rhodamine 110-labeled PEG has occurred.
  • FIG. 11A is a graph showing the time-dependent change in FRET signal intensity in blood vessels as a relative value to the intensity in blood vessels of normal tissue.
  • FIG. 11B is a graph showing time-lapse changes in FRET signal intensity in blood vessels and in tumor interstitial tissue. It is shown as a relative value to the intensity in normal tissue blood vessels immediately after administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Polymers & Plastics (AREA)
  • Dispersion Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Polyamides (AREA)

Abstract

Ce copolymère séquencé contient un segment polymère hydrophile et un segment polymère hydrophobe, le segment polymère hydrophile et le segment polymère hydrophobe étant liés par un groupe de liaison divalent qui contient une structure représentée par la formule générale (I) (dans la formule, X1 à X4 représentent, indépendamment, des atomes d'hydrogène ou un groupe attracteur d'électrons. Cependant, au moins l'un parmi X1 à X4 représente un groupe attracteur d'électrons. Les * représentent une liaison.).
PCT/JP2019/001089 2018-01-16 2019-01-16 Copolymère séquencé, composition de micelle et composition pharmaceutique WO2019142823A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018005217A JP7100457B2 (ja) 2018-01-16 2018-01-16 ブロックコポリマー、ミセル組成物、及び医薬組成物
JP2018-005217 2018-01-16

Publications (1)

Publication Number Publication Date
WO2019142823A1 true WO2019142823A1 (fr) 2019-07-25

Family

ID=67302255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/001089 WO2019142823A1 (fr) 2018-01-16 2019-01-16 Copolymère séquencé, composition de micelle et composition pharmaceutique

Country Status (2)

Country Link
JP (1) JP7100457B2 (fr)
WO (1) WO2019142823A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031774A3 (fr) * 2020-08-07 2022-03-24 Cornell University Composés thérapeutiques cure-pro de dégradation ciblée de protéines du domaine bet et leurs procédés de fabrication et méthodes d'utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105273205A (zh) * 2015-10-09 2016-01-27 华东师范大学 以苯硼酸酯为连接单元的嵌段聚合物及其合成方法和应用
CN108727581A (zh) * 2017-04-18 2018-11-02 华东师范大学 以苯硼酸酯为连接单元的两亲性喜树碱高分子前药及其制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105273205A (zh) * 2015-10-09 2016-01-27 华东师范大学 以苯硼酸酯为连接单元的嵌段聚合物及其合成方法和应用
CN108727581A (zh) * 2017-04-18 2018-11-02 华东师范大学 以苯硼酸酯为连接单元的两亲性喜树碱高分子前药及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHONGCHONG FENG ET AL.: "A Self-Assembled Ratiometric Polymeric Nanoprobe for Highly Selective Fluorescence Detection of Hydrogen Peroxide", LANGMUIR, vol. 33, no. 13, 2017, pages 3287 - 3295, XP055628645 *
YAN XU ET AL.: "Nanomicelles based on a boronate ester-linked diblock copolymer as the carrier of doxorubicin with enhanced cellular uptake", COLLOIDS AND SURFACES B: BIOINTERFACES, vol. 141, 2016, pages 318 - 326, XP029465863, DOI: 10.1016/j.colsurfb.2016.01.044 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031774A3 (fr) * 2020-08-07 2022-03-24 Cornell University Composés thérapeutiques cure-pro de dégradation ciblée de protéines du domaine bet et leurs procédés de fabrication et méthodes d'utilisation
GB2614981A (en) * 2020-08-07 2023-07-26 Univ Cornell Therapeutic cure-pro compounds for targeted degradation of bet domain proteins, and methods of making and using them

Also Published As

Publication number Publication date
JP7100457B2 (ja) 2022-07-13
JP2019123805A (ja) 2019-07-25

Similar Documents

Publication Publication Date Title
Cai et al. Micelles of different morphologies—advantages of worm-like filomicelles of PEO-PCL in paclitaxel delivery
Pan et al. PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy
JP5848332B2 (ja) 光学造影および療法のタンデムのための官能性架橋型ナノ構造物
EP2609935B1 (fr) Sonde de type nanoparticule fluorescente à commutation et procédé d'imagerie utilisant des particules fluorescentes l'utilisant
JP5429642B2 (ja) 薬剤の局所導出を対象とした注射可能なポリマー／脂質ブレンド
JP2007509978A (ja) トコフェロール修飾治療薬化合物
WO2012040513A1 (fr) Compositions et procédés d'administration de bêta-lapachone
CN1761485B (zh) 含略微水溶性抗癌剂和新型嵌段共聚物的胶束制剂
JPH11335267A (ja) 水難溶性薬物を含有するポリマーミセル系
US20150258219A1 (en) Electrostatic-bonding-type vesicle including metal microparticles
Li et al. Photodynamic therapy-mediated remote control of chemotherapy toward synergistic anticancer treatment
Liang et al. Carboplatin-loaded SMNDs to reduce GSH-mediated platinum resistance for prostate cancer therapy
Lu et al. Complete regression of xenograft tumors using biodegradable mPEG-PLA-SN38 block copolymer micelles
CN113546045B (zh) 恢复肿瘤微环境失活树突状细胞功能的纳米制剂及应用
WO2019142823A1 (fr) Copolymère séquencé, composition de micelle et composition pharmaceutique
Ruan et al. Non-invasive imaging of breast cancer using RGDyK functionalized fluorescent carbonaceous nanospheres
US20160128971A1 (en) Nanoparticle Compositions
CN114904012B (zh) 一种活性氧自补充的两亲性嵌段共聚物-药物偶联物、其制备方法及其用途
CN107519496B (zh) 一类l-肉毒碱两亲性衍生物及其修饰的纳米粒及其用途
CN108997575A (zh) 聚乙二醇-b-聚酪氨酸-硫辛酸共聚物、聚多肽胶束及其制备方法与应用
CN118043077A (zh) 载药单分子纳米聚合物、前药、胶束、药物递送系统及制备方法和用途
Liao et al. Preparation of galactosyl nanoparticles and their targeting efficiency to hepatocellular carcinoma
KR102407261B1 (ko) 나노 항암제형 및 그 제조 방법
Ma et al. Folate‐PEG‐PROTAC Micelles for Enhancing Tumor‐Specific Targeting Proteolysis In Vivo
CN110575549B (zh) 一种tbFGF配体修饰的具有肿瘤主动靶向功能的脂质体及其制备方法与用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19741159

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19741159

Country of ref document: EP

Kind code of ref document: A1